Posted by admin on July 1st, 2007 — in newsletter
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Second generation antihistamines and pregnancy
Volume 14, No. 1, July 2007
Inquiries to health care providers about the use of antihistamines during pregnancy are common since 20-30% of pregnant women have allergic symptoms (Ellegard et al., 2006). Avoiding known triggers (pets, mold, dust mites, and cigarette smoke), elevating the head end of the bed, and using a nasal saline spray may help avoid or alleviate symptoms (Blaiss, 2003). If these recommendations are not helpful, then providing judicious treatment with antihistamines may benefit the pregnancy by aiding in asthma control, and promoting better sleep and emotional status in pregnant women (Keles, 2004).
The first generation antihistamines (i.e. chlorpheniramine which can be found in Chlor-Trimeton Allergy) are preferred for pregnancy because they have been around longer and better studied during pregnancy. However, second generation antihistamines may be preferred by women due to their lower rates of CNS side effects, such as sedation and performance impairment (Blaiss, 2003). Therefore, this Risk Newsletter will discuss pregnancy outcomes following use of the second generation antihistamines, cetirizine (Zyrtec), fexofenadine (Allegra), and loratadine (Claritin).
Cetirizine
Cetirizine is marketed as Zyrtec. Sedative effects of this medication have been disputed; sedation seen with this medication appears to be dose dependent. While cetirizine is less sedating than the first generation antihistamines, it may be more sedating than loratadine or fexofenadine (Horak and Stubner, 1999).
The frequency of malformations was not increased among the offspring of pregnant rats or rabbits treated with up to 500 times the maximum human dose of cetirizine (Kamijima et al., 1994).
A controlled prospective study by a Canadian teratology service found no significant differences in miscarriage, birth weight, or the rates of major or minor malformations in 33 infants with first trimester cetirizine exposure (Einarson, et al., 1997). No major malformation were identified in another clinical series of 16 infants whose mothers took cetirizine during the first trimester (Wilton, et al., 1998). While reassuring, these studies are of limited value since at least 800 pregnancies would need to be evaluated to identify a 2-fold increase in congenital anomalies (Einarson, et al., 1997).
In Sweden, medicine exposures are entered into a national database following an interview with a midwife in early pregnancy. The pediatrician subsequently updates the registry with the resulting pregnancy outcomes. This dataset identified 917 women who were taking cetirizine in early pregnancy. This group did not have a significant increase in
congenital anomalies (Kallen, 2002). Although the study is large, specific timing, dose, and duration of medication is not available.
Cetirizine is also a metabolite of hydroxyzine, which has not been associated with major malformation in several clinical series totaling 187 infants who were exposed during the first trimester (Heinonen et al., 1977; Erez et al., 1971; Diav-Citrin et al., 2003; Einarson et al., 1997).
In summary, based on available pregnancy data, cetirizine is unlikely to increase the chance for congenital anomalies. Additional studies on larger numbers of pregnancies are still indicated.
Fexofenadine
Fexofenadine is marketed as Allegra. The sedative properties of fexofenadine are thought to be negligible (Horak and Stubner, 1999).
There are no published animal studies on fexofenadine. Animal studies done by the manufacturer have not shown an increase in birth defects at doses 4-30 times the human dose (Sanofi-Aventis, 2006). However, rat pups had dose related decreased weight gain and survival.
A post-marketing cohort study in England identified 23 infants whose mothers had taken fexofenadine in the first trimester. There were no major malformations although one case of “positional talipes” was reported, which is unlikely to be caused by a medicine (Craig-McFeely, et al., 2001).
Fexofenadine is a metabolite of terfenadine. Administration of terfenadine (which is no longer on the market) and fexofenadine lead to similar serum concentrations of the active metabolite so pregnancy outcomes are likely to also be similar (Loebstein et al., 1999) The Swedish Medical Birth Registry identified 1164 women treated with terfenadine in early pregnancy, and they did not have rates of congenital anomalies any higher than the general population (Kallen, 2002).
Similarly, a multicenter prospective controlled study found no congenital anomalies in 65 infants with terfenadine first trimester exposure (Loebstein et al., 1999). The mean daily dose ranged from 30-120 mg. Duration of use was not reported. While reassuring, this study has only an 80% power to rule out a 6.5-fold increased risk for malformations. Of note is that the birth weights were lower in the exposed group. However, the authors pointed out that the birth weight rates <10th percentile for gestational age did not differ between the exposed and control groups, which argues against a major clinical effect. Daily dose, duration of therapy, time of exposure, concomitant maternal asthma or steroid use did not correlate with the lower birth weight. Additional studies would need to address whether terfenadine plays a causative role in low birth weight.
While the animal and human metabolite data does not suggest an increase in birth defects, further studies on larger numbers of pregnant women are needed.
Loratadine
Loratadine is marketed as Claritin. Several studies have not seen a significant sedative effect with loratadine (Horak and Stubner, 1999). Performance impairment has been reported at doses higher than the recommended dose (Horak and Stubner, 1999).
Concern of an association between early pregnancy use of loratadine and hypospadias was raised by the Swedish Medical Birth Registry when an incidence of hypospadias twice that of the general population (but an absolute risk of <1%) was reported (Kallen, 2002). This dataset from 1995-2001 found 15 infants with hypospadias out of 2,780 loratadine exposed infants. The majority of infants had mild glandular hypospadias which makes the association with early pregnancy medicine exposure questionable in terms of biological plausibility (Diav-Citrin, et al. 2003).
Additional surveillance from 2001-2004 found only two more cases of hypospadias out of 1911 infants when 4.3 cases were expected (Kallen and Olausson, 2006). This negative follow-up study led the authors to note that the most likely explanation of the discrepancy was that the first finding was a chance event based on multiple analyses of the data.
Furthermore, two case control studies with 558 and 227 cases of hypospadias also found no association with maternal loratadine use (Werler et al., 2004; Pedersen et al., 2006). Animal data also did not support an association since McIntyre et al. (2003) reported no increase in hypospadias or other androgen mediated endpoints in animals given up to 120
times the human dose.
A prospective controlled study by the Israeli Teratogen Information Service did not find an increase in major malformations with 126 infants with exposure to loratadine during the first trimester or in the case of 175 infants with exposures at anytime during pregnancy (Diav-Citrin, et al., 2003). This study had the power to detect a 3-fold increase in major anomalies. There were also no cases of hypospadias in this study. The median daily dose was 10 mg with a median duration of 8 days.
Additionally, there was no significant differences in birth weight, premature delivery, or stillbirth. There was a significantly higher rate of miscarriage in the loratadine group, although the loratadine miscarriage rate of 11.4% was within general population rate. The authors felt a likely explanation was that the loratadine group contacted the teratogen service
significantly earlier in gestation and also had higher maternal ages compared to the control groups.
Finally, another multicenter study that also investigated the use of loratadine in the first trimester did not find an increase in congenital anomalies in 143 infants (Moretti et al., 2003). This study had an 80% power to detect a 3.5- fold increase in malformations. No cases of hypospadias were observed in the exposed group either. There was also no significant increase in miscarriage, birth weight, or gestational age at delivery. The median daily dose was 10 mg and median total dose in the first trimester was 50 mg (range of 10-1470 mg).
Based on the combined animal and human studies, loratadine does not appear to significantly increase the risk of hypospadias or non-genital congenital anomalies.
Pseudoephedrine
All of these second generation antihistamines can be purchased in formulation with pseudoephedrine, i.e. Zyrtec-D, Allegra-D, and Claritin-D. Studies have not associated pseudoephedrine with congenital anomalies in over 2000 pregnanicies (Jick et al., 1981; Aselton et al., 1985; Heinonen et al., 1977; Rosa, 1993).
However, weak associations with vascular disruptions, such as gastroschisis, have been reported, and cigarette smoking may further exacerbate the risks. (Werler et al., 1992, 2002, 2004). Although weak, these associations have not been entirely discounted due to the vasoactive properties of decongestants. If truly causative, absolute risks would still be <1%. Preferentially, antihistamines are taken alone, especially during the first trimester.
Summary
The use of first generation antihistamines is preferred in pregnancy over the use of second generation antihistamines due to their longer availability on the market. However, women who do not respond to chlorpheniramine can be counseled that the available studies for cetirizine, fexofenadine, and loratadine do not show an increased risk for congenital anomalies. Larger numbers of human pregnancies are still needed, particularly for fexofenadine. Avoidance of combination therapy with pseudoephedrine, at least in the first trimester, is also preferred.
Contributors
Kate Durda, BA
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
References
· Aselton P et al. (1985): First-trimester drug use and congenital disorders. Obstet Gynecol 65(4):451-455.
· Blaiss MS (2003). Management of rhinitis and asthma in pregnancy. Ann Allergy Asthma Immunol 90:16-22.
· Craig-McFeely PM et al. (2001). Evaluation of the safety of fexofenadine from experience gained in general practice use in England in 1997. Eur J Clin Pharmacol 57:313-320.
· Diav-Citrin O et al. (2003). Pregnancy outcome after gestational exposure to loratadine or antihistamines: a prospective controlled cohort study. J Allergy Clin Immunol 111:1239-1243.
· Einarson A et al. (1997). Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Immunol 78:183-186.
· Ellegard E (2006) Pregnancy Rhinitis. Immunol and Allergy Clin of North Am 26:119-135.
· Erez S et al. (1971) Double-blind evaluation of hydroxyzine as an
· antiemetic in pregnancy. J Reprod Med 7(1):57-59.
· Heinonen OP et al. (1977) Birth Defects and Drugs in Pregnancy. Littleton, Mass.: John Wright-PSG, 1977, pp 335-337, 346-347, 438-439.
· Horak F and Stubner UP (1999). Comparative tolerability of second generation antihistamines. Drug Saf 20:385-401.
· Jick H et al. (1981) First-trimester drug use and congenital disorders. JAMA 246(4):343-346.
· Kallen B (2002). Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 11:146-152.
· Kallen B and Olausson PO (2001). Monitoring of maternal drug use and infant congenital malformations. Does loratadine cause hypospadias? Int J of Risk & Safety in Med 14:115-119.
· Kallen B and Olausson PO (2006). No increased risk of infant hypospadias after maternal use of loratadine in early pregnancy. Int J Med Sci 3:106-107.
· Kamijima M et al. (1994) [Reproductive and developmental toxicity studies of cetirizine in rats and rabbits.] Kiso to Rinsho 28(7):1877-1903.
· Keles N (2004) Treatment of allergic rhinitis during pregnancy. Am J Rhinol 18:23-28.
· Loebstein R et al. (1999) Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study. J Allery Clin Immunol 104:953-6.
· McIntyre BS et al. (2003). Effects of perinatal loratadine exposure on male rat reproductive organ development. Reprod Toxicol 17:691-697.
· Moretti ME et al. (2003). Fetal safety of loratadine use in the first trimester of pregnancy: A multicenter study. J Allergy Clin Immunol 111:479-483.
· Pederson L et al. (2006) Maternal use of loratadine during pregnancy and risk of hypospadias in offspring. Int J Med Sci 3(1):21-25.
· Rosa F (1993): Personal Communication. Cited in: Briggs et al. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2005, p 1371.
· Sanofi-Aventis (2006). Allegra Product Information.
· Werler MM et al. (1992) First trimester maternal medication use in relation to gastroschisis. Teratol 45:361-367.
· Werler MM et al. (2002) Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol 155(1):26-31.
· Werler MM et al. (2004). Evaluation of an association between loratadine and hypospadias - United States, 1997-2001. MMWR 53:219-221.
· Werler MM et al. (2004) Vasoactive exposures, vascular events, and hemifacial microsomia. Birth Defects Res A Clin Mol Teratol 70(6):389-395.
· Wilton LV et al. (1998). The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 105:882-889.
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Posted by admin on April 1st, 2006 — in newsletter
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Neonatal Complications Associated with Late Pregnancy Use of Selective Serotonin Reuptake Inhibitors
Volume 13, No. 2, April 2006
The prevalence of depression among women peaks during the childbearing years (Burke et al., 1991). With up to 14% of pregnant women displaying symptoms of depression, treatment of major depression during pregnancy is quickly becoming a major public concern (Evans et al., 2001).
In addition to concerns that women with untreated depression are less likely to follow through with prenatal care and more likely to develop unhealthy behaviors or consider suicide, some studies have suggested that maternal depression is associated with pregnancy complications such as pre-term birth and low birth weight, as well as adverse cognitive/emotional effects in the child (reviewed in Bonari et al., 2004; Mian 2005). Further, for pregnant women with a history of major depression, relapse occurred during pregnancy in 68% of those who discontinued their medications, as compared to 26% of those that continued taking medication for their depression (Cohen et al., 2006). The potential for relapse and the possible adverse effects of depression itself on the pregnancy need to be considered when discussing whether or not a specific patient should remain on antidepressants throughout pregnancy.
Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants that increase the levels of circulating serotonin in the body, are just as effective as older tricyclic antidepressants and have fewer side effects (nausea, insomnia, sexual dysfunction, etc.) and higher tolerability in general (reviewed in Zohar and Westenberg, 2000). As a result, the prevalence of those taking SSRIs to treat their depression has increased dramatically in the past decade (Meijer et al., 2004).
A number of studies have found no association with congenital anomalies and SSRIs with use during the first trimester of pregnancy (reviewed in Nonacs and Cohen, 2003; Wen and Walker 2004). In contrast to this reassuring data, a retrospective and unpublished investigation by GlaxoSmithKline, the makers of paroxetine (Paxil), suggests an increased risk for cardiovascular defects (most commonly ventricular septal defects) of 2% compared to 1% in the general population(reviewed in Williams and Woolerton 2005; GlaxoSmithKline study EPIP083 2005). Additional studies are still needed for confirmation since controlled prospective studies have not seen an increase in congenital anomalies with paroxetine.
There is also accumulating reports regarding concerns of SSRI use after the first trimester. Therefore, this newsletter will focus on the neonatal effects that have been associated with use of SSRIs during the second half of pregnancy, such as poor neonatal adaptation, and the recent reported association with persistent pulmonary hypertension of the newborn (PPHN).
Poor Neonatal Adaptation
Goldstein (1995) reviewed 112 prospective pregnancy outcomes on the use of fluoxetine (Prozac) that were voluntarily reported to the manufacturer, Eli Lilly. He found that 15/115 (13%) of infants experienced different postnatal complications, such as irritability, hyperbilirubinemia, or sleepiness, which he noted was similar to the National Hospital Discharge Survey. There was also no pattern of complications and no dose relationship to further a cause and effect relationship between fluoxetine and the complications. However, absence of a specific control group and a high rate of unknown outcomes limited his conclusions.
Subsequently, Chambers et al. (1996) prospectively followed 73 pregnant women taking fluoxetine during the third trimester. The authors reported poor neonatal adaptation among 31.5% of infants exposed to fluoxetine in the third trimester, compared to 8.9% among infants exposed early in pregnancy (Chambers et al. 1996). With exclusion of the premature infants, 23% of late exposed infants were admitted to the special care nursery compared to 9.5% of early exposed infants or 6.3% of infants never exposed to fluoxetine. Health care workers, however, were not blinded to maternal medication use when examining the infants, a possible study bias.
Similar results were noted in a study of 55 infants exposed to paroxetine during the third trimester. In this study, 22% of infants experienced neonatal complications (including 3 premature infants), as compared to 6% of unexposed infants or infants exposed only in the first and second trimester (Costei et al., 2002). Of the 12 infants that had complications, respiratory distress was noted in nine, hypoglycemia in two, and jaundice in one. Symptoms disappeared in one to two weeks.
Oberland et al. (2004) performed a prospective cohort on three small groups of infants. Twenty-eight infants were exposed to SSRIs alone (paroxetine, fluoxetine, and sertraline), 18 infants had exposure to an SSRI and the benzodiazepine clonazepam, and 23 control infants had no medication or depression exposure. Twenty-five percent of the SSRI group alone, 39% of the SSRI group plus clonazepam, and 9% of control infants had symptoms of poor neonatal adaptation.
Symptoms included mild respiratory distress, transient tachypnea of the newborn, and hyptotonia. All symptoms resolved in 48 hours and no significant differences in development were noted at follow-up at 2 and 8 months of age using the Bayley Scales of Infant Development.
Based on their findings, the authors recommended avoiding polypharmacy when possible and specifically monitoring mothers and infants when paroxetine was used in combination with clonazepam. They also noted that their data should not preclude the urgency to treat maternal depression or anxiety when warranted.
Sivojelezova et al. (2005) prospectively followed 132 women taking citalopram (Celexa) in whom 54% of the total group took citalopram throughout pregnancy. Following third trimester exposure, 16% of infants were admitted to the special care nursery versus 4% of infants not exposed to citalopram during the third trimester. Additionally, Malm et al. (2005) used Finnish population based registries to identify 597 women who purchased SSRIs in the third trimester. Citalopram(N=228) and fluoxetine (N=239) were most commonly purchased while paroxetine (N=64), sertraline (N=41), and fluvoxamine (N=27) were also purchased. There was a small but significant difference in that 15.4% were treated in the special care nursery versus 11.2% with only first trimester purchase. An obvious criticism of this study is that purchasing the medicine does not necessarily mean the medicine was taken during pregnancy.
Levinson-Castiel (2006) identified 60 infants with prolonged exposure to SSRI paroxetine (N=37), fluoxetine (N=12), citalopram (N=8), venlafaxine (n=2), and sertraline (N=1). Symptoms of neonatal abstinence syndrome were present in 30% of the exposed infants versus none of the control infants. Clinical assessment was not made blinded and medicine use was based on maternal report. The most common symptoms were tremors, gastrointestinal disturbances (poor feeding, vomiting, loose stools), and sleep disturbances. Maximum mean daily symptoms occurred within the first 48 hours. None of the infants in this study required any treatment for the symptoms.
A dose relationship with increasing symptoms and increasing dose was seen for paroxetine (the only medicine that could be studied for dosing) but no cut-off point of an increased risk could be identified due to the small sample size. Based on their findings, the authors recommended that exposed infants should be closely monitored by using a standardized protocol for a minimum of 48 hours and should not be discharged early from the hospital.
The results of a meta-analysis of studies involving late gestational SSRI exposure, including many of the ones described previously, indicated an overall neonatal behavioral syndrome risk ratio of 3.0 (95% CI, 2.0-4.4) (Moses-Kolko E 2005). Paroxetine and fluoxetine were reported most often but may reflect their more common use. The authors noted that tapering and then discontinuing SSRIs a couple weeks prior to the due date and then resuming treatment right after delivery may be an option for some women. They did note that a late tapering has not been proven effective for avoidance of neonatal complications and that it puts patients at risk for postpartum depression.
It is unclear whether the symptoms noted in some infants born after in utero exposure to SSRIs is due to withdrawal from medication at delivery or to serotonergic overstimulation due to exposure late in pregnancy. The symptoms of these syndromes overlap in adults, and appear to overlap in infants as well (Jaiswal et al., 2003).
Persistent Pulmonary Hypertension of the Newborn
Persistent pulmonary hypertension of the newborn (PPHN) is described as a failure of normal pulmonary vascular relaxation shortly after birth, which ultimately results in unoxygenated blood being shunted into the systemic circulation (via patent ductus arteriosus and/or foramen ovale) and profound hypoxemia (reviewed in Dakshinamurti 2005). This condition is associated with substantial morbidity and, despite treatment, can result in death.
A recent study published in the New England Journal of Medicine found that SSRI use after the 20th week of gestation is associated with PPHN (Chambers et al., 2006). This study was prompted by the authors original cohort study that identified two infants with PPHN following third trimester fluoxetine use. For this case-control study of 377 infants with PPHN and 836 controls, mothers were interviewed within 6 months of delivery regarding their medical and obstetric histories, habits, occupations, and medication use during the period of 2 months before conception and the end of pregnancy. The mothers were explicitly asked whether they had taken medications for depression, and if they responded positively, they were provided a list of antidepressant medications from which to identify the one(s) they had taken. The specific SSRI medications that participants reported included citalopram, fluoxetine, paroxetine, and sertraline. Doses of medication and the number of women reporting use of each medicine was not listed.
Fourteen infants with PPHN had been exposed to SSRIs, as compared to only 6 control infants. This resulted in an odds ratio of 6.1. Given the general population rate of 1-2/1000 for PPHN, this translates into an absolute risk of 0.6-1.2%. 12/14 mothers with infants with PPHN continued the SSRI at least into the eights months of pregnancy. Using 26 gestational weeks as a cutoff therefore yielded identical results.
The authors of this study point out that such an association cannot establish causality, but that there is biological plausibility to their finding. The lungs have been reported to act as a reservoir for SSRIs, the vasoconstrictive properties of SSRIs may increase pulmonary vascular resistance, and the mitosis-inducing properties of the drugs may result in the over-proliferation of the smooth muscle cells in the lung (Chambers et al., 2006). Further, the authors also suggest the idea that SSRIs affect the synthesis of nitric oxide, which is known to play a role in regulation of vascular tone and reactivity as yet another mechanism for the occurrence PPHN in SSRI-exposed infants (Chambers et al., 2006). They propose that PPHN may represent the severe end of the neonatal complications (Chamber et al., 2006).
Although the study design was the most appropriate in order to assess this rare outcome, its retrospective design makes it vulnerable to recall bias, especially with prompting women with medicine names. The authors point out that the same association was not found with tricyclic antidepressants even with medicine name prompting. It is still important to replicate these findings before definitive conclusions can be drawn.
Summary
Use of SSRIs late in pregnancy is associated with an approximate 20-30% chance for nonspecific and typically transient neonatal complications. Therefore, these infants should be carefully monitored in the newborn period. While an initial study on these affected infants did not find development impairment at eight months of age, longer term neurobehavioral evaluations in this subpopulation are still needed. It should be noted that the SSRI associated neonatal complications can also be seen with other types of antidepressants and in a smaller number of infants whose mothers do not take any antidepressants.
An approximate 1% link between PPHN and late pregnancy SSRI needs to be replicated for verification but may represent the severe end of these neonatal complications. These findings act as a reminder that a woman’s individual clinical state should be considered when deciding to keep a patient on a psychotropic medicine throughout pregnancy. Due to concerns with untreated maternal depression, continuing treatment in women with clinical depression may still be the least risky option for many woman.
References
- Bonari L, et al.(2004). Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 49(11):726-734.
- Burke KC, et al. (1991). Comparing age at onset of major depression and other psychiatric disorders by birth cohorts in five US community populations. Arch Gen Psychiatry 48(9):789-95.
- Chambers C, et al . (1996). Birth outcomes in pregnant women taking fluoxetine. New Engl J Med 335:1010-5.
- Chambers C, et al. (2006). Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New Engl J Med 354:579-87.
- Cohen L, et al. (2006). Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 295(5):499-507.
- Costei A, et al. (2002). Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 156:1129-32.
- Dakshinamurti S (2005). Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 39(6):492-503.
- Evans J, et al. (2001). Cohort study of depressed mood during pregnancy and after childbirth. BMJ 323(7307):257-60.
- GlaxoSmithKline study EPIP083 (2005). GSK medicine: bupropion and paroxetine. Epidemiology study: preliminary report on bupropion in pregnancy and the occurrence of cardiovascular and major congenital malformation. Available: http://ctr.gsk.co.uk/summary/paroxetine/epip083.pdf (Accessed 30 March 2006).
- Goldstein D (1995). Effects of third trimester fluoxetine exposure on the newborn. J Clin
- Psychopharmacol 15:417-20.
- Jaiswal S, Coombs R, Isbister G (2003). Paroxetine withdrawal in a neonate with historical and
- laboratory confirmation. Eur J Pediatr 162:723-4.
- Levinson-Castiel R, at al. (2006) Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 160:173-6.
- Malm H, et al. (2005). Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol 106:1289-96.
- Meijer W, et al. (2004). Incidence and determinants of long-term use of antidepressants. Eur J Clin Pharmacol 60(1):57-61.
- Mian A (2005). Depression in pregnancy and the postpartum period: balancing adverse effects
- of untreated illness with treatment risks. J Psychiatr Prac 11:389-396.
- Mose-Kolko EL, et al. (2005) Neonatal signs after late in utero exposure to serotonin reuptake inhibitors. JAMA 293:2372-2383.
- Nonacs R, Cohen L (2003). Assessment and treatment of depression during pregnancy: an
- update. Psychiatr Clin North Am 26(3):547-62.
- Oberland TF, et al. (2004) Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry 65:230-237.
- Sivojelezova A, et al. (2005) Citalopram use in pregnancy: Prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet & Gynecol 193:2004-9.
- Wen S, Walker M (2004). The use of selective serotonin reuptake inhibitors in pregnancy. J Obstet Gynaecol Can 26(9):819-22.
- Williams M, Wooltorton E (2005). Paroxetine (Paxil) and congenital malformations. CMAJ 173(11):1320-1.
- Zeskind P, Stephens L (2004). Maternal selective serotonin reuptake inhibitor use during
- pregnancy and newborn neurobehavior. Pediatrics 113:368-75.
- Zohar J, Westenberg H (2000). Anxiety disorders: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 403:39-49.
Contributors
Erin Rooney, BA
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
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Posted by admin on January 1st, 2006 — in newsletter
PDF Version
Organic Solvents During Pregnancy: An Update on Occupational Exposure
Volume 13, No. 1, January 2006
Organic solvents are a diverse group of liquids that are used to dissolve other materials like oils, resins, and rubber (McMartin et al., 1998). Examples of organic solvents include: aliphatic hydrocarbons (mineral spirits, varnish, kerosene); aromatic hydrocarbons (benzene, toluene, xylene); halogenated hydrocarbons (carbon tetrachloride, trichloroethylene); aliphatic alcohols (methanol); glycols (ethylene glycol); and glycol ethers (methoxyethanol) (McMartin et al., 1998). While it is likely erroneous to make general statements about organic solvents due to their diverse nature, human reproductive studies have only studied organic solvents collectively. This newsletter will provide an updated review of these studies. See 1995 Risk Newsletter Volume 3(3) for the original newsletter.
Exposure to organic solvents occurs most frequently from inhalation or skin contact. Exposure is nearly unavoidable in the general population since organic solvents are present in many household products such as paints, aerosol sprays, spot removers, lighter fluids, inks, and gasoline (Koren 2005). Household exposure is typically of a low level, episodic nature. This type of exposure is likely to be of little concern although conservative measures should include minimizing use, wearing protective clothing, such as gloves, making sure ventilation is adequate, or ideally having someone else use the product in the woman’s absence. Occupational exposure is more of a concern because it typically involves higher dose, chronic exposure. Organic solvents are used in a wide range of industries such as dry cleaners, laboratories, paint manufacturers, chemical manufacturers of inks and plastics, beauty salons, carpentry, and funeral services (Koren, 2005). Moreover, some of these fields are female dominated.
Intentional Solvent Abuse
Individuals may purposefully inhale organic solvent vapors to attain a feeling of euphoria by coating rags with spray paint and directly inhaling the rag as it covers their nose and mouth. Chronic toluene abuse (one-four 16 ounce cans per day) is associated with a myriad of toxic symptoms such muscle weakness, neuropsychiatric disturbances, and renal tubular acidosis. (Pearson et al., 1994). Chronic abusers typically reach levels 50 x the Occupational Safety and Health Administration (OSHA) permissible levels(Wilkins-Haug, 1997).
Although causation is not proven, a congenital solvent syndrome from purposeful abuse of toluene or gasoline has been suggested by case series and uncontrolled cohorts. These reports have included premature delivery, low birth weight, microcephaly, develop-mental delay, growth retardation, and characteristic facial features similar to infants with fetal alcohol syndrome (Arnold et al., 1994; Pearson et al., 1994). While fetal alcohol syndrome was not ruled out, case reports have also described infants with renal tubular dysfunction which is associated with solvent and not alcohol abuse (Lindermann, 1991; Erramouspe et al., 1996). Additionally, some infants have smelled of solvents at birth (Koren, 2005).
Occupational Exposure Occupational exposures are difficult to assess for several reasons. First epidemiological reproductive data is typically sparse and high dose animal data is difficult to interpret to lower level human exposure. Secondly, the dose of exposure is also difficult to gauge unless specific airborne studies have been performed by an industrial hygienist. Odor is often an inaccurate way to assess the dosage of most organic solvents (McMartin et al, 1998).
Infrequently, organic solvents (such as toluene) can be monitored via blood or urine tests. Thirdly, occupational exposures typically include multiple exposures which confound outcome information for any one agent. In summary, available studies are limited by the lack of quantified measure of the exposure and the fact that exposures take place in diverse settings with different doses, durations, and combinations of chemicals.
Miscarriage and Major Malformations
Occupational studies have yielded conflicting results on whether rates of miscarriage and congenital anomalies are increased following maternal exposure. McMartin et al. (1998) performed a meta-analysis of epidemiological studies on pregnancy outcomes following maternal organic solvent exposure. Five retrospective studies were included for spontaneous abortion (N= 2,899 patients) and five retrospective studies were utilized for major malformation analysis (N= 7,036 patients). While some prior studies have suggested an increased rate of miscarriage, the rate of spontaneous abortion was not significantly increased when analyzed in this meta-analysis. However, the rate of major malformations was significantly increased with an odds ratio of 1.64 (CI 1.16-2.30). Assuming a background risk of 3%, this study suggests the absolute risk for malformations would be 4.9%.
Limitations of the McMartin et al. (1998) meta-analysis include that the studies analyzed were looking at different organic solvents, unknown dosages, and wide durations of exposure in a wide range of occupational environments. Despite these limitations, the authors supported the current recommendation that pregnant women should limit their exposure to organic solvents as much as possible. The authors also pointed out that these risks should be further investigated in a prospective study. Khattak S et al. (1999) prospectively followed 125 pregnant women who were occupationally exposed to organic solvents. All women worked for at least the entire first trimester.
Hours were not documented. The majority of women were factory workers, laboratory technicians, artists, chemists, painters, and printers. The most commonly reported organic solvent exposures were aliphatic and aromatic hydrocarbons, phenol, trichloroethylene, vinyl chloride, and acetone. The exposed group had a significantly higher rate of malformations compared to the control group. There were 13 major malformations in the exposed group compared to only one malformation in the control group. While the control group had an unusually low rate of malformations, the exposed rate was still greater than historic controls. Additionally, a dose response relationship was suggested in that at least 12/13 of the infants with malformations occurred in women who reported work-related illness such as irritation of the eyes or respiratory system, headaches, and breathing difficulties.
There was no pattern to the malformations to suggest cause and effect. Malformations included ventricular septal defect, clubfoot, laryngolmalacia, diaphragmatic hernia, neural tube defect, congenital deafness, micropenis, cloacal extrophy, left inguinal hernia, congenital hydronephrosis, neuronal migration defect, and hemivertebrae. However, the authors argued that diverse exposures should not be expected to create a homogenous pattern. The authors concluded that additional studies are needed to confirm their findings but in the interim it is prudent to minimize women’s exposure to organic solvents and particularly to take precaution to avoid symptomatic exposure.
Neurological effects
Organic solvents like toluene are considered neurotoxins since acute exposures have documented effects on the central nervous system in adult workers. A subset of adults with a long history of occupational exposure have cognitive deficits and women with purposeful abuse have delivered infants with developmental delay (Koren, 2005). Therefore, fetal exposure raises a significant concern for adverse cognitive function following exposure to known neurotoxins. Similar to major malformations and miscarriage, results however have been inconsistent.
Eskenzai et al. (1988) assessed neurocognitive functioning and growth in 41 children age 3-4 years old whose mothers had been occupationally exposed to organic solvents. Using maternal reports and the McCarthy Scales of General Abilities, no differences in neurobehavioral development or growth were identified in the exposed versus control group.
Till et al. (2001a) also evaluated long-term cognitive and behavioral functioning of 28 children ages 3-7 years old who were exposed to a wide range of organic solvents in utero. No group differences were observed on measures of attention, visuo-spatial ability, or fine-motor ability. However, exposed children scored significantly lower on receptive language, expressive language, and graphomotor ability, suggesting detrimental effects on selective cognitive functions.
Laslo-Baker et al. (2004) examined the long-term neurodevelopment effects of 32 children age 3-9 years old whose mothers had been exposed to organic solvents at work during their pregnancy. Mothers reported exposures to a total of 78 different organic solvents for 1-40 hours per week (mean, 24 hours) and for 8-40 weeks (mean, 32 weeks) during their pregnancy. Exposed mothers reported a high level of protective equipment. Occupations listed were diverse including painter, laboratory technician, factory worker, hair stylist, graphic designer, funeral embalmer, and science teacher. After controlling for demographic variables and maternal IQ and education, there were no significant differences in global, verbal, or performance IQ. The authors however reported differences in more subtle areas of neurodevelopment. Exposed children had lower test scores in subtests of recall, attention, and language. No dose relationship (which would further causation) was found between the length and total hours of exposure and any of neurodevelopmental scores.
Visual impairments
Noting that impairment of color vision discrimination can be altered by certain solvent exposures in adult workers, Till et al. (2001b, 2005) conducted two studies to examine visual impairments in infants and children whose maternal parents were occupationally exposed to organic solvents during pregnancy.
Till et al. (2001b) measured color vision and visual acuity in 32 exposed children whose mothers worked in diverse occupations with multiple exposures during their pregnancies. Overall, results showed that exposed children had significantly higher error scores on color discrimination and visual acuity. Three of the 32 exposed children suffered from clinical red-green color vision loss compared to none of the control children. The authors commented that these visual deficits are of concern because they may have implications for higher level cognitive functioning, such as learning to read. A dose response relationship, which would argue for causation, was not found.
In 2005, Till et al. tested 21 exposed infants in which maternal qualitative exposure levels were gathered prospectively. This study found a significant decrease in contrast sensitivity as well as grating acuity (dependant upon the level of exposure) in exposed infants compared to controls. Regarding color vision, 26.3% of exposed infants showed abnormal red-green color vision compared to 0% of controls. These findings suggest that prenatal solvent exposure is associated with selective visual deficits.
Summary
Maternal intentional abuse of organic solvents has suggested that a congenital solvent syndrome, similar to fetal alcohol syndrome, may exist. Effects of doses not toxic to the mother warrant further investigation. Available occupational exposure studies are severely limited in that they study multiple diverse exposures together and that there is no quantified measure of the exposures.
Not surprising, the available data is inconsistent. There is some evidence of an increased risk for congenital anomalies, particularly in women who reported symptoms related to their occupational exposure. Initial data suggests that there may be detrimental effects on subtle cognitive functions or visual color acuity. Given the inconclusive but concerning information, occupational exposure to known neurotoxins should be minimized or ideally avoided. If air monitoring is available, OSHA dose standards that are established for adult health, and may or may not adequately protect fetal health, should not be exceeded. Mothers are encouraged to limit the time they are exposed to organic solvents and to wear protective clothing, such as solvent resistant gloves and splash-proof eye goggles. Respirators need to be specifically approved for organic solvents and individuals would need to be assessed and fitted to use them. Engineering controls, such as a chemical hood, which would contain chemicals in their own ventilation system are preferred.
References
· Arnold GL, Kirby RS, Langendoerfer S, Wilkins-Haug L (1994). Toluene embryopathy: clinical delineation and developmental follow-up. Pediatrics 93(2):216-20.
· Erramouspe J, Balvez R, Fischel D (1996) Newborn renal tubular acidosis associated with prenatal maternal toluene sniffing. J Psych Drugs 28:201-4.
· Eskenazi B, Gaylord L, Bracken MB, Brown D (1988) In utero exposure to organic solvents and human neurodevelopment. Dev Med Child Neurol 30(4):492-501.
· Khattak S, K-Moghtader G, McMartin K, Barrera M, Kennedy D, Koren G (1999) Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study. JAMA 281:1106-1109.
· Koren G (2005) Occupational toxicology of organic solvents-the reproductive context. 18th International Conference of Organization of Teratology Information Services.
· Laslo-Baker D, Barrera M, Knittel-Keren D, Kozer E, Wolpin J, Khattak S, Hackman R, Rovet J, Koren G (2004) Child neurodevelopment outcome and maternal occupational exposure to solvents. Arch Pediatr Adolesc 128:956-961.
· Lindermann R (1991) Congenital renal tubular dysfunction associated with maternal sniffing of organic solvents. Acta Paediatr Scand 80(8-9):882-4.
· McMartin KI, Chu M, Kopecky E, Einarson TR, Koren G (1998) Pregnancy outcome following maternal organic solvent exposure: a meta-analysis of epidemiologic studies. Amer J Indust Med, 34:228-292.
· Pearson MA, Hoyme HE, Seaver LH, Rimsza ME (1994) Toluene embryopathy: delineation of the phenotype and comparison with fetal alcohol syndrome. Pediatrics 93(2):211-215.
· Till C, Koren G, Rovet JF (2001) Prenatal exposure to organic solvents and child neurobehavioral performance. Neurotoxicol Teratol 23(3):235-45.
· Till C, Westall CA, Rovet JF, Koren G (2001) Effects of maternal occupational exposure to organic solvents on offspring visual functioning: a prospective controlled study. Teratology 64(3):134-41.
· Till C, Westall CA, Koren G, Nuiman I, Rovet JF (2005) Vision abnormalities in young children exposed prenatally to organic solvents. Neurotoxicology 26(4):599-613.
· Wilkins-Haug L (1997) Teratogen Update:Toluene. Teratology 55:145-151.
· Wilkins-Haug L and Gabow PA (1991) Toluene abuse during pregnancy: obstetric complications and perinatal outcomes. Obstet Gynecol 77:504-9.
Contributors
Lauren Bowling, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
No Comments »
Posted by admin on September 1st, 2005 — in newsletter
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Paternal exposure to chemotherapy
Volume 12, No. 5, September 2005
How many environmental agents with mutagenic properties have been found to increase the rate of genetic disorders in humans (Brent, 2005)? The answer: None. Infertility is the only established outcome following certain paternal exposures. For example, clinicians were never able to document an increase of genetic disease in the offspring of male atomic bomb survivors. Unfortunately, the topic of male-mediated teratogenesis has not been thoroughly studied and the available research is inadequate to rule out any increased risk for adverse pregnancy outcome. Because an increase in genetic disease would be at a much lower magnitude than an increase in congenital anomalies following a maternal teratogen exposure, further studies with very large populations are still needed.
The maturation of sperm takes approximately 3 months. Mutations are more likely to occur in the actively reproducing cells like spermagonia and are less likely to occur in female oocytes (Davis et al., 1992). Therefore, preconception exposures are a greater theoretical concern for males. There are several mechanisms by which paternal exposure could theoretically result in reduced fertility or exert teratogenic effects on the fetus:
·Medicines could exert a direct effect on sperm causing anatomic abnormalities with reduced sperm motility or function or even induce chromosomal anomalies or new gene mutations
·Medicines could interfere with the pituitary-hypothalmic function (decrease testosterone or libido) and subsequently reduce fertility
·Medicines could lead to direct exposure of the developing fetus through contaminated seminal fluid via unprotected intercourse
This newsletter will focus on studies addressing the first mechanism. Since ionizing radiation and antineoplastic drugs are biologically plausible agents for inducing mutations in sperm, possible paternal teratogenecity with various cancer treatments will be discussed.
Survivors of childhood cancer
There is concern for long lasting effects in the sperm of male survivors since cancer therapies are targeted to induce cell damage. These concerns are further prompted by the presence of higher rates of chromosomal abnormalities in sperm of some successfully treated patients (Martin et al., 1999; Frias et al., 2003).
However, while male infertility has been documented with germ cell loss due to radiation or antineoplastic drug treatment, an increased frequency of adverse pregnancy outcomes has not been documented in the offspring of survivors of childhood cancer.
For example, the National Cancer Institute collaborated with three hospital-based cancer registries and two population based registries to evaluate childhood cancer (diagnosis < age 20 years) survivors’ pregnancy outcomes. There were no differences in the rates of cytogenetic diseases, singlegene defects, or simple malformations in the offspring when compared with sibling controls (Byrne et al., 1998). Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P = 0.3; not significant).
Several other large population studies report the same findings. This includes the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study started in 1994. This database was used to review 4,214 livebirths from childhood cancer survivors. Again there were no significant differences between the two study groups. The total rate of cytogenetic abnormalities, single gene defects, and malformations was 3.7% in the survivor offspring and 4.1% in the siblings (Boice et al., 2003). Additionally, when cancers with a known single gene inheritance were excluded, no increase
in offspring childhood cancer was seen.
A study conducted using the Danish Cancer Registry of childhood cancer survivors compared the pregnancy outcomes to their unaffected siblings (Winther et al., 2004). The cancer survivor group had 2,630 live births from 4,676 childhood cancer survivors. There was no difference in the rate of chromosomal abnormalities between the groups.
It should be noted that a limitation of these studies is that the individual treatment regiments have not been evaluated separately. There may be subtle long-term differences between treatment types that are not detectable by grouping all survivors together(Wyrobek et al., 2005).
Testicular Cancer
Testicular cancer and Hodgkin’s disease represent two of the most common cancers in young males.
Several researchers have noted oligospermia in patients with testicular cancer even prior to treatment (Gandini et al., 2003). Bahadur et al. (2005) analyzed semen quality in 314 males before and after gonadatoxic therapy over a 26 year period. The testicular cancer group (N=102) had the lowest level of sperm concentration of all disease categories before treatment. Following cytotoxic treatment, this group had the lowest level of azoospermia (12%) but the highest level of oligospermia (38%). The rates of normal sperm counts after treatment (50%), however, were also the highest of all the cancer types evaluated.
Testicular cancer is commonly treated with the polychemotherapy regimen bleomycin, etoposide and cisplatin (BEP). Recovery of sperm function following treatment has not been predictable. While azoospermia following BEP occurred initially in all patients in the Bahadur et al. study, 50-80% of men recovered some level of motile sperm 2-5 years following treatment.
Petersen et al. (1994) found a dose-dependent effect of cisplatin and impaired spermatogenesis by analyzing sperm samples in 33 patients treated with a conventional dose of BEP and 21 patients treated with high dose BEP. The conventionally treated group had a higher sperm count (19% azoospermic) than the high dose group (47% azoospermic) following treatment.
Chromosomal abnormalities in sperm were found to be increased up to one year post treatment for testicular cancer (Martin et al., 1999) but not increased 2-13 years after BEP chemotherapy (Martin, 1998). Bahadur et al. (2005) reported that waiting 1.5-2 years may allow for a sufficient turn over of cells to expel any mutagenic effect but then recommended waiting a more practical 6-12 months prior to attempting conception.
There is limited information on the pregnancy outcomes of fathers treated specifically for testicular cancer. The majority of research has focused on issues of fertility and sperm quality.
Hartmann et al. (1999) distributed a questionnaire on fertility and sexual function to patients treated for testicular cancer. Twenty-one out of the 40 couples (53%) that wanted children were able to achieve pregnancy at a median time of 54 months (3-108 months) after treatment ended. Although the authors reported no major birth defects, one child reportedly had cryptorchidism and one had hip dysplasia. Normal development in all children was reported up to a median age of 62 months (1-180 months). In another study, 15 patients treated for testicular cancer by polychemotherapy fathered 20 children with no congenital malformations (van der Kolk, et al., 1990). The mean time from the end of treatment to conception was 39 months (9-82 months). Development of the children was reportedly normal in the children age 3 months-6 years old.
Hodgkin’s Disease
Akin to testicular cancer, several researchers have noted that 30-65% of men have oligospermia or other alterations of semen quality pre-treament with Hodgkin’s disease (Gandini et al., 2003).
Sperm from men treated for Hodgkin’s disease with Novantrone, Oncovin, Vinblastine and Prednisone (NOVP) chemotherapy was examined for frequency of chromosomal abnormalities. Sperm was collected before treatment, shortly after treatment, and 1-2 years after treatment. Researchers examined the chromosomes that are involved in the most common aneuploid syndromes, chromosomes 18, 21, X, and Y. They found a 2-14 fold elevation in abnormal chromosome number in the sample collected shortly after treatment but did not find an increase 1-2 years post treatment (Frias et al., 2003). A similar study found that sperm aneuploid levels were transient and returned to pre-treatment levels approximately 100 days after the completion of NOVP chemotherapy (Robbins et al., 1997).
Swerdlow et al. (1996) found no excess of stillbirths, low birthweight, chromosome abnormalities, or congenital malformations, and no cancers in 49 offspring of women and men previously treated for Hodgkin’s disease. Sixteen of the children were conceived after chemotherapy, 25 after radiotherapy, and 8 after a combined modality therapy. Sixteen of the children had been conceived less than 5 years after treatment. Additionally, there were no major or minor birth defects among 26 offspring of male patients treated for Hodgkin’s disease (Aisner et al., 1993). The median treatment free interval at the birth of the child was 8 years (1.25-16).
The previous studies with testicular cancer and Hodgkin’s disease illustrate that men should not be counseled that infertility is a definite result of treatment. Cryopreservation of semen prior to treatment is also recommended. Depending on the post thaw semen quality, patients can be advised whether additional fertility assistance procedures should be utilized. A follow-up study on 29 patients did not find a difference in successful pregnancy based on the malignancy type which led to the sperm cryopreservation (Agarwal et al., 2004). If cryopreservation is not performed and normal
fertility does not resume, in-vitro fertilization with single sperm (ICSI) could be attempted post treatment.
Methotrexate
Methotrexate interferes with DNA synthesis and cellular replication. In this way it is effective against malignant cells and cellular proliferation in cancerous tissues. Methotrexate is becoming increasingly prescribed for rheumatoid arthritis and psoriasis. The exposure of fetuses to methotrexate when ingesting directly by women increases the chance for birth defects when taken during the first trimester (and particularly between 8-10 weeks gestation) when the limbs and skull are still forming.
Oligospermia has been seen in individuals taking methotrexate as part of cancer treatment. Whether low dose monotherapy methotrexate taken for rheumatoid arthritis or psoriasis reduces male fertility is still not clear. Reversible sexual dysfunction was reported in three men with rheumatoid arthritis who were treated with weekly doses of 12.5 mg methotrexate. However, two case series published in the 1970s found no change in sperm concentration, motility or quality in 22 men treated with methotrexate for psoriasis (French and Koren, 2003).
While specific studies have not been performed, there are no reports of genetic disease following paternal methotrexate exposure. Therefore, the concern remains theoretical. 6-Mercaptopurine (6-MP) Azathioprine (Imuran) is metabolized to 6-mercaptopurine (6-MP). Both 6-MP and azathioprine appear to work by inhibition of nucleic acid synthesis. 6-MP has been used as a chemotherapeutic agent and in some transplant recipients. These agents are now commonly prescribed to treat inflammatory bowel disease (IBD). Long-term 6-MP treatment in male mice did not impair sperm production or sperm morphology or increase congenital anomalies in offspring (Ligumsky et al., 2005). However, a significantly high rate of embryonic resorption was observed, which the authors postulated could indicate occult sperm damage.
Semen was collected from 23 patients with IBD that had been on azathioprine treatment for at least 3 months. This small study showed no negative association between azathioprine therapy and semen quality (Dejaco et al., 2001). Human paternal studies have yielded conflicting findings in regards to adverse pregnancy outcomes. Studies that have suggested an increased risk for congenital anomalies have been criticized for their small sample size, methodology, and timing contradictions.
Congenital anomalies were seen in 3.3% of 273 pregnancies and 4.8% of 42 pregnancies in male renal or cardiac transplant recipients taking azathioprine (Polifka et al., 2004). These rates are similar to the baseline risk of congenital malformation in the general population. 6-MP use was analyzed in relation to birth outcomes in fathers with IBD. Thirteen pregnancies that had been conceived within 3 months of 6-MP use were compared to a control group consisted of 37 pregnancies that had been conceived at least 3 months after 6-MP use. There were two birth defects and two miscarriages in the infants whose fathers were using 6-MP at the time of conception, and no birth defects and one miscarriage in the group with more remote use.
Based on the better outcomes with the remote use, the authors suggested that males should stop this medicine and wait three months before attempting to conceive. (Rajapakse et al., 2000). However, the rate of birth defects and miscarriage in the control group were lower than expected. Due to the small sample, the results may reflect chance.
A second study in 2003 found no increased risk of birth defects. The authors identified 37 pregnancies in which men were exposed to 25-175 mg 6-MP at the time of conception, 44 pregnancies in which men stopped taking 6-MP at various times prior to conception, and 73 pregnancies in which there was no exposure to 6-MP (Francella et al., 2003). There was one birth defect in the group with exposure at conception, three birth defects in the group with exposure prior to conception (10 months earlier, 3 years earlier, and 4 years earlier), and two birth defects in the group with no exposure. These authors concluded that there is no need for males to discontinue the medicine.
A third study suggested an increased risk for congenital anomalies. Norgard et al. (2004) used a Denmark population database to identify 54 children fathered by men who had filled a prescription for either 6-MP or azathioprine at any point before conception. Four of the 54 children (7.4%) had congenital abnormalities, compared with 2,334 of the 57,195 children (4.1%) fathered by men who had not filled such a prescription. The congenital abnormalities in the exposed group included polysyndactylia; esophageal atresia; hydronephrosis with megaloureter; and a ventricular septal defect. There was no known underlying single gene or chromosomal abnormality.
Additionally, the odds ratio was not statistically significant between the exposed and control group outcomes. Also, the timing of the last prescription for the drugs and conception among the 4 cases with abnormalities ranged from 9 months to 38 months, also casting doubt on the causative effect of the medications upon subsequent birth defects (Cohen, 2004). In fact, none of the 19 pregnancies for which prescriptions for either drug were filled within 3 months of conception resulted in congenital abnormalities.
The question of an increased risk of congenital abnormalities in pregnancies fathered by men on azathioprine or 6-MP based on the available studies should be viewed with skepticism and the benefit to male health kept in mind (Cohen, 2004). Additional studies on larger populations are still needed.
Summary
All men requiring chemotherapy should be offered cryopreservation of sperm before cancer treatment. Individuals receiving cancer treatment that can affect male fertility and sperm quality should be counseled about appropriate contraception for the duration of treatment since infertility cannot not be assumed. It is advisable that couples wait at least 3 months (the time period of one complete spermatogenesis cycle) to one year before attempting conception. Banked sperm may reduce the risk of genetic abnormalities that theoretically could be induced in the stem germ/spermatogonia cells and thus never be eliminated from the mature sperm cells. However, couples should be counseled that there is no evidence of an increased risk for genetic disease in the offspring and that a waiting period is based only on theoretical concerns.
References
· Agarwal A, et al. (2004) Fertility after cancer: a prospective review of assisted reproductive outcome with banked semen
specimens. Fertility and Sterility 81(2):342-348.
· Aisner J, et al. (1993) Pregnancy outcome in patients treated for Hodgkin’s disease. J Clin Oncol 11:507-512.
· Bahadur G, et al. (2005) Semen quality before and after gonadotoxic treatment. Human Reproduction 20(3):774-771.
· Boice JD, et al. (2003) Genetic effects of radiotherapy for childhood cancer. Health Phys 85(1):65-80.
· Brent R (2005) The mutagenic and oncogenic risks of preconception drug, chemical and radiation exposure to male and female gonadocytes. OTIS 18th International Conference.
· Byrne J, et al. (1998) Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 62:45-52.
· Cohen RD (2004) Sperm, sex, and 6-MP:The perception on conception. Gastroenterology 127(4):1263-1264.
· Davis DL, et al. (1992) Male-mediated teratogenesis and other reproductive effects: biologic and epidemiologic findings and a plea for clinical research. Reproductive Toxicology 6:289-292.
· Dejaco C, et al. (2001). Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 121(5): 1048-53.
· Francella A, et al. (2003) The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disese: a
retrospective cohort study. Gastroenterology124:9-17.
· French A and Koren G (2003) Effect of methotrexate on male fertility. Canadian Family Physician 49:577-578.
· Frias S, et al (2003) NOVP chemotherapy for Hodgkin’s disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, 21. Cancer Res 63(1): 44-51.
· Gandini L, et al. (2003) Testicular cancer and Hodgkin’s disease: evaluation of semen quality. Human Reproduction 18(4):796-801.
· Hartmann JT, et al. (1999) Long-term effects on sexual function and fertility after treatment of testicular cancer. Br J Cancer 80(5-6):801-807.
· Ligumsky M, et al. (2005) Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice. Scand J Gastroenterol 40(4):444-9.
· Martin R (1998) Human sperm chromosome complements in chemotherapy patients and infertile men. Chromosoma 107(6-7): 523-7.
· Martin R, et al (1999) Analysis of sperm chromosome complements before, during, and after chemotherapy. Cancer Genet Cytogenet 108(2): 133-6.
· Norgard B, et al., (2004) The risk of congenital abnormalities in children fathered by men treated with azathioprine or 6-MP before conception. Aliment Pharm Ther 19:679–685.
· Petersen PM, A et al (1994) Dose-dependent impairment of testicular function in patients treated with cisplatin-based
chemotherapy for germ cell cancer. Ann Oncol 5(4): 355-8.
· Polifika JE and Friedman JM (2002) Teratogen update: Azathioprine and 6-mercaptopurine. Teratology 65:240-261.
· Rajapakse RO, et al. (2000) Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 95(3): 684-8.
· Robbins WA, et al. (1997) Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Nat Genet 16(1): 74-78.
· Swerdlow AJ, et al. (1996) Fertility, reproductive outcomes, and health of offspring, of patients treated for Hodgkin’s disease: an investigation including chromosome examinations. Br J Cancer 74(2):291-296.
· Van der Kolk BM, et al. (1990) Children born after their fathers had been treated with chemotherapy for testicular cancer. Eur J Obstet Gynecol Reprod Biol 34(1-2):167-170.
· Winther JF, et al. (2004) Chromosomal abnormalities among offspring of childhood cancer survivors in Denmark: a
population based study. Am J Hum Genet 74: 1282-5.
· Wyrobek AJ, et al. (2005) Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies. J Natl Cancer Inst Monogr 34:31-35.
Contributors
Olivia Hess, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
No Comments »
Posted by admin on July 1st, 2005 — in newsletter
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Methylmercury and Pregnancy
Volume 12, No. 3, July 2005
Mercury is a naturally occurring substance that exists in a variety of chemical forms.
Elemental (inorganic) mercury is found in thermometers and dental amalgams. Mercury vapor (inorganic) is produced by the burning of fossil fuel, or by volcanic eruption, and is dispersed widely in the atmosphere. It is returned to the Earth’s surface via rainwater and undergoes biosynthesis in aquatic environments to become organic mercury, also called methyl mercury (MeHg). Small fish consume the deposited MeHg and bioaccumulation occurs up through the food chain. This issue of Risk Newsletter focuses on the reproductive risks of MeHg mercury. See Risk Newsletter Volume 8 (3) for a reproductive review regarding elemental mercury.
Historical Perspective
High doses of MeHg can cause harmful neurological effects. In adults, MeHg acts on the central nervous system causing an initial sensation of “pins and needles,” which may further progress to ataxia, dysarthria, constriction of the visual fields, and hearing loss. The phenotype and insight into effects on fetal development have been documented following various adult MeHg poisonings.
In 1953 it was reported that villagers in Minimata, Japan developed neurological disease following high level exposure to MeHg. A factory located near Miniamata Bay had dumped their inorganic mercury waste into the bay. It was eventually estimated that the amount of mercury dumped exceeded 100 tons (Tedeschi, 1982). Fish consumed the MeHg and the villagers’ diet largely consisted of the contaminated fish. Residents experienced ataxia, sensory/motor impairment, speech impairments and visual disturbances (Tedeschi, 1982). There were about 380 confirmed cases of MeHg poisoning with 52 fatalities (Tedeschi, 1982). Additionally, pregnant women consuming the contaminated fish gave birth to infants with cerebral palsy, mental retardation, and seizures. This condition is sometimes referred to as Congenital Minimata Disease.
In 1971, another epidemic of MeHg poisoning occurred in Iraq when grain treated with MeHg as an antifungal agent was mistakenly ground into bread and eaten directly instead of being planted (Moienafshari, 1999). Some 6000 persons were admitted to the hospital and there were over 450 deaths (Clarkson, 2002, Tedeschi, 1982). Again the offspring of pregnant women were noted to have higher rates of microcephaly, cerebral palsy, and sensory impairments.
Based on this Iraqi population, a 5% risk for neurological damage was suggested following mercury levels of 10-20 ug/g in maternal hair. This should be viewed as a tentative estimate since many children born to women with hair levels >100 ug/g had normal outcomes and a more sophisticated re-analysis suggested no adverse neurological damage with maternal hair < 80 ug/g (Bellinger, 2003). In comparison, the average United States diet results in maternal hair concentrations of less than 1 ug/g (McDowell, 2004, Davidson, 2005)
In both the Japan and Iraq populations, neurological disease was noted in children born to mothers with only mild, transient paresthesias (or no signs at all) suggesting a heightened fetal sensitivity (Bellinger, 2003).
Recent population studies
Populations in archipelago environments in which diets consist largely of fish have made possible longitudinal prospective studies of MeHg exposure in non-poisoning situations. While levels of MeHg were comparable between studies, disparate results have made it difficult to draw conclusions regarding safety threshold levels.
The Faroe Islands cohort included 917 children enrolled between 1986 and 1987 who were then evaluated at 7 years of age for cognitive deficits (Grandjean et al., 1997). Pilot whale meat is a staple food in this population and the main source of MeHg exposure. Mercury concentrations were measured in both cord blood and maternal hair (mean 4.27 ug/g). All analyses were carried out using MeHg concentrations from cord blood.
Clinical examination and neurophysiolocial testing did not reveal any obvious mercury related anomalies. However, following multiple regression analysis 9 out of 20 neuropsychological measures showed mercury-associated deficits. Deficits were most apparent in measures of language, attention, and memory, with fewer effects seen in domains of visuospatial and motor functioning.
Of note, they saw effects even when they excluded children with maternal hair mercury concentrations above 10 ug/g. Fish in the Seychelle Islands have similar MeHg concentrations as do fish in the United States, however, fish consumption is greater with an average of 12 weekly fish meals versus one or less for the United States (Myers et al., 2003). The Seychelles archipelago cohort consisted of 643 mother-child pairs enrolled between 1989 and 1990. Prenatal exposure to MeHg was detemined by measuring total Hg in maternal hair during pregnancy. Children were followed for 9 years and evaluated for neurocognitive, language, memory, motor, perceptual-motor, and behavorial functions through specific testing. The authors controlled for caregiver IQ, socioeconomic status, and home environment stimulation. The mean prenatal total MeHg exposure was 6.9 ug/g.
Only 2 of 21 end points were associated with prenatal MeHg exposure, namely, improved scores on the hyperactivity domain of the Connor’s teacher rating scale and decreased performance on the grooved pegboard non-dominant hand in males only. Based on further analysis, these findings were thought to be due to chance. The authors concluded that their study did not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption (Myers et al., 2003).
While both studies are high quality with regard to methodology , there are several possible explanations for the incongruent results between the Faroe and Seychelle Island studies (Davidson, 2005). For example, sources of MeHg exposure differed; whale meat in the Faroe Islands and ocean fish in the Seycelle Islands. Pilot whale meat has much higher levels of mercury than other seafood and the blubber also contains more polycholorinated biphenyls (PCBs) and other chemicals.
Measurement procedures also differed between studies. Cord blood concentrations used in the Faroe Island cohort are indicative of concentrations only in the third trimester, whereas MeHg concentrations in maternal hair used in the Seycelle study indicate exposure throughout pregnancy.
This difference may reflect effects of episodic versus long-term exposure. The disparate results could also lie in population differences in genetic, nutritional, and social-environmental areas (Bellinger, 2003). Daniels et al. (2004) evaluated maternal fish consumption and very early offspring cognitive development in a cohort of 7421 British children born in 1991-1992. Mercury levels were measured in cord tissue in 1054 children. Maternal and child fish intake was assessed by patient questionnaire and developmental tests were performed at 15 and 18 months of age. Maternal fish intake was categorized into rarely or never, once per 2 weeks, 1-3 times per week, and 4 or more times fore week. The authors assumed the each fish meal averaged 4.5 ounces.
Maternal fish intake was associated with increased umbilical cord mercury concentrations but the overall cord mercury levels were low (median 0.01ug/g wet weight) and not associated with developmental outcomes. Maternal fish intake during pregnancy was actually associated with a subtle but consistently higher developmental scores for language comprehension and social activity compared to women who did not eat fish. The association was strongest for women eating fish, 1-3 times per week. The authors concluded that fish intake could subtly enhance early child development. However, it cannot be known from this study whether it was the fish consumption itself or an associated factor, such as an overall better diet or better caregiving, that contributed to the outcome.
FDA Advisory
The March 2004 advisory from the U.S. Food and Drug Administration (FDA) and the Environmental Protection Agency made the following recommendations for women who may become pregnant, pregnant women, nursing mothers, and young children:
·Avoid shark, swordfish, king mackeral, and tilefish (larger fish with longer life spans accumulate the highest levels of MeHg)
·Eat up to 12 ounces (2 average meals) of other cooked fish weekly
·Commonly eaten fish that are low in mercury include but are not limited to canned light tuna, shrimp, salmon, catfish, and pollock
·http://www.cfsan.fda.gov/~frf/sea-mehg.html contains mercury level listing of other fish
·Since albacore (”white”) tuna has more mercury than canned light tuna, when choosing two meals of fish and shellfish, eat up to 6 ounces (one average meal) of albacore tuna per week.
·Check local advisories about the safety of fish caught by family and friends in your local lakes, rivers, and coastal areas. If no advice is available, eat up to 6 ounces (one average meal) per week of fish you catch from local waters, but don’t consume any other fish during that week.
One weeks’ consumption does not significantly alter the body mercury levels so these are “on average” guidelines
Summary
Fish is an important source of protein and omega 3 fatty acids before, during, and after pregnancy. In order to accrue the benefits of fish but maintain lower mercury levels, an average of 12 ounces of certain fish per week is recommended. This FDA recommendation is thought to be conservative given the lack of consensus findings of adverse neurological effects with non poisoning situations. While MeHg can be measured in hair (chronic exposure) or blood (recent exposure), a risk assessment based on the results is unclear so routine pregnancy testing is not recommended.
References
·Bellinger DC (2003) Mercury in fish: implications for pregnant women. Human Teratogens Course: Harvard Medical School .
·Clarkson TW (2002) The three modern faces of mercury. Environmental Health Perspectives 110(1):11-23.
·Daniels JL, et al. (2004) Fish intake during pregnancy and early cognitive development of offspring. Epidemiology 15(4):394-402.
·Davidson PW, Myers GJ, Weiss B (2004) Mercury exposure and child development outcomes. Pediatrics
113(4):1023-1028.
·Grandjean P, et al. (1997) Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury Neurotoxicology and Teratology 19(6):417-428.
·Mahaffey KR (1999) Methylmercury: a new look at the risks. Public Health Reports. 114: 397-415.
·Marsh DO, et al. (1987) Fetal methylmercury concentration in single strands of maternal hair and child effects. Arch
Neurol 44:1017-1023.
·McDowell MA, et al. (2004) Hair mercury levels in the U.S. children and women of childbearing age:reference range data
from NHANES 1999-2000. Environ Health Perspect 112:1165-1171.
·Moienafshari R, Bar-Oz B, and Koren G (1999) Occupational exposure to mercury: what is a safe level? Canadian Family Physician 45:43-45.
·Rustam H, Hamdi T (1974) MeHg poisoning in Iraq a neurological study. Brain 97:499-510.
· Tedeschi LG (1982) The Minamata Disease The American Journal of Forensic Medicine and Pathology 3(4): 335-338.
US Department of Health and Human Services and the Environmental Protection Agency (2004) What You Need to
Know About Mercury in Fish and Shellfish: EPA and FDA Advice For:Women Who Might Become Pregnant
Women Who are Pregnant Nursing MothersYoung Chil dren http://www.cfsan.fda.gov/~dms/admehg3.html
Contributors
Hazel Perry, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
No Comments »
Posted by admin on May 1st, 2005 — in newsletter
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Update on Proton Pump Inhibitors During Pregnancy
Volume 12, No.2, May 2005
GERD
Gastro-esophageal reflux disease (GERD) is a chronic disease characterized by repeated or prolonged exposure of the lining of the esophagus to the acidic contents of the stomach. Common symptoms include heart burn and acid regurgitation. Approximately 22% of pregnant women will suffer from reflux during the first trimester, 39% develop it by the second trimester, and up to 72% of women develop it by the third trimester (Tytgat et al, 2003).
GERD rarely causes serious complications during pregnancy, but symptoms may be unpleasant and require treatment. There is a common treatment protocol for pregnant women outlined in the literature. GERD is typically treated with dietary and lifestyle changes, along with periodic use of over-the-counter calicium and magnesium based antacids (Tytgat el al., 2003). If this approach is not effective, the H2-blocker rantidine is often tried concurrently with antacids (Katz et al., 1998; Richter, 2003). Proton pump inhibitors are generally reserved for more severe cases.
Proton pump inhibitors are effective treatments for conditions such as GERD because they block enzymes in the wall of the stomach that produce acid. A variety of GERD medications were reviewed in the June 1999 (RISK//NEWSLETTER 7(5)); this newsletter serves as an adjunct to that issue.
This newsletter will focur on the proton pump inhibitors omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), and esomeprazole magnesium (Nexium).
Omeprazole (brand name: Prilosec)
Omeprazole was approved by the FDA in 1989. Currently, it is the best studied proton pump inhibitor for use during pregnancy. A reproductive study in rats and rabbits found no teratogenic effect in fetal development after administering doses up to 250-500 times greater than the recommended human dose (Lalkin et al., 1998). There was a slight increase in fetal loss at the top doses.
Although there are individual case reports of congenital anomalies, controlled studies have not found an increased risk of major malformations. A prospective cohort study by Lalkin et al. (1998) described 113 pregnancies exposed to omeprazole compared to a control group taking H2- blockers and a control group with no prescription GERD medications. Eighty-five percent of the women took omeprazole during the first trimester, while 15% continued use through delivery.
There were no significant differences in the number of congenital anomalies, miscarriages, mean birthweight, or premature delivery between the three groups. Based on the small sample size, this study had an 80% power to identify a 5-fold increased risk.
Two databases, one from England and the other from Italy, were combined in a study published in 1999 that was designed to assess the incidence of congenital malformations in women who had received a prescription for an acid-suppressing drug including omeprazole during the 1st trimester (Ruigomez et al., 1999). Omeprazole was taken in 134 pregnancies, resulting in 139 live births. There was no significant increase in the rate of malformations.
A review of the Swedish medical birth registry by Kallen (2001) identified 955 infants exposed to omeprazole during pregnancy. Eighty-six percent of the infants were exposed only during the first trimester. Specific data on dose and timing was not available. The authors found no significant increase in congenital anomalies, low birth weight, low Apgar scores, or perinatal survival.
Most recently, a multicenter prospective case controlled study by Diav-Citrin et al. (2005) identified 295 women exposed to omeprazole during pregnancy. Sevnty-nine percent of exposures occurred during the first trimester only. The median dose was 20 mg (20-40 mg) and median duration of use was 22 days (4-47 days). The incidence of congenital anomalies in the study population was not greater than the observed frequency in the control group. This sample size was noted to have an 80% power to detect a 2.72-fold increase of major malformations. There were also no significant differences in the rates of miscarriage, ectopic pregnancies, stillbirths, or preterm deliveries. There was a significant 60 g reduction in the median birth weight in the exposed group which has not been replicated in other studies.
Brunner et al. (1998) identified nine cases of maternal exposure to omeprazole: four women were treated during the first trimester and of those, three women continued taking omeprazole until delivery. Five women were treated during the third trimester only. There were no congenital anomalies reported. Brunner et al. followed-up with the children on an average of 5 years (2-12 years) and reported normal development in all nine children.
Lansoprazole (brand name: Prevacid)
Lansoprazole was approved by the FDA in 1995. A reproductive study in rats and rabbits by Schardein et al. (1990) found no adverse effect on fertility and no increased incidence of congenital anomalies after administering doses 16 to 40 times the recommended human doses.
The largest study sample size on lansoprazole consisted of only 62 pregnancies exposed to lansoprazole, 55 of which were during the first trimester (Diav-Citrin et al., 2005). The median dose was 30 mg (30-60 mg) and the median duration of use was 14 days (7-32 days). The incidence of congenital anomalies in the study population was not greater than the observed frequency in the control group. This sample size had an 80% power to identify a 4.75-fold increase risk of major malformations. There were no significant differences in the rates of miscarriages, ectopic pregnancies, stillbirths, or the rate of preterm deliveries.
Rabeprazole (brand name: Aciphex)
Rabeprazole was approved by the FDA in 1999. In preclinical studies reported by the manufacturer, no teratogenic effects were seen in rats or rabbits at 8-13 times the human dose (Product information, Aciphex, 1999). Administered doses of 195 times the human dose during late pregnancy and lactation in rats decreased weight gain of the pups. Currently there are no studies evaluating the safety of rabeprazole use during pregnancy in humans.
Pantoprazole (brand name: Protonix)
Pantoprazole was approved by the FDA in 2000. A reproductive study by the manufacturer in rats and rabbits found no adverse effects in fetal development after administering doses 16 to 88 times greater than the recommended human dose. (Product information, Protonix, 2001).
Diav-Citrin et al. (2005) prospectively followed 53 pregnancies exposed to pantoprazole. Forty-seven exposures occurred during the first trimester. All women took 40 mg omeprazole daily for a median duration of 14 days (7-23 days). There were no significant differences in the rates of miscarriages, ectopic pregnancies, stillbirths, or rate of preterm deliveries. The incidence of congenital anomalies in the study population of 48 infants was not greater than the observed frequency in the control group. This study had an 80% power to identify a 4.9-fold increase risk of major malformations.
Esomeprazole (brand name: Nexium)
Esomeprazole was approved by the FDA in 2001. An animal study by the manufacturer found no adverse effects in fertility or embryo development after administering oral doses to rats up to 57 times the human dosage and oral doses to rabbits up to 35 times the human dose (Product information, Nexium, 2001).
There are no human studies specific to esomeprazole. However, due to the chemical similarities to omeprazole, studies on the latter should have some relevance. Omeprazole is a racemate, meaning it contains two compounds (isomers) with the same chemical components but different spatial dispositions which leads to different pharmacological properties (Kendall 2003). Esomeprazole is one of isomers of omeprazole.
Summary
During pregnancy, dietary changes and limited use of antacids and/or rantidine is typically the primary treatment for GERD. Proton pump inhibitors are typically reserved for pregnant women with moderate/severe gastrointestinal symptoms for which the former treatments are ineffective. As a class, current data does not suggest that proton pump inhibitors represent an increased risk for major malformations. However, only omeprazole has several human studies for better confirmation. Chronic use throughout pregnancy is not well studied.
References
· Briggs, G et al. (2002) Drugs in Pregnancy and Lactation, 6th Edition. MD: Lippincott Williams & Wilkins.
· Brunner G, et al. (1998) Omeprazole for peptic ulcer disease in pregnancy. Digestion 59: 651-654.
· Diav-Citrin O, et al. (2005) The safety of proton pump inhibitors in pregnancy: a multicenter prospective controlled study. Aliment Pharmacol Ther 21(3): 269-275.
· Kallen BA. (2001) Use of omeprazole during pregnancy: no hazard demonstrated in 955 infants exposed during pregnancy. Eur J Obstet Gynecol Reprod Biol 96(1): 63-68
· Kendall MJ (2003) Review article: esomeprazole-the first proton pump inhibitor to be developed as an isomer. Aliment Pharmacol Ther 17 (Suppl.1)1-4.
· Katz PO, Castell DO. (1998) Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin North Am 27(1): 153- 167.
· Lalkin A, et al. (1998) The safety of omeprazole during pregnancy: a multicenter prospective controlled study. Am J Obstet Gynecol 179:727–30.
· Nikfar S, et al. (2002) Use of proton pump inhibitors in pregnancy ad rates of major malformations: a metaanalysis. Dig Dis Sci 47(7): 1526-1529.
· Product information (1999) Aciphex. Eisai.
· Product information (2001) Nexium. Astra Zeneca.
· Product information (2001) Protonix. Wyeth-Ayerst.
· Rayburn W, et al. (1999) Antacids vs. antacids plus non-prescription ranitidine for heartburn during pregnancy. Int J Gynecology & Obstetrics 66: 35-37.
· REPROTOX online teratology database www.reprotox.org
· Richter JE. (2003) Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin North Am 32(1): 235-26.
· Ruigomez A et al. (1999). Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. Am J Epidemiol 1999;150:476–81.
· Schardein JL, et al. (1990) Reproductive and developmental toxicity studies of lansoprazole (AG-1749) in rats and rabbits. Yakuri Chiryo 18 (Suppl 10): 119-129.
· Tytgat GN, et al. (2003) Contemporary understanding and management of reflux and constipation in the general population and pregnancy: a consensus meeting. Aliment Pharmacol Ther 18: 291-301.
· Wilton LV, et al. (1998) The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 105: 882-889.
Contributors
Dania Stachiw, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
No Comments »
Posted by admin on April 1st, 2005 — in newsletter
PDF Version
The Newer SSRI Anti-Depressants and Pregnancy
Volume 12, No. 1, April 2005
The prevalence of clinical depression during pregnancy has been estimated to be 7-12% by a recent meta-analysis. (Bennett et al., 2004). Additionally, in over 3000 obstetric patients screened, 20% had high scores on Centre for Epidemiological Studies Depression Scale (Bonari et al., 2004).
Therefore, it is not surprising that the Illinois Teratogen Information Service receives many requests for information regarding pharmacological treatment of depression during pregnancy.
The decision of whether or not to keep a woman on medication during pregnancy is complex. The many possible adverse effects of untreated depression must be considered. There is a growing body of literature on an association of obstetrical complications with untreated maternal depression. Women with untreated depression are also more likely to use alcohol, tobacco, and illicit drugs (Zuckerman et al., 1989). They may be less able to motivate themselves to attend prenatal appointments or follow medical advice and have poor nutrition (Bonari et al., 2004). The risk of self injury and suicide is a real concern. Thus, it is essential to consider each case individually prior to making medicine changes.
While past newsletters (March 1995 and 1999) have discussed the selective serotonin reuptake inhibitors (SSRIs), Prozac, Zoloft, and Paxil, this newsletter reviews current literature regarding prenatal exposure to the newer SSRIs, Lexapro and Celexa. NonSSRIs antidepressants,
Wellbutrin and Effexor, are also discussed.
Lexapro (escitalopram)
Escitalopram is an SSRI used in the treatment of depression. Escitalopram, marketed as Lexapro, is the active isomer of citalopram, thus the two compounds are chemically similar.
Congenital anomalies
Unpublished animal studies examining the effects of prenatal exposure to escitalopram have been conducted by the manufacturer (Forrest Labs). No increase in congenital anomalies was seen at doses 75X the maximum recommended human dose (MRHD) in rats. Decreased fetal body weights, delays in ossification, slightly increased offspring mortality, and signs of maternal toxicity were observed at the higher doses.
To date there have been no human studies examining the effects of prenatal exposure to escitalopram. There is human data, however, about citalopram use in pregnancy, the results of which should have some application to escitalopram.
Celexa (citalopram)
Citalopram, marketed as Celexa, is an SSRI used to treat depression. Due to the relatively recent marketing of this medication (approved by the FDA in 1998), data examining the effects of prenatal exposure, particularly long term development, is limited.
Congenital anomalies
Unpublished experimental animal studies examining the effects of prenatal exposure to citalopram have been conducted by the manufacturer (Forrest Labs). Teratogenic effects (cardiovascular and skeletal defects) were only observed at the highest doses when maternal toxicity symptoms were present. Lowered birth weights and increased offspring mortality were also present at the higher doses. No adverse effects were seen with rabbit studies with doses 5X MRHD.
Two small prospective human studies have been performed examining birth outcomes following prenatal exposure to citalopram. One study prospectively followed a group of 10 women taking citalopram 20-40mg/day throughout pregnancy and one woman taking citalopram starting in the second trimester (Heikkinen et al., 2002). These women were being treated for either depression or panic disorders. There were no major malformations present and no differences in the Apgar scores or birthweight compared to a control group.
Additionally, a larger prospective study from a drug recording program of the Swedish Medical Birth Registry reported the pregnancy outcomes of 531 infants prenatally exposed to SSRIs, 365 of which were exposed to citalopram (Ericson et al., 1999). This registry identifies early pregnancy exposures, but timing and dosing were poorly specified. Of those infants exposed to citalopram, there was no increase in major malformations and no pattern to any of the birth defects.
The authors also noted that due to two reports to the FDA, they specifically checked but did not find any cases of optic nerve hypoplasia, although the infants were evaluated only in the perinatal period. They did find a small but significant increase in prematurity (OR 1.6) in women taking any SSRIs. It is not clear what role the medicine, maternal condition, or life style factors associated with the maternal condition played.
Neonatal withdrawal
Nordeng et al. (2001) described 5 possible cases of neonatal withdrawal with various SSRIs, including one case of an infant whose mother took 20mg/day of citalopram from months 5-7 and an increased dose of 30mg/day from months 7-9. The infant was born at term and had light abstinence symptoms with increased tonus in his extremities and neck, and was jittery. All symptoms, with the exception of tonus, resolved within seven days of birth (Nordeng et al., 2001). No medical treatment was needed.
Laine et al. (2003) prospectively followed 20 infants exposed to the SSRIs citalopram (N=10) and Prozac (N=10) compared to control group of healthy women not receiving psychotropic medication. While they found a 4-fold increase in serotonergic symptoms (tremor, restlessness and rigidity) in SSRI-exposed infants ages 1-4 days, there were no significant differences in symptom scores when only the citalopram group was compared to the controls. No differences were found in vital signs such as blood pressure, heart rate and body temperature between the two groups, with the exception of a statistically significant increase in heart rate in the SSRI group at 2 weeks of age. No specific medical treatment was needed.
Long term development
Psychotropic medications alter neurotransmitter levels in the maternal brain, thus there is a theoretical risk that they can also alter the developing fetal brain. These brain alterations could potentially lead to behavioral or learning deficiencies.
In the study by Heikkinen et al. 2002 (discussed previously), 11 infants who were exposed to citalopram in utero were followed until age 1 year. The body weights of all infants were normal at one year, as was the neurological development. One child could not walk at the age of 1 year, but the neurological status of this child was evaluated as normal 6 months later (Heikkinen et al., 2002). Due to the limitation of the small sample size and limited follow up time, further investigation in this area is necessary.
Wellbutrin/Zyban (bupropion) Bupropion is an aminoketone used both as an antidepressant (Wellbutrin) and as an aid in smoking cessation (Zyban).
Congenital anomalies
One study in rabbits only saw an increase in skeletal anomalies and delayed ossification at the highest dose when maternal toxicity was present (Tucker, 1983). This same study reported that high doses given to pregnant rats produced maternal toxicity, but that no congenital anomalies were found in the offspring.
The majority of human data on pregnancy exposure is available through a bupropion pregnancy registry maintained by the manufacturer, GlaxoSmithKline. The registry prospectively collected pregnancy exposure information and outcomes since September 1997. Controls were not used. The current update of this registry (February 2004) indicated that 534 pregnancy outcomes have been prospectively analyzed with 354 live births following first trimester exposure. Of these first trimester exposures, there were 12 pregnancy outcomes resulting in birth defects (3.4%), which is not higher than the general population.
However, of the 12 birth defects, 7 were isolated heart defects. Therefore there is continued study to assess an association specifically with cardiac defects.
Additionally, a prospective controlled study found no increase in the rate of malformations in 136 women taking bupropion in the first trimester (Chun-Fai-Chan et al., 2005). Forty-five women took bupropion throughout pregnancy. There were 72 livebirths and no major malformations reported. Due to the small sample size this study had a 80% power to identify a 5-fold increase risk for malformations.
There were also no differences in birth weight, gestational age at birth, or stillbirth compared to the controls. There was a significant increase risk for miscarriage among women taking any antidepressant or taking bupropion (12.3-15.4%) compared to a control group without depression (6.7%). In addition to the medicines, this latter finding could reflect factors with the maternal depressive condition or simply reflect an unusually low miscarriage rate in control women.
Neonatal withdrawal
No reports of neonatal withdrawal have been published.
Long term development
There are at present no published studies examining the long term effects on development in children prenatally exposed to bupropion.
Effexor (venlafaxine)
Venlafaxine is a bicyclic antidepressant marketed as Effexor.
Congenital anomalies
Unpublished animal data available from the manufacturer (Wyeth) reported no increase in malformations in the offspring of rats given up to 11 times and rabbits given up to 12X MHRD. Decreased weight and viability were noted in offspring at 10X MHRD in rats. Another study by da-Silva et al. produced similar results in rats prenatally exposed to venlafaxine (da-Silva et al., 1999).
They found no increased risk for congenital malformations, but did find a slight decrease in birth weight of litters exposed to venlafaxine. Data obtained from the U.K. Drug Safety Research Unit included pregnancy outcomes for 26 live births in women who took venlafaxine during pregnancy (Einarson et al., 2001). No major malformations were reported.
A larger study by Einarson et al. (2001) prospectively collected information about birth outcomes of 150 women exposed to venlafaxine during pregnancy, 126 of which used the medication during the first trimester and 34 throughout the pregnancy.
Seventy percent of the woman took 75mg venlafaxine (range: 37.5-300mg). The authors compared pregnancy outcomes of this group to two control groups, women who used SSRI’s during pregnancy and women who did not take antidepressants. Pregnancy outcomes such as the number of live births, spontaneous abortions, preterm delivery, birth weight and major malformations were examined. The pregnancy outcomes were not statistically different between the three groups for any of these factors. The results from this study are promising, but are limited by the small sample size which provides only an 80% power to detect a 4-fold increase in malformations.
Neonatal withdrawal
The WHO Collaborating Centre for International Drug Monitoring in Sweden described 17 reports of neonatal withdrawal syndrome, of which only 6 were regarded as potentially related (Sanz et al., 2005).
An individual case report in a German journal described an infant with restlessness, hypertonia, jitteriness, irritability and poor feeding (de Moor et al., 2003). The diagnosis of neonatal withdrawal was further suspected when there was a temporary improvement after administration of low dose (1 mg) venlafaxine. After 8 days, with no further treatment, the infant’s symptoms resolved.
Long term development
The long term effects on development in children prenatally exposed to venlafaxine has not been studied.
Summary
Reproductive studies to do not suggest an increase in congenital anomalies for any of the four medications discussed, although the studies are still limited by their small sample sizes. Studies with sample sizes less than 150 women allow at most a 4 fold detection of increased risk (Einarson and Einarson, in press). Further evaluation of a possible association with bupropion and cardiac defects is still needed.
Exposure to antidepressants which inhibit serotonin reuptake during the third trimester of pregnancy carries the risk of a neonatal withdrawal/serotonergic syndrome. Reported symptoms are non specific and typically self limiting. Symptoms most commonly reported include agitation, irritability, hypotonia, hypertonia, hyperreflexia, drowsiness, persistent crying, and sucking problems
(Prescrire International, 2004). Small nonblinded case series suggest such findings occur in 20-30% of infants with third trimester exposure to the older SSRIs (Prozac, Paxil, and Zoloft) compared to 6-9% of control infants (Prescrire International, 2004).
Individual case reports of withdrawal-like symptoms also exist for Celexa and Effexor. However, discontinuing antidepressants near delivery is controversial due to maternal and infant adverse effects with postpartum depression. Longterm studies on whether there are any effects on neurobehavioral outcomes are absent. Currently there only studies on early childhood development for Prozac and the tricyclic antidepressants.
It should be noted that stopping medication is not a “no risk” option since there are concerns to a pregnancy with untreated maternal depression. The severity of maternal symptoms should help dictate medicine use during pregnancy.
References
Bennett, et al. (2004) Prevalence of depression during pregnancy: systematic review. Obstet Gynecol 103(6):698-709.
Bolton HL, et al. (1998) Incidence and demographic correlates of depressive symptoms during pregnancy in an inner London population. J Psychosom Obstet Gynaecol 19(4):202-9.
Bonari L, et al. (2004) Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 49(11)726-735.
Chun-Fai-Chan, et al. (2005) Pregnancy outcome of women exposed to bupropion during pregnancy: A prospective comparative study. Am J Obstet Gynecol 192(3):932-936.
da-Silva et al. (1999) Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy. Braz J Med Biol Res 32(1):93-8.
de Moor RA, et al. (2003) [Withdrawal symptoms in a neonate following exposure to venlafaxine during pregnancy] Ned Tijdschr Geneeskd. 12;147(28):1370-2.
Ericson A, et al. (1999) Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 55:503-508
Einaron TR and Einarson A (In press) Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies Pharmacoepidemiology and Drug Safety.
Einarson A, et al. (2001) Pregnancy outcome following gestation exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiarty 158:1728-1730.
Forest Laboratories (2005) Product information.
GlaxoSmithKline Bupropion Pregnancy Registry (2004) Research Triangle Park, NC.
Heikkinen T, et al. (2002) Citalopram in pregnancy and lactation. Clin Pharmacol Ther 72(2):184-91.
Kessler R, et al. (1993) Sex and depression in the National Comorbidity Survey I: Lifetime prevalence, chronicity and recurrence. Journal of Affective Disorders 29:85-96.
Laine K, et al. (2003) Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiarty 60:720-726.
Nordeng, et al. (2001) Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 90:288-291.
Prescrire International (2004) Neonatal complications after intrauterine exposure to SSRI antidepressants. 13(71)103-104.
Sanz EJ, et al. (2005) Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 365:482-487.
Tucker WE (1983) Preclinical toxicology of bupropion: An overview. J Clin Psychiatry 44:60-62.
Zuckerman, et al. (1989) Depressive symptoms during pregnancy: relationship to poor health behaviors. Am J Obstet Gynecol 160:1107-1111.
Contributors
Michelle Martin, BS
Genetic Counseling Intern
Jennifer Sloan, PhD
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
No Comments »
Posted by admin on August 1st, 2004 — in newsletter
PDF Version
The New Antiepileptic Drugs and Pregnancy
Volume 11, No.3, August 2004
This issue of Risk Newsletter explores the current data on the following second generation antiepileptic drugs (AEDs): Lamictal, Trileptal, Topamax, and Neurontin.
About 1 in every 200 pregnant women has epilepsy, and up to 35% of women with epilepsy have increased seizure activity during pregnancy (AAN, 1998). The latter may be due to changes in sex hormones, metabolism, sleep patterns, or medication compliance (Morrell, 2003). The majority of these pregnancies have normal outcomes; however, there are specific maternal and fetal concerns related to uncontrolled seizures. While studies are not conclusive, seizures during pregnancy have been associated with such obstetrical complications as prematurity and stillbirth (Morrell, 2003, AAN, 1998). Seizures can result in maternal and fetal hypoxia and acidosis, which potentially could lead to neurological damage or be life-threatening. Therefore, treatment during pregnancy is typically instituted when a woman has a history of seizures within the past 24 months. If therapy is to be withdrawn during pregnancy, it is ideally attempted 6 months prior to conception to allow time to evaluate for seizure recurrence (AAN, 1998).
The risk for congenital malformations ranges from 4-10% following monotherapy treatment with older, “first generation” AEDs (Dolk and McElhatton, 2002). This is a 2- to 3-fold increased risk compared to the general population. Although this increased risk was once thought to be due to the underlying maternal seizure disorder, it is now largely attributed to the use of AEDs (Holmes et al., 2001). A woman’s risk for congenital anomalies increases with polytherapy (AAN, 1998). Therefore, monotherapy treatment with the medicine most effective for the specific seizure type is preferred.
Second generation AEDs have been available since 1993. Unfortunately, these medications have not been well studied and, consequently, risks to the fetus are largely unknown. Of studies that have been published, major malformations is the only outcome variable evaluated. Studies have not been conducted to determine if there are any patterns of minor malformations or developmental impairment (i.e., anticonvulsant embryopathy).
Lamictal (generic name: lamotrigine)
For second generation AEDs, the largest dataset on pregnancy outcomes is available for lamotrigine (LTG), a medicine chemically unrelated to the first generation AEDs. While LTG decreases fetal folate levels in rats, it does not decrease human adult blood folate levels (GlaxoSmithKline, 2004). It is not known if human fetal folate levels are altered with LTG or whether higher maternal folic acid supplements (4-5 mg daily) is beneficial for women taking Lamictal.
Marchi et al., (2001) treated pregnant rats during organogenesis with four times the recommended human dose of LTG. Offspring demonstrated low birth weight and altered brain structure, which included increased volume and diameter of the cerebral structure, increased density of the subcortical layer, and ventricle dilation (Marchi et al., 2001). The relevance of these findings to human pregnancy is unknown. Experimental animal studies by the manufacturer did not find an increase in congenital malformations associated with LTG (GlaxoSmithKline, 2004).
Sabers et al., (2004) reported on the outcomes of 147 human pregnancies with various AED exposures. Seventy-four percent of the total group were on monotherapy AED treatment, and 80% of the total group took folic acid supplements, with the majority taking 5 mg daily. Of the total group, 35% were treated with LTG. For monotherapy treatment with LTG, there were no major malformations. There was one case of a ventricular septal defect in a LTG exposed pregnancy also treated with oxcarbazepine.
The largest dataset on LTG exposure during pregnancy has been collected by the manufacturer’s pregnancy registry. This is a voluntary, noncontrolled prospective registry with 20-30% of women lost to follow-up. As of March 2003, the registry had outcomes for 414 first trimester exposures to LTG monotherapy. There were 12 infants with major malformations for a rate of 2.9%. The spectrum of birth defects observed and the proportion of malformations were not different from the baseline risks. This sample size was sufficient to detect, with 80% power, a 1.79-fold increase in the proportion of major birth defects. Additionally, an abstract from the United Kingdom Lamictal registry reported on 390 first trimester pregnancy exposures. There were 8 major malformations for a malformation rate of 2.1%, which was within the rate present in the general population (GlaxoSmith Kline, 2004).
Based on available data, LTG does not appear to significantly increase the chance for congenital anomalies. Long-term data regarding any possible neurobehavorial effect of LTG exposure in utero is not available.
Trileptal (generic name: oxcarbazepine)
There were no significant increases in congenital anomalies when pregnant mice were treated with 20-46 times the human dose of oxcarbazepine (OXC) (Bennett et al., 1996). However, studies conducted by the manufacturer demonstrated increased craniofacial, cardiovascular and skeletal malformations in rats treated during organogenesis with 1.2 times and 4 times the maximum recommended human dose of OXC. In rabbits, there was an increase in fetal loss but no teratogenicity associated with OXC administration at 1.5 times the maximum human dose (Novartis Pharmaceuticals, 2004).
Reports on human pregnancy exposure to OXC are limited and most studies do not specify whether the women were on OXC monotherapy or polytherapy. In one study with 12 pregnancies exposed to OXC during the first trimester, three pregnancies resulted in miscarriage, while nine pregnancies resulted in newborns without structural malformations (Friis et al., 1993).
Another study of 37 women exposed to OXC, alone or in conjunction with other AEDs, demonstrated two cases of ventricular septal defects. One case was exposed to OXC alone and the other was exposed to OXC and LTG, as mentioned previously (Sabers et al., 2004).
Additional reports specifying OXC monotherapy during the first trimester total 13 pregnancies, one of which resulted in an unspecified malformation (Kaaja et al., 2003; Wide et al., 2004). Meischenguiser et al., (2004) reported on the Argentinian experience of 35 monotherapy exposures with no major congenital anomalies. There was also one cardiac anomaly with 20 cases of OXC polytherapy (Meischenguiser et al., 2004). In the case of the cardiac anomaly, the pregnancy was exposed to 1200 mg OXC and 150 mg phenobarbital. Since the numbers of pregnancies are small, it cannot be known whether the reported physical birth defects were due to OXC or to other factors.
It should be noted that OXC is a derivative of carbamazepine (brand name: Tegretol), a first generation AED and folate antagonist. Carbamazepine is associated with a 6.5% congenital malformation rate and a 1% chance for neural tube defects (Wide et al., 2004). Based on what is known about carbamazepine, maternal serum AFP screening, targeted fetal ultrasound and fetal echocardiogram should be performed in pregnancies treated with OXC.
Topamax (generic name: topiramate)
Topiramate (TPM) is structurally and pharmacologically different from other classes of AED (Ohman et al., 2002). According to the manufacturer, when TPM was administered to pregnant mice, rats and rabbits during organogenesis, increased fetal mortality and teratogenic effects were observed at doses lower than the recommended human dose. Craniofacial and limb malformations were seen most frequently. These malformations were consistent with malformations observed in animals treated with similar medications, the carbonic anhydrase inhibitors. However, since these malformations have not been observed in humans treated with other carbonic anhydrase inhibitors, the manufacturer suggests these effects may be species-specific (Ortho-McNeil Pharmaceutical Communication, 2003).
In the case of TPM, human reproductive data is limited to individual case reports and small case series. A report of 5 pregnant women on TPM polytherapy revealed no congenital malformations at delivery (Öhman et al., 2002). A postmarketing survey by the manufacturer noted that there were 10 pregnancies treated with monotherapy and no congenital malformations identified (Ortho MacNeil Pharmaceutical Communication, 2003).
There is a single case report of an in utero exposure to 1400 mg daily of TPM throughout gestation that resulted in an infant with multiple minor anomalies comprising of hirsutism, third fontanelle, anteverted nares, nail hypoplasia and consistent with the effects seen with first generation AEDs (Hoyme et al., 1998). Additionally, the manufacturer noted that they had received case reports of hypospadias (Ortho MacNeil Pharmaceutical Communication, 2003). No causal relationship could be established with this type of data. Due to the limits in available human reproductive data, fetal risks have not been determined following TPM exposure.
Neurontin (generic name: gabapentin)
A study in mice, rats, and rabbits did not observe any developmental toxicity of gabapentin (Petrere and Anderson, 1994). However, the manufacturer noted that offspring of mice and rats treated with one to four times the recommended human dose of gabapentin (GBP) had delayed ossification of several skeletal bones. Studies on rabbits demonstrated increased fetal loss rates at one-fourth the maximum human dose but no increase in malformations (Pfizer Pharmaceuticals, 2004).
A post-marketing surveillance study of GBP included 11 pregnancy outcomes with first trimester GBP exposure. No congenital abnormalities were observed (Wilton and Shakir, 2002).
The Boston GBP registry collected a combination of retrospective and prospective reports to comment on 51 pregnancies with 44 livebirths. Monotherapy accounted for 33% of the cases, and 81% of the pregnancies were exposed to GBP throughout pregnancy. There were two major congenital anomalies (one complicated with valproate) for a major malformation rate of 4.5% (Montouris, 2003). Due to small sample size, this is considered a very tentative estimate.
Summary
Lamictal is the only second generation AED with sufficient reproductive data suggesting it does not significantly increase the chance for congenital anomalies. Information on possible longterm neurobehavorial effects however is pending.
Antiepileptic Drug Registry
More studies are needed to assess the risks of AED use during pregnancy since discontinuing medication is not an option for most women with epilepsy. The Genetics and Teratology Unit at Massachusetts General Hospital has established the first US hospital-based AED registry. The purpose of the registry is to provide a faster method for establishing the effects of each AED during pregnancy and to provide better counseling and management to pregnant women with epilepsy.
Ascertaining whether a medication has detrimental effects requires large numbers of pregnant women. About 400 women taking a single AED must be enrolled before any study can statistically identify a doubling of the baseline risk for physical birth defects. Many more women are needed to detect more subtle effects of any medication. This AED registry does not release outcome data until statistical significance is reached. Although this has been a source of frustration for health care professionals, the risk of major malformations in various series of 25 birth outcomes has ranged from 3% to 35% for the same AED (Holmes, 2004 OTIS update). Therefore, the registry does not want either to falsely reassure or falsely alarm until the data is statistically significant.
Health care professionals can obtain more information about the AED registry by calling 1-888-233-2334, or visiting http://www.mgh.harvard.edu/aed/ Physicians can refer interested women to these same contacts, but only pregnant women can enroll themselves in the registry.
References
American Academy of Neurology (1998) Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standard Subcommittee of the AAN Neurology 51(4): 944-948.
Bennett GD, et al. (1996) Teratogenicity of carbamazeping-10, 11-epoxide and oxcarbazepine in the SWV mouse. J Pharmacol Exp Ther 279(3): 1237-1242.
Dolk H and McElhatton P (2002) Assessing epidemiological evidence for the teratogenic effects of anticonvulsant medications. J Med Genet 39:243-244.
Friis ML, et al. (1993) Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment. Acta Neurol Scand 87 (3):224-227.
GlaxoSmithKline – Lamotrigine Pregnancy Registry Interim Report. Issued July 2004;1-49.
Holmes LB (2004) Update on the Risk of New Anticonvulsants. OTIS 17th International Conference. Vancouver, BC, Canada.
Holmes LB, et al (2001) The Teratogenicity of Anticonvulsant Drugs. N Engl J Med 344:1132-8.
Kaaja E, et al. (2003) Major malformations in offspring of women with epilepsy. Neurology 60: 575-579.
Marchi NSA, Azoubel R, Tognola WA (2001) Teratogenic effects of lamotrigine on rat fetal brain. Arq Neuropsiquiatr 59(2-B): 362-364.
Meischenguiser R, et al. (2004) Oxcarbazepine in pregnancy: clinical experience in Argentina. Epilepsy and Behavior 5:163-167.
Montouris G (2003) Gabapentin exposure in human pregnancy: results from the Gabapentin Pregnancy Registry. Epilepsy and Behavior 4:310-317.
Morrell M (2003) Reproductive and Metabolic Disorders in Women with Epilepsy. Epilepsia 44 (Suppl. 4)11-20.
Novartis Pharmaceuticals Corporation (2004) Trileptal (oxcarbazepine) package insert.
Öhman I, et al. (2002) Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia 43 (10): 1157-1160.
Petrere JA and Anderson JA (1994) Developmental toxicity studies in mice, rats, and rabbits with the anticonvulsant gabapentin. Fundam Appl Toxicol 23:585-9.
Contributors
Amber Pakilit, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
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Posted by admin on June 1st, 2004 — in newsletter
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Common Summertime Exposures During Pregnancy
Volume 11, No.2, June 2004
Sunscreen
Heightened attention to health risks from sun overexposure has increased the use of sunscreens, both in the general population as well as in pregnancy (Benson, 2000). Sunscreens can come in various formulations (creams, lotions, sprays, etc.) and are also present in many cosmetic products. A few common sunscreen ingredients include oxybenzone, avobenzone (Parsol 1789), p-Aminobenzic acid (PABA), octyl methoxycinnimate, and octocrylene (Benson, 2000).
Although there is a lack of specific human pregnancy teratology studies, reassurance can be gathered from their common use during pregnancy and the absence of adverse pregnancy reports.
Additionally, some high dose experimental animal studies are available. For example, Stroeva, et al. (1998) noted that when pregnant rats were directly injected with PABA, there was no increase in congenital malformations. Octocrylene has also been studied in pregnant rats and rabbits. When orally administered to rats and topically applied to rabbits, no teratogenic effects were seen (Odio et al, 1994).
The route of administration is also an important principle in teratology. Since sunscreen is topically applied to the skin, systemic absorption (and therefore fetal exposure) is expected to be low. Depending on the particular ingredient, it is estimated that only 1-10% of topically applied sunscreen is absorbed into the blood system (Benson, 2000).
There is a medical benefit of sunscreen use in protecting individuals from the damaging effects of the sun. For this reason, sunscreen has been used for many years as a method of preventative health care (Benson, 2000). It is important that a pregnant woman, like all women, protect herself from overexposure to the sun. Although specific pregnancy studies are limited, conservative, but appropriate use of sunscreens on exposed areas of skin should not be a concern for the developing fetus.
Self-tanners
Self-tanning creams, lotions, and sprays typically contain an active ingredient called dihydroxyacetone (DHA) at concentrations of 3-5% (Levy, 1992). When applied topically, DHA temporarily enhances pigmentation of the skin. Due to the topical route of administration, systemic absorption is expected to be low. One in vitro study estimated that while 22% of the applied dose penetrated human skin, only 0.5% of this application would be systemically absorbed (Yourick et al, 2004).
As with sunscreen, while there are no adverse pregnancy reports, there are also no human pregnancy studies on DHA. However, there are no experimental animal studies on DHA either. Since self-tanners do not have the medical benefit that sunscreen has, a woman may feel more comfortable erring on the side of caution and deciding to avoid the use of self-tanners during pregnancy. If a woman does choose to use tanning creams during pregnancy, it is important to remember that they do not provide protection from the sun and that the small amount of expected absorption can be further decreased with less frequent use and with application to smaller areas of the body.
West Nile Virus
In 1999, New York City was the cite of an outbreak of encephalitis and meningitis caused by the West Nile Virus (WNV), originally described in 1937 in Uganda (Alpert et al, 2003; Chappa et al, 2003). The disease is transmitted to humans primary through the bites of infected mosquitoes.
Symptoms of infection typically develop within 3-14 days after being bitten, and can vary from mild to severe. Many people infected with WNV do not develop any symptoms. The mild form of WNV typically presents as a sudden fever, often with nausea, vomiting, eye pain, skin rash, headache, or myalgia. Less than 1% of cases result in more serious neurological disease, with advanced age being a risk factor. Clinical information can be located online at http://www.cdc.gov/ncidod/dvbid/westnile/resources/fact_sheet_clinician.htm
In 2002, the Centers for Disease Control and Prevention (CDC) reported the first case of intrauterine transmission from a woman who had WNV encephalitis during the 27th week of pregnancy (Alpert et al, 2003). The child was born with both ocular and neurologic complications. Serum studies on the infant indicated the presence of WNV-specific antibodies. Although this case demonstrated intrauterine WNV infection, no causal relationship between WNV and the congenital anomalies was established.
However, after this case was reported, a registry was formed by the CDC and local state and health departments to follow birth outcomes among women with WNV illness during pregnancy (O’Leary, 2004). During 2002, three additional infants of mothers infected with WNV were born full term with normal appearance and negative laboratory studies. Since 2003, the registry has identified 74 women who acquired WNV illness while pregnant. Preliminary data for 49 known outcomes includes 42 livebirths, 5 first trimester miscarriages, and two elective terminations. Of the 42 livebirths, specimens were available from 29 to check for WNV antibodies. There was evidence of intrauterine infection in 1 infant who did not have clinical evidence of illness.
Additionally, in three other cases with suspected, but unconfirmed intrauterine infection, there was 1 infant fatality secondary to lissencephaly and superimposed WNV infection, one case of a neonatal rash that resolved, and one case of a neonatal rash with fever (O’Leary, 2004).
If WNV is diagnosed during pregnancy, ultrasound at 2-4 weeks post symptoms can evaluate the fetus for signs of viral infection (CDC, 2004). While amniotic fluid could be tested for evidence of WNV infection, the sensitivity, specificity, and predictive value are not known, nor is the clinical consequence of fetal infection (CDC ,2004). Physicians aware of instances of WNV in pregnancy are asked to contact their state health department or the CDC. A list of follow-up clinical newborn evaluations can be found online at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5307a4.htm
In an attempt to minimize the risk of contracting WNV during pregnancy, the CDC recommends that women who live in areas with WNV-infected mosquitoes use insect repellant over their clothes and on exposed skin, and when possible avoid outdoors during dawn and dusk, the peak hours of mosquito activity (CDC, 2004).
DEET
DEET is an acronym for Diethyltoluamide, which has been marketed in the United States since the late 1950s. According to the CDC, it is the most effective repellant for the prevention of mosquito bites. DEET is a common component of many insect repellents such as “Off”. In a study investigating the absorption of DEET following dermal application in a group of male volunteers, it was found that on average, only 5.6% of DEET was systemically absorbed at undiluted concentrations (Selim et al, 1995).
DEET has been reported to produce dermatitis in sensitive adult individuals (Koren et al, 2003). Initial concern about DEET in pregnancy stemmed from case reports of seizures following misuse of DEET in children (Zadikoff et al, 1979). However, causation related to DEET was not proven. Additionally, a more recent study did not find a higher incidence of severe adverse events in children compared to adults (Koren et al, 2003).
Very high dose animal studies in rats and rabbits (undiluted DEET administered via a stomach tube) found no increased incidence of congenital anomalies (Schoenig GP et al, 1994). At the highest doses, decreased fetal body weights were found. However, the latter may be related to the toxicity of the mother animal and reduced maternal food consumption.
There is an isolated case report of an adverse pregnancy outcome in association with the daily use of DEET throughout the pregnancy, but cause and effect were not established because there were additional medicine exposures (Schaefer et al, 1992).
Unfortunately, there is no specific controlled data available on human first trimester exposure to DEET to confirm the reassuring animal data. However, there is a controlled human pregnancy study that evaluated DEET exposure during the second and third trimesters of pregnancy.
A double-blinded, randomized, therapeutic trial of insect repellents for the prevention of malaria was conducted in Thailand (McGready et al, 2001). 897 women between three and seven months of pregnancy participated and were randomly allocated to either receive a 20% DEET solution and thanaka (a common local cosmetic paste used as a carrier for the repellent), or thanaka alone. 449 women were exposed to the DEET and thanaka combination, while 448 women were exposed to the thanaka alone. 741 live born singletons were available for follow-up studies. In 50 women randomly selected who received DEET, 4 (8%) showed evidence of DEET in the cord blood, indicating that placental transfer can occur. However, there were no differences in survival or growth parameters between the two groups, and for those infants followed for the first year of life (81%), no differences were noted in neurological development.
It should be noted that repellents containing a higher concentration of DEET provide longer-lasting protection but not more effective protection. A repellent therefore should be chosen with the lowest concentration needed for the amount of time spent outdoors. The CDC notes that a product containing 20% DEET provides almost 4 hours of protection while a product with 6.65% DEET provides almost 2 hours of protection and a products with 4.75% DEET provides roughly 1 and one half hour of protection.
Patient information on the use of DEET during pregnancy can be found at www.otispregnancy.org under the fact sheet listings.
In summary, both experimental animal studies and one controlled human study during the second and third trimesters regarding the use of DEET found no increase in congenital anomalies.
Limiting the number and amount of DEET applications should reduce systemic absorption and therefore reduce fetal exposure. Other recommendations listed earlier include wearing protective clothing (i.e. long sleeves, socks) when possible and then spraying DEET over clothing, rather than directly on skin, not spraying directly onto abraided skin, and avoiding outside activities during peak hours of mosquito exposure. After returning indoors, the CDC recommends washing any treated skin with soap and water. They also recommend removing any items outside and around the home that contain standing water where mosquitoes can lay their eggs.
References
Abdel-Rahman A, et al. (2004) Neurological deficits induced by malathion, DEET, and permethrin, alone or in combination in adult rats. J Toxicol Environ Health A.67(4):331-56.
Alpert SG, et al. (2003) Intrauterine West Nile Virus: ocular and systemic findings. Am J Ophthalmol 136 (4):733-735.
Benson H (2000) Assessment and clinical implications of absorption of sunscreens across skin. Am J Clin Dermatol 1(4):217-224.
Chapa JB, et al. (2003) Wile Nile encephalitis during pregnancy. Obstet and Gynecol 102 (2):229-231.
CDC (2004) Interim guidelines for the evaluation of infants born to mothers infected with WNV during pregnancy. MMWR Weekly 53 (7); 154-157.
CDC WNV Chapter http://www.cdc.gov/ncidod/dvbid/westnile/index.htm
Hayden C, et al. (1997) Systemic absorption of sunscreen after topical application. Lancet 350 (9081):863-4.
Koren G, et al. (2003) DEET-based insect repellents: safety implications for children and pregnant and lactating women. CMAJ 169 (3):209-211.
Levy SB (1992) Dihydroxyacetone-containing sunless or self-tanning lotions. J Am Acad Dermato 27: 989-993.
Odio MR, et al. (1994) Evaluation of subchronic (13 week), reproductive, and in vitro genetic toxicity potential of 2-ethylhexyl-2-
cyano-3,3-diphenyl acrylate (octocrylene). Fundam Appl Toxicol 22:355-368.
O’Leary D (2004) Fifth National Conference on WNV in US: Denver, Colorado.
Schaefer C, et al. (1992) Intrauterine diethyltoluamide exposure and fetal outcome. Reprod Toxicol 6 (2):175-6.
Schoenig GP, et al (1994) Teratologic evaluations of N, N-diethyl-M-toluamide (DEET) in rats and rabbits. Fundam Appl Toxicol 23 (1):63-9.
Selim S, et al. (1995) Absorption, metabolism, and excretion of N,N-diethyl-M-touamide following dermal application to human volunteers. Fundam Appl Toxicol 25:95-100.
Stroeva OG (1998) Effect of para-aminobenzoic acid on the development of rat embryos when applied to pregnant females. Ontogenez 29(6):444-9.
Zadikoff CM (1979) Toxic encephalopathy associated with use of insect repellant. J Pediatr 95 (1):140-142.
Contributors
Sarah Lewis, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
No Comments »
Posted by admin on March 1st, 2004 — in newsletter
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Influenza, Vaccination, and Pregnancy
Volume 11, No. 1, March 2004
Influenza
Influenza is an acute viral infection involving the respiratory tract. It is caused by a number of serologically distinct viral strains, such as influenza A (with many subgroups) and B, both of which cause epidemic human disease (Bridges et al., 2003). Influenza typically presents as a sudden onset of a respiratory infection with additional features of fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis (Bridges et al., 2003). In some persons, influenza can lead to more serious complications by aggravating underlying medical conditions (such as pulmonary or cardiac disease) or result in a secondary bacterial pneumonia or primary influenza viral pneumonia (Bridges et al., 2003).
The incubation period for influenza is about 1-4 days, with persons becoming infectious the day before symptoms begin through 5 days or so after the onset of the illness (Larsen, 1982). Children can be infectious for a longer period. In immunocompetent individuals, influenza usually resolves after several days, although cough and malaise can persist for 2 or more weeks.
Influenza during pregnancy
Influenza has been studied to evaluate whether pregnancy increases maternal complications. Among pregnant women, an influenza-associated increased mortality has been documented during the influenza pandemics of 1918-1919 and 1957-1958 (Bridges et al., 2003). Additionally, individual case reports suggest that pregnancy (particularly the third trimester) may increase the risk for serious medical complications of influenza, possibly as a result of pregnancy associated increases in heart rate and oxygen consumption; decreases in lung capacity; and changes in immunologic function (Bridges et al., 2003, Steininger et al., 2003). For every 1,000 pregnant women vaccinated, it has been estimated that about 1-2 hospitalizations could be prevented (Bridges et al., 2003).
Influenza has also been studied during pregnancy to see whether there is a resulting increase in fetal loss. Stanwell-Smith et al. (1994) reported on a possible association of influenza A with fetal loss based on a sudden increase (within a period of three weeks) of 12 fetal losses at one health center that normally experiences 12-15 losses for the entire year. They noted that in the small number of women who miscarried or had a stillbirth, these women were significantly more likely to have experienced a flu-related illness during their pregnancy compared to control women who had delivered a liveborn (Stanwell-Smith et al., 1994). Additionally, eight out of eight women with losses and zero out of the six control women who were tested had serological evidence of a recent infection with influenza A. Although a suggestive cluster, larger studies are needed to confirm or refute this association.
Influenza has been evaluated as a possible cause of congenital malformations. In an experimental animal model, sub-lethal doses of influenza A strains were administered intranasally to pregnant mice. However, there was no increase in congenital anomalies in the offspring (Mackenzie et al., 1977). Two Irish studies from the 1950s reported on a possible relationship between maternal influenza and human fetal malformations (primarily neural tube defects). This population has a higher frequency of neural tube defects. In the first study, a history of influenza (but not serological evidence) was obtained at delivery. Of the women that gave birth to infants with malformations, 18.4% reported an exposure to influenza compared to 3.6% of the mothers of normal infants (Coffey and Jessop, 1955). However, this type of study is susceptible to recall bias where women with infants with malformations are more likely to remember and report exposures than women whose infants have no malformations. Although the second study also reported an increased malformation rate among babies born to mothers who had influenza during pregnancy compared with those not exposed (3.6% and 1.6% respectively), the findings were still in the overall range of the expected general population risks (Coffey and Jessop, 1959).
Several more recent studies have refuted these findings (Record, 1961). For example, the population incidence of influenza infection during the first trimester was not increased among a cohort of 248 mothers who had a pregnancy with anencephaly (Saxen et al, 1990). Furthermore, additional studies that incorporated serologic evidence of infection, rather than maternal report or infection prevalence, have not identified an increased risk of malformations (Brown, 1970, Elizan et al., 1969, Warrell et al., 1981).
In summary, the available data indicates that influenza itself is unlikely to be the direct cause of congenital malformations. However, a fever greater or equal to 102 degrees F and lasting more than 24 hours during 4-6 weeks gestation has been associated with neural tube defects (Chamber et al., 1998).
Some authors have suggested an exposure to influenza during pregnancy is a neurodevelopmental risk factor for schizophrenia. For example, Mednick et al. (1988) and O’Callaghan et al. (1991) noted a significant increase in schizophrenia among individuals who were in their second trimester of fetal life during the 1957 pandemic of ‘Asian’ A2 influenza . However, there is no direct evidence that the subjects were exposed to influenza, rather the evidence is based on the prevalence of the infection during fetal life. The mechanism underlying this possible association is also not clear and evidence has accumulated against any association with schizophrenia (Selten and Slaets, 1994, Torrey et al.,, 1991). Currently, there is no conclusive evidence either in favor or against an association between schizophrenia and prenatal exposure to influenza (Cooper, 1992 and Limosin
et al., 2003).
Vaccination
The influenza vaccine is the primary method for preventing influenza and complications. When the vaccine and circulating viruses are antigenically similar, the vaccine is expected to prevent influenza in 70-90% of healthy adults <65 years old (Bridges et al., 2003). The primary target group for influenza vaccination includes persons who are at high risk for serious complications from influenza, such as persons aged >50 years old or persons <50 years old who have chronic underlying medical conditions.
The Advisory Committee on Immunization Practices of the Centers for Disease Control added pregnant women in the second and third trimesters to the list of high-risk groups for whom the influenza vaccination is indicated. The American College of Obstetrics and Gynecology also recommends that women who will be beyond the first trimester of pregnancy during the influenza
season should be vaccinated (ACOG Committee Opinion, 2003). Administering the vaccine after
the first trimester is a reasonable precaution to minimize exposures during organogenesis. However, it is considered undesirable to delay vaccinating pregnant women in the first trimester who are at high risk for pulmonary complications (ACOG Committee Opinion, 2003).
Vaccination during pregnancy
Live virus vaccines are of theoretical concern since a live virus has the potential to replicate itself and infect the mother and fetus. However, the influenza vaccine contains an inactivated virus without this added theoretical concern. Additionally, available studies have not identified a pregnancy risk with exposure to the influenza vaccine at any stage of pregnancy. For example, in a study of 650 pregnancies exposed to the inactivated influenza vaccination during the first four months of pregnancy, no increase over the expected number of malformations was observed (Heinonen, 1977).
Deinard and Ogburn (1981) performed a prospective study on 176 women who were immunized with a killed virus vaccine during their pregnancy (41 in the first trimester, 58 in the second trimester and 77 in the third trimester). Pregnancy outcomes were compared with a control group that did not receive the vaccine. No significant association was found between the outcome of pregnancy, infant mortality, and infant’s physical or neurological development at 8 weeks of age (Deinard and Ogburn, 1981).
Sumaya and Gibbs (1979) followed 56 women vaccinated with an inactivated influenza virus during the second and third trimesters of pregnancy. Their main focus (and conclusion) of the study was that immunization of pregnant women can provide only short term protection of the newborn infant. The authors did note that the course and outcome of pregnancy of the immunized women were similar to that of matched controls of unimmunized women.
In 2003, an intranasal, cold-adapted, live, attenuated influenza vaccine (LAIV) was approved for use in healthy individuals aged 5-49 (Harper et al., 2003). LAIV contains attenuated viruses theoretically still capable of replication. There is no animal or human data regarding the safety of LAIV in pregnancy. Because of the lack of information, the theoretical concern with live viruses in pregnancy, and the availability of an inactivated vaccine, LAIV is not recommended for pregnancy.
References
ACOG Committee Opinion #282 (2003) Immunization during pregnancy. Obstet Gynecol 101:207-12.
Adams W, et al. (1993) Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia. Br J Psych 163:522-534.
Bridges CB, et al. (2003) Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 52 (No. RR-08):1-36.
Brown GC (1970). Maternal virus infection and congenital anomalies: A prospective study. Arch Environ Health 1970;21:362.
Chambers CD, et al. (1998) Maternal fever and birth outcome: A prospective study. Teratology 58(6):251-7.
Coffey VP and Jessop WJE (1955) Congenital abnormalities. Irish J Med Sci (6th Ser) 349:30.
Coffey VP and Jessop WJE (1959). Maternal influenza and congenital deformities: A prospective study. Lancet 2:935-938.
Cooper SJ (1992) Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Br J Psych 161:394-396.
Deinard A and Ogburn P (1981) A NJ/8/76 Influenza vaccination program: Effects on maternal health and pregnancy outcome. Am J Obstet Gynecol 141:240-245.
Elizan TS, et al. (1969) Viral infection in pregnancy and congenital CNS malformations in man. Arc Neurol 20:115.
Harper S, et al. (2003) Using live, attenuated influenza vaccine for prevention and control of influenza: Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 52 (NO. RR-13);1-8.
Heinonen OP (1977) Birth Defects and Drugs in Pregnancy. Littleton Ma; John Wright-PSG Pp. 314-321, 436.
Larsen JW (1982) Influenza and pregnancy. Clin Obstet Gynecol 25(3):599-603.
Limosin F, et al. (2003) Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand 107:331-33.
Mackenzie JS, et al. (1977) Influenza A virus and its influence on the outcome of pregnancy in the mouse. Dev Biol Stand 39:489-96.
Mednick S, et al. (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psych 45:189-192.
O’Callaghan E, et al. (1991) Schizophrenia following prenatal exposure to influenza epidemics between 1939 and 1960. Lancet 337:1248-1250.
Record RG (1961) Anencephaly in Scotland. Br J Prev Soc Med 15:93-105.
Saxen L, et al. (1990) Influenza Epidemics and Anencephaly. Am J Public Health 80:473-475.
Selten JPC and Slaets JPJ (1994) Evidence against maternal influenza as a risk factor for schizophrenia. Br J Psych 164:674-676.
Stanwell-Smith R, et al. (1994) Possible association of influenza A with fetal loss: investigation of a cluster of spontaneous abortions and stillbirths. Commun Dis Rep CDR Rev 4(3): R28-R32.
Steininger C, et al (2002) Influenza A virus infection and cardiac arrhythmia during the neonatal period. Scand J infect Dis 34:782-784.
Sumaya C and Gibbs R (1979) Immunization of pregnancy women with influenza A/New Jersey/ 76 virus vaccine: Reactogenicity and immunogenicity in mother and infant. J Infect Dis 404:141-146.
Torrey E, et al. (1991) An Influenza epidemic and the seasonality of schizophrenic births. In Second World Congress and Viruses and Mental Helath (ed. E. Kurstak) pp.109-116. New York: Plenum.
Warrell MJ, et al. (1981) Examination for Influenza IgA and IgM antibodies in pregnancies associated with neural tube defects. J Med Micobiol 14:159.
Contributors
Jennifer Croft, BS
Genetic Counseling Intern
Mara Gaudette, MS, CGC
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Northwestern Reproductive Genetics, Inc.
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Posted by admin on December 1st, 2003 — in newsletter
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Toxoplasmosis Update
Volume 10, Issue 3
Toxoplasmosis infection is caused by the Toxoplasmosis gondii parasite. This parasite can be found in undercooked meat, soil, and cat feces. The life cycle of the parasite is completed in a cat host, and when the cat releases feces (into the litter box or soil) the parasite becomes infectious after several days to weeks. Oocytes can remain infectious in cat feces buried in warm, moist soil for up to one year (Jones et al., 2002). Transmission to humans occurs by three principle routes. About 50% of infection cases are attributed to persons ingesting undercooked infected meat (particularly pork, mutton, wild game) or foods that have come into contact with infected meat (Jones et al., 2002). Secondly, persons can unknowingly ingest infectious oocytes from coming into contact with feces in the cat litter box or in the soil (while gardening or eating unwashed fruits and vegetables). Finally, there can be maternal-fetal transplacental transmission.
Symptoms of toxoplasmosis infection can include swollen lymph nodes, fatigue, muscle aches, malaise, fever, and other flu or mononucleosis-type symptoms. However, up to 90% of immunocompetent persons are asymptomatic (Jones et al., 2002).
Congenital Toxoplasmosis
In the United States it is estimated that between 1-10/ 10,000 infants are born annually with congenital toxoplasmosis (Lopez et al., 2000). Symptoms of infection may not be evident on ultrasound or at birth, but can occur months or several years or more after birth. Nonspecific ultrasound findings can include the most common finding of hydrocephalus (Hohlfeld et al., 1991), intracranial calcifications, microcephaly, intrauterine growth retardation, hydrops, and echogenic bowel. Symptoms in the neonate can include chorioretinitis (most common finding), pneumonia, myocarditis, erythroblastosis, anemia, jaundice, nephritis, myositis, and rash. Possible long-term effects seen in infants with congenital toxoplasmosis include seizures, mental retardation, spasticity, deafness, and blindness. Two states (MA and NH) currently perform newborn screening for congenital toxoplasmosis. For over two decades France (and several other European countries) have been performing universal prenatal screening for congenital toxoplasmosis with monthly repeated serologic testing of nonimmune women (Romand et al., 2001). This practice has not been adopted by the United States. Opponents of universal screening in the United States point out that the frequency of congenital infection in the United States is 10 fold lower than France, and they note the inherent limitations in both diagnostic and therapeutic options (Bader et al., 1997). Screening in the United States is typically initiated following suspicious ultrasound findings.
Timing in Pregnancy for Infection
The placental infection transmission rate is variable depending on the gestational age at the time of maternal infection. Women infected before conception, with rare exception, do not transmit the infection to the fetus, whereas women infected closer to term have a transmission rate estimated to be as high as 90% (Friedman and Polifka, 1994). Following a primary infection, the transmission rates in the 1st trimester ranges from <1-15%, approximately 30% for the second trimester, and approximately 60% for the 3rd trimester (Antsaklis et al., 2002). While fetal infection is more likely later in pregnancy, the severity of congenital infection is inversely related to the age at maternal infection. For example, one small prospective study noted that severe congenital toxoplasmosis occurred in 6% of infants and perintatal death in 5% of infants when infection occurred in the first trimester, while there were no cases of severe symptoms in the infants of 128 women infected in the third trimester (Friedman and Polifka, 1994). This study, however, does not rule out the possibility of severe symptoms with third trimester exposure.
Prenatal Diagnosis
The first step prior to prenatal diagnosis is to confirm maternal infection typically with antibody detection. Maternal serum is tested for the presence of toxoplasmosis-specific IgG and IgM antibodies. If IgG is negative, there is no evidence of maternal infection. However, if an acute infection is suspected, samples can be retested in three weeks. If IgG is positive, maternal infection has occurred at some time, and in order to determine the approximate time of infection, maternal serum is tested for the presence of toxoplasmosis-specific IgM antibodies (see Table 1 adapted from Jones et al., 2002). If IgG is positive, and IgM is negative, then maternal infection occurred more than a year ago (no increased risk to the fetus). If both IgG and IgM are positive, maternal infection occurred within the last year, or it is a false-positive IgM result.
Treatment
Maternal infection during pregnancy is treated with spiramycin from the time of diagnosis until term, unless fetal infection is detected. If fetal infection is detected, mothers can be treated with pyrimethamine and sulfadiazine or sulfadoxine (Jones et al., 2002). It has been suggested that this treatment reduces the transmission rate of infection by 50%, but this has also been refuted (Foulon et al., 1999, Gilbert et al., 2003). For example, one multicenter European study evaluated 140 infants (at birth and at one year of age) of women with confirmed seroconversion during pregnancy. Only 25 women-infant pairs hadn’t received treatment. When gestational age at infection was accounted for, prenatal antibiotic treatment did not reduce the rate of fetal transmission. However, treatment was associated with a significantly reduced rate of serious sequelae among infected infants (Foulon et al., 1999).
Infants diagnosed prenatally or postnatally are treated with pyrimethamine and sulfadiazine for the first year of life, and then are screened periodically for associated problems. This has been documented to provide a much more favorable outcome compared to infected infants who were not treated or only treated for one month (McAuley et al., 1994).
Possible Teratogenicity of Spiramycin, Pyrimethamin, and Sulfonamides
Spiramycin is a macrolide antibiotic used in pregnancy to treat maternal toxoplasmosis infections. No adequate pregnancy studies have been published. A Hungarian case-control study of macrolide antibiotics used in pregnancy did not identify an increased risk of congenital abnormalities. However, since this study included only 12 cases with exposure to spiramycin, it had little potential to detect an increased teratogenic risk with the individual macrolide antibiotics (Briggs, 2002) (REPROTOX- spiramycin). Spiramycin has not been approved for use in the United States by the Food and Drug Administration (FDA) and is therefore considered an experimental drug (orphan). It can be obtained from the FDA. Physicians who are interested in obtaining the drug, should contact the FDA at 301-827-2335 (March of Dimes, 2001).
Pyrimethamine is a folic acid antagonist used in combination with sulfonamides for treatment and prophylaxis of malaria and toxoplasmosis. Human doses have been found to be teratogenic in rats and include cleft palate, mandibular hypoplasia, limb defects, and neural tube defects) (Shepard, 1995). However, limited studies on pyrimethamine in human pregnancy has not identified this medicine as teratogenic. If this drug is used during pregnancy, folic acid supplementation is recommended, especially during the first trimester (Briggs, 2002) (REPROTOX- pyrimethamine).
Sulfonamides are a group of antimicrobial agents with primarily bacteriostatic effects on microorganisms. Sulfonamides readily cross the placenta during all stages of gestation. Human birth defects have not been associated with this group of drugs even when administered during the first trimester. The number of human case studies available for the sulfonamides is still small, however, and there are animal data suggesting that sulfonamides can cause malformations in some species. There are also concerns for use of these agents near term because of possible effects on newborns including jaundice, hemolytic anemia, and theoretically, kernicterus (Briggs, 2002) (REPROTOX- sulfonamides).
Prevention
Preventative strategies for pregnant women (Lopez et al., 2000) include:
· Cook their meat until it is no longer pink and the juices run clean
· Wear gloves when gardening
· Wash and peel all fruits and vegetables
· Clean cooking surfaces and utensils after they have contacted raw meat, poultry, seafood, and unwashed fruits and vegetables
· Wash hands carefully after handling raw meat, fruit, vegetables, and soil
· Do not change a cat’s litter, or if you must, use gloves and then wash hands thoroughly
· Do not feed cats raw or undercooked meat, and keep cats inside
Health Education Recommendations (Pawlowski, 2001) include:
· Provide health education materials in waiting rooms in outpatient clinics, clubs for pregnant women, ladies weekly magazines, and television
· Promote the educational role of medical personnel
· Preventative education should especially be targeted for pregnant women 20 years old or younger (this age group had the lowest levels of knowledge and highest frequency of congenital toxoplasmosis)
Helpful Websites:
Center for Disease Control: Fact Sheet on Toxoplasmosis
www.cdc.gov
ITIS (1994 ) Original Toxoplasmosis Newsletter
www.fetal-exposure.org
March of Dimes: Fact Sheet on Toxoplasmosis
www.modimes.org
Organization of Teratology Information Services: Patient Fact Sheet on Toxoplasmosis
www.otispregnancy.org
References:
Antsaklis A, et. al. (2002)Prenatal Diagnosis of Congenital Toxoplasmosis. Prenatal Diagnosis (22):1107-1111.
Bader T, et al. (1997) Prenatal Screening for Toxoplasmosis. Obstetrics and Gynecology 90:457-464.
Briggs GG, et al. (2002) Drugs in Pregnancy and Lactation, 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins. Pp. 1200-1202, 1268-1270, 1291-1295.
Dunn D, et. al. (1999) Mother-to-child transmission of toxoplasmosis:risk estimates for clinical counseling. The Lancet 353:1829-1833.
Foulon W, et. al. (1999) Treatment of toxoplasmosis during pregnancy: A mulitcenter study of impact on fetal transmission and children’s sequelae at age 1 year. American Journal of Obstetrics and Gynecology 180(2)410-415.
Ficker-Hildago H, et. al. (1997) Prenatal Diagnosis of Congenital Toxoplasmosis: Comparative Value of Fetal Blood and Amniotic Fluid Using Serological Techniques and Cultures. Prenatal Diagnosis 17(9)831-835.
Friedman and Polifka (1994) Teratogenic Effects of Drugs. Baltimore, MD: The John Hopkins University Pres. Pp. 616-618.
Gay-Andrieu F, et al. (2003) Fetal Toxoplasmosis and negative amniocentesis: necessity of an ultrasound follow-up. Prenatal Diagnosis 23:558-560.
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Posted by admin on October 1st, 2002 — in newsletter
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Crohn’s Disease in Pregnancy
Volume 10, Issue 2
Crohn’s disease, an inflammatory bowel disease is a serious, chronic condition of the gastrointestinal tract with unknown cause. However, it does appear have a strong genetic component in some families (CCFA 1999). Crohn’s disease causes diarrhea, abdominal cramps, pain, fever, and occasionally rectal bleeding. Subsequently, an individual with Crohn’s disease suffers from a loss of appetite and weight loss. The symptoms of the disease usually manifest themselves between the ages of fifteen and thirty (Moser et al., 2000, CCFA 1999). Unlike ulcerative colitis, which affects the mucosal layer of the bowel, Crohn’s disease affects all layers (CCFA 1999).
There is consensus that patients with active disease should avoid pregnancy (Moser et al., 2000, Connell and Miller, 1999). The effects of active inflammation are believed to be more harmful to a fetus than the effects of treatment; subsequently disease activity plays a more important role in determining fetal outcome than drug treatment. In order to maintain remission, treatment during pregnancy is justified (Connell and Miller, 1999).
Connell and Sandborn (1999) suggest fertility is relatively normal in patients that are treating their Crohn’s disease. However, some data suggest that even in remission, regardless of the type of treatment, Crohn’s disease may cause pregnancy complications (Kornfeld et al., 1997). For example, an association between Crohn’s disease and poor maternal weight gain, vaginal bleeding, premature rupture of the membrane, miscarriage and low birth weight independent of medication use has been raised (Moser et al., 2000). In fact, the severity of the disease is related to the severity of the complications experienced in pregnancy (Mogadam et al., 1981).
Corticosteroids, aminosalicylic acids, immunosuppressives, methotrexate, and antibacterial medications are used in the treatment of Crohn’s disease. These medications are also used to maintain remission. This newsletter will review these medications.
Corticosteroids
Corticosteroids are frequently used in the treatment of Crohn’s disease, with prednisolone being the most common choice. Prednisolone in doses of 40mg or more resulted in an overall remission in 67% of patients whereas doses of 60mg yielded remission in 83% of patients. This medication, however, can aggravate pregnancy complications, such as glucose intolerance, hypertension, sodium retention and peripheral oedema. Abrupt cessation of high dose, or prolonged use of prednisolone may induce maternal adrenal insufficiency and supplemental treatment may be needed during labor (Connell and Miller, 1999).
In humans, the concentration of prednisolone in the fetus has been found to be approximately 10% of that in maternal circulation. This is comparatively different from other corticosteroids; for example, dexamethasone crosses the placenta freely and is used in the treatment of congenital adrenal hyperplasia. This small amount of prednisolone is unlikely to cause fetal adrenal suppression (Connell and Miller, 1999). However, there are case reports of neonatal adrenal insufficiency. Thus, it is recommended that prednisolone be used with caution in pregnancy.
The Motherisk Teratogen Information Service documented a slight increased risk of cleft palate in association with prednisolone (Park-Wyllie L, et al., 2000). In most studies, prednisolone was not found to be associated with an increase in congenital anomalies (Reprotox #1359). However, early studies found that it may be associated with fetal growth retardation, stillbirth, placental insufficiency, reduced neonatal birth weight and fetal distress. It is unclear if these complications are due to the medication or to the underlying condition, and subsequent studies have not confirmed these findings (Connell and Miller, 1999 and Illinois Teratogen Information Service, 2000). The Crohn’s and Colitis Foundation of America has stated that prednisolone is appropriate to use as treatment in pregnant women (Connell and Sandborn, 1999).
Aminosalicylates
Sulfasalazine
Sulfasalazine (Azulfidine®) is used in the induction and maintenance of remission of mild to moderate inflammatory bowel disease. Sulfasalazine is a 5-aminosalicylic acid conjugated to a sulfapyridine. Sulfapyridine is thought to be responsible for the drug’s adverse side effects, which include nausea, vomiting and hepatitis (Connell and Miller, 1999 and Connell and Sandborn 1999).
Most studies on animals do not show an increase in congenital malformations associated with sulfasalazine (Reprotox #1253). There are case reports of human pregnancies with maternal sulfasalazine use resulting in various isolated anomalies (Connell and Miller 1999). However, this medication has been used extensively in pregnancy with no apparent increase in the risk of miscarriage, congenital anomalies or prematurity (Connell and Miller 1999 and Mogadam et al., 1981). The concentration of sulfasalazine in cord blood is approximately equal to that of the maternal concentration. Sulfasalazine inhibits both metabolism and transportation of folic acid. Norgard et al., (2001) studied sulfasalazine use in pregnancy because of its effect on folate metabolism. This study did not find an increase in any congenital malformations, including neural tube defects, with use of this medication. However, supplementation of 1mg twice daily of folic acid is recommended for pregnant women taking this drug (Connell and Miller 1999 and Connell and Sandborn 1999).
5-Aminosalicylic acid
5-Aminosalicylic acid (5-ASA) was developed as an alternative to sulfasalazine. Asacol®, Pentosa®, Dipentum®, and Rowasa® are brand names for 5-ASA (Connell and Sandborn 1999). Because it lacks the sulfapyridine, it does not produce the same side effects as sulfasalazine. 5-ASA is most often used to treat acute episodes of Crohn’s disease, but also to maintain remission. It is usually well tolerated, but there are reports of occasional myocarditis, pancreatitis or renal toxicity (Connell and Miller 1999 and Connell and Sandborn 1999).
Human data has shown that 5-ASA is found in very low concentrations in the fetus. Overall, at therapeutic doses, 5-ASA is unlikely to produce any adverse pregnancy effects, nor does it appear to be associated with an increased risk of congenital malformations (Connell and Miller 1999 and Connell and Sandborn 1999).
Immunosuppressives
Azathioprine (Imuran®) and Mercaptopurine (Purinethol®) are purine antimetabolites used in the treatment of active Crohn’s disease. After absorption, azathioprine is metabolized to 6-mercaptopurine. These drugs are used for severely ill Crohn’s patients when other drug treatments fail (Korelitz 1990). Patients taking these medications may experience such complications as reversible pancreatitis, myelotoxicity, hepatotoxicity, hypersensitivity reactions and opportunistic infections (Connell and Miller 1999 and Korelitz 1990).
Current Research Studies
ITIS is currently enrolling and following up on pregnancies as part of the following studies. If you have a patient who would like to participate in one of the studies, please contact ITIS at (800) 252-4847.
Asthma Medications in Pregnancy Project
Rheumatoid Arthritis in Pregnancy Study
Ondansetron in Pregnancy Study
While azathioprine has been found to cross the placenta, low amounts of the active metabolite are found in fetal blood. In humans, azathioprine circulates in the fetus primarily as the inactive metabolite, thiouric acid. It appears that the fetus may be protected from adverse effects of the medication because the fetal liver lacks the enzyme, inosinate pyrophosphorylase, which converts azathioprine to its active metabolites. Most studies on the affects of azathioprine in pregnancy involve pregnant renal transplant patients rather than patients with Crohn’s disease. Many studies found an increased risk of fetal growth retardation, lymphopenia, decreased thymus size and prematurity (Bermas and Hill, 1995, Connell and Miller, 1999 and Witter et al., 1981). This risk was increased above the risk for renal transplant patients who did not take azathiaprine. Still, the malformation rate was 3.9%, which is close to the general population rate. The association between azathioprine and IUGR appears to be the highest when used in combination with a corticosteroid such as prednisone. Thus the direct role of azathioprine in infants with IUGR is difficult to determine as other medications (corticosteroids have been associated with IUGR), maternal hypertension, maternal vascular disease, and maternal renal impairment may also have a role.
Connell and Miller (1999) stated that because there have been isolated cases of neonatal myelotoxicity and immunosuppression, a dose of 2mg/kg/day or less should be used in pregnancy. However, this dose may not be high enough to produce a therapeutic effect. Another alternative is to reduce maternal dose in the third trimester.
A potential risk for chromosome anomalies has been raised following a case report of a woman with lupus who took the drug during two different pregnancies. She delivered two infants with separate de novo translocations. Due to these being isolated cases it is unlikely a true association. However, further investigation is required to determine if this is a true risk from gestational exposure to azathioprine (Bermas and Hill, 1995, Connell and Miller 1999, Reprotox #1459, 1980 and Witter et al., 1981).
There is one study of azathioprine use in pregnant patients with inflammatory bowel disease. This study did not find an increased risk for congenital abnormalities or subsequent health problems (Connell and Miller, 1999 and Connell and Sandborn 1999). Still, due to the potential risks, azathioprine and mercaptopurine are usually not prescribed in pregnancy unless the disease is severe (Connell and Sandborn 1999).
azathiaprine or mercaptopurine (Rampton 20001). It is also used in nonsurgical treatment of ectopic pregnancy due to its abortifacient properties (Bermas and Hill 1995 and Reprotox #1036)). Patients who take this medication may experience: hypersensitive pneumonitis, hepatic fibrosis, myelotoxicity, nausea, increased hepatic enzyme activity, skin rash and reversible oligospermia (Connell and Miller 1999). Methotrexate does not appear to have any long term effects on fertility (Bermas and Hill 1995).
Methotrexate is contraindicated in pregnancy for many reasons. It is a folic acid antagonist which crosses the placenta, and therefore poses a potential increased risk for neural tube defects. Additionally, methotrexate is embryotoxic and teratogenic in animals and humans (Bermas and Hill 1995, Connell and Sandborn 1999, Connell and Miller 1999 and Rampton 2001). Many abnormalities such as large fontanelles, craniosynostosis, abnormal head shape, hypertelorism, and skeletal deformities have all been reported with use of methotrexate in human pregnancy (Connell and Miller 1999). These abnormalities were primarily noted in children born to mothers given 10mg of methotrexate. Studies on this population of women also revealed a miscarriage rate of approximately 44%. The average dose used in these women was from 7.5mg-10mg (Bermas and Hill 1995). There appears to be a critical time period for exposure of 6-8 weeks postconception. There are cases of first trimester exposure to methotrexate in which no teratogenic effect was detected. Four cases of exposure to methotrexate during the early first trimester (0 -6 weeks post conception) all resulted in healthy newborns. An additional study identified eight pregnancies for which methotrexate was given to treat rheumatoid arthritis early in pregnancy. There were five healthy newborns and three spontaneous abortions.
Methotrexate has also been associated with fetal growth retardation resulting from bone marrow suppression. Finally, there are case reports of an association between maternal methotrexate use and fetal chromosome abnormalities (Connell and Miller 1999). Rampton (2001) recommends that use of this medication in either partner be discontinued six months prior to conception.
Antibacterials
Metronidazole
Metronidazole (Flagyl®) is mostly used for treatment of perianal Crohn’s disease. Mothers taking metronidazole may experience nausea, anorexia, metallic taste, glossitis, and peripheral neuropathy. Sporadic cases of midline facial defects in humans, as well as rare reports of bone disorders, have been reported (Connell and Sandborn1999). Therefore, it has been suggested
that the use of this medication should be limited to the second and third trimesters of pregnancy (Connell and Miller 1999). However, two large meta-analysis showed no increased risk for congenital malformations, miscarriage, intrauterine growth retardation or prematurity with maternal metronidazole use (Connell and Miller 1999, Reprotox #1129). A recent prospective cohort study followed 132 first trimester exposed pregnancies and did not find an increased incidence of congenital malformations (Diav-Citrin et al 2001). Often metronidazole is used to treat bacterial vaginosis during pregnancy.
Ciprofloxacin
Ciprofloxacin is a quinolone. It can be used as an alternative to metronidazole to treat Crohn’s disease (Connell and Sandborn 1999). Quinolones as a class have a high affinity for bone tissue, and juvenile animals may develop arthropathy following exposure in pregnancy (Reprotox #1965). However, other animal studies did not find an increased risk of congenital malformations associated with maternal ciprofloxacin use. Additionally, a prospective study on thirty-eight pregnant women receiving ciprofloxacin during pregnancy did not associate this medication with an increased risk of malformations, including musculoskeletal problems. It should be noted, however, that there are no studies of ciprofloxacin use during pregnancy as the primary treatment for inflammatory bowel disease (Connell and Miller 1999 and Reprotox #1965).
New Therapies
There are no reproductive data available regarding newer treatments for Crohn’s disease in pregnancy. These therapies may include: Tissue necrosis factor-A, mycophenolate mofetil, interleukin-10, short chain fatty acids and Tacrolimus. Due to the lack of data, use of these medications in pregnancy is not recommended.
Summary
Pregnancy should be avoided when a patient has active Crohn’s disease. The complications of active disease regardless of medication use are poor maternal weight gain, vaginal bleeding, premature rupture of the membranes, low birth weight, and miscarriage. It is recommended that pregnancy be undertaken only when the disease is in remission. Treatment during pregnancy is recommended to control maternal disease and decrease the risk for disease related complications. Any alterations to dosage should be done prior to pregnancy and it is not recommended that dosage be decreased during pregnancy. The majority of studies have found that decreasing dosage during pregnancy increases the rate of relapse and complications due to active or uncontrolled disease.
References:
Bermas BL and Hill JA (1995) Review: Effects of Immunosuppressive Drugs During Pregnancy. Arthritis and Rheumatism 3 (12):1722-1732
Connell and Miller (1999) Treating Inflammatory Bowel Disease During Pregnancy Drug Safety 4:311-323
Connell WR and Sandborn WJ (1999) Drug Therapy for IBD During Pregnancy. http://www.ccfa.org/medcentral/library/family/drugpreg.htm
Crohn’s and Colitis Foundation of America (1999) Questions & Answers about Crohn’s Disease. http://www.ccfa.org/Physician/crohnsb.html
Diav-Citrin O et al (2001). Pregnancy outcome after gestational exposure to metronidazole: a prospective controlled cohort study. Teratology 63:186-192.
Korelitz BI (1990) Antimetabolites in Inflammatory Bowel Disease: Long Term
Experience. Mount Sinai J of Medicine 57(5):297-304
Kornfeld D, Cnattingius S, Ekbom A (1997) Pregnancy outcomes in women with
Inflammatory bowel disease - A population-based cohort study. Am J Obstet Gynecol 177(4):942-946
Mogadam M, Dobbins WO, Korelitz BI, Ahmed SW (1981) Pregnancy in InflammatoryBowel Disease: Effect of Sulfasalazine and Corticosteroids on Fetal Outcome. Gastroent 80:72-76
Moore AJ, Okun NB, Mayes DC, BaileyRJ (2000) Crohn’s Pregnancy and Birth Weight. Am J of Gastroent 95(4):1019-1026
Norgard B, Czeizel AE, Rockenbaur M, Olsen J, Sorensen HT (2001) Population-based Case control study of the safety of sulfasalazine use during pregnancy. Alimentary Pharmcology & Therapeutics 15(4):483-486
Park-Wyllie L, Mazzotta P Pastuszak A, Moretti ME, Beique L, Hunnisett L, Friesen MH, Jacobson S, Kasapinovic S, Chang D, Diav-Citrin O, Chitayat D, Nulman I, Einarson TR, Koren G(2000) Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62(6):385-92
Rampton DS (2001) Methotrexate in Crohn’s disease. Gut 48(6):790-791
Reprotox, www.reprotox.org #1359, 1253, 1459, 1980, 1129, 1036, 1965
Witter FR, King TM, Blake DA (1981) The Effects of Chronic Gastrointestinal Medication on the Fetus and Neonate. Obstet & Gyne 58(5):79S-84S
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Posted by admin on September 1st, 2002 — in newsletter
PDF Version
Malaria Prevention & Pregnancy
Volume 10, Issue 1, September 2002
Contributers
Kelly Akin, BS
Genetic Counseling Intern Northwestern University Graduate Program in Genetic Counseling
Carrie L. McMahon, MS
Coordinator, Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
Reprogenic Research Inc.
Malaria infection during pregnancy poses significant health risks to both the pregnant mother and her fetus. Since no method of malaria prevention is 100% effective, it is best to avoid travel to malarious regions during pregnancy. As this is not always possible, the Centers for Disease Control and Prevention (CDC) have developed guidelines and recommendations for pregnant women traveling to malarious regions. The purpose of this newsletter is to summarize the current guidelines and recommendations for preventing malaria during pregnancy.
Facts About Malaria
Malaria is a serious and potentially fatal disease transmitted by an infected female Anopheles mosquito. There are four Plasmodium species that cause malaria in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. Classic symptoms of malaria include high fever with chills, rigor, sweats, and headache. The onset of symptoms typically occurs between 10 days to four weeks following infection, but can range anywhere from eight days to one year. Malaria is endemic in large regions of Central and South America, Haiti, and the Dominican Republic, Africa, the Indian sub-continent, Southeast Asia, the Middle East, and Oceania. Malaria affects 300-500 million people worldwide annually, and results in 1.1-2.7 million deaths per year (MMWR, 1990). In the United States, there are approximately 1000 cases of malaria per year that result from imported infection (Hulbert, 1992). Pregnancy can make a woman more susceptible to malaria, or increase the level of parasite in the blood.
Risks associated with malaria infection during pregnancy
Maternal Risks
Malaria tends to run a more severe course in pregnant women than in non-pregnant women. Symptomatic pregnant women may experience anemia, hypoglycemia, pulmonary edema, fever and headache. Atypical manifestations of malaria are particularly more common in the second half of pregnancy. Generalized immunosuppression, reduction in gammaglobulin synthesis, inhibition of the reticulo-endothelial system, and decreased levels of anti-malarial antibodies during pregnancy are thought to cause an increased susceptibility to infection. Factors that increase the risk for more severe malarial infection include non-immunity and primigravidy (Nosten et al, 1991).
Placental Changes
When a pregnant women is infected with malaria, there is a chance that the placenta will become infected as well. The placenta is actually the preferred site of sequestration and development of the malaria parasite.
Intervillous spaces become filled with parasites and macrophages, and thus interfere with oxygen and nutrient transport to the fetus. Infected primigrada have approximately a 30-40% risk for placental infection, whereas multigravidae have an approximate 15-20% risk.
The difference in risk is possibly due to formation of anti-adhesion antibodies during previous pregnancies (www.geocities.com/HotSprings/resort/5403/preganncy.htm).
Fetal Risks
Malaria during pregnancy poses significant risks to the fetus. Studies have shown that maternal infection is significantly correlated with low birth weight (Nyirjesy et al, 1993). Pregnancy loss, premature birth, stillbirth, placental insufficiency, and intrauterine growth retardation have all been observed in developing fetuses of non-immune infected mothers.
Complications during pregnancy that can adversely affect the fetus include maternal high grade fever, placental insufficiency, hypoglycemia and anemia (Ibhanesebhor, 1995). Although rare, transplacental spread of malaria parasites can lead to congenital malaria in the new born (Nyirjesy et al, 1993).
Congenital Malaria
Congenital malaria occurs in up to 7.4% of non-immune mothers, and results most often in patients with P. falciparum infection. The predominant clinical features include fever, respiratory distress, pallor, anemia, hepatomegaly, jaundice and diarrhea (Covell, 1950).
Preventing malaria in pregnancy
The following guidelines and recommendations have been taken from the Centers for Disease Control and Prevention website: www.cdc.gov/travel/mal_preg_pub.htm.
Due to the increased morbidity and mortality associated with malaria during pregnancy, pregnant women should avoid traveling to malarious regions if possible. Antimalarial agents may be necessary during pregnancy for the prevention or treatment of malaria. Quinine derivatives are the classical drugs used for malaria, of which the most useful is chloroquine. Chloroquine is the drug of choice for the prophylaxis and treatment of malaria during pregnancy due to the substantial amount of literature on its “safety” during pregnancy.
I. Pregnant women traveling to malaria-risk areas in Mexico, Haiti, the Dominican Republic, and certain countries in Central America, the Middle East, and Eastern Europe should take either chloroquine or hydroxychoroquine sulfate as their antimalarial.
a. Chloroquine (500 mg/week) (or chloroquine deritive Hydroxychloroquine sulfate at 400mg/week):
- Should be taken 1 week before arrival
- Then, once per week, on the same day each week, while in the malarious region.
- Then, once per week for 4 weeks after leaving the region.
Possible side effects: (rare) nausea, vomiting, headache, dizziness, blurred vision and itching.
II. Due to chloroquine-resistance, pregnant women traveling to malaria-risk areas in South America, Africa, the Indian subcontinent, Asia, and the South Pacific should take mefloquine as their antimalarial drug.
a. Mefloquine (250 mg/week):
- First dose 1 week before arrival in malarious region.
- Then, once per week, on the same day of the week, while in region.
- Then, once per week for 4 weeks after leaving the region.
Possible side effects: (rare) nausea, dizziness, difficulty sleeping, and vivid dreams. Very rare symptoms include seizures, hallucinations, and severe anxiety.
Malaria medications
Chloroquine
Several research studies have analyzed the effects of chloroquine use during pregnancy (Anonymous, 1983; White, 1996; Wolfe and Cordero, 1985). Wolfe and Cordero (1985) reported on the outcome of 169 births in which doses (average 300mg) of chloroquine were ingested once per week during pregnancy. In this study, two infants were born with anomalies including Tetralogy of Fallot and congenital hypothyroidism. This study showed that the rate of birth defects with use of chloroquine during pregnancy is not significantly higher than the background rate of birth defects of 3-5%.
Chloroquine is often the medication of choice for malaria treatment during pregnancy. Chloroquine should not be used if the woman has a history of liver disease or glucose-6-phosphate dehydrogenase deficiency.
Small amounts of chloroquine are transferred into breast milk. However, because the exposure to nursing infants is low, harmful effects are considered unlikely (Committee on Drugs, American Academy of Pediatrics, 1994).
Mefloquine
Mefloquine use during pregnancy has not been shown to be associated with an increased risk for pregnancy loss, or other adverse effects during the second and third trimesters (Steketee et al, 1996). One study evaluated over 500 pregnancies that included first trimester exposure to Mefloquine and did not find a significantly increased risk for birth defects (Phillips-Howard et al, 1998). This study did show an apparent increased risk for pregnancy loss. The authors concluded that the rate of pregnancy loss was not increased when compared to the high background rate of the population studied (Phillips-Howard et al, 1998).
Additional studies evaluating 167 women and 218 women, respectively, did not find an increased risk for a congenital malformation or miscarriage (Harinasuta, 1990; Elefant, 1991).
Small amounts of Mefloquine are excreted into breast milk. However, adverse effects from exposure to nursing infants are not expected because the amount ingested would be very small (Edstein et al, 1988).
Doxycycline
While doxyclcline has been used for the treatment of malaria, pregnant women should avoid taking doxycycline for malaria prevention during pregnancy. Doxycycline is a tetracycline derivative that is assumed to cause similar effects of tetracycline exposure during pregnancy including staining of the teeth in the fetus and depressed fetal bone growth (Rendle-Short, 1962).
Malarone
Malarone is a combination of atovaquone and proguanil HCl used in the prophylactic treatment of malaria. There are no adequate or well-controlled studies of Malarone use or its individuals components in pregnancy. Proguanil has been used for in Europe with no reported complications or increased incidence of malformations. This agent has been found to reduce folate levels; however, neural tube defects have not been reported to date (GlaxoSmithKline, July 2001). If a patient requires proguanil therapy, it is recommended that she receive additional folic acid.
Over the past few years, atovaquone in conjunction with proguaril has been prescribed as an anti-malarial therapy. Atovaquone is highly lipophilic and highly protein bound. There is currently no human reproduction data available regarding this agent. Personal European and American physician experiences have not documented an increased risk for a conjenital anomaly or other adverse effects (personal communication, London School of Tropical Medicine, John Hopkins Tropical Medicine Department, 2001).
In summary, to date there is no indication that Malarone or it’s individual components are teratogenic. However, clearly well-controlled studies are required to firmly establish an accurate risk assessment. If a person is inadvertently exposed to Malarone early in the first trimester, there is no data to suggest the pregnancy is at an increased risk for complications. If a patient requires an anti-malaria medication for use during pregnancy, a better suited agent such as mefloquine would be recommended.
Summary
Malaria infection during pregnancy is serious and increases the risk for maternal complications and fetal loss. If there has been a previous exposure, there is thought to be some level of immunity established. However, pregnancy may actually increase susceptibility, as this is a time in which cell-mediated immunity is decreased. If maternal infection occurs during pregnancy, the concern is that the infection will affect the placenta. It has been found that the intensity of the infection in the placenta is directly related to the severity of the effect on the fetus. The most common effect of a placental infection is low birth weight, as less blood and nutrients are available to the fetus. There is increased risk for miscarriage, premature delivery, stillbirth, jaundice, liver enlargement, and anemia. If a pregnant woman is traveling to an area where malaria is prevalent, prophylactic treatment is recommended.
Current Research Studies
ITIS is currently enrolling and following up on pregnancies as part of the following studies. If you have a patient who would like to participate in one of the studies, please contact ITIS at (800) 252-4847.
Asthma Medications in Pregnancy Project
Rheumatoid Arthritis in Pregnancy Study
Ondansetron in Pregnancy Study
References:
Anonymous. Malaria in pregnancy. Lancet (1983) 2:84-5.
Anonymous. From the Centers for Disease Control. Recommendations for the prevention of malaria among travelers. JAMA (1990); 263(20):2729, 2734, 2737.
CDC website: Malarone for Malaria Treatment and Prophylaxis. www.cdc.gov/travel/diseases/malaria/malarone.htm
CDC: Preventing Malaria in the Pregnant Woman - www.cdc.gov/travel/mal_preg_pub.htm
CDC: Pregnancy, Breast Feeding, and Travel - www.cdc.gov/travel/pregnant.htm
Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics (1994) 93:137-150.
Covel G. Congenital malaria. Trop Dis Bull 1950; 47:1147-67.
Edstein M et al. Excretion of mefloquine in human breast milk. Chemotherapy (1988) 34:165-9.
Elefant E et al (1991). Exposure to mefloquine: follow-up of 218 pregnancies. Presentation at OTIS 1991 annual meeting.
GlaxoSmithKline 2001
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Posted by admin on March 12th, 2002 — in newsletter
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Organ Transplantation and Pregnancy
Volume 9, Issue 3, March 2002
Kristin Augustine, BS, Carrie L. McMahon, MS, and Eugene Pergament, MD, PhD, FACMG
As the number of patients receiving an organ transplant has increased over the past decade, so has the number of organ transplant recipients of reproductive age. This circumstance has therefore demanded an increased awareness of the factors relevant to organ transplantation and pregnancy. This Risk Newsletter is intended to serve as a review of the major issues and medications associated with organ transplantation and pregnancy.
Transplantation and Pregnancy
In general, pregnancy is well tolerated in women with good pre-pregnancy graft function following all types of organ transplants. Throughout pregnancy, it is important that immunosuppressive therapy be maintained, as a small percentage of transplant recipients will have rejection episodes during pregnancy. No specific pattern of malformation has been identified in babies born to mothers who have had organ transplants. Each year new and more powerful immunosuppressive agents enter the market, and on the whole the data regarding potential teratogenicity is limited. However, medical experience has demonstrated that despite the medications and changes in maternal physiology in women post-transplantation, successful pregnancy can be maintained (Armenti et al, 2000).
Since even large individual centers have limited experience with pregnancies in transplant recipients, registry data and surveys provide the primary outcome data from various recipient groups (Armenti et al. 2000).
Obstetric Management Issues
Current recommendations suggest that women who have undergone any type of transplant wait 18 months to 2 years after the surgery to conceive a pregnancy. This allows the graft time to stabilize function, and immunosuppression to achieve appropriate maintenance levels. Post-transplantation pregnancies should be monitored as high-risk. Vigilant monitoring of transplant function, hematology, blood pressure control, diagnosis and treatment of rejection, treatment of any infections, and serial fetal surveillance is critical in the prenatal care of the transplant patient. Women who have had transplantations are very likely to experience premature delivery (prior to 37 weeks gestation), regardless of type of transplant or drug therapy. Vaginal delivery is always the aim, and is not contradicted even in the case of renal transplant (does not cause mechanical injury to a renal transplant; graft does not obstruct birth canal). It may be necessary to increase the levels of prophylactic steroids at delivery, and all surgical procedures should be covered by prophylactic antibiotics (Armenti et al. 2000). Pain relief is possible using the same medications commonly used in healthy women.
Transplant Medications in Pregnancy
Corticosteroids (Prednisone)
Prednisone (Deltasone) is a glucocorticoid that becomes active biologically after its conversion to prednisolone in the liver. There are reports that have indicated that prednisone, like the naturally occurring glucocorticoid, cortisone, causes cleft palate in mice and rats. Although an increase in cleft palate or other major malformations was not uncovered in a prospective study of 184 women who used prednisone prenatally (Carmichael et al, 1999), three retrospective epidemiology studies have associated oral clefting with human pregnancy exposure to corticosteroids based on small numbers of affected children with exposures (Rodriguez-Panilla, 1998). Odds ratios in
these reports were in the 3 to 5 range. In a study of 1,184 live born children with non-syndromic oral clefts, a relationship between exposure to corticosteroids during the first trimester and in increased risk for cleft lip was demonstrated (OR = 6.55; p = 0.015) after controlling for confounders such as smoking, hyperthermia, and affected first-degree relatives (Rodriguez-Pinella and Frias, 1998). Thus, corticosteroid use should be avoided in the first trimester if at all possible.
Data available from both animal experiments and clinical observations suggest that prenatal exposure to prednisone may retard fetal growth and be associated with an increased incidence of low birth weight among offspring. In some cases, this outcome has been attributed to the underlying disease for which the corticosteroids were given (often asthma, collagen-vascular disease or transplantation) (Fitzsimmons, 1986). Other investigators, however, have observed a high incidence of fetal growth retardation in the offspring of renal transplant patients treated with glucocorticoids, despite good graft function and normal or only slightly elevated blood pressure (Pirson et al, 1985). Maternal effects of prednisone, other than immunosuppression, include peptic ulcer disease, osteoporosis, increased bruisability, pancreatitis, increased risk for hypertension, aseptic necrosis of the bone, weight gain, fluid retention, glucose intolerance. These maternal effects seem to be related to the dose and duration of therapy (Sims, 1991).
A population based case control study was also performed in Hungary over the period 1980-1994 to examine the teratogenic potential of oral and topical corticosteroid treatment in pregnancy. In this study, corticosteroid exposure in pregnancy was 1.55% among 20,830 cases of babies with congenital malformations and 1.41% among 35,727 healthy control births. Therefore, the adjusted odds ratio in this analysis of case control pairs did not identify an association between the rate of congenital abnormalities and corticosteroid treatment in the second and third month of gestation (Czeizel and Rockenbauer, 1997). In addition, the American Academy of Pediatrics classified prednisone and prednisolone as compatible with breastfeeding.
Cyclosporine A (NeoralÒ)
Cyclosporine A (NeoralÒ) is a systemic immunosuppressant. Cyclosporine is a potent immunosuppressive agent used to prolong the survival of allogenic transplants involving the skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress humoral immunity and cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, and graft versus host disease. Cyclosporine crosses the placenta and the fetal levels of this drug may range between 30 and 64% of the maternal plasma concentration; substantial amounts can be located in amniotic fluid and placental tissue (Ostensen, 1992). Elimination of cyclosporine is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of cyclosporine from blood is generally biphasic, with a terminal half-life of approximately 8.4 hours (range 5-18 hours). The bioavailability of cyclosporine is dependent upon the patient population. The bioavailability is estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients (Novartis, 2000). Cyclosporine is extensively metabolized by the P-450 3A enzyme student in the liver, and to a lesser degree in the GI tract, and the kidney. In the manufacturer studies on pregnancy, cyclosporine was not teratogenic in appropriate test systems.
In a manufacturer’s study of 116 pregnancies in women receiving cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom received cyclosporine throughout the entire gestational period, the only consistent patterns of abnormality were premature birth (gestational period 28 to 36 weeks) and low birth weight for gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) had complications including pre-eclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and/ or fetoplacental dysfunction. Pre-term delivery occurred in 47%. Neonatal complications occurred in 27%. Growth retardation has also been observed in human pregnancies involving cyclosporine, but several of these cases also included gestational exposure to corticosteroids, which may have played a role in stunting fetal growth. Comparison of the risk of abortion and preterm delivery in small numbers of transplant patients receiving either cyclosporine or prednisolone and azathioprine suggest that the incidence of these outcomes may be increased by exposure to cyclosporine.
In an earlier study of 75 pregnancies in 70 mothers taking cyclosporine A prenatally, growth retardation and prematurity occurred in about 40% of neonates. It is important to note that these mothers were almost all taking prednisone concomitantly. The average birth weight was 2,093 gm (Ostensen, 1992).
In a 1999 meta-analysis performed on Medline, EMBASE, IPA, Cochrane, and Toxline databases, studies were selected for freedom from selection bias and the inclusion of more than 10 cyclosporine A exposed neonates. In this analysis, thirteen studies met the inclusion criteria for congenital malformations (6 with control groups), nine for prematurity (4 with a control group) and 4 for low birth weight (2 with a control group). The overall odds ratio for congenital malformations of 3.47 (CI 0.86-14.4) was not statistically significant. The odds ratio for prematurity of 1.47 (CI 1.00-2.15) was statistically significant; overall prematurity rate was 58.9% in the cyclosporine A exposed group. The prevalence of low birth weight was also statistically significant with an odds ratio of 1.59 (CI 1.05-2.40), thus indicating a statistically significant risk of low birth weight for infants with fetal exposure to cyclosporine A (Bar-Oz et al, 1999).
Since cyclosporine is excreted in human milk, breast-feeding should be avoided. However, estimates of neonatal exposure to cyclosporine in breast milk indicate that it is likely to be far less than the levels to which the fetus had been exposed prenatally.
Azathioprine (ImuranÒ)
Azathioprine is metabolized to 6-mercaptoprine, a substance which can cross the placenta. Early in pregnancy, the fetal liver is unable to metabolize this substance as it does not make the necessary enzyme. There are reports of infants born to renal transplant recipients exposed to azathioprine with an increased risk for congenital malformations ranging from 6.4%-9%. However, there are no specific patterns of malformation noted. The more comprehensive European Dialysis and Transplant Association (EDTA) report on 490 pregnancies (500 babies) concluded that azathioprine and prednisone immunosuppression was not associated with more congenital malformations in post-transplant mothers than seen in the general population (Rizzoni et al, 1992).
Congenital anomalies were observed in four (4%) of 103 infants born to women who had received renal transplants prior to becoming pregnant (Cararach et al, 1993). Approximately 90% of these women were treated with azathioprine during pregnancy. All of the reported anomalies were different. In another series of cases, an analysis of 40 pregnancies in systemic lupus erythematosus patients, no increased risk for congenital malformations was identified (Ostensen, 1992). Although there is a lack of evidence that azathioprine exposure is associated with a marked increase in birth defects or miscarriage, growth retardation has been reported in fetuses exposed to this and other cytotoxic agents, especially when used in combination with prednisone and at higher doses (Pirson et al, 1985). Maternal use of azathioprine has also been associated with neonatal immunosuppression, leukopenia, and/or pancytopenia (Davison et al, 1985). It is not known how often immunologic or hematologic complications in the newborn should be expected following maternal azathioprine therapy; however, one study found an association between maternal leukopenia and hematologic abnormalities in the offspring (Davison et al, 1985). It should be noted that many of the reports concerning azathioprine involve coadministration of other medications (especially prednisone) and involve women with serious medical illnesses such as renal failure. As this drug is excreted in small amounts in breast milk, breastfeeding while receiving azathioprine is not recommended.
Mycophenolate mofetil (Cell Cept®)
Mycophenolate mofetil is an immunosuppressant used in organ transplantation and rheumatoid arthritis. The manufacturer reports that doses roughly equivalent to those used clinically in transplant patients caused fetal resorptions and malformations in pregnant rats and rabbits. The malformations consisted largely of defects of the head and eyes, and were found in the absence of signs of maternal toxicity. This raises a greater level of concern for the potential for adverse effects on fetal development.
There are reports on 6 pregnancies (all transplant patients) that have included fetal exposure to CellCept®, none of these reports found major malformations in the offspring, but all were born prematurely. These cases, which have included first trimester exposures, may provide some reassurance that this agent can be used in pregnancies without frequent adverse developmental effects, but they are not sufficient to conclude that the use of this agent during pregnancy is safe (Pergola et al, 2001). Additionally, there is a case report in the literature of a kidney transplantation in the first trimester of pregnancy with subsequent exposure to mycophenolate mofetil, tacrolimus, and prednisone throughout the entire pregnancy. The baby girl was born prematurely at week 37 ½ with the only detectable abnormalities being hypoplastic nails and shortened 5th fingers (Pergola et al, 2001).
Polydrug Transplant Therapy
It may be more difficult to identify specific cause and effect relationships with certain immunosupressants and adverse pregnancy outcomes as more women are on treatment regimens consisting of combinations of the newer agents. However, with lowered doses of multiple agents, there is less exposure to each drug individually, and therefore, the potential for teratogenicity is theoretically less. However, there is the risk for potentiating effects among several drugs as well as unknown interactions, with the potential for adverse fetal outcomes (Armenti et al. 2000). Further investigation is required to accurately assess risk.
Pregnancy Outcomes in Various Transplant Recipients
LIVER
In a University of Washington Medical Center study between 1991-1999, six pregnancies were followed in women with prior orthotopic liver transplantation. Four of the six pregnancies were complicated by chronic hypertension, fetal growth restriction, and preterm delivery; all pregnancies were complicated by renal insufficiency. Pregnancies complicated by second- trimester renal insufficiency are at risk for preeclampsia, fetal growth restriction and fetal demise. It is believed that better obstetric outcome can occur in women with mild renal insufficiency and well-controlled chronic hypertension. In planned pregnancies, preconceptional hypertensive control may decrease the risk for preeclampsia and poor obstetric outcome (Carr et al, 2000). Generally, female liver recipients can have successful pregnancies while on cyclosporine A drug therapies (Scantlebury et al, 1990). In a registry report of 58 female liver recipients in 89 pregnancies (the majority on cyclosporine A therapy), there was no specific pattern of malformation reported in the newborn (Armenti et al, 2000).
KIDNEY
Kidney transplantation restores ovulatory menstrual cycles and fertility, which is often impaired while in dialysis. Maternal and fetal complications have been observed in pregnancy following renal transplantation. The most serious maternal complication is the rejection of the transplanted kidney; however, overall, the rejection rate has not been seen to increase during pregnancy compared to the general rate. Women who are post-kidney transplant are at increased risk for hypertension during pregnancy and must be carefully monitored by both obstetrician and nephrologist (Muirhead et al, 1992). There is also a high risk for infection and prophylactic antibiotic therapy should be administered for any invasive procedure, including amniocentesis (Framarino et al, 1993). Fetal problems that have been observed in this population include premature birth (19-45%) and IUGR (ranging from 13-25%) (Penn et al, 1980). In a retrospective case series of 44 consecutive pregnancies compared to maternal age matched controls, significantly more stillbirths (12/44; p = 0.037), preterm deliveries (p <0.001), and increased incidence of low birth weight (p < 0.001) were noted in the renal transplant group. The offspring followed in this study (n = 32) had normal postnatal growth and development, with the exception of three offspring with developmental delay. Further studies will be needed to determine if this is a coincidence or an association (Sgro et al, 2002). The rate of miscarriage does not appear to be increased in the renal transplant population. Congenital malformations resulting from drug therapy exposure also do not seem to be increased in this population (Framarino et al, 1993). Some studies have indicated difference in perinatal outcome specific to the type of medication administered for immunosuppressive therapy following kidney transplantation. Specifically, in a comparison of 57 babies born to mothers on azathioprine and 94 babies born to mothers on cyclosporine A, the babies with prenatal exposure to azathioprine had a significantly higher mean birthweight (2567 +/- 491.1 gm) compared to those exposed prenatally to cyclosporine A (2252 +/- 629.2 gm), with no incidence of congenital anomalies observed in either group (Toma et al, 1999).
BONE MARROW TRANSPLANTATION
Before transplantation, high dose cyclophosphamide (and/or cyclophosphamide plus irradiation) is used to prepare most patients for the transplant. These treatments, in combination with patient age at transplant seem to be significant factors with respect to the development of ovarian failure. In general, women over 25 who were treated with cyclophosphamide plus irradiation experienced primary ovarian failure. Therefore, this may need to be addressed with respect to future reproductive planning when choosing a treatment method for women in need of bone marrow transplantation. There are reports of successful pregnancies found in the literature. There are numerous reports which suggest that there is no increased risk of congenital anomalies in the offspring of transplant recipients. The prenatal course may be at increased risk for complications such as preeclampsia and prematurity (Sims, 1991).
HEART AND HEART LUNG
There are successful reports of pregnancies following heart and heart-lung transplants. An international study by Wagoner et al (1993) did not find a significant difference in neonatal complications or maternal graft survival in an analysis of 35 recipients with 47 pregnancies. There were 7 deaths in this group over 5.6 years of post-partum follow-up: three deaths were due to non-compliance and one due to allograft vasculopathy. No structural malformations were identified. There is still only a limited amount of data regarding lung recipients; however, concern has been raised about the significant rejection and mortality rates. There are however, a few successful case reports (Armenti et al, 2000).
MALE TRANSPLANT RECIPIENTS
There are many reports of male transplant recipients fathering successful pregnancies.
In a study of 204 male transplant recipients, 288 pregnancies were successfully completed and there were 2 neonatal deaths (total = 290). Analysis of outcomes in relation to the immunosuppressive regimens including Neoral and MMF (Cell Cept) revealed one child with ureteral obstruction, correctable by surgery, and one child with hydrocele (Armenti et al, 2000). The National Transplnatation Pregnancy Registry has data on 19 male transplant patients who fathered children while taking mycophenolate mofetil; none of these men had children with congenital malformations (Pergola et al, 2001). In a smaller study, specifically following the outcomes for 11 fathers treated with cyclosporine A, all newborns were healthy and had a mean birth weight of 2,730 gm (Ostensen, 1992).
CONCLUSIONS
In general, as the number of successful organ transplants increases, the desire for transplant recipients to become pregnant will also increase. In planning a pregnancy in an organ recipient, there are numerous additional concerns for both the health of the mother and the fetus. First and foremost, it is important and necessary to attempt to design an immunosuppressive regimen which will keep the mother healthy and minimize risk of a rejection episode. At the same time, special considerations must be taken for the potential teratogenic effects of any agent on a fetus. For example, alternating a poly drug therapy regimen to exclude corticosteroids in the first trimester may be a way to minimize any potential risk for oral clefting. It may be more prudent to choose drugs which have been on the market longer and therefore are better studied in pregnant women. This becomes more of a concern as new anti-rejection drugs enter the market each year. By working closely with patient, obstetrician, and the specialist (dependent upon type of transplant), a poly drug regimen can be designed to optimize, although not guarantee, safety for both mother and fetus.
References
Armenti VT, Moritx MJ, Radomski JS, Wilson GA, Gaughan WJ, Coscia LA, Davison JM (2000) Pregnancy and Transplantation Graft 3(2):59-63.
Bar-Oz B, Ma J, Tsao S, Hackman R, Zamin M, Einarson TR, Koren GL (1999) The Effects of Cyclosporine Therapy on Pregnancy Outcome in Organ Transplanted Women: A Meta-Analytical Review Teratology 59:440.
Carmichael SL; Shaw GM (1999) Maternal corticosteroid use and risk of selected congenital anomalies Am J Med Genet 86:242-4.
Cararach V, Carmona F, Monleon FJ, Andreu J (1993) Pregnancy after renal transplantation: 25 years experience in Spain. Br J Obstet Gynaecol 100:122-125.
Carr DB, Larson AM, Scmucker BC, Brateng DA, Carithers RL, Easterling TR (2000) Maternal hemodynamics and pregnancy outcome in women with prior orthotopic liver transplantation. Liver Transplantation. 6(2)213-221.
Czeizel AE, Rockenbauer M (1997) Population Based Case Control Study of Teratogenic Potential of Corticosteroids. Teratology 56:335-340.
Davison JM et al. (1985) Maternal azathioprine therapy and depressed haematopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol 92:233-9.
Fitzsimons R et al. (1986) Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 78:349-53.
Framarino ML, Poli L, Pierucci F, Paolucci A, Pretagostini R, Di Nicuolo A, Berloco P, Alfani D, Piccioni M, Veneziano M, Cortesini L, Marzetti L (1993) Pregnancy and Kidney Transplantation: Clinical Problems and Experience. Transplantation Proceedings 25(3):2188-2189.
Muirhead N, Sabharwal AR, Rieder MJ, Lazarvotis AI, Hollomby DJ (1992) The outcome of pregnancy following a renal transplantation – the experience of a single center. Transplantation 54(3):429-432.
Ostensen M (1992) Treatment with Immunosuppressive and Disease Modifying Drugs During Pregnancy and Lactation. American Journal of Reproductive Immunology 28: 148-152.
Penn I, Matowski EL, Harris P (1980) Kidney Int 18:221.
Pergola PE, Kancharla A, Riley D (2001) Kidney Transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation 71:994-997.
Pirson et al. (1985) Retardation of fetal growth in patients receiving immunosuppressive therapy. N Engl J Med 313:328.
Pirson Y et al. (1985) Retardation of fetal growth in patients receiving immunosuppressive therapy [letter]. N Engl J Med 313:5.
Rodriguez-Panilla E, Martinez-Frias ML (1998) Corticosteroids during pregnancy and oral clefts: A case-control study Teratology 58:2-5.
Scantlebury V, Gordon R, Tzakis A (1990) Childbearing after liver transplantation. Transplantation 49:317-321.
Sgro MD, Barozzino T, Mirghani HM, Sermer M, Moscato L, Akoury H, Koren G, Chitayat D (2002) Pregnancy Outcome Post Renal Transplantation. Teratology 65:5-9.
Toma H, Kazunari T, Tokumoto T (1999) Pregnancy in women receiving renal dialysis or transplantation in Japan: A Nationwide Survey. Nephrol Dial Trnasplant 14: 1511-1516.
Wagoner LE, Taylor DO, Olsen SL (1993) Immunosuppressive therapy, management and outcome of heart transplant recipients during pregnancy. J Heart and Lung Transplant 12:993-1000.
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Posted by admin on February 1st, 2002 — in newsletter
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Asthma and Pregnancy
Volume 9, Issue 2. February, 2002
Theresa Frezzo, BS, Carrie L. McMahon, MS, and Eugene Pergament, MD, PhD, FACMG
Approximately 6 million women under the age of 45 are affected with asthma (1). It is estimated that 0.5-1.3% of all pregnancies are complicated by maternal asthma, making asthma one of the most common complications of pregnancy (2).
The Effects of Pregnancy on Asthma
Asthma symptoms vary in relation to the severity of the disease during pregnancy. Approximately 1/3 of asthmatic women report more severe symptoms during pregnancy than before. 1/3 report less symptoms, and 1/3 report their asthma symptoms remain unchanged during pregnancy. About 2/3 of all women report some dyspnea during pregnancy.
Asthmatics enter pregnancy with preexisting problems limiting breathing and lung function. In all pregnant women, changes in function and capacity of the lungs, and pressure on the chest wall are attributed to the circumferential expansion of the uterus. Consequently, during pregnancy asthmatic women need to be particularly aware of their ability to inhale adequate amounts of air (3).
Several theories have been postulated about the discrepancies between changes in asthmatic symptoms during pregnancy compared to preconception. There have been reports of individual women who experience improvement of symptoms with one pregnancy, and worsening of disease in their next. Beecroft et al (4) suggested that the sex of the fetus might influence the course of asthma during pregnancy. In a blind prospective study, they found that 50% of mothers of females reported increased asthmatic symptoms during pregnancy compared to 22.2% of mothers of males. Furthermore, mothers of males tended to report an improvement in their asthmatic symptoms (44.4%), while none of the mothers of females indicated any improvement. These researchers postulate that the adrenergic surge experienced by a woman while carrying a male fetus might mitigate her asthma.
The Effects of Asthma on Pregnancy
Asthmatic women are at an increased risk for several complications during pregnancy. Adverse fetal outcomes associated with asthma include pre-term delivery, low birth weight, small size for gestational age and increased length of hospital stay. The pregnant woman with asthma is at risk for experiencing preeclampsia, placenta previa, caesarian delivery and increased length of hospital stay (2).
In pregnancy, the arterial blood gases are typically close to the following values: PO2 remains near 100 mm Hg, arterial pH increases to 7.40 to 7.45, and arterial PCO2 slightly decreases to 25 to 32 mm Hg. Hypoxia is the state when oxygenation of the arterial blood and tissues falls below normal. Status asthmaticus or severe asthmatic exacerbations can result in this dangerous state. A minimal change in maternal blood oxygen concentration may result in appreciable changes in fetal oxygen content. Fetal oxygen requirements increase exponentially with gestational age. The exact level of hypoxia that causes fetal death is unknown. A maternal PO2 <60 mm Hg portends fetal jeopardy. For these reasons, it is crucial for the asthmatic mother to realize that she is breathing for herself as well as he fetus (3). Relative maternal hypoxia has been shown to lower infant birth weight in otherwise normal pregnant women, e.g., women who live at a high altitude (5).
Pulmonary function can be quantified by FEV1 (Forced Expiratory Volume during 1 second) and compared to a predictive value based on height and weight. Schatz et al (5) studied pulmonary function throughout pregnancy in 360 asthmatic women. They found a small, but statistically significant correlation between infant birth weight and average maternal FEV1, measured monthly throughout pregnancy: the lower the mother’s pulmonary function, the lower the weight of her baby. Even when these clinicians controlled for smoking during pregnancy, this correlation remained significant (5).
Controlling Asthma During Pregnancy
The results from studies on the safety of asthma medications during pregnancy have been conflicting. It is difficult to determine if adverse pregnancy outcome(s) in an asthmatic woman is a result of the disease, or other confounding factors. Most studies conclude that asthmatic medications are non-teratogenic (6,7,8,). However, these conclusions are difficult to interpret because the study populations tend to be small.
Common Asthma Medications
Often asthma treatment involves the use of corticosteroid In general, the use of coricosteroids (inhaled and/or oral) during pregnancy has been associated with an increased risk for cleft lip, with or without cleft palate. A population study, carried out in Spain, examined 1,184 infants and found that maternal use of coricosteroids correlated with a 6-fold increase in risk for cleft lip, with or without cleft palate. Although this figure appears to represent a large increase in risk, there were, in fact, only 2 cases of oral clefting associated with corticosteroid exposure, compared tot he expected rate of 0.2 (8).
At Northwestern University, 80 pregnancies with first trimester exposure to oral and/or inhaled corticosteroids were evaluated and 2 infants were found to have congenital malformations. There were no infants in this series born with an oral cleft; the malformations included one infant with a ventricular septal wall defect and the other with Down syndrome. Since the general population risk for birth defects is between 3-5%, the 2.5% of infants with congenital malformations in this study was well within the expected range. This study concluded that use of corticosteroids during pregnancy did not increase this risk (9).
Most studies do not support a large teratogenic risk, however the association of corticosteroid use and clefting cannot be excluded. For more information regarding Corticosteroid Use in Pregnancy, please see RISK Newsletter Volume 8 No.1, April 2000.
Several reviews of current literature have assessed the safety of common asthma medications during pregnancy (10,11). These will be briefly reviewed in the remainder of this newsletter.
Inhaled Corticosteroids:
(beclomentasone, budesonide, fluticasone)
These are long-acting, prophylactic medications. Studies have demonstrated that continued use of inhaled corticosteroids throughout pregnancy does not increase the risk for birth defects or other pregnancy complications. Inhaled corticosteroids are considered the prophylactic medication of choice in pregnant women with persistent asthma, with beclomethasone being the preferred inhaled corticosteroid during pregnancy.
Oral Corticosteroids:
(prednisone, prednisolone)
Most studies assure non-teratogenicity of these medications, but there have been reports of an increased risk for oral clefting (see information above). Oral ingestion of medication increases maternal serum concentration of the corticosteroid above that of inhaled doses. One study found oral corticosteroid use associated with a slight increased occurrence (1-2%) of preeclampsia, preterm birth and low birth weight, with a does-response relationship. This association was not replicated in groups using inhaled corticosteroids. However, the risk/benefit ratio warrants use of oral corticosteroids during pregnancy in patients with severe asthma (6). Derivatives of cortisone and prednisone are recommended since they are more readily inactivated by the placenta, as opposed to tamethosone or dexamethasone, which are not.
Short-Acting Beta Agonist:
(metapoterenol, terbutaline, albuterol)
Numerous studies found no adverse effect associated with using these medications during pregnancy. This medicine is usually inhaled, for fast-acting relief of asthmatic symptoms. Albuterol is the medication of choice in this category for use in pregnancy.
Salmetrol:
This medication is taken by some patients prophylactically to prevent an asthma attack. This newer long-acting prophylactic inhaler has very limited human research. Use of salmetrol is not recommended during pregnancy unless its therapeutic benefits cannot be matched by other medications.
Nebulized Ipratropium:
This medication is used for treatment of acute asthmatic symptoms. Animal studies suggest iprotropium can be considered for pregnant women who do not respond to inhaled beta agonist therapy, but there is no data on human exposure.
Neodocrimil:
No studies on the teratogenic effect of nedocromil are available. It is generally not as effective as inhaled corticosteroids and is not recommended for use in pregnancy over better-researched alternatives, unless a patient has responded well previously.
Leukotrine Modifiers:
This type of medication seems to be very effective in prophylactic management of mild to moderate asthma, but has not been compared to older medications. No human data exploring its use during pregnancy has been published. It is not recommended for use during pregnancy, unless it has shown increased therapeutic effects in a patient over better-known medications.
Theophylline:
This medication is used as a fast-acting bronchodilator. Some research indicates an associated risk for preterm birth, congenital malformations, and preeclampsia, while other studies have not found such associations. The effectiveness of theophylline, as compared to medications with established effectiveness, is questionable. Theophylline therapy is not recommended for use.
SUMMARY
In conclusion, aggressive treatment of maternal asthma during pregnancy is often appropriate. The goal of this treatment is to avoid asthma attacks throughout pregnancy. Since maintenance of a mother’s health is crucial for optimal pregnancy outcome, good control of asthmatic symptoms, and avoidance of asthmatic emergencies is essential. Women with controlled asthma can expect to have the same pregnancy outcomes as non-asthmatic women (9).
References:
(1) Middleton, Ed. (1998) Allergy: Principles and Practice, 5th Edition Mosby, Inc. St Louis.
(2) Demissie K, Breckenridge MB, Rhoads GC (1998) Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 158:1091-1095.
(3) Coleman MT, Rund DA (1997) Nonobstetric conditions causing hypoxia duringpregnancy: asthma and epilepsy. Am J Obst Gynecol 177:1-7.
(4) Beecroft N, Cochrane GM, Milburn, HJ (1998) Effect of sex of fetus on asthma during pregnancy: blind prospective study. BMJ 317:856-857.
(5) Schatz M, Zeiger RS, Hoffman CP, and Kaiser-Permanente Asthma and Pregnancy Study Group (1990) Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Chest 98:389-392.
(6) Schatz M, Zeiger RS, Harden K, Hoffman CP, Chilingar L, Petitti D (1997) The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 100:301-306.
(7) Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, Saunders B,Porreco R, Sperling W, Kagnoff M, Benenson AS (1995) Perinatal outcomes in the pregnancies of asthmatic women: a prospective analysis. Am J Respir Crit Care Med 151:1170-1174.
(8) Rodriguez-Pinilla E, Martinez Frias ML (1998) Corticosteroids during pregnancy andoral clefts: a case-control study. Teratology 58:2-5.
(9) Greenberger PA, Patterson R (1988) The outcome of pregnancy complicated by severe asthma. Allergy Proc 9:539-543.
(10) Luskin AT (1999) An overview of the recommendations of the Working Group on Asthma and Pregnancy. J Allergy Clin Immunol 103:S350-S352.
(11) Position Statement (2000) The use of newer asthma and allergy medications during pregnancy. Annals Allergy Asthma Immunol 84:475-480.
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Posted by admin on December 12th, 2001 — in newsletter
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Mercury Exposure and Pregnancy
Vol 8, No.3; December 2001
Carrie McMahon, M.S., CGC and Eugene Pergament, MD, PhD.
Mercury
Mercury is a metal that occurs in several forms in the natural environment. In the elemental or metallic form, mercury is an odorless liquid present in thermometers, medical instruments, and barometers. If mercury combines with such elements as chlorine, sulfur or oxygen, the result is inorganic mercury or mercury salts. Most inorganic mercury is in the form of white powder or crystal. Organic mercury results from the combination of mercury with carbon. Organic mercury (methyl mercury) is generally found at hazardous waste sites in the form of white crystalline solids. (1)
Historic mercury exposures
Abnormalities caused by methyl mercury (organic mercury) were reported in the mid 1960’s when an outbreak of cerebral palsy and microcephaly in newborns was reported in the fishing village of Minimata Bay, Japan (2,3). Fetal intoxication with organic mercury has been referred to as Minimata disease since that outbreak. In Iraq, seed grain contaminated with methyl mercury was mistakenly used to make bread. Infants exposed in utero were found to have psychomotor retardation and cerebral palsy (4,5). Due to these historical methyl mercury exposures, there is continued concern about mercury exposure. However, most people are not exposed to methyl mercury but rather to elemental mercury. While there has been much concern raised lately regarding methyl mercury contaminated fish (swordfish, shark, large tuna), most do not have levels of methyl mercury which reach the FDA limit for human consumption of 1ppm. It is generally recommended that fish be eaten infrequently (no more that once a week) as part of a balanced diet during pregnancy. Elemental mercury will be the focus of this newsletter.
How is elemental mercury used?
Elemental mercury is mined for use in thermometers, barometers, and batteries. Silver-colored dental fillings (amalgams) are about 50% elemental mercury. In certain Mexican-American and Asian populations, elemental mercury has been used to treat stomach disorders. It has also been used in Latin American and Caribbean cultures for occult practices(1).
How might one be exposed to elemental mercury?
The most common route of exposure is through the breaking of a thermometer. Broken medical devices, old barometers and manometers, and dental fillings are also sources of exposure. People who participate in mining and refining operations for gold and silver ores may also be exposed. Recently Nicor, a company who supplies natural gas, has been the focus of the media for possible elemental mercury exposures in the greater Chicago, IL area.
How does elemental mercury enter and leave the body?
The primary route of absorption of elemental mercury is inhalation. Studies have shown that exposure to 0.1-0.2 mg/m3 mercury vapor resulted in 74-80% of inhaled mercury vapor being retained in human tissues. The body slowly eliminates mercury: the half-life of mercury is one month. Absorption after ingestion is low, approximately less than 1%, because the gastrointestinal tract is unable to absorb this form. This is true for topical exposure as well. Mercury readily diffuses across the alveolar membrane of the lungs. It is lipid soluble and therefore quickly attaches to red blood cells and cells of the central nervous system. Mercury that enters the body will be transformed into mercuric chloride. Mercury can enter the bloodstream and stay in the body for months. Absorbed mercury will remain mostly in the kidneys and brain. Elemental mercury enters through the respiratory system and will leave the body in urine, feces and breath. Mercury that is swallowed is not rapidly absorbed into the bloodstream and leaves the body in the feces.
Exposure Limits
The current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for mercury vapor is 0.1 milligram per cubic meter (mg/m(3)) of air as a ceiling limit. A worker’s exposure to mercury vapor should not exceed this ceiling level.
The National Institute for Occupational Safety and Health (NIOSH) has established a recommended exposure limit (REL) for mercury vapor of 0.05 mg/m(3) as a time-weighted average (TWA) for up to a 10-hour workday and a 40-hour workweek. NIOSH also assigns a “Skin” notation, which indicates that the cutaneous route of exposure, including mucous membranes and eyes, contributes to overall exposure (6). This level The NIOSH limit is based on the risk of central nervous system damage, eye, skin, and respiratory tract irritation (6). The American Conference of Governmental Industrial Hygienists (ACGIH) has assigned mercury vapor a threshold limit value (TLV) of 0.025 mg/m(3) as a TWA for a normal 8-hour workday and a 40-hour workweek and considers mercury vapor an A4 substance (not classifiable as a human carcinogen). The ACGIH also assigns a “Skin” notation to mercury vapor (7).
Table 1. Recommended airborne concentration of mercury (8)
Values
Mercury Vapor
Ethyl and Methyl Mercury
Threshhold limit value (time-weighted average)
0.05 ug/m3
0.01ug/m3
Threshhold limit value (ceiling)
0.1 ug/m3
0.04ug/m3
Short-term exposure limit
0.03ug/m3
0.03ug/m3
Immediately dangerous to life and health
No data
10mg/m3
Occupational Limits in Pregnant Women
Pregnant women should not work in areas with high levels of mercury vapor. The recommended threshhold limit value of 0.05 ug/m3 for mercury vapor may not provide sufficient protection for fetuses. Therefore, women of childbearing age should not be exposed to mercury vapor concentrations of 0.01mg/m3 or greater (8).
What are the symptoms of elemental mercury exposure?
The central nervous system is very sensitive to the effects of mercury. Symptoms may include personality changes (e.g. shyness, irritability), tremors, vision changes, and difficulties with memory. Motor system disturbances may be reversible but cognitive impairments, primarily memory deficits, may be permanent.
The kidney is also affected by elemental mercury exposure. The effects to the kidney generally disappear once the body clears itself of mercury, if damage was not too severe. In addition, short-term exposure to elemental mercury can cause nausea, vomiting, diarrhea, lung irritation, increased blood pressure, and skin and eye irritation (1).
How can exposure to elemental mercury be measured?
A number of methods are used to determine the amount of elemental mercury exposure. Urine provides better information about recent exposures than long-term exposures and whole blood may be used to quantify these exposures as well. Short-term exposure can also be measured in expired air but only within a few days of exposure.
Exposure in pregnancy
The effects of mercury have not been systematically investigated in pregnancy. Mercury readily crosses the placenta. Several studies have found no effect on fertility following immediate or chronic inhalation of elemental mercury in humans (9,10). In another study, women occupationally exposed to elemental mercury and elemental mercury vapor had more spontaneous abortions, stillbirths and congenital malformations and irregular, painful or hemorrhagic menstrual disorders than a control group of women not exposed to mercury (11). Reproductive difficulties and menstrual problems correlated with levels of mercury identified in pubic and scalp hair, suggesting a dose-response relationship. A study of 349 women exposed to unspecified amounts of elemental mercury in the workplace concluded that complications of childbirth were increased compared to nonexposed women and that these depended on length of exposure and concentration of mercury vapors (12).
A study on female rats exposed to 2.5 mg/m3 of elemental mercury vapors per day found an increase in the length of menstrual cycle and hypothesized an effect of mercury on the central nervous system(13). In a preliminary report on pregnant squirrel monkeys, daily exposure to mercury vapor caused a variety of adverse effects including abortion, neonatal mortality, reduced brain weights and structural abnormalities(14). Details on amounts of mercury vapor, however, were not quantified.
Dental personnel
Dental hygienists and dentists may be exposed to considerable amounts of mercury vapor in the workplace. One study found levels of mercury in the placenta of exposed dental workers to be 2 times higher than levels found in non-exposed women (15). Studies conducted on dental personnel have not shown a higher incidence of spontaneous abortions (16) nor have they shown an increase in birth defects or developmental effects (17). In a study evaluating the association between nitrous oxide exposure and spontaneous abortion, exposure to dental amalgamans was measured. A relative risk of 1.8 was identified for exposure to more than 50 amalgams/week and spontaneous abortion (18,20). In a recent study in sheep, mercury was radiolabeled to determine the amount reaching the fetus (19). Neither maternal nor fetal toxic events were associated with the large quantities of dental amalgam used in the sheep. Nevertheless, the authors suggest avoiding mercury containing amalgams during pregnancy.
Paternal exposure
There have been a number of studies examining the association of paternal exposure and an increased risk for spontaneous miscarriage (21,22). The studies did not control for possible maternal exposure and therefore any association was questionable.
Exposure to a broken thermometer
A broken fever thermometer is unlikely to threaten the health of the consumer or a pregnancy, especially if cleaned up properly and in a timely manner (see below). If elemental mercury is not cleaned up or if it becomes heated, the risks to the consumer and, more importantly, young children, becomes higher.
How to clean up a broken thermometer
· Don’t panic.
· People not involved in the cleanup should leave the area.
· Minimize tracking by removing shoes and clothing.
· Pick up free mercury with masking tape or a medicine dropper and store in a sealed plastic container.
· Ventilate room by opening doors and windows.
· Avoid vacuuming for 1-2 weeks (avoids aerosolizing the mercury and contaminating the vacuum cleaner).
· After all visible mercury has been collected, use a mercury cleanup kit to clean the spill area and work it into the cracks with a broom or brush. Do not add water. Materials in the mercury spill kit will rapidly bind to the remaining mercury and can be swept up with a broom and dustpan. Wash the area with trisodium phosphate detergent solution and rinse with water.
· Contaminated carpeting should be removed and discarded, starting with the spill room.
· Contaminated materials and mercury collected from small spills may be discarded along with household trash, but should be placed outside in a safe place until the household trash is picked up.
Referral Sources:
Poison Control
Illinois Teratogen Information Service 1-800-252-4847
Illinois Department of Public Health 1 888 522-1282
Nicor Gas Mercury Information Line: 1 888 288-8110
Websites:
Agency for Toxic Substances and Disease Registry (ATSDR)
http://www.atsdr.cdc.gov/tfacts46.html
Mercury Facts: Illinois Department of Public Health
http://www.idph.state.il.us/envhealth/factsheets/mercuryspills.htm
Mercury Fact Sheet Environmental Protection Agency
http://www.epa.gov - Home Page
References:
1.) Toxicological Profile for Mercury (update). U.S. Department of Health & Human Services May 1994.
2.) Matsumoto H et al: Fetal Minimata disease. J Neuropath Exp Neurol 24:563-74,1965.
3.) Muramaki U: The effect of organic mercury on intrauterine life. Acta Exp Biol Med Biol 27:301-36, 1972.
4.) Marsh DO et al: Fetal methylmercury poisoning: Clinical and toxicological data on 29 cases. Ann Neurol 7:348-53, 1980.
5.) Amin-Zaki L et al: Perinatal methylmercury poisoning in Iraq. Am J Dis Child 130:1070-6, 1976.
6.) NIOSH (1992). Recommendations for occupational safety and health: Compendium of policy documents and statements. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 92-100.
7.) ACGIH (1994). 1994-1995 Threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.
8.) Moienafshari R, Bar-Oz B, Koren G. Occupational Exposure to Mercury. What level is safe? Canadian Family Physician 46: 43-45, 1999.
9.) Alcer KH, Brix KA, Fine LJ, Kallenbach LR, Wolfe RA: Occupational mercury exposure and male reproductive health. Am J Ind Med 15:517-29, 1989.
10.) Cordier S, Deplan F, Mandereau L, Hemon D: Paternal exposure to mercury and spontaneous abortions. Br J Ind Med 48:375-81, 1991.
11.) Sikorski R, Juszkiewicz T, Paszkowski T, et al. Women in dental surgeries: Reproductive hazards in occupational exposure to elemental mercury. Int Arch Occup Environ Health 59:551-557, 1987.
12.) Mishonova VN, Stepanova PA, and Zarudin VV. Characteristics of the course of pregnancy and births in women with occupational contact with small concentrations of elemental mercury vapors in industrial facilities. Gig Truda Prof Zabol 24(2):21-23, 1980.
13.) Baranski, B, Szymczyk, I. 1973, Effects of mercury vapor upon reproductive functions of female white rats. Med. Pr 24:248.
14.) Berlin M, Jua J, Logdberg B, Warfvinge K: Prenatal exposure to mercury vapor: effects on brain development. Fund Appl Toxicol 19:324-6, 1992.
15.) Ericson A, Kallen B: Pregnancy outcome in women working as dentists, dental assistants or dental technicians. Int Arch Occup Environ Health 61:329-33, 1989.
16.) Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ: Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993-997.
17.) Heidam LZ: Spontaneous abortions among dental assistants, factory workers, painters, and gardening workers: a follow up study. J Epidemiol Commun Health 38:149-55, 1984.
18.) Patterson JE et al: Mercury in human breath from dental amalgam. Bull Environ Contam Toxicol 34: 459-68, 1985.
19.) Anonymous: Dental Amalgam: a scientific review and recommended Public Health Service Strategy for research, education and regulation. Dept Health and Human Service, Washington, DC. January, 1993.
20.) Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide and spontaneous abortion in female dental assistants. Am J Epidemiol 1995;141:531-7.
21.) Cordier S, Deplan F, Mandereau L, Hemon D: Paternal exposure to mercury and spontaneous abortions. Br J Ind Med 48:375-81, 1991.
22.) Rowland AS: Reproductive effects of mercury vapor. Fund Appl Toxicol 19:326-9, 1992.
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Posted by admin on February 1st, 2001 — in newsletter
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The Treatment of Nausea and Vomiting in Pregnancy (NVP)
Vol. 8, No. 2 February 2001
Carrie McMahon, MS, CGC and Eugene Pergament, MD, PhD
Nausea and vomiting are the most common complaints of the first trimester, affecting between 60 and 70% of pregnant women. For most women, nausea begins between the 2nd and 5th week and ends between the 8th and 14th week post-conception. For 35% of pregnant women, nausea and vomiting are severe enough that they lose time from work (Gadsby et al, 1993).
Hyperemesis gravidarum is a severe form of pregnancy-induced nausea characterized by persistent vomiting, ketonuria and severe weight loss and dehydration. This condition affects approximately 0.5-2.0% pregnant women and, if left untreated, can lead to coma, convulsions and fetal loss. Up to 60% of women who suffer from hyperemesis gravidarum develop secondary clinical depression. Treatment may involve medication, IV fluids, acupressure and enteral nutrition (Goodwin, 1998).
Although hyperemesis has been proposed as a potential teratogen, a 1996 retrospective case control study reported similar incidences of fetal outcomes between patients suffering from hyperemesis gravidarum and controls (Tsang et al, 1996). Several additional studies have replicated this finding.
Despite their discomfort, women can be reassured that their nausea may be serving as a predictor of good pregnancy outcome. A statistical meta-analysis of 11 epidemiological studies indicated a strong significant association of nausea and vomiting of pregnancy with decreased risk of miscarriage in the first 20 weeks of gestation (RR=0.36)(Weigel).
The use of any medication in pregnancy involves weighing the risks of the medication against the risks associated with maternal disease. Nausea and vomiting can pose a serious risk to the health of the mother and the developing fetus. In light of that fact, health care providers should be familiar with medications used to treat nausea and vomiting, including their potential teratogenic risks. The major types of these medications will be reviewed here.
Bendectin/ Diclectin
Bendectin is a combination drug, consisting of doxylamine (a sedative-antihistamine) and pyridoxine (vitamin B6), which was available in the US prior to 1983 for the treatment of nausea and vomiting of pregnancy. Amidst litigation over infants born with limb reduction defects, Merrell Dow, the manufacturer of Bendectin, removed it from the US market in 1983. At that time, nearly 40% of pregnant women had taken or were taking Bendectin. As a result of the removal of Bendectin from the US market, the incidence of hyperemesis gravidarum has increased three-fold. The product remains available in Canada under the name Diclectin. Doxylamine is marketed in the US as Unisom sleep tablets, and some physicians continue to treat affected patients with a combination of half a Unisom tablet and 10mg of vitamin B6.
More than 30 million women took Bendectin from 1956 to 1983. At least 25 epidemiological studies and 2 meta-analyses have been performed regarding its use during pregnancy, making it the world’s most studied drug in pregnancy. Both of the meta-analyses and the large case-control studies support the conclusion that Bendectin is not teratogenic.
Individual case-control and cohort studies initially raised the possibility of specific types of defects associated with Bendectin use, including heart disease, cleft palate, cleft lip and limb-reduction defects. Most of these studies (including the case control study that identified limb reduction defects as a potential association) did not report a statistically significant increase for the specified association. The results of these studies were inconsistent and were not reproduced in later investigations.
Two case control studies (Eskenazi et al, 1982; Aselton P et al, 1984) suggested a possible association between first trimester use of Bendectin and pyloric stenosis in exposed newborns. However, an increased risk of pyloric stenosis was not observed in several larger case-control studies. Eskenazi et al suggested that a slightly increased risk for pyloric stenosis could result from a confounder such as an increase in nausea in pregnant women with a genetic predisposition to gastrointestinal malformations.
Diclectin is the only anti-emetic approved in Canada for the treatment of nausea and vomiting of pregnancy. The company that continues to make Diclectin (Duchesnay, Inc) will most likely be able to market the drug in the United States in the near future.
Vitamin B6 (pyridoxine)
Many women choose to take vitamin B6 as a “natural” alternative to medication to treat nausea during pregnancy. In fact, women who take a multivitamin containing vitamin B6 during the first six weeks of pregnancy experience significantly less nausea than women who do not take a multivitamin (Emelianova et al, 1999). Vitamin B6 use has been associated with a lower risk for congenital heart defects in human studies (Boneva et al, 1999) and oral clefting in rats (Jacobsson and Granstrom, 1997). Vitamin B6 may also play a role in the reduction in neural tube defects associated with multivitamin use.
Because pyridoxine is included in most multivitamins and in the preparation of Bendectin, which has been widely studied in pregnancy, data suggests that it is not teratogenic. Standard doses range from 10-25mg. As with most vitamins, megadoses of vitamin B6 are neither necessary nor recommended.
Phenothiazines: Prochlorperazine, Chlorpromazine, and Promethazine
As a class, phenothiazines appear to confer little risk to the developing fetus. The Collaborative Perinatal Project followed 1309 pregnancies with first trimester exposure to phenothiazines. No statistically significant increase in birth defects was found. A statistically insignificant increase in the incidence of cardiac defects was observed. The authors suggest that the finding is of borderline significance (Slone et al, 1977). Milkovich et al (1976) reported a prospective observational study of nearly 2,000 women treated for nausea and vomiting at the Kaiser medical facilities in San Francisco. Of those, 543 took phenothiazines; no increase in congenital anomalies was observed.
Prochlorperazine (Compazine, prochlorpemazine)
Prochlorperazine is used as both an antipsychotic and an antiemetic. Prochlorperazine is currently the most commonly prescribed medication in the US for the treatment of nausea and vomiting in pregnancy. It is available in suppository form.
Of the 1309 women exposed to phenothiazines in the Perinatal project, 887 took prochlorperazine. In the Kaiser prospective study, 433 women took prochlorperazine during the first trimester. Both of these studies suggested that prochlorperazine is not teratogenic.
In a Swedish prospective study of women taking anti-emetic drugs in pregnancy, congenital dislocation of the hip (CDH) was seen more frequently among the 91 women taking prochloperazine. Because the medication was only taken during the first trimester, biologic plausibility is hard to establish. The authors suggested that an endocrine disturbance leading to CDH may have resulted in increased nausea in these expectant mothers (Kullander and Kallen, 1976). No other studies have reported an association between prochlorperazine and CDH.
Chlorpromazine (Thorazine)
Chlorpromazine is a phenothiazine tranquilizer that is also used as an antiemetic.
An early animal study suggested that chlorpromazine might cause cleft palate in mice (Walker and Patterson, 1974). However, this malformation has never been reported with chlorpromazine use in human pregnancy.
In the Collaborative Perinatal Project, the frequency of congenital anomalies was no greater than expected among the children of 142 women treated with chlorpromazine during the first four months of pregnancy or the children of 284 women treated anytime during pregnancy (Heinonen et al, 1977).
Rumeau-Rouquette et al (1976) reported an increase in the rate of congenital anomalies in infants born to mothers who took phenothiazines in pregnancy. Congenital anomalies occurred in 3.5% of pregnancies with phenothiazine exposure and less than 1.6% in the control population. (The expected rate of congenital anomalies in control populations is approximately 3.5%.) In the study, no pattern of anomalies could be established. This study did not examine potential confounding factors such as maternal use of tobacco or alcohol, which could be important since phenothiazine therapy is known to decrease the clearance rate of ethanol from the blood (Rawat, 1980). Transient neonatal withdrawal symptoms have been described with high doses of chlorpromazine (150-250mg/day) used to treat psychiatric illness (Auerbach et al, 1992). When used for the treatment of nausea and vomiting, the typical dose is 10-25 mg/day, which has not been associated with neonatal withdrawal.
Promethazine (Phenergan)
Promethazine is a phenothiazine with antihistaminic activity. Promethazine is the medication most commonly used by practitioners to treat hyperemesis, the most severe form of nausea and vomiting of pregnancy. It is also used as an adjunct to narcotic analgesia during labor. It is typically given as a slow intravenous bolus.
Several studies have reported finding no association between use of promethazine during pregnancy and an increased risk of birth defects in the offspring (Golding et al, 1983; Heinonen et al, 1977). Fourteen pregnancies exposed to promethazine during the first trimester and a total of 746 pregnancies exposed to promethazine at any time during gestation were identified through The Collaborative Perinatal Project. The data obtained from this study suggests that promethazine is not associated with an increased risk of major or minor birth defects.
Some studies suggest that the use of promethazine during labor induces respiratory distress in the newborn (Crawford, 1963). Additionally, the use of promethazine during labor may impair platelet aggregation in both the mother and in the newborn. While this effect has not been associated with significant clinical bleeding problems, the degree of platelet impairment was comparable with that seen with aspirin use and therefore it may be advisable for pregnant women to avoid promethazine near term (Whaun et al, 1980; Corby and Shulman, 1971).
Antihistamines: Diphenhydramine, Dimenhydrinate, Meclizine, and Cyclizine
As a class, antihistamines have not been shown to increase the incidence of congenital malformations (Greenberger and Patterson, 1979), although some particular antihistamines have been associated with birth defects in retrospective studies.
Diphenhydramine (Benadryl)
Diphenhydramine is a commonly used antihistamine.
In a retrospective case-control study, Saxen (1974) found that first trimester use of diphenhydramine was more common among 599 children born with oral clefts (20 exposures) than among 590 controls without clefts (6 exposures). Another retrospective case-control study observed that significantly fewer infants with malformations were prenatally exposed to antihistamines, particularly diphenhydramine, than were controls (Nelson and Forfar, 1971). In a retrospective study of drugs used during the first trimester, only one of 361 infants born to women taking diphenhydramine was found to have a congenital anomaly (Jick et al, 1981).
Heinonen et al. (1977) conducted a prospective cohort study and observed no significant increase in the incidence of major or minor malformations among 595 infants exposed to diphenhydramine in the first trimester or 2948 infants exposed at any time during pregnancy.
Dimenhydrinate (Dramamine)
Dimenhydrinate is an antihistamine commonly used for the prevention of motion sickness. Chemically, dimenhydrinate is the chlorotheophylline salt of diphenhydramine. Several cohort studies, including the Collaborative Perinatal Project, have examined the use of dimenhydrinate in pregnancy and have not found any increased rate of congenital anomalies.
Meclizine (Antivert, Bonine)
Meclizine is a piperazine antihistamine used as an antiemetic in the treatment of vertigo and motion sickness.
The reproductive effects of this drug have been studied extensively in the rat where cleft palate and other oral abnormalities are noted after exposure to doses 25 to 50 times the human therapeutic dose (King et al, 1966). Meclizine has not been shown to be teratogenic in mice, rabbits, pigs, or monkeys (Girugea and Puigdevall, 1966; Wilson, 1972). Fetal edema has been suggested as the mechanism by which this and related compounds induce orofacial malformations (Posner and Darr, 1970).
Several epidemiologic studies have reported an increased incidence of cleft palate among infants born to mothers exposed to meclizine during early in pregnancy (Mellin and Katzenstein, 1963). One study of more than 3000 infants exposed to meclizine during pregnancy found 12 with cleft lip or palate (just under 0.4%)(Lenz, 1966), compared with a population incidence of 0.1%. However, the difference was not statistically significant. In contrast, Michaelis et al (1983) reported on 628 women who had used either meclizine or one of three other antiemetic drugs during the first 10 weeks of pregnancy. This and other epidemiologic studies, encompassing several thousand births and including the Kaiser prospective study, have failed to associate meclizine use during pregnancy with an increase in congenital anomalies (Shapiro, 1978; Slone et al, 1977).
Although outcome data is limited, other piperazines have not been shown to be associated with oral clefting.
Cyclizine
Cyclizine is an antihistamine used as an antiemetic for the prevention of motion sickness and postoperative nausea and vomiting.
Animal studies regarding the use of cyclizine in pregnancy indicate a potential association with cleft palate and micromelia (King and Howell, 1966; Steffeck et al, 1968). A proposed mechanism of teratogenic action involves the binding of an active metabolite of these compounds to cartilage by displacing calcium, and the induction of fetal edema as a simple mechanical cause for the observed orofacial malformations.
Epidemiological investigations have not indicated an increase in malformations after fetal cyclizine exposure. Retrospective cohort studies found no increase in the number of cyclizine exposures among infants with cleft palate or limb malformations. Subsequently, both prospective and retrospective cohort studies have failed to identify an association between the first trimester use of antihistamines (including cyclizine) and oral clefts or other malformations (Milkovich and Van den Berg, 1976; Nelson and Forfar, 1971; Saxen, 1974).
Trimethobenzamide (Tigan)
Although trimethobenzamide is structurally related to the antihistamines, it has little activity as a histamine blocker. Its mechanism of action is unknown.
A prospective study evaluating the teratogenicity of several antinauseant drugs followed 193 women who took trimethobenzamide during the first trimester (Milkovich and Van den Berg, 1976). The incidence of major congenital anomalies discovered by age 5 was 3.5% in women who had received no medications for nausea and 5.8% in women who had received trimethobenzamide. This difference was significant at the p=0.05 level. However, no particular type of anomaly was predominant in this group. The Collaborative Perinatal Project followed the infants of 340 women treated with trimethobenzamide during the first four months of pregnancy and the infants of 700 women who used trimethobenzamide at any time during gestation (Heinonen et al, 1977). The frequencies of major and minor anomalies were no greater than expected among the treated groups. Similarly, no malformations were observed among the infants of more than 120 women treated with trimethobenzamide during the first trimester of pregnancy in the Boston Collaborative Drug Surveillance Program (Jick et al, 1981; Aselton et al, 1984).
Ondansetron (Zofran)
Ondansetron is a selective antagonist at the 5-HT3 serotonin receptor. Traditionally, it is used as an antiemetic in conjunction with surgery and cancer chemotherapy and radiation. Ondansetron is also occasionally used to treat severe cases of hyperemesis gravidarum.
Several case reports describe successful pregnancy outcomes following the use of ondansetron in pregnancy, including one case in which high doses of ondansetron were administered repeatedly throughout the first trimester (Guikontes et al, 1992; World, 1993). Still, epidemiological studies have not been reported. In 1996 Sullivan et al published the results of a randomized clinical trial to determine the efficacy of ondansetron in pregnancy, but pregnancy outcomes were not included in the data and have not been published by the authors.
Metoclopramide (Reglan)
Metoclopramide is a dopamine receptor-blocking drug that has is used to treat gastroesophageal reflux, chemotherapy-induced nausea, and nausea associated with cesarean section. It is also effective for women who vomit after eating.
Metoclopramide crosses the placenta readily. When administered before cesarean section, clinically significant neonatal effects have not been observed, even in the presence of measurable serum drug levels in the newborn (Bylsma-Howell et al, 1983). Controlled studies regarding first trimester use of metoclopramide have not been performed.
Teratogenic effects of metoclopramide have not been observed in mice, rats, or rabbits (Watanabe et al, 1968).
Ginger Root (Zingiber officinale)
Ginger has been used for centuries as a natural remedy to nausea. However, because ginger has been used to promote menstruation, megadoses of ginger are contraindicated in pregnancy. Fischer-Rasmussen, et al (1991) conducted a double-blind randomized trial of the efficacy of powdered ginger root (250 mg) compared with placebo in hyperemesis gravidarum. Twenty-seven women participated; all received ginger and placebo at some point in the trial. A significantly greater relief of the symptoms was found after ginger treatment compared to placebo, and no side effects were observed. Pregnancy outcomes included 1 spontaneous miscarriage, 1 elective termination, and 25 liveborn infants with no evidence of congenital malformations.
Summary
Because it has been studied extensively, Bendectin/ Diclectin (doxylamine plus pyridoxine) is the drug of choice for the treatment of nausea and vomiting in pregnancy. Its reintroduction into the US market will provide welcome relief to millions of women. Data suggests that chlorpromazine, diphenhydramine, dimenhydrinate and cyclizine are also good choices. Although trimethobenzamide and meclizine are probably not teratogenic, additional data is needed to fully evaluate their effects on the developing fetus. Ondansetron, metoclopramide and ginger should be used with caution, particularly during the first trimester, as epidemiological studies have not been performed to evaluate their potential teratogenicity.
References
Aselton P et al: Pyloric stenosis and maternal Bendectin exposure. Am J Epidemiol 1984;120:251-6.
Aselton P, Jick H, Milunsky A, et al.: First-trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451-455.
Auerbach JG, Hans SL, Marcus J, Maeir S. Maternal psychotropic medication and neonatal behavior. Neurotoxicol Teratol. 1992;14(6):399-406.
Boneva RS, Moore CA, Botto L, Erickson JD. Am J Epidem. Nausea during pregnancy and congenital heart defects: a population-based case-control study. 1999;149(8):717-25.
Bylsma-Howell M et al: Placental transport of metoclopramide: assessment of maternal and neonatal effects. Can Anaesth Soc J 1983;30:487-92.
Corby DG, Shulman I: The effects of antenatal drug administration on aggregation of platelets of newborn infants. J Pediatr 1971;79:307-13.
Cordero JF et al: Is Bendectin a teratogen? J Am Med Assoc 1981;245:2307-10.
Crawford JS. The effects of drugs used in labor on the fetus and newborn. Clin Pharmacol Ther 1963;4:628-53.
Emelianova S, Mazzotta P, Einarson A, Koren G. Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation. Clin Invest Med 1999;22(3):106-10.
Eskenazi B, Bracken MB: Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 1982;144:919-924.
Fisher-Rasmussen W et al. Ginger treatment of hyperemesis gravidarum. Eur J OB Gyn Reprod Biol. 1991;38:10.
Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract. 1993;43:245-8.
Girugea M, Puigdevall J: Experimental teratology with meclozine. Med Exp 1966;15375-15388.
Golding J et al. Maternal Antinauseants and Clefts of Lip and Palate. Hum Toxicol 1983;2:63-73.
Goodwin TM. Hyperemesis gravidarum. Clin Ob & Gyn 1998:41(3):597-605.
Greenberger P, Patterson R: Safety of therapy for allergic symptoms during pregnancy. Obstet Gynecol Surv 1979;34:284-6.
Guikontes E, Spantideas A, Kiakakis J. Ondansetron and hyperemesis gravidarum. Lancet 1992;340:1223.
Heinonen OP, Slone D, Shapiro S: Birth Defects and Drugs in Pregnancy. Littleton, Mass. Publishing Sciences Group, 1977, pp 323-324, 327, 330, 437, 489.
Jacobsson C, Granstrom G. Effects of vitamin B6 on beta-aminoproprionitrile-induced palatal cleft formation in the rat. Cleft Palate-Craniofacial J. 1997;34(2):95-100.
Jick H, Holmes LB, Hunter JR, et al.: First-trimester drug use and congenital disorders. JAMA 1981;246:343-346.
King CTG and Howell J: Teratogenic effect of buclizine and hydroxyzine in the rat and chlorcyclizine in the mouse. Am J Obstet Gynecol 1966;95:109-111.
King CTG et al: Antihistamines and teratogenicity in the rat. J Pharmacol Exp Ther 1965;147:391-8.
Kullander S, Kallen B. A Prospective Study of Drugs and Pregnancy. II. Anti-emetic drugs. Acta Obstet Gynecol Scand 1976;55:105-111.
Lenz W: Malformations caused by drugs in pregnancy. Am J Dis Child 1966;112:99-106.
McKeigue PM, Lamm SH, Linn S, Kutcher JS: Bendectin and birth defects: I. A meta-analysis of epidemiologic studies. Teratology 1994;50:27-37.
Mellin GW, Katzenstein M: Meclozine and foetal abnormalities. Lancet 1963;1:222-3, 1963.
Michaelis J et al: Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformation. Teratology 1983;27:57-64.
Milkovich L, Van den Berg BJ: An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976;125:244-8.
Mitchell AA et al: Birth defects in relation to Bendectin use in pregnancy. Am J Obstet Gynecol 1983;147:737-742.
Nelson MM, Forfar JO: Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Br Med J 1971;1:153-7.
Posner HS, Darr A: Fetal edema from benzhydroylpoperizines as a possible cause of oral-facial malformations in the rat. Toxicol Appl Pharmacol 1970;17:67-75.
Rawat AK: Psychotropic drug metabolism in fetal alcohol syndrome. Adv Exp Med Biol 1980;132:561-8.
Rumeau-Rouquette C et al: Possible teratogenic effect of phenothiazines in human beings. Teratology 1976;15:57-64.
Saxen I: Cleft palate and maternal diphenhydramine intake. Lancet 1974;1:407-8.
Shapiro S et al: Meclizine in pregnancy in relation to congenital malformations. Br Med J 1978;1:483.
Slone D et al: Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. Am J Obstet Gynecol 1977;128:486-8.
Steffeck AJ et al.: Chlorcyclizine produced cleft palate in the ferret. Arch Oral Biol 1968;13:1281-1283.
Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:1565-8.
Tsang IS, Katz VL, Wells SD. Maternal and fetal outcomes in hyperemesis gravidarum. Intl J Gyn Ob. 1996;55(3):231-5.
Walker BE, Patterson A: Induction of cleft palate in mice by tranquilizers and barbiturates. Teratology 1974;10:159-64.
Watanabe N et al: Teratogenicity of metoclopramide. Yakugaku Kenkyu 1968;39:92-106.
Weigel RM, Weigel MM. Nausea and vomiting of early pregnancy and pregnancy outcome. A meta-analytical review. Br J Ob Gyn. 1989;96(11):1312-8.
Whaun JM et al. Effect of prenatal drug administration on maternal and neonatal platelet aggregation and PF4 release. Haemostasis 1980;9:226-37.
Wilson JG: Abnormalities of intrauterine development in non- human primates. Acta Endocrinol 71(suppl 166):261-292, 1972.
World MJ: Ondansetron and hyperemesis gravidarum. Lancet 1993;341:185.
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Posted by admin on January 1st, 2001 — in newsletter
PDF Version
Updates Presented at the Organization of Teratology Services, 14th Annual Conference 2001
The Illinois Teratogen Information Service continues to strive to provide current information regarding pregnancy exposures to patients and health care providers in the state of Illinois. This special edition of the RISK NEWSLETTER provides information on recent teratology studies regarding:
Paroxetine
Rubella Vaccination
Azithromycin, and
Loratadine
Paroxetine:
Birth Outcomes Among Pregnant Women Taking Paroxetine (Paxil®)
Unfred Cl et al. Teratology 63(6); June 2001
The California Teratogen Information Service performed a prospective cohort study of 101 pregnancies exposed to paroxetine and 195 controls. The data from this study did not support a significant increase in risk for a congenital malformation. Of note, within the paroxetine group, there was a greater risk for prematurity if used late in pregnancy. However, the paroxetine exposed group also had more exposure to caffeine, tobacco, alcohol and illicit drugs. No difference in the rate of minor malformation, gestational age, or low birth weight was found between the two groups
As the authors discuss, the paroxetine exposed group in this population had more risky behaviors than the control group, which may be a result of the underlying maternal condition. This may be meaningful to clinicians who counsel and manage these patients
Rubella Vaccination:
Pregnancy outcome following rubella vaccination : A prospective controlled study. Levichek Z et al. Teratology 63(6); June 2001
There have been several cases of first trimester exposure to the rubella vaccine with no adverse effects reported. In addition, the CDC has collected over 300 reports of infants with gestational exposure to the vaccine, with no cases of birth defects reported.
The Motherisk Program conducted a prospective controlled study evaluating exposure to the rubella vaccine 3 months pre- or post-conception. There were 94 exposed pregnancies which were matched to a control group of 95 pregnancies for age, smoking, and alcohol use. There were no differences in rates of malformations, rate of prematurity , or developmental milestones between the two groups. The only difference noted between the two groups was that the exposed group had a higher incidence of therapeutic abortion (n=7) than the control group (n=0). Five of the seven women reported that the vaccine exposure influenced their decision to terminate, and two reported terminations was recommended by their physician.
While a live attenuated vaccine virus such as the virus in the rubella vaccine has been documented to cross the placenta, this study supports previous data that rubella vaccination in pregnancy DOES NOT affect pregnancy outcome rates of malformation or developmental milestones. Based on this data and previously reported data, therapeutic abortion following exposure is NOT WARRANTED.
In addition , the recommended waiting period before becoming pregnant after a rubella vaccine has been decreased from 3 months to 28 days (MMWR 12/14/01 50(49);1117).
Azithromycin:
Pregnancy outcome following gestational exposure to azithromycin: A prospective controlled study.
Woodland AM et al. Teratology 63(6). June 2001\par}
Azithromycin (Zithromax ®) is a macrolide antibiotic. Initial pregnancy data was limited to one study evaluating first trimester exposure.
The Motherisk Program conducted a prospective controlled study evaluating exposure to azithromycin. The study group was matched by two control groups, one diseased matched and the other non teratogenic exposed. The exposed group consisted of 47 pregnancies, 25 with first trimester use, 15 with second trimester use, and 7 with third trimester use. Two miscarriages and one major malformation was reported. This data, while limited, does not suggest an increased risk for a major malformation .
Loratadine:
Pregnancy outcome following gestational exposure to loratadine and other antihistamines: a prospective controlled cohort study.
Diav-Citrin OS et al. Teratology 63(6); June 2001.
Loratadine (Claritin®) is a relatively new non-sedating antihistamine.
The Israeli Teratogen Information Service conducted a prospective controlled study in which pregnancy outcome was compared between three exposure groups; loratadine , other antihistamines, and nonteratogenic exposure. There were 93 exposed pregnancies in the loratadine group (63 1st trimester), 223 in the other antihistamines groups (107 1st trimester) and 629 in the non teratogenic exposed group. There was no difference in the rate of major malformations between the three groups . This data, while limited, does not suggested an increased risk for a major malformation with loratadine use in pregnancy.
Contributors:
Carrie L. McMahon, MS
Coordinator , Illinois Teratogen Information Service
Eugene Pergament, MD, PhD, FACMG
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Posted by admin on October 1st, 2000 — in newsletter
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The Effects of Hallucinogen Use During Pregnancy
Vol 8#2, October 2000
Christopher Dvorak, BA; Carrie L. McMahon, MS; Eugene Pergament, MD, PhD, FACMG
Hallucinogens are drugs that can cause a change in the user’s mental state to the point where the perception of objective reality is distorted. These drugs are sometimes referred to as illusionogenic, psychedelic, or mind-expanding, and have long been used in cultural and religious contexts. Hallucinogens vary greatly in chemical structure, and can exist naturally or be produced synthetically. For example, Lysergic Acid Diethylamide (LSD) was first synthesized in Europe in the late 1930s. There was little recognition that certain drugs had hallucinogenic properties in modern society until research began on the therapeutic effects of LSD in the 1950s. Hallucinogens were widely used in the youth culture of the 1960s and 1970s, and during the 1980s, their popularity declined. Some recent studies have indicated that hallucinogen use is again on the rise.
Lysergic Acid Diethylamide (LSD)
LSD is a semi-synthetic alkaloid derived from lysergic acid, which is found in argot, a fungus that grows on rye and other grains. Commonly referred to as “acid,” the drug is often encountered in tablet, capsule or liquid form (sometimes added to absorbent paper). It is odorless and colorless with a slightly bitter taste. The effects of the drug last roughly 2 to 12 hours. Physical effects include increased blood pressure, dilated pupils, and rapid heartbeat. Muscular weakness, trembling, nausea, chills, and hyperventilation occur frequently. Motor skills and coordination may be impaired.
Sensations and feelings change much more dramatically than the physical signs. The user may feel several different emotions at once or swing rapidly from one emotion to another. Mood-swings, the intensification or merging of the auditory, olfactory and visual systems, and an alteration in the sense of time and space are also experienced. More negative effects include panic, serious depression, anxiety, and even psychotic reactions.
Most animal studies on LSD have not shown adverse effects on pregnancy, other than fetal loss at high doses (Alexander et al, 1970). However, central nervous system and ocular defects were associated with fetal LSD exposure in studies involving mice and hamsters (Auerbach et al, 1967; Geber et al, 1967). Sally Long (1972) examined the reports of 162 children of parents who took LSD before or during pregnancy. Of these children, seven were thought to have defects that could potentially be attributed to LSD intake. These included mostly cases of limb defects and one case of megacolon. Another series of cases reported by Jacobson et al (1972) included reports of sacral myelomeningocele, heart defects, including tetrology of Fallot and an AV malformation, various limb defects and hydrocephalus. It was also speculated at the time that LSD could directly alter DNA and result in cellular abnormalities. Apple et al (1974) observed an exposed fetus with extensive ocular malformations (including marked cortical degeneration of the left eye lens and partial opaqueness of the cornea) and anencephaly.
However, there is no solid epidemiological evidence of a cause-and-effect relationship between LSD use and congenital anomalies (McGlothlin et al, 1970). The greatest drawback to the aforementioned studies on LSD and hallucinogens in general is that people who use LSD as a recreational drug during pregnancy are more likely to use other drugs as well (e.g., cannabis, alcohol, tobacco), more likely than someone in the average population to have infectious diseases such as gonorrhea and hepatitis, and more likely to be exposed to additional risk factors that could also have an adverse effect on pregnancy. Since the 1970s, there have been few studies done on the teratogenic effects of LSD.
Psilocybin (Psilocin)
Psilocybin is the active ingredient in the Psilocybe mexicana mushroom and other mushroom species. It is a derivative of tryptamine, and is chemically related to LSD. The drug is often encountered in a crude mushroom form or as a capsule containing a powdered material of any color. Effects usually last several hours. A small dose may produce sensations of mental and physical relaxation, detachment, mood changes, and perceptual distortions. Disrupted thought patterns often lead to reports of profound spiritual experiences. Larger doses can produce nausea, dizziness, anxiety, lightheadedness, shivering, abdominal discomfort, and numbness. Other reported effects include a sense of time passing slowly, yawning, facial flushing, sweating, depersonalization, feelings of unreality, and an inability to concentrate.
Rolsten (1967) found psilocybin not to be teratogenic in pregnant mice. No human case reports or studies have been done regarding the teratogenicity of this substance.
Dimethyltryptamine (DMT)
DMT (dimethyltryptamine) is a chemical resembling psilocin. It can be found in the human brain and in plant substances such as Piptadina peregrina. The drug is often encountered in liquid form, and other substances such as marijuana are sometimes soaked in a DMT solution to add potency. The effects, which are similar to those of LSD, begin almost immediately after ingestion and last approximately 30 to 60 minutes. Anxiety reactions and panic states are more frequently associated with DMT than with other hallucinogens, probably because of the unexpected rapidity of its effects. There have been no human studies on possible teratogenic effects of this chemical.
Mescaline
Mescaline is prepared from the peyote cactus, and has been used for centuries in religious rituals by some Indians in the southwest. For preparation, parts of the cactus are dried and ground, and sometimes put into capsules. Mescaline can also be synthesized in a powder form. At low doses, effects last between 1 and 18 hours. Physical effects include a rise in body temperature, dilated pupils, nausea, vomiting, and muscular relaxation. Common mental effects include an inability to think clearly, visual hallucinations, and a heightened sensory perception. High doses can cause hypotension, a slow respiratory rate, dry skin and headache. Geber’s (1967) animal study involving pregnant hamsters reported an increase in central nervous system defects, but a dose-response relationship was not seen. In a study by Dorance et al (1975), 57 Huichol Indians with a lifelong individual history of ingestion of peyote were compared with 50 Huichol Indian controls and ten laboratory controls for effects on lymphocyte chromosomes. The frequency of abnormalities in the experimental and control groups did not differ significantly, and no effects on lymphocyte chromosomes were found.N-methyl-3,4-methylenedioxyamphetamine, 3,4-methylene-dioxymethamphetamine (MDMA)
MDMA is chemically related both to mescaline and to the amphetamines. Its common street name is “Ecstasy”. MDMA commonly exists in a powder form and occasionally as a liquid. At low doses, effects appear 30 to 60 minutes after ingestion and persist for approximately eight hours. Users generally report a sense of well-being along with heightened tactile sensations, intensification of feelings, and increased self-insight. Higher doses produce effects similar to those of LSD, including hallucinations or sensory distortions. Psychological difficulties including confusion, depression, sleep problems, and paranoia have been reported and can occur during and sometimes weeks after taking MDMA.
Physical effects include an increase in heart rate and blood pressure, dilated pupils, dry nose and throat, muscle tension, involuntary teeth clenching, nausea, blurred vision, rapid eye movement, faintness, chills, and sweating. Occasionally, adverse after-effects do occur, usually in the form of marked physical exhaustion coupled with anxiety, lasting up to two days. At high doses, serious physical reactions requiring immediate medical treatment have occurred, and MDA associated deaths and near deaths have been reported.
When Colado et al (1997) administered a large dose of MDMA to rats during days 14 through 17 of gestation, hyperthermia was induced and a reduction in maternal weight gain and litter size was observed in exposed animals. However, the researchers were unable to find the same neurotoxic effects in offspring compared to the initially exposed rats. One prospective study in humans by McElhatton et al followed 127 pregnancies in which 71 cases involved exposure to ecstasy alone and 56 included exposures to other illicit drugs in addition to ecstasy. An analysis of outcomes in 78 of these pregnancies uncovered apparent increases in the incidence of club foot in female infants and congenital heart disease. Two infants with congenital heart defects were identified in this study giving an overall incidence of 26 per 1000 births (as opposed to 5-10 per 1000). However, the two infants in question were exposed to (1) ecstasy and alcohol at 6 weeks and (2) ecstasy, amphetamine and gamma hydroxybutyric acid at 0-7 weeks. Another case of a congenital heart defect after prenatal ecstasy exposure was reported by Rost van Tonningen et al (1998), but in both studies, the limitations of small sample size and other possible environmental influences could not be ruled out.
Nutmeg
The known active ingredient in this common household spice is elemicin, a compound chemically related to mescaline. Nutmeg oil is also a component of Vicks Vaporub, a commonly used nasal decongestant and cough suppressant. Low doses of nutmeg may result in a mild and brief euphoria, lightheadedness, and CNS stimulation. At higher doses, there can be hallucinations, panic, excessive thirst, agitation, anxiety, increased heartbeat, and vomiting. Recovery from nutmeg intoxication is slow and often involves unpleasant hangover effects.
There is one report of nutmeg intoxication during pregnancy involving a woman in her 30th week of gestation, who accidentally prepared and ate some cookies containing approximately 25 times the amount of nutmeg suggested by her recipe. Her symptoms were sinus tachycardia, hypertension and a sensation of impending doom. The fetal heart rate temporarily increased, but leveled off within 12 hours of maternal exposure. Her baby was delivered 10 weeks later with no complications.
Phencyclidine (PCP)
PCP was developed in the 1950s as an intravenous anesthetic. The use of PCP in humans was discontinued in 1965, because it was found that patients often became agitated, delusional, and irrational while recovering from its anesthetic effects. It is usually encountered as a white crystalline powder that is readily soluble in water or alcohol, and it has a bitter taste. PCP may be encountered in a variety of tablets, capsules, and colored powders.In low doses, PCP produces muscle stiffness and a lack of coordination, a slight increase in breathing rate, slurred speech, drowsiness, confusion, and a generalized numbness of the extremities. Nausea and vomiting may also develop, as well as profuse sweating, flushing, and increased heart rate. At high doses, anesthesia, blurred vision, flicking up and down of the eyes, loss of balance, drooling and dizziness may occur. Strange and violent behavior can result, sometimes involving paranoia, catatonia, and garbled speech. People who use PCP for long periods report memory loss, difficulties with speech and thinking, depression, and weight loss. Coma or death may result from severe side effects induced by large doses (uncontrollable convulsions, respiratory depression, high fever, and a sudden surge of blood pressure resulting in intracranial hemorrhage), or from an accidental injury or suicide during PCP intoxication.
PCP is known to cross the placenta in humans and other animals, and it also enters the breast milk (Niholas et al, 1982). Animal studies by Jordan (1979) and Marks (1980) have found the drug to be teratogenic at very high doses, with abnormalities that include skeletal dysplasias and cleft palate. There are isolated reports of birth defects in human babies exposed to the drug in utero. In a case reported by Golden et al (1980), asymmetrical facial growth and persistent spasticity were observed. Other reports of anomalies in the offspring of phencyclidine-using women include a case of microcephaly reported by Straus et al (1981) and one case of multiple birth defects by Michaud et al (1982). The defects included an absence of the septum pellucidum, hypoplasia of the optic nerves, chiasm and tracts, moderate hydrocephalus, and agenesis of the posterior lobe of the pituitary. Other congenital anomalies observed by Michaud involved the cardiovascular, respiratory, urinary, and musculoskeletal systems. However, a study by Wachsman et al (1989) looked at 57 infants exposed to PCP (and, in some cases, other substances) during pregnancy. No overall increased risk of congenital anomalies was noted. Other studies have obtained similar results (Patrucha et al, 1983; Chasnoff et al, 1983).
In one study (Harry et al, 1992), mild behavioral and developmental abnormalities were found among preschool children exposed to phencyclidine prenatally. However, Wachsman et al (1989) and Chasnoff et al (1983) found no behavioral differences at one year of age in 62 infants exposed to PCP in utero when compared to non-exposed infants. As with the previous drugs, the multiple risk factors associated with maternal PCP use make an analysis of teratogenicity difficult.
Postnatal symptoms of maternal PCP use have been more widely observed (Wachsman et al, 1989; Strauss et al, 1981). The manifestations resemble those of maternal narcotic use, and include jitteriness, hypertonia, vomiting, diarrhea, lethargy, irritability, and flapping tremors.
Summary
There is a lack of epidemiological evidence showing that hallucinogens adversely effect pregnancy outcome. Therefore, risk assessments cannot be made with any certainty. In the case of MDMA and PCP, studies are still in progress that may better characterize fetal effects. Other drugs, e.g. LSD, have not been studied over the past decades. Individuals using hallucinogens during pregnancy are often exposed to additional risk factors, making counseling difficult. The avoidance of these substances during pregnancy should be stressed.
References
Addiction Research Foundation Website: http://www.arf.org/isd/pim/hallucin.html
Alexander GJ et al: Lysergic acid diethylamide intake in pregnancy: fetal damage in rats. J Pharmacol Expt Ther 173:48-59, 1970.
Apple DJ and Bennett TT: Multiple systemic and ocular malformations associated with maternal LSD usage. Arch Ophthalmol 92: 301-3, 1974.
Auerbach R and Rugowski JA: Lysergic acid diethylamide: effects on embryos. Science 157:1325-6, 1967.
Chasnoff IJ et al: Phencyclidine effects on the fetus and neonate. Dev Pharmacol Ther 6:404-8, 1983.
Colado MI, O’Shea E, Granados R et al: A study of the neurotoxic effect of MDMA (’ecstasy’) on 5-HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy. Br J Pharmacol 1997; 121: 827-33.
Dorrance DL et al: Effect of peyote on human chromosomes. Cytogenetic study of the Huichol Indians of northern Mexico. JAMA 234:299-302.
Geber WF: Congenital malformations induced by mescaline, lysergic acid diethylamide and bromolysergic acid in the hamster. Science 158:265-6, 1967.
Golden NL et al: Angel dust: possible effects on the fetus. Pediatrics 65:18-20, 1980.
Jacobsen CB and Berlin CM: Possible reproductive detriment in LSD users. JAMA 222:1367-1373, 1972.
Jordan RL et al: Phencyclidine-induced morphological and behavioral alterations in the neonatal rat. Pharmacol Biochem Behav 11[suppl]:39-45, 1979.
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Posted by admin on September 1st, 2000 — in newsletter
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Antifungals
Vol. 8, Issue 1 September 2000
Antifungal use during pregnancy is common because pregnant women are more susceptible to fungal infections. In addition, pregnancy is more commonly associated with more serious systemic fungal infections, such as mycoses, that require treatment. There are three types of treatment that can be used for fungal infections: topical, vaginal and systemic/oral. The following review provides a summary of current data on the use of each type of fungal medication in pregnancy (over the counter medications and prescription medications are abbreviated in the sub-headings as (OTC) and (P) respectively).
TOPICAL THERAPY:
The use of antifungals in the topical treatment of infections of hair, skin and nails is common. Prescription and over the counter treatments are available for a variety of infections. To date, no topical antifungal treatments have been shown to be teratogenic during human pregnancy.
IMIDAZOLES: COLTRIMAZOLE-(OTC),KETOCONAZOLE-(P) and MICONAZOLE-(OTC)
Imidazoles are active in treating ringworm, tinea versicolor and cutaneous candidal infections. Animal studies have suggested teratogenicity of some imidazoles in high oral doses, but not with topical use. Topical agents are absorbed less by the body when compared to oral preparations, and have not been found to be teratogenic (King et al 1998). Jick (1999) reported on 492 women exposed to various topical azoles (ketoconazole, miconazole and econazole). A relative risk of 2.1 (95% CI 0.7-6.8) was not statistically significant for an increased risk of congenital malformations, when compared to matched controls. There is some suggestion that ketoconazole and miconazole could inhibit testosterone synthesis in utero, which could potentially inhibit genital development of a male fetus. However, this has not been documented in any controlled studies. Surveillance data from the Michigan Medicaid study reported by Rosa et al (1987, did not find an increased risk for congenital malformations with miconazole or clotrimazole use during pregnancy.
AMPHOTERICIN B-(P)
Topical use of amphotericin B has shown minimal absorption through the skin. Limited human surveillance data do not indicate any harm to mother or fetus, but relative safety is still unknown (King et al, 1998).
VAGINAL THERAPY:
Inflammation of the vagina is extremely common in the general population. Symptoms include soreness, irritation, and discharge. Differential diagnoses (excluding sexually transmitted diseases) for symptoms of vaginal irritation include candida vulvovaginitis (VVC), bacterial vaginosis (BV), trichomoniasis, and atrophic vaginitis. VCC is one of the most common fungal infections, affecting 50% of women by age 25. Some of the more common treatment options for the above-mentioned conditions are described below; all of which are over the counter (OTC) with the exception of terconazole.
COLTRIMAZOLE- (OTC) Gyne-LotriminÒMycelexÒ
Clotrimazole is an OTC medication used to treat VVC. Clotrimazole is minimally absorbed (3-10%). The Michigan Medicaid Surveillance study reported on 1086 pregnancies exposed to clotrimazole during the first trimester (King et al, 1998). There were 74 pregnancies with a birth defect (RR=1.09, 95% CI 0.9-1.4), and 112 spontaneous abortions (RR=1.34, 95% CI 1.1-1.7). These data suggest a slight increase in spontaneous abortions, but no increase in birth defects, with first trimester exposure to clotrimazole. Clotrimazole is thought to be safe during the second and third trimesters of pregnancy (King et al, 1998). Czeizel et al (1999) studied the possible teratogenicity of clotrimazole for topical and vaginal therapy using a case-control surveillance study of 18,515 exposed pregnancies during three specific time intervals; first month, second and third month, and fourth through ninth month. Using 32,804 controls, they determined that clotrimazole use was not associated with an increase in congenital anomalies (OR=0.72, 95% CI 0.54-0.95). Further research has indicated that the use of clotrimazole may have a protective effect on preterm delivery. Czeizel and Rockenbauer (1999) determined that the use of clotrimazole during pregnancy significantly reduced the incidence of preterm births (t=8.86, P,0.001). These authors suggest that because clotrimazole effectively treats maternal infection, its use during pregnancy is indicated to eliminate maternal infection associated with prematurity.
MICONAZOLE-(OTC) MonistatÒ
Miconazole (monistatÒ) is one of the most commonly used over the counter medications for yeast infections. It is used topically (see above) and intravaginally for VVC treatment. Vaginal use has shown minimal systemic absorption (1.4%) (King et al, 1998). The Michigan Medicaid surveillance (Rosa et al 1987) reported on 2236 exposed pregnancies and 144 birth defects. These data do not support a significant increase in fetal malformations above the general population (RR=1.02, CI 0.9-1.2). The same surveillance study reported a slightly significant increase in spontaneous abortions in women who were prescribed miconazole 120 days before pregnancy loss, when compared with full term deliveries (RR=1.36, CI 1.1-1.6). Lack of controlled studies on the safety of miconazole use during pregnancy, however, does not provide an accurate estimate of potential risk.
NYSTATIN - MycostatinÒ
Nystatin is a polyene antifungal and is available over the counter. Vaginal preparation is the only type of application available due to toxicity by IV or oral administration. Nystatin is poorly absorbed systemically after topical or mucosal application. Specific use of nystatin has not been studied during pregnancy. Animal studies do not show an increased in congenital malformations (Rosa et al, 1987). Surveillance studies by the Collaborative Perinatal Project and Collaborative Drug Surveillance program did not find an increase of congenital malformation with first trimester use. Rosa et al (1987) reported data from the Michigan Medicaid study on women who received prescriptions for nystatin during the first trimester of pregnancy. Of 848 pregnant women, 66 deliveries were linked to birth defects. Their results were not statistically significant for an increase in birth defects over the general population (RR=1.25, CI 0.97-1.6). Surveillance by the Michigan Medicaid study did not show a significant increase in spontaneous abortions (SAB) in women who were prescribed nystatin 120 days prior to pregnancy loss when compared to full term deliveries (RR=0.87, CI 0.6-1.2). Although these data do not suggest a risk to human pregnancy, the lack of controlled human studies makes it difficult to establish relative safety.
OTHER IMIDAZOLES
Butoconazole –(OTC) FemstatÒ
Butoconazole is minimally absorbed systemically (5.5%). Clinical trials suggest relative safety with use during the second and third trimesters of pregnancy (King et al, 1998). However, these data are not from controlled studies and therefore, butoconazole should be used with caution during pregnancy.
Tioconazole-(OTC) VagistatÒ
Tioconazole is minimally absorbed systemically (5%-16%). Clinical trials suggest relative safety with use during the second and third trimesters of pregnancy (King et al, 1998). However, these data are not from controlled studies and therefore, tioconazole should be used with caution during pregnancy.
Terconazole- (P) TerazolÒ
Tioconazole is thought to have negligible systemic absorption. There are currently no human data to determining safety during pregnancy. (King et al, 1998)
SYSTEMIC THERAPY:
Systemic (oral/IV) antifungal medications are used to treat serious fungal infections, such as meningitis. Cryptococcal meningitis is an infection that apparently does not cross the placenta (Chen et al, 1996), but failure to treat can compromise maternal health and thus the health of the fetus. Because of their toxicity, use of systemic antifungals during pregnancy is limited to life-threatening infections. There is relatively little data on the more potent systemic antifungals. However, the triazole class of systemic antifungals (including fluconazole and itraconazole) are less toxic alternatives and therefore have been studied more commonly in pregnant women. This review will concentrate on oral and IV preparations of systemic antifungal medications that have been well studied during pregnancy. This comparison will highlight differences in toxicity and how they affect pregnancy.
TRIAZOLES
ITRACONAZOLE –(P) (Oral- SporanoxÒ) Itraconazole is another azole preparation that is related to ketoconazole and fluconazole and is used orally to treat fungal infections. Jick (1999) reported on 88 women exposed to oral itraconazole; however, dose was not reported. When compared to matched controls, itraconazole exposed women had a relative risk of only 0.6 (95% CI 0.2-1.6) of having a baby with congenital anomalies. Other data on the use of oral itraconazole during pregnancy is limited to case reports, which have also failed to suggest an increased risk for fetal birth defects.
FULCONAZOLE-(P) (IV and Oral - DiflucanÒ) Triazole used to treat systemic fungal infections (candidiasis, cryptococosis, coccidioiidomycosis and meningitis) penetrates the CNS and is present in high concentrations in the cerebral spinal fluid (CSF). Animal studies have shown teratogenic effects when fluconazole is administered at high doses (20-40X the normal human dose), including structural and craniofacial anomalies. Lee et al (1992) reported 3 patients exposed prenatally to fluconazole. These patients showed a pattern of Antley-Bixler-like malformations. Pursley et al (1995) reported 3 patients (2 siblings) exposed to high oral doses throughout the first trimester (400mg/day for first 24 weeks, 400mg/day for first 4 months, 800mg/day for first 7 weeks). These patients exhibited craniofacial, skeletal, and cardiac anomalies. One of the three patients was reported to have the previous diagnosis of Antley-Bixler syndrome. They concluded that fluconazole is teratogenic in humans and it is likely that other related azoles are also teratogenic. Kyrieckos and Bartley (1997) reported a single patient with fetal exposure to fluconazole in the first 9 weeks gestation [400mg/day (0-4/5 weeks gestation), 800mg/day (4/5- 9 weeks gestation)] for a maternal meningitis infection. Amphotericin B 50mg (3x/week) was also given over the next three months with fluconazole treatment resuming at 22 weeks (1200mg/day). This patient also presented with Antley-Bixler-like phenotype. Although this pregnancy was complicated with many other medications besides the two antifungals, Kyrieckos and Bartley (1997) concluded that fluconazole is teratogenic capable of producing Antley-Bixler-like phenotype when women are exposed to high doses for long duration in early pregnancy. Antley-Bixler phenotype includes the following features: brachycephaly, depressed nasal bridge, dysplastic ears, frontal bossing, midfacial hypoplasia, pear shaped nose, proptosis, large anterior fontanelle, long philtrum, craniosynostosis, choanal stenosis/atresia, femoral bowing, radiohumeral synostosis, femoral fracture, thin ribs, multiple contractures, long palms and fingers, camptodactyly, rockerbottom feet, cardiac defects, cleft palate and early death.
Inman et al (1994) studied 60 pregnancies [6 SAB, 11 TAB, 44 births (1 set of twins)] of women with vaginal candidiasis. All but one had single oral exposures of 150mg (time of exposures not ascertained) of fluconazole. No fetal abnormalities were found in any of the 44 live born infants. They concluded that low doses of oral fluconazole for the treatment of vaginal candidiasis during pregnancy does not increase the risk for fetal malformations.
Masrroiacovo et al (1996) performed a prospective cohort study from the Italian Teratogen Information Service (ITIS). Of the women exposed to fluconazole, 90.7% was for oral treatment of vaginal candidiasis. The majority of the women were exposed to single low doses (oral) of fluconazole (median 200mg) during the first trimester. The only significant difference between exposed and control groups was an increased therapeutic abortion (TAB) rate in the exposed group. With these results they concluded that single low doses of fluconazole during the first trimester are not associated with an increased risk for SAB, stillbirth or congenital anomalies.
Sorensen et al (1999) preformed a retrospective study of 165 women who had received fluconazole prescriptions just before or during pregnancy, and compared them to 13,327 women that did not receive prescriptions. Their study found no increase in congenital malformations with single exposures to fluconazole before conception or during pregnancy. However, this study has many confounding variables primarily receiving a prescription does not ensure that the medication was taken. This is a large source of bias in the study.
Jick (1999) reports on 234 women of which 92% were exposed to single 150 mg doses of fluconazole. When compared to 492 matched controls, a relative risk of 1.1 (95% CI 0.4-3.3) for congenital abnormalities was calculated. Three of their patients exposed to high doses exhibited limb deformities that suggested a pattern of malformations. These data suggest possible teratogenicity of fluconazole at high dose.
IMIDAZOLES
KETOCONAZOLE-(P) (oral - NizoralÒ)
Numerous problems have been reported with the use of systemic ketoconazole during pregnancy. It has been shown to be teratogenic and embryotoxic at high doses in animals, with additional data to suggest prolonged gestation. Ketoconazole crosses the placenta and is thought to inhibit gonadal and adrenal steroid synthesis in humans. It has been suggested that ketoconazole use during pregnancy could inhibit sexual differentiation, although to date there are not human data to prove such an association (King et al 1998). McGregor and Pont (1990) indicated that therapeutic doses (200mg and 400mg/day) have not been associated with a major block in steroid synthesis.
Ketoconazole is also used to treat Cushing syndrome. Two case reports of treatment for Cushing’s are the only data on human exposure during pregnancy. No adverse outcomes were reported. In Amado et al (1990) treatment was administered during the third trimester, when the sex of the fetus was already identified. In the second case report (Berwaerts et al, 1999) the patient received ketoconazole therapy from 1-3 weeks and 7-37 weeks of pregnancy. The pregnancy ended in a vaginal delivery at 37 weeks of a normally developed male infant. From this case report, Berwarts et al (1999) argue that ketoconazole is safe to administer during pregnancy. However, lack of data still make it difficult to establish safety.
MICONAZOLE-(NP) (IV)
Miconazole use in IV form has not been studied in human pregnancy. Animal studies do not show teratogenicity in high doses, but it has been reported to be embryotoxic and to prolong pregnancy. Due to limited data, adverse maternal side effects, and the availability of other systemic antifungals, miconazole should be avoided during pregnancy (King et al, 1998).
OTHER SYSTEMICS
METRONIDAZOLE (P) Metronidazole is an antimicrobial agent that is primarily used to treat protozoan infections. There has been controversial evidence regarding its use during pregnancy. However, more recent epidemiological studies have led to more conclusive support for its use during pregnancy. Previously, it was hypothesized that metronidazole could increase the risk for birth defects and possibly for cancer due to its mutagenic capabilities. Olson Robbie et al (1983) reviewed the use of metronidazole in obstetrical practices. Their literature substantiated that metronidazole crosses the placenta and is found in high concentrations in fetal tissue and amniotic fluid. Their study reports on 597 women exposed to oral metronidazole during pregnancy for a treatment period of 7 to 10 days. When compared to 283 untreated controls, there were no significant differences in stillbirths or prematurity. There was no evidence to suggest teratogenicity. Their paper suggested further studies on the carcinogenesis of metronidazole were needed. Burtin et al (1995) did a meta-analysis on the safety of metronidazole use during pregnancy. They reported on 7 studies (6 prospective of 253 first trimester exposed women and 1 retrospective of 1083 exposed women) in which there was no increased risk for teratogenicity with metronidazole use during pregnancy (OR=0.93, 95% CI, 0.73-1.18). Czeizel and Rockenbauer (1998) did a case-control study on the use of oral metronidazole during the various times of pregnancy (first month, second to third month and fourth to ninth months). Their data did not suggest an overall increase in congenital abnormalities between cases and controls (OR=1.12, 95% CI, 0.83-1.50) with second and third month exposures. However, certain birth defects were found at a slightly higher incidence in the case populations, and exposure throughout pregnancy did show a slight increase in congenital anomalies (OR=1.25, 95% CI, 1.11-1.42). Cleft lip with or without cleft palate and neural tube defects were increased with first month exposures, poly/syndactyly, anal atresis/stenosis, and hydrocephaly were increased with second and third month exposures and cardiovascular congenital abnormalities were increased in the case population with exposures between the 4th and 9th months. These data can be explained by embryology. The most critical timing for heart development is between the 3rd and 9th weeks. The authors did suggest that due to the retrospective nature of the study, these findings were possibly due to confounding factors. Caro-Paton et al (1997) did a meta-analysis on the teratogenicity of metronidazole. They looked at all cohort and case-control studies that estimated a risk of congenital malformations after metronidazole exposure during pregnancy. They concluded that first trimester exposure to metronidazole does not significantly increase the risk for congenital abnormalities (OR=1.08, 95% CI, 0.9-1.29) . The nature of this study did not allow for analysis of specific birth defects. In general, data do not suggest an overall increase in congenital anomalies with metronidazole use during pregnancy. However, even though some studies examined second and third trimester exposures, there are no data regarding the risk for prematurity, low birth weight or stillbirth associated with metronidazole use during that period of pregnancy.
The question of increased cancer risk in children exposed to metronidazole during pregnancy has been studied by Purushottam et al (1998). They studied a retrospective cohort of children under the age of 5. In their study they did not find an increased risk for tumor development (leukemia, neuroblastoma, CNS tumors, and other cancers) in children exposed prenatally to metronidazole when compared to non-exposed controls. Further analysis of the carcinogenicity of metronidazole has not shown an increase in risk for tumor formation in women followed 20 years after treatment for vaginal trichomoniasis (Beard et al; 1998). These findings were based on 771 women, and did not show evidence for mutagenic properties of metronidazole treatment.
Similarly to clotrimazole, metronidazole has also been thought to be protective against preterm labor be induced by maternal infection. In a placebo controlled trial by McDonald et al (1997), pregnant women using metronidazole had a significantly reduced risk for preterm labor when compared to the placebo group in two categories: women who previously had experienced preterm labor, and women with previous preterm labor that also had bacterial vaginosis. This study did not find a significant difference between treatment and control populations in women without any history of preterm labor (infection or no infection).
FLUCYTOSINE-(P)
Flucytosine is limited to the treatment of yeast infections, and resistance is developed rapidly following treatment. Data suggest that flucytosine is teratogenic in rats at doses less that the normal human dose (mg/kg basis). Flucytosine is known to cross the placenta. Case reports of use during the second and third trimesters have not shown adverse outcomes (only 3 reports). Due to its mechanism of action, flucytosine has the potential to cause congenital defects in humans and is therefore contraindicated in pregnancy (King et al 1998).
GRISEOFULVIN-(P)
Griseofluvin is used to treat ringworm. It has been reported to be embryotoxic in animals and crosses the placenta in humans. There is some suggestion of an association between first trimester exposure and an increased incidence of conjoined twins (2 case reports), but further epidemiological studies failed to support these preliminary findings. Other data regarding the use of griseofluvin during pregnancy is limited to case reports. These limited findings specifically reported by the FDA might be associated with an increased risk for miscarriage, but these data have not been confirmed by controlled studies. However, due to limited information, it is suggested that griseofluvin use be avoided during pregnancy (King et al, 1998).
TERBINAFINE-(P)
To date there is minimal data on the use of terbinafine for fingernail and toenail infections during pregnancy. Animal studies reveal that there is no evidence for fetal harm. However, there have been no controlled studies on human use during pregnancy (King et al 1998).
POTASSIUM IODIDE –(P)
Oral iodides are used to treat cutaneous infections. In general, iodides are thought to be contraindicated in pregnancy because they have been associated with congenital goiter that can be fatal in newborns (King et al 1998).
AMPHOTERICIN B -(P)
Amphotericin B is a polyene antifungal that has been used for more than 30 years, with numerous adverse effects (transient azotemia, febrile reactions, shaking chills, nephrotoxicity, thrombophlebitis, electrolyte disorders and anemia). Amphotericin B is used to treat numerous types of infections including: histoplasmosis, blastomucosis, cryptococcosis, coccidioidomycosis, visceral leishmaniasis, and cryptococcal meningitis. Oral preparations of amphotericin B are still the chosen antifungal for severe infections. Amphotericin B is known to cross the placenta and enter the fetal circulation. It is also available in topical form for less severe infections but is minimally absorbed by the skin.
Oral/IV formulations of amphotericin B are commonly prescribed during pregnancy. King et al (1998) reviewed its use during pregnancy, and 26 additional cases of amphotericin B use during pregnancy. Because of the toxicity of amphotericin B, adverse maternal reactions were commonly reported which included: anemia, acute nephrotoxicity, fever, chills, headache, nausea and vomiting. Fetal effects that were most commonly seen included: anemia, low birth weight, microcephaly, transient acidosis, increased serum creatine (SCr) levels, respiratory failure, transient maculopapular rash. Their review of the data concluded that Amphotericin B is the drug of choice for life threatening fungal infections during pregnancy. Its use in human pregnancy has not shown consistent adverse fetal effects. Maternal toxicity is common and pregnant women should be closely monitored if taking amphotericin B.
Lipid formulations have been more recently introduced into the treatment of fungal infections especially for women that are intolerant of amphotericin B (King et al, 1998). Abelcet is used for invasive fungal infections. Animal studies have not shown detrimental effects to the fetus with 0.64X the human dose. There is currently no human data on its use during pregnancy. Amphotec is prescribed primarily for aspergillosis infections. Animal studies have not shown detrimental effects to the fetus with 1.1X the human dose, however, there are currently no data on use during human pregnancy. Ambisome is used to treat febrile neutropenic patients, aspergillus, candida or cryptococcus species and visceral leishmaniasis treatment. Animal studies have shown significantly higher spontaneous abortion rate with 0.5-2X the human dose. One human case report of AmBisome treatment of Mediterranean visceral leishmaniasis (18mg/kg total dose) in a pregnant patient resulted in a normal pregnancy.
SUMMARY:
It is important to weigh the risks and benefits of any drug usage during pregnancy. In the context of antifungal medications, it is necessary to consider the potential risks to both mother and fetus if the infection goes untreated. Current literature does not address the risks of an untreated infection. If an infection worsens during pregnancy, a higher dose may be needed, which may affect the fetus. In general, there is a higher rate of relapse with certain infections when a woman is pregnant (especially candidal vaginitis). This can be important to consider when treating fungal infections in pregnant women. Overall, data differs on the various types of antifungals available. Choosing one that is favorable for treating the particular infection while considering the potential risks to the fetus is critical when managing the treatment of a pregnant woman.
References:
Amado JA et al. Successful Treatment with Ketoconazole of Cushing’s Syndrome in Pregnancy. Postgrad. Med J. 66:221-3;1990.
Beard CM et al. Cancer After Exposure to Metronidazole. Mayo Clin Proc. 63:147-53;1998.
Berwaerts J, Verhelst C, Mahler C and Abs R. Cushing’s Syndrome in Pregnancy Treated by Ketoconazole: Case Report and Review of the Literature. Gynecol Endocrinol. 13:175-82;1999.
Burtin Pascale et al. Safety of Metronidazole in Pregnancy: A Meta-Analysis. Am J Obstet & Gynecol.172:525-9;1995.
Caro-Paton, T et al. Is Metronidazole Teratogenic? A Meta-Analysis. Br J Pharmacol. 44:179-89;1997.
Chen, Chie-Pein and Wang, Kuo-Gon. Cryptococcal Meningitis in Pregnancy. Am J Perinatology. 13(1):35-36;1996
Coleman T, King P, Rogers D, Cleary J, Chapman S. Antifungal Therapy During Pregnancy. Clinical Infectious Diseases. 27:1151-60; 1998.
Czeizel AE, Toth, Marta, Rockenbauer, Magda. No teratogenic Effect After Clotrimazole Therapy During Pregnancy. Epidemiology. 10:437-440;1999.
Czeizel AE, Rockenbauer, Magda. A Lower Rate of Preterm Birth After Clotrimazole Therapy During Pregnancy. Pediatric and Perinatal Epidemiology. 13:58-64;1999.
Czeizel AE, Rockenbauer, Magda. A Population Based Case-Control Teratologic Study of Oral Metronidazole Treatment During Pregnancy. Br J Obstet & Gynecol. 105:355-27;1998.
Inman W, Pearce G, Wilton L. Safety of Fluconazole in the Treatment of Vaginal Candidiasis. Eur J Clin Pharmacol. 46:115-8;1994.
Jick, Susan S. Pregnancy Outcomes After Maternal Exposure to Fluconazole. Pharmacotherapy. 19(2):221-22; 1999.
Kyrieckos A, Bartley D. Multiple Malformation Syndrome Following Fluconazole Use in Pregnancy: Report of an Additional Patient. Am J. Med Genet. 72:253-256;1997.
Lee BE, Feinberg M, Abraham JJ, Murthy ARK. Congenital Malformations in an Infant Born to a Woman Treated with Fluconazole. Pediatric Infectious Disease Journal. 11:1062-4;1992.
McDonald HM et al. Impact of Metronidazole Therapy on Preterm Birth in Women with Bacterial Vaginosis Flora (Gardnerella vaginalis): a Randomized, Placebo Controlled Trial. Br J Obstet & Gynecol. 104:1391-1397;1997.
McGregor JA, and Pont A. Contraindication of Ketoconazole in Pregnancy. Am J Obstet & Gynecol. 150:793-4;1990.
Mastroiacovo P, Mazzone T, Botto L, Serafini MA, Finardi A, Caramelli L, Fusco D. Prospective Assessment of Pregnancy Outcomes After First-Trimester Exposure to Fluconazole. Am. J Obstet & Gyne. 175:1645-50;1996.
Olson Robbie, Marilyn and Sweet, Richard. Metronidazole use in Obstetrics and Gynecology: A Review. Am J Obstet & Gynecol. 145:865; 1983.
Pursley T, Blomquist I, Abraham J, Andersen F, Bartley J. Fluconazole-Induced Congenital Anomalies in Three Infants. Clinical Infectious Diseases. 22:336-40;1996.
Purushottam BT et al. Prenatal Exposure to Metronidazole and Risk of Childhood Cancer. Cancer. 83:1461-8;1998.
Rosa L, Baum C, Shaw M. Pregnancy Outcome After First-Trimester Vaginitis Drug Therapy. Obstet & Gyne. 69(5)751-55;1987.
Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schonheyder HC, Olsen J, Czeizel AE. Risk of Malformations and other Outcomes in Children Exposed to Fluconazole In Utero. Br. J Clin Pharmacol. 48:234-238;1999.
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Posted by admin on May 1st, 2000 — in newsletter
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Corticosteroids in Pregnancy
Vol. 8, No.1 May 2000
Coicosteroids refer to a group of hormones made within the adrenal cortex. Since these hormones play a critical role in maintaining carbohydrate reserves, they are often referred to as glucocorticoids and these words are often used interchangeably. The excess or deficiency of these hormones affects virtually every tissue in the body.
Corticosteroids were synthesized for their anti-inflammatory properties about fifty years ago (Reinisch et al, 1978). They are commonly used during pregnancy to reduce the immune response in allergic or inflammatory diseases, such as asthma, lupus, rheumatoid arthritis, or skin diseases. Other indications include: promoting fetal lung maturity, treating infertility and maintaining pregnancy, or as replacement hormone therapy. Corticosteroids all cross the placenta, but some corticosteroids are more readily inactivated than others (Roubenoff et al, 1988). Prednisone and cortisone are the preferred medication for treating maternal disease, since they have shorter half lives, while dexamethasone and betamethasone are used if the fetus requires specific treatment, such as for respiratory distress.
Physicians may be wary of prescribing corticosteroids because animal studies in rodents and rabbits have demonstrated that high doses consistently cause cleft palate (Walker, 1971; Pinsky and DiGeorge, 1965; Walker, 1967). Human studies, most of which rely on retrospective data, show varied and conflicting results. The association between corticosteroids and oral clefting remains controversial. Case reports include a spectrum of various defects such as cataracts, cyclopia, interventricular septal defect, gastroschisis, cleft lip, hydrocephalus, coarctation of the aorta, clubfoot; thus, no pattern of malformation has been established. Clinical observations suggest that corticosteroid use may be associated with low birth weight, intrauterine growth retardation, and in some cases, stillbirth has been reported (Reinisch et al, 1978; Warrell and Taylor, 1968). Schatz et al (1997) reported that mothers who took oral corticosteroids for asthma had an increased risk for preeclampsia. Studies have also been complicated by oral versus inhaled versus topical doses. When assessing reports of pregnancy outcome, such as low birth weight or prematurity, it is important to keep in mind the effect of maternal disease, such as lupus and asthma, both of which have been associated with increased risk for adverse outcomes. This RISK//NEWSLETTER will discuss the major types of corticosteroids.
General Studies
Although various types of corticosteroids are available, few studies have looked at the teratogenic potential of each one separately. Most of the studies analyzed the various drugs together, making it difficult to assess the teratogenic risk for a specific medication. In addition, women are often prescribed corticosteroids as part of a regimen of various medication combinations, so there may be some synergistic effect that is difficult to ascertain. While there have been mixed findings in regards to oral clefting, available studies do not suggest an overall increase in malformations after in utero exposure to corticosteroids. In published cases, the rate of malformations for therapeutic corticosteroid use was 4.4% (Roubenoff et al, 1988). No cleft palate defects were noted in 26 babies exposed to high doses of prednisone throughout pregnancy for treatment of maternal lupus (Fine et al, 1981). The Michigan Medicaid surveyed newborns exposed to prednisone (N=236), prednisolone (N=143), and methylprednisone (N=222). The data found no association between corticosteroid use and congenital defects, except perhaps for prednisolone, which had a 7.7% incidence for total number of birth defects. No cases of oral clefting were reported (Briggs et al, 1998). Fraser and Sajoo (1995) surveyed the available literature from 1952-1994 and found 457 exposed patients, in which the frequency of malformations was 3.5%. Although single case reports may reflect reporting bias, the two cases of cleft palate observed was higher than the 0.2 cases expected, and a possible association could not be excluded.
Corticosteroids and clefting
Data from three retrospective epidemiological studies have examined the association of oral clefting with exposure to corticosteroids during pregnancy. The Malformation Drug Exposure Surveillance Project (MADRE) compared congenital malformations with 1st trimester drug exposures from six different countries (Australia, France, Israel, Italy, Japan, and South America). Seven out of 1448 infants with facial clefts (CL, N=5; CL±CP, N=2) were exposed to systemic corticosteroids (Briggs update, June 1999). The Hungarian Case-Control Surveillance of Congenital Abnormalities found no significant association between oral corticosteroid treatment and congenital anomalies, with 1.55% of 20,830 malformed infants exposed to corticosteroids during the first trimester compared to 1.41% of 35, 727 controls (Cziezel and Rockenbauer, 1997). This study looked at ointment, spray, and systemic exposures; the systemic exposures were primarily dexamethasone, prednisolone, and cortisone. A significantly higher use of both systemic and ointment corticosteroids use in the first month of gestation was found in the three cases of cleft lip with or without cleft palate (Odds ratio:5.88; CI 1.7-20.32). The case-control Spanish Collaborative Study of Congenital Malformations surveyed 1,184 cases of liveborns with nonsyndromic clefts and examined systemic exposures to prednisolone, hydrocortisone, prednisone, and triamcinolone. After controlling for four potential confounding factors (maternal smoking, family history of first degree relatives with clefts, maternal hyperthermia, and first trimester exposure to anticonvulsants, benzodiazepenes, metronidazole, or sex hormones), the authors concluded that prenatal exposure to a corticosteroid carried a six times greater risk for cleft lip with or without cleft palate.
The incidence of cleft lip with or without cleft palate is about 1 to 2 per 1000, and the incidence of cleft lip is 1 per 2500 in the general population. The criticism of the above studies is that the findings of cleft lip with or without cleft palate could be in part due to chance. Closer inspection of the data, however, lends more credence to the suggestion that corticosteroid exposure may be associated with a higher incidence of oral clefting. The critical period in pregnancy for oral palate formation is between the 8th and 11th weeks of gestation based on the last menstrual period. For indications of corticosteroid use that is not essential to maternal health, it may be prudent to discuss with the patient other options during the specific period of palate formation.
The main confounding variables in these studies are maternal disease and the effect of other maternal medication use. In evaluating the risks versus benefits of corticosteroids, the important factor to keep in mind is the importance of maternal of health in any pregnancy outcome. In addition, the route of exposure is important in determining the risk of a medication to pregnancy. Topical preparations are less systemically available than oral or inhaled doses, and thus are unlikely to reach the fetus in exposures great enough to cause an increased risk for congenital defects. Consideration should be taken when prescribing corticosteroid use in the first trimester of pregnancy, since the safety of these drugs remains controversial.
Reproductive data on specific corticosteroids
Hydrocortisone/Cortisone (Cortef, Hydrocortone)
The inactive precursor, cortisone has half-life of 8-12 hours (Melby, 1977), and is reduced by the liver to hydrocortisone. Hydrocortisone is used for a variety of purposes. It is most typically used topically to treat eczema or other related skin diseases, and has also been found effective in treating hyperemesis gravidarum. The following studies cited are based on systemic exposures; no reproductive studies on topical exposure to hydrocortisone are available.
As with other corticosteroids, hydrocortisone and cortisone exposure in pregnant mice and rabbits have shown an increased incidence of cleft palate and other pregnancy complications, such as IUGR, and shortening of the head and mandible (Fraser et al, 1951). Human doses are lower, especially if a topical preparation is used. A study by Czeizel et al (1997) identified 191 women exposed to topical cortisone during pregnancy and found no significant increase in birth defects. The Collaborative Perinatal Project followed women exposed to hydrocortisone (N=21) and cortisone (N=34) in the first trimester. While the number of exposure is limited, no increase in congenital malformations was found. Various case reports of birth defects exist but no pattern of defects was evident. In summary, it is unlikely that a topical exposure to hydrocortisone and its inactive precursor, cortisone, significantly increases the risk for oral clefts or other types of birth defects.
Prednisolone/Prednisone (Blephamide, prelone)
Prednisolone, the active metabolite of prednisone, has a half life of 12 – 36 hours (Melby, 1977), and is widely used to treat collagen-vascular diseases (rheumatoid arthritis) and as an immunosuppressant. It is also used to treat pregnant women with antiphospholipid antibodies.
An early study reported an increased risk for stillbirths following prednisone therapy (Warrell, 1968). Increased infant mortality has not been confirmed by other studies, and the findings have been largely attributed to the risks inherent in maternal disease such as lupus. Reinisch et al (1978) looked at prednisone use for infertility and maintenance of pregnancy. In 14% of prednisone exposed pregnancies, the babies were small for dates, i.e., less than 2,500 grams, as compared to 1.5% of controls. Fine et al (1981) followed 26 babies who were exposed primarily to prednisone during organogenesis as a result of maternal lupus. No cases of cleft palate were noted; low prevalence of congenital abnormalities was found. Immunosuppression was a concern for these neonates of mothers treated with prednisone, since the babies had reduced thymic size and transient lowered lymphocyte counts.
The Michigan Medicaid study retrospectively surveyed newborns exposed to prednisolone (N=143) and prednisone (N=236). Observed versus expected major malformations for each were as follows: 11/6 (7.7%) and 11/10 (4.7%). The data did not support an association between drugs and congenital defects, except perhaps for prednisolone use and total number of birth defects. The Motherisk Program in Toronto, a teratogen information service, prospectively followed 187 pregnant women exposed to prednisone for disease and 127 pregnant women exposed because of fertility treatment. In comparing the results to 188 control women, no statistically significant difference in rates of major malformations was found. However, in the exposed group, a cluster of cleft palate (3/455) was reported. Therefore, prednisone and its derivatives may present a small but statistically significant increased risk for cleft palate but they otherwise do not appear to be associated with adverse effects in mother or fetus.
Dexamethasone (Decadron, Maxidex)
Dexamethasone is a glucocorticoid most commonly used in the third trimester to reduce fetal respiratory distress, and is also found in some topical preparations. It is also used in the first trimester to treat the virilization associated with congenital adrenal hyperplasia, since it suppresses adrenal function.
The safety and effectiveness of dexamethasone therapy is debatable but most authors agree that this treatment has been effective in some populations (Seckl et al, 1997). More importantly, this drug exposure is not associated with long term adverse effects in the offspring (Collaborative Group on Antenatal Steroid Therapy, 1984).
No human studies have been reported on dexamethasone use during early pregnancy, since it is primarily used in the third trimester. As found with other corticosteroids, the principle birth defect produced in animals is cleft palate; however, in rhesus monkeys, high doses of dexamethasone have induced cranial malformations (Jerome et al, 1988). Animal studies in rabbits have shown that dexamethasone use was associated with retinopathy of prematurity, although no proof of this association has been demonstrated in human populations (Batton et al, 1992). Concern that corticosteroid use could effect long-term central nervous system development arose because it was shown that rats’ brains displayed a decrease in dendritic branching after hydrocortisone administration. Also, in rhesus monkeys, suppression of bodily growth and brain development, specifically the cerebellum, has been shown (Uno et al, 1990).
The long-term effects of dexamethasone therapy in babies may include increased fetal death, growth retardation, adult hypertension, and psychological effects (Seckl et al, 1997). The Collaborative Group on Antenatal Steroid Therapy followed for three years approximately 400 children who were part of a randomized trial to evaluate the efficacy and safety of antenatal dexamethasone for respiratory distress. The rationale for a three year follow up was that outcome in these first few years are less affected by environmental factors and therefore may more accurately reflect the effects of acute perinatal events. No statistically significant differences for head circumference and neurologic abnormalities between placebo and steroid groups were noted. In addition, no detectable growth, physical, motor, or developmental deficiencies within the first three years of life could be attributed to dexamethasone. The demonstrated benefits of dexamethasone use to reduce complications of respiratory distress seem to outweigh any potential risks for adverse effects. Due to its longer half life of 36 –54 hours (Melby, 1977), dexamethasone is generally not suggested for treatment of maternal disease. It may be prudent to use another more well-studied corticosteroid during the first and second trimesters.
Betamethasone (Diprosone, Celestone)
Betamethasone is a synthetic corticosteroid used to promote fetal lung maturation in the third trimester, and is also found in some topical preparations. Since betamethasone is an isomer of dexamethasone, the information on dexamethasone may also be relevant.
Betamethasone, like all the other glucocorticoids, has been associated with clefting in mice, rats, and rabbits, but it is also associated with an increased incidence of omphalocele and umbilical hernia in rats (Mosier et al, 1982; Ishimura et al, 1975). These studies show decreased cell number in the lung, and impaired myelination and cellular development of the central nervous system, as well as suppression of the immune system (MacArthur et al, 1981).
Several studies have followed prematurely-born children whose mothers were given betamethasone as part of a randomized, placebo control trial (MacArthur et al, 1981; Schmand et al, 1990; Doyle et al, 1989). No difference between placebo and steroid groups existed in cognitive or psychological development, and in physical growth. Schmand et al. (1990) found an increased number of hospital admissions due to infectious diseases in early childhood, possibly demonstrating some proof of immune system suppression in offspring due to antenatal betamethasone exposure. In one study, betamethasone was shown to mildly constrict the ductus arteriosus, but the findings were not clinically significant (Wasserstrum et al, 1989). In general, there seems to be no long-term side effects of betamethasone use in the third trimester. Like dexamethasone, betamethasone is typically not suggested for treatment of maternal disease; no studies have been reported to evaluate the risks of its use during the first and second trimesters.
Beclomethasone (Beclovent, Vancenase, Beconase)
Beclomethasone is the most commonly used inhaled corticosteroid in pregnancy to control the symptoms of asthma. Only about 10 to 20 percent of the inhaled dose of corticosteroid reaches the lungs (Glaxo group, 1980), and topically, it has almost no systemic activity. The aerosol dosage in an inhaled dose which is less than one sixth of an oral corticosteroid and controls symptoms as well or better than the oral preparations (Brompton Hospital, 1974)).
Two clinical human studies have investigated the pregnancy outcomes of women who received beclomethasone; some of these women also received prednisone for severe asthma. One study evaluated the outcome of 45 pregnancies, 33 of which were prospectively followed and 12 of which were retrospectively collected. Beclomethasone was used in the first trimester and throughout pregnancy. The overall risk for malformations was 2.3%; one infant had a cardiac malformation (Greenberger and Patterson, 1983). Fitzsimons et al (1986) reported the outcome of 56 pregnancies in which women with severe asthma were treated with prednisone and/or beclomethasone dipropionate. No maternal, neonatal deaths, or malformations occurred. The rate of low birth weight was 17.2%, compared to the general population’s rate of 6.8%.
Twenty patients out of 600 in the Brompton Hospital/ Medical Research Council Collaborative Trial were exposed to beclomethasone throughout pregnancy. No malformations or abortions were described. The Michigan Medicaid Study surveyed 395 newborns that had been exposed to beclomethasone in the first trimester. A total of 16 (4.1%) major birth defects were observed and 16 were expected. The findings from these various studies do not support an association between beclomethasone use and congenital defects.
Triamcinolone (Azmacort, Nasacort)
Triamcinolone is a synthetic fluorinated corticosteroid typically used to treat asthma symptoms or for skin conditions. Depending on preparation, it can be administered orally, parenterally, topically, or by oral inhalation.
Triamcinolone is a potent teratogen in animals, producing cleft palate in pregnant mice, rabbits, and hamsters (Walker, 1965; 1967; 1969; Shah, 1976). In three species of nonhuman primates (bonnet monkeys, rhesus monkeys, and baboons), doses of triamcinolone acetonide at approximately 300 times the human dosage produced central nervous system and craniofacial malformations, as well as growth retardation (Parker and Hendrickz, 1983; Tarara et al, 1989). These findings, in particular the primate studies, have caused concern that triamcinolone may also produce human developmental effects similar to the teratogenic effects seen in animals.
There is limited human experience with triamcinolone exposure in pregnancy. The Collaborative Perinatal Project identified eight triamcinolone-exposed mother-child pairs in a group of 56 women who were exposed to first trimester corticosteroids; two infants had malformations (3.6%) in the entire group. Dombrowski et al (1996) reported pregnancy outcomes for 15 women treated with inhaled triamcinolone. No increase in adverse outcome or birth defects were noted; in fact, triamcinolone compared favorably with other medications in efficacy and safety. One case report of topical triamcinolone use for atopic dermatitis suggested that excessive use of this corticosteroid may be associated with severe intrauterine growth retardation in the exposed offspring (Katz et al, 1990). Although preliminary studies do not suggest an association of triamcinolone use with adverse outcomes, additional studies are ongoing to fully evaluate its safety for use during pregnancy.
Clobetasol and Fluocinodide (Cormax, Lidex)
Virtually no human data for use during pregnancy is available on these two topical corticosteroids typically used to treat psoriasis and other skin conditions. They are both considered “potent” topical preparations but since no information on their reproductive effects are available, their risk is undetermined.
Summary
While most studies do not show a large teratogenic risk, the association with corticosteroid use and clefting cannot be excluded. Avoidance of such medication exposure during specific times may be important to discuss, particularly for indications in which the medication is not essential for maternal health. For maternal disease, derivatives of cortisone and prednisone are suggested since they are more readily inactivated by the placenta, as opposed to dexamethasone and betamethasone, which are more likely to reach the fetus in the active state. As with any medication, use of a corticosteroid must be weighed against the severity of maternal disease.
References
Batton et al. Pediatrics 90:534-6, 1992
Briggs et al. Drugs in Pregnancy and Lactation 5th Ed. Williams and Wilkins, 1998
Brompton Hospital/ Medical Research Council Collaborative Trial. Lancet 2:303-307, 1974.
Collaborative Group on Antenatal Therapy. J Pediatrics 104:259-67, 1984
Cziezel A and Rockenbauer M. Teratology 56:335-340, 1997
Diav-Citrin O et al. (in abstract) The Motherisk Program, 1998
Dombrowski MP et al. Maternal Fetal Med 5:310-3, 1996
Doyle LW et al. Obstet Gynecology 73:743-6, 1989
Fine LG et al. Ann Intern Med. 94, 667-77, 1981
Fitzsimons R et al. J Allergy Clin Immun. 78:349-53, 1986
Fraser FC and Sajoo A. Teratology. 51:45-6, 1995
Greenberger PA & Patterson R. Annals of Intern Med. 98:478-80, 1983
Katz VL et al. Am Jour Obst Gyne 162:396-7, 1990
Ishimura K et al. Oyo Yakuri 10:685-694, 1975
Jerome CP and Hendrickx AG. J Med Primatol 17:195-203, 1988
MacArthur BA et al. Pediatrics 68:638-43, 1981
Melby J. Annual Rev of Pharm & Tox. 17:511-27, 1977
Mosier HD et al. Dev Pharmacol Ther 4:89-105, 1982
Parker RM and Hendrickz AG. Teratology. 28:35-44, 1983
Ramsey-Goldman R and Schilling E. Pregnancy and Rheumatic Disease. 23(1):149-167, 1997
Reinisch JM et al Science. 202:436-8, 1978
Rodriquez-Pirilla E and Martines-Frias ML Teratology 58:2-5
Roubenoff R et al Seminars in Arthritis and Rheumatism 18(2):88-110
Schatz M et al. J Allergy Clin Immunol. 100:301-6, 1997
Schmand B et al Pediatrics 86(1):58-64, 1990
Shah RM and Kilistoff A. J Embryolo Exp Morphol 36:101-8, 1976
Seckl JR et al. JAMA 277:1077-9, 1997
Tarara RP et al. Teratology 39:75-84, 1989
Uno H et al. Brain Res Dev Brain Res. 53:157-67, 1990
Walker BE. Teratology 4:39-42, 1971
Walker BE. Science. 149:862-3, 1965
Walker BE. Proc Soc Exp Biol Med. 125:1281-4, 1967
Walker BE. Anat Rec. 163:281, 1969
Warrell DW and Taylor R. Lancet 1:117-8, 1968
Wasserstrum N et al. Obst. Gyne. 74(6):847-900
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Posted by admin on February 2nd, 2000 — in newsletter
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Acne and Pregnancy
Vol 7#5, February 2000
Kathleen O’Connell, BA; Megan Shepard, BA; Kelly Ormond, MS, CGC; Eugene Pergament, MD, PhD, FACMG
A variety of medications are prescribed for the treatment of acne, some taken orally, others topically. When assessing the possible risk of these medications during pregnancy, the route of the exposure is important to consider. Topical creams and gels are less systemically available than medicines taken orally, ultimately meaning that the fetus is exposed to less of the medication. As with any decision about medication during pregnancy, the potential risks must be weighed against its benefits for the patient. Since there are various acne medications available, it may be possible for a woman to find a combination of medications that is both effective and does not put her pregnancy at risk for major malformations. This newsletter examines various medications used in the treatment of acne.
Common medications
Benzoyl Peroxide (Benzac, Benzamycin, Beroxyl, Desquam, Triaz, Vanoxide)
Benzoyl peroxide is a topical treatment for acne that has antibacterial effects and induces skin peeling. About 5% of each topical dose is absorbed sytemically. There are not any animal or human reproductive studies on benzoyl peroxide, and therefore its potential teratogenic risk is undetermined. However, benzoyl peroxide is commonly used, and there are no case reports about benzoyl peroxide and birth defects in the literature. This, combined with its topical exposure, provides some reassurance that the risk of malformations is likely to be low.
Hydrocortisone (Vanoxide-HC; w/ benzoyl peroxide)
Hydrocortisone is a corticosteroid used topically to treat acne and other dermatologic conditions. There have been no reproductive studies on topical exposures to hysdrocortisone specifically, and as such its risk in pregnancy is undetermined.
A literature review of oral cortisol exposures during pregnancy did not find an increased risk for malformations in the exposed group, but it was found that the exposed group did have an increased risk for prematurity and other complications for the mother and fetus (Aron et al., 1990). The doses in the studies reviewed were presumably much larger than a dose from a topical exposure. Fraser et al. (1995) surveyed 468 women exposed to all corticosteroids in general, and noted no significant increase in birth defects. However, this study did note an increase in cleft palate versus that expected (2 vs. 0.2). Because an increase in clefting has been observed in mice exposed to corticosteroids (Fraser et al., 1951), this finding is of potential concern.
Most other studies of oral and inhaled corticosteroids have not found a significant increase in birth defects or in clefts specifically (Czeizel and Rockenbauer, 1997; Fitzsimons et al., 1986; Rodriquesz-Pinella and Martinez-Frias, 1998; Schatz et al., 1997). Finally, a retrospective study by Czeizel et al. (1997) followed 191 women exposed to topical cortisone during pregnancy and found no significant increase in birth defects. In summary, although there is a potential connection between oral corticosteroids and cleft palate identified in the human and animal studies by Fraser et al. (1951 and 1995), it is unlikely that a topical exposure to hydrocortisone significantly increases the risk of birth defects, including oral clefts.
Salicylic Acid (Sal Ac)
Salicylic acid is used to treat acne, warts and other dermatological problems. There are no studies specifically looking at topical salicylic acid in pregnancy. Oral salicylic acid (aspirin) has not been associated with an increase in malformations if used during the first trimester, but use in late in pregnancy has been associated with bleeding, especially intracranial bleeding (Rumack et al., 1981). The risks of aspirin late in pregnancy are probably not relevant for a topical exposure to salicylic acid, even late in the pregnancy, because of its low systemic levels. Topical salicylic acid is common in many over-the-counter dermatological agents, and the lack of adverse reports suggests a low teratogenic potential.
Antibiotics/Anti-infectives
Erythromycin (A/T/S 2% acne gel, Benzamycin, Emgel, Erycette, T-Stat, Theramycin)
Erythromycin is an antibiotic that is commonly prescribed in pregnancy. Although often taken orally to treat infection, it is also used topically for acne. Erythromycin crosses the placenta minimally; the fetal blood concentration is only 2-10% of the maternal serum concentration, and the medication is quickly metabolized by the body.Takaya et al. (1965) found no increased malformations in mice exposed to 1-20 times the human dose. Human studies on erythromycin have all examined oral exposures. Retrospective studies of 79 and 6972 women exposed in first trimester had no significant increase in birth defects (Heinonen et al., 1977; Briggs, 1998). Jick et al. (1981) examined the prescription records of women exposed to erythromycin during the first trimester and also found no increase in birth defects (n=100-200). Because of these studies and the fact that this medication is commonly prescribed, it is generally assumed that topical erythromycin does not pose a significant increased risk for birth defects.
Clindamycin (Cleocin)
Clindamycin is an antibiotic related to erythromycin and available both orally and topically for the treatment of acne. It has been studied in both mice and rats at doses up to 180 mg/kg/day without teratogenic effects (Weinstein et al., 1976; Philipson et al., 1976).The retrospective Michigan Medicaid study identified 647 women exposed to clindamycin in the first trimester (both oral and topical exposures) and did not note an increased risk for major malformations. Furthermore, a study of 104 women exposed to clindamycin in the second and third trimesters did not suggest an increased risk for prematurity or placental complications (McCormack et al., 1987). This medication is unlikely to significantly increase the risk for birth defects in either its oral or topical form.
Tetracycline
Tetracycline is an antibiotic taken orally to treat acne. This medication belongs to a family of antibiotics that includes minocycline and doxycycline. The half-life of tetracycline is 11-22 hours, so most of the medication is removed from the body in 5 days.Two retrospective studies found no increase in the incidence of major malformations when women were exposed to tetracycline in the first trimester (Heinonen et al., 1977; Briggs, 1998). However, discoloration of deciduous teeth and the crowns of permanent teeth was seen in children who were exposed to tetracycline after the fourth month of gestation. Studies performed by Cohlan et al. (1961), Kline et al. (1964) and Kutscher et al. (1966) established that infants exposed to tetracycline in utero after the fourth month of gestation may have discoloration of deciduous (”baby”) teeth, cavities, and enamel hypoplasia in their teeth. It is believed that tetracycline causes dental discoloration and bone depression because it acts on the calcification process in development. The critical period for calcification begins at four months’ gestation and ends twelve months post-partum. Therefore, tetracyline should be avoided after the sixteenth week of gestation and throughout lactation.
The degree of dental staining appears to proportional to the dose of the medication (Egerman et al., 1992). Cohlan et al. (1961) also found that tetracycline caused long bone growth depression of 40% which normalized when the use of the medication was suspended.
Doxycycline and minocycline, two medications structurally-related to tetracycline, are also used to treat acne. These medications have not been as well-studied as tetracycline; it is, however, generally assumed that doxycycline and minocycline similarly affect the fetal calcification process. Therefore, these medications should also be avoided after the first trimester of pregnancy through the breastfeeding period.
Sodium Sulfacetamide (Sulfaset, Klaron, Novacet, Sebizon)
Sodium sulfacetamide is a topical anti-infective medication used to treat acne and seborrheic skin conditions. It belongs to the class of medications termed sulfonamides, and most reproductive studies examine sulfonamides as a class and in oral dosages, making it difficult to extrapolate the potential risk for a topical medication such as sulfacetamide.
The maternal use of sulfonamides near delivery can lead to newborn toxicity, resulting in anemia and jaundice and, theoretically, kernicterus, although this has yet to be documented in the literature. (Briggs, 1998). There have been two large retrospective studies of sulfonamide exposure, which involved 1445 and 3465 women exposed in the first trimester; neither study found an increased risk for malformations from the class in general (Heinonen et al., 1977; Briggs, 1998).
In contrast, other case controlled studies raised concerns about sulfonamide use in pregnancy. A 1971 case-control study by Nelson et al. determined the pregnancy exposures of 1369 patients, 468 of whom had babies with congenital malformations. They observed that significantly more mothers of the babies with birth defects took sulfonamides than the control mothers (Nelson et al., 1971). Saxon et al. (1975) looked retrospectively at 599 children born with oral clefts. The mothers of children with malformations in addition to the oral clefts were more likely to have taken sulfonamides than mothers of children with isolated oral clefts.
Because topical sulfacetamide has never been specifically studied to determine its potential teratogenic risk, one cannot definitively conclude that it does not cause birth defects. However, because it is topical and, for the most part, sulfonamides as a class do not appear to significantly increase the risk for birth defects, it is unlikely that topical sulfacetamide causes a significantly increased risk for malformations.
Breastfeeding while using sulfonamides is probably not a risk to a healthy infant. At most 1-2% of a maternal, oral dose of sulfonamides enters the breastmilk (Adair, 1938; Hac, 1939). However, sulfonamides can potentially cause anemia and jaundice in stressed, premature or hyperbilirubinemic infants. In addition, if an infant has G-6-PD deficiency breastfeeding should be avoided while taking sulfonamides , as sulfonamides act as oxidative stressors and can result in a hemolytic crisis.
Retinoids Isotretinoin (Accutane, Roaccutane)
Isotretinoin is an oral retinoid used to treat cystic acne. A known teratogen, this medication is contraindicated during pregnancy due to the characteristic malformations it causes. The pattern includes defects of the CNS, thymus, craniofacial and cardiovascular systems, as well as conotruncal malformations. Isotretinoin is thought to affect initial differentiation and migration of cephalic neural crest cells, and the critical period for this medication is 2-5 weeks post conception. Because the teratogenicity of Accutane is fairly well-known, we have chosen to focus upon other common acne medications in this review, rather than summarizing the literature about isotretinoin (for more details, see RISK/NEWSLETTER 3/96). Despite the half-life of approximately 1 day (manufacturer insert), due to the teratogenicity of this medication it is recommended that isotretinoin be discontinued at least one month prior to attempting pregnancy (Braun et al., 1984; Benke, 1984; Rosa, 1983; McBride, 1985; Rizzo et al., 1991).
Tretinoin (Avita cream, Retin A)
Tretinoin is a component of various topical acne creams. Because this medication is related to isotretinoin, there is concern that tretinoin could potentially have similar teratogenic effects on the fetus. Two case reports have described infants born to women using topical tretinoin during the first trimester of pregnancy. The infants had malformations that mimic the birth defects associated with isotretinoin (Camera et al., 1992; Lipson et al., 1993). In contrast, a prospective cohort study failed to find an association between birth defects and 215 women exposed to tretinoin in the first trimester (Jick et al., 1993). Shapiro et al. (1997) did not find a significant increase in number of livebirths, SAB’s, low birth weight, major malformations, duration of pregnancy, and cesarean sections in 94 women exposed to tretinoin versus controls.
A dose-response relationship potentially could play a role in the effects of tretinoin; it is of note that 5-31% of tretinoin is absorbed sytemically, depending on whether the skin is healthy or dermatitic. Although prospective studies have shown no increase in congenital anomalies, the case reports and biological plausibility of the anomalies raise concern about this medication. While such risks are likely to be low given the low topical absorption, health professionals should encourage women to weigh the risk and benefits of tretinoin during pregnancy.
Adapalene (Differin Gel)
Adapalene is a retinoid used in a topical gel form for the treatment of acne. As such, there are theoretical risks for retinoid embryopathy. However, the manufacturer reports that only trace amounts of adapalene are absorbed from the skin (trace is defined as less than 0.25 ng/ml). The manufacturer’s studies on pregnant rats and rabbits using doses 120-150 times the maximum human topical dose did not show an increased risk of adverse outcome or malformations. There has been one human case report of adapalene use during weeks 4-13 of pregnancy; the fetus had IUGR, anophthalmia and agenesis of the optic chiasm, and the pregnancy was aborted at 13 weeks (Autret et al., 1997). The anomalies seen in this pregnancy are not typical of those seen with other retinoid exposures. In addition, as with any case report, the malformations could be coincidental and unrelated to the adapalene. There have not been any other human studies or case reports to date. The overall risk of adapalene is undetermined because there have not been any human studies. However, because only trace amounts of the gel are absorbed into the skin, it is unlikely that doses large enough to induce malformations could reach a fetus.
Other medications
Azelaic Acid (Azelex)
Azelaic acid is a topical cream for acne. The manufacturer’s studies in animals do not show an increase in malformations at doses much higher than the maximum human dose. There have not been any human reproductive studies to date. While it is reassuring that animal studies do not show teratogenicity and that the fetal dose is small because the medication is topical, the risk of azelaic acid is undetermined because there have been no human studies.
Conclusions/Summary
In summary, acne medications present a range of risks during pregnancy. Because of its proven teratogenicity, it is well known that isotretinoin (Accutane) should not be taken during pregnancy. Additionally, tetracycline and its derivatives should not be used after 16 weeks gestation due to its effects on calcium-containing tissue, particularly teeth. The risks of other medications such as tretinoin are less certain, while some commonly used medications, like benzoyl peroxide, do not appear to pose a significant risk for malformations. Because of the widely known teratogenic effects of isotretinoin, many women are wary of acne medications in general during pregnancy. However, there are a wide variety of medications available for the treatment of acne, many of which pose a minimal risk if applied topically during pregnancy.
References
Adair (1938). JAMA. 111:766-70.Aron et al. (1990)
Autret et al. (1997). Lancet. 350:339.
Benke PJ (1984). JAMA. 251:3267-9.
Braun JT et al. (1984). Lancet 1:506-7.
Briggs et al. (1993). Drugs in Pregnancy and
Lactation 5th Ed. Williams and Wilkins, 1998.
Camera, G et al (1992). Lancet, 339:687.
Cohlan SQ et al. (1961). Antimicrobial Agents and
Chemotherapy. 340-7.
Czeizel and Rockenbauer (1997). Teratology. 56(5): 335-40.
Egerman et al. (1992). Obstet Gynecol Clin NA. 19(3):551-61.
Fitzsimons et al. (1986) J Allergy Clin Immunol 78:349-53.
Fraser et al. (1951). Pediatrics. 8:527-33.
Fraser et al. (1995). Teratology. 51(1):45-6.
Hac (1939). Am J Obstet Gynecol. 38:57-66.
Heinonen et al., Birth Defects and Drugs in Pregnancy.
Littleton, MA:Publishing Sciences Grp, 1977
Hill RM (1984). Lancet. 1:1465.
Jick H. et al. (1981). JAMA. 246(4):343-6.
Jick S et al. (1993). Lancet, 341:1181-1182.
Kline et al. (1964). JAMA. 188:178-80.
Kutscher et al. (1966). Am J Obstet Gynecol. 96:291-2.
Lipson AH et al (1993). Lancet, 341:1352-3.
McBride WG. (1985). Lancet. 1:1276.
McCormack et al. (1987). Obstet Gynecol. 69:202-7.
Nelson et al. (1971). BMJ. 1:523-7.
Philipson et al. (1976). Clin Pharm Ther. 19:68-77.
Rizzo R et al. (1991). Teratology. 44:599-604.
Rodriquez-Pinella and Martinez-Frias (1998)
Teratology 58:2-5.
Rosa FW. (1983). Lancet. 2:513.
Rumack et al. (1981). Obstet Gynecol. 58(Sup):52S-6S
Saxon et al. (1975). Int J Epidem. 4:37-44.
Schatz et al. (1997) J Allergy Clin Immunol 100:301-6
Shapiro L et al (1997). Lancet, 350:1143-4.
Takaya (1965)
Weinstein et al. (1976) Am J Obstet Gynecol. 124:688-91
Additional Useful Review Articles:
Duff, P. (1992). “Antibiotic use in Obstetrics andGynecology.” Obstet Gynecoly Clin NA 19(3).
Reed BR. (1997). Dermatologic drug use during pregnancy and lactation. Derm Clinics, 15(1):197-206.
Robert E and Scialli A (1994). Topical medications during pregnancy. Reproductive Toxicology 8(3):197-202.
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Posted by admin on February 1st, 2000 — in newsletter
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Surgery and Pregnancy
Vol 7#5, February 2000
Kim Kitson, BA; Kelly Ormond, MS, CGC; Eugene Pergament, MD, PhD, FACMG
Up to two percent of all pregnant women undergo surgery during pregnancy. Each year, thousands more women of reproductive age chronically inhale trace amounts of anesthetic gas while working in operating rooms and dental offices. The risks and benefits of possible surgery or occupational exposure must be carefully considered in any pregnancy. This RISK//NEWSLETTER will review the potential reproductive risks in women acutely exposed to anesthesia during surgery or chronically exposed to anesthetic gases in their occupation.
Surgery and anesthesia in pregnancy
Knowledge regarding the safety of surgery and anesthesia during pregnancy is based primarily on animal studies and retrospective human surveys conducted mostly in the 1970’s and early 1980’s. These studies have a number of confounding variables. Women are generally given multiple anesthetic agents and other agents (including analgesics, antiemetics and sedatives), making it difficult to discern the effects of individual agents. When surgery is combined with anesthesia, it is not possible to determine whether adverse outcomes are due to the operative procedure, the underlying maternal condition, maternal stress, fever or the anesthetic agent. While animal studies make it possible to separate the procedural risks from risks associated with the anesthesia exposure, even in animal studies, it remains difficult to determine if the observed effect is due to the anesthetic or to the physiological changes caused by anesthesia. Variations in genetic susceptibility also make it difficult to generalize these studies to humans because of interspecies variation.
Most human studies have not found a significant difference in the overall rate of congenital anomalies among women receiving general anesthesia while undergoing surgery (Knill Jones, 1972; Duncan et al., 1986; Mazze et al., 1989). Further analysis of the Mazze et al. study did note a significant increase in the incidence of neural tube defects (NTDs); six NTDs were observed while only 2.5 were expected. There were no indications that any one anesthetic was the cause of the NTDs, and researchers could not rule out other factors such as the underlying disease, the neuroendocrine events associated with the stress of surgery, or the trauma of the operation as the cause of the increased incidence NTDs. The authors report that the association could be a random finding because the observation developed as a result of searching a large data base, rather than as a consequence of testing a hypothesis regarding the effect of surgeries on NTDs. No other studies have found similar increases in NTD incidence, and as such, the association between NTDs and maternal surgery during the period of neural tube formation must be regarded as unproven (Kallen et al., 1990).
For women undergoing general anesthesia and surgery during pregnancy, aside from malformations, several studies have noted an increase in spontaneous abortions (Brodsky et al. 1980; Duncan et al., 1986), in infants with very low (<1500 gm) or low (<2500 gm) birth weights and in infant mortality (Mazze et al., 1989).
Occupational expsoure to anesthestic agents
Not unlike the confounding factors associated with surgery, occupational exposure studies are confounded by a number of factors, particularly that the control groups in these studies often consisted of non-working women. One study found that employed women had higher levels of education and income, earlier prenatal care, greater weight gain during pregnancy, and they were slightly less likely to be heavy smokers. Employed women were also had fewer previous births and more spontaneous abortions and stillbirths than their unemployed counterparts (Savitz et al., 1990). Factors such as standing, heavy lifting, long work hours and changing shift work may also contribute to the confounding biases of these studies.
Finally, it is important to note that these studies were performed in the 1970’s, when ventilation and scavenger systems in hospitals and dental operating rooms were not as efficient as those produced today; women in these studies were probably exposed to significantly higher levels of anesthetic gas than current workers. Nevertheless, a report in 1994, warning exposed workers of the potential harmful effects of nitrous oxide, was published by the United States National Institute for Occupational Safety and Health (NIOSH) (Boivin, 1997).
Common General Anesthetic Agents
Most human data available on individual anesthetic agents comes from the Collaborative Perinatal Project (Heinonen et al., 1977). Data are reported individually for each agent despite the fact that women in this study were probably given more than one anesthetic at surgery in every case. Consequently, the information available is difficult to interpret. Unfortunately, for many of these agents reproductive risk assessment is limited to this retrospective human data, coupled with minimal animal data. Friedman (1988) provides a comprehensive review of the available literature on a larger number of anesthetic agents.
Parenteral anesthesia
Thiopental
Thiopental is a rapidly acting barbiturate that has been used since the 1930s. In studies with rats and mice treated with 1.5-3 times the human dose, thiopental was not found to be teratogenic (Persaud, 1965). In a retrospective study of 152 women treated with thiopental during the first four months of pregnancy, there was no increase in congenital anomalies (Heinonen et al., 1977).
Methohexital
Methohexital is a short acting barbiturate. A manufacturer study using pregnant rabbits and rats found no increase in fetal abnormalities. Forty-one women treated with methohexital during the first four months of pregnancy did not result in a significant increase in the number of congenital anomalies (Heinonen et al., 1977).
Thiamylal
Thiamylal is an ultra-short acting barbiturate, similar to Thiopental. Treating pregnant mice with thiamylal resulted in an increase in limb anomalies, which sometimes are a sign of maternal toxicity (Friedman, 1988). Among the children of 21 women treated with this agent during the first four months of pregnancy, the frequency of congenital anomalies was not increased (Heinonen et al., 1977).
Etomidate
Etomidate is an imidazole hypnotic used for the induction of general anesthesia. In rats exposed to up to forty times the recommended human dose, the frequency of malformations was no greater than expected (Friedman, 1988). No epidemiological studies have been reported of women treated with etomidate during pregnancy having children with congenital anomalies, and therefore the risk associated with etomidate in human pregnancy remains unknown.
Ketamine
Rats exposed to ketamine at doses more than ten times those used in humans were not found to have an increased incidence of malformations (Friedman, 1988). No epidemiological studies have been reported of congenital anomalies in children born to women treated with ketamine during pregnancy, and therefore the risk associated with ketamine in human pregnancy remains unknown.
Inhaled anesthetics
Nitrous oxide
Growth retardation and malformations have been observed in the offspring of pregnant rats exposed to high or chronic doses or nitric oxide (Mazze et al., 1984). In contrast, other studies found that increased rates of resorptions (analogous to spontaneous abortion) but no increase in malformations in exposed rats (Mazze et al., 1982; 1984; 1986). The incidence of congenital anomalies among children of 76 women anesthetized with nitrous oxide during the first four months of pregnancy was no greater than expected (Heinonen et al., 1977). One study reports an association between use of this agent during the first trimester and an increased incidence of spontaneous abortion (Brodsky et al. 1980). A subsequent larger study did not confirm an increased incidence of spontaneous abortion among women treated with nitrous oxide (Mazze et al. 1989).
Halothane
Halothane is a halogenated hydrocarbon. Rodent studies initially found exposure to high or prolonged halothane concentrations to be associated with an increase in birth defects specifically involving the skeleton (Basford et al., 1968). Subsequent studies have not found an association between moderate doses of halothane in pregnant rodents and birth defects (Mazze et al 1986), and it is possible the malformations noted by Basford were due to maternal toxicity. The Collaborative Perinatal Project found that the frequency of congenital anomalies was not significantly increased among children of 25 women who received halothane during the first 4 months of pregnancy (Heinonen et al., 1977).
Enflurane
Among the offspring of rabbits treated with enflurane during pregnancy, limb and abdominal wall defects were observed more often than expected (Freidman, 1988). Pregnant mice exposed to anesthetic concentrations of enflurane had an increased frequency of cleft palate, ventriculomegaly, and hydronephrosis (Wharton et al., 1979). Other studies have not found enflurane during pregnancy to be associated with increased risk for birth defects (Mazze et al., 1986; Freidman, 1988). There are no epidemiological studies of congenital anomalies in children of women treated with enflurane during pregnancy, and therefore the risk associated with enflurane in human pregnancy remains uncertain.
Isoflurane
Pregnant mice exposed to light doses of isoflurane were found to have an increased frequency of cleft palate, skeletal variations and fetal growth retardation (Mazze et al., 1985). At doses similar to those used in humans, other investigators have not observed teratogenic effects among the offspring of pregnant rats or rabbits treated repeatedly with isoflurane (Kennedy et al., 1977; Mazze et al., 1986). There are no epidemiological studies reporting congenital anomalies in children born to women exposed to isoflurane during pregnancy. Therefore, its risk in human pregnancy remains undetermined.
Methoxyflurane
Offspring of rats and mice treated with methoxyflurane had an increase in skeletal anomalies in one study (Schwetz 1970). A subsequent study found no increase in the number of malformations among the offspring of mice treated with this agent during pregnancy, although fetal growth retardation and delayed skeletal development occurred (Wharton, 1980). No epidemiological studies of congenital anomalies in children born to women exposed to methoxyflurane during pregnancy have been reported, and its risk remains undetermined.
Local Anesthetics
Because local anesthetics are used by topical application or injection, their systemic absorption is often limited. In situations where systemic absorption by the mother is virtually absent, no significant teratogenic effect would be expected regardless of the potential teratogenic activity of the agent. The Collaborative Perinatal Project is the primary source of epidemiological data on possible teratogenic effects of local anesthetic agents. In addition to the previously discussed limitations, this study does not distinguish medicaitons by route of exposure. Therefore, topical application, local injection, regional infiltration and spinal infusion are all considered together. This study evaluated the possible teratogenicity of several local anesthetic agents including procaine, lidocaine, mepivacaine, benzocaine, propoxycaine, and tetracaine. Based on the limited information available, it seems unlikely that these topical agents are associated with a high risk of teratogenic effects in humans (Friedman, 1988).
Summary
Information regarding the safety of anesthesia and surgery during pregnancy is limited and confounded by many factors. In the case of surgery, it is important to weigh the risks and benefits of the procedure against any possible risks. Based on the information reviewed in this newsletter, there does not appear to be an increased risk for congenital malformations associated with anesthetic use. The possible association between anesthesia/surgery and a risk for neural tube defects is unclear and warrants further study. Occupational exposure to anesthetics has been shown to increase the risk of spontaneous abortion by 1.5 to two times the background risk. Given the methodological weakness of these studies, there is a possibility that this increase is coincidental. With all exposures, particularly occupational ones, it is best to limit the exposure as much as possible.
References
Basford A, Fink B (1968). Anesthesiology 29:173-4.
Boivin JF (1997). Occup Environ Med 54:541-548.
Brodsky JB et al (1980) Am J Obstet Gynecol 138:1165-7.
Cohen ENet al. (1971) Anesthesiology 34:343-347.
Duncan PG et al (1986) Anesthesiology 64:790-4.
Friedman, JM (1988). Teratology 37:69-77.
Källén B, Mazze RI (1990) Teratology 41:717-20.
Kennedy GL et al (1977). Drug Chem. Toxicol. 1:75-88.
Knill-Jones RP et al. (1972) Lancet 1:1326-1328.
Mazze RI, Källén B (1989) Am J Obstet Gynecol 161:1178-85.
Mazze RI et al (1986). Anesthesiology 64:339-44.
Mazze RI et al. (1982). Teratology 26:11-16.
Mazze RI et al. (1984). Teratology 30:259-265.
Savitz DA et al. (1990) Am J Epidem 132:933-45.
Tannenbaum TN, Goldberg RJ (1985) J Occup Med 27:9659-668.
Wharton RS et al. (1979)Teratology 19:53A.
Wharton RS et al. (1980) Anesth. Analg. 59:421-425.
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Posted by admin on June 2nd, 1999 — in newsletter
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Gastroesophogeal Reflux (GERD) Medications in Pregnancy
Deborah Lilienthal, BS; Kelly Ormond, MS, CGC, Eugene Pergament, MD, PhD
Volume 7(5), June 1999
Gastroesophageal reflux disease (GERD) is the movement of acidic gastric contents into the lower esophagus. Often described as heartburn or “acid indigestion,” reflux occurs in approximately two thirds of all pregnancies. Almost everyone experiences gastroesophogeal reflux at some time, although in some individuals reflux is frequent or severe enough to require daily medication. There is also a growing percentage of women with GERD prior to pregnancy who will require maintenance medications throughout gestation. The origin of GERD is multifactorial, but the predominant factor is a decrease in lower esophageal sphincter pressure. Since mechanical factors and female sex hormones, especially progesterone, play a role in GERD (Baron and Richter, 1992), heartburn is more common during the last months of pregnancy, when the growing fetus presses against the stomach and hormones are at high levels. This RISK//NEWSLETTER will present information on the reproductive risks of GERD medications.
Mild heartburn may be treated with lifestyle and dietary modifications. Good posture while eating and avoiding lying down after meals may reduce the occurrence of heartburn. Smoking should also be avoided because it increases stomach acidity.
Antacids
Antacids are commonly used by many women during pregnancy. Available without a prescription, they neutralize stomach acid to provide temporary relief. A variety of antacids are available. The most common antacids on the market are: Mylanta (calcium carbonate and magnesium hydroxide); Maalox (magnesium hydroxide and aluminum hydroxide); Tums (calcium carbonate); and Rolaids (calcium carbonate and magnesium hydroxide). Although there is little empiric data on human exposure to antacids, they are a common exposure in pregnancy, and as such are unlikely to significantly increase the risk for birth defects at therapeutic doses.
Aluminum Hydroxide
Animal studies of aluminum hydroxide at oral doses up to 64 times the human dose did not show significant maternal or developmental toxicity (Domingo et al., 1989; Gomez et al., 1990; Colomina et al., 1994). Therefore, at usual human doses, aluminum hydroxide is not likely to increase the risk for birth defects.
Calcium Carbonate
In an animal study done by Shackelford et al. (1993), rats were given up to 1.25% dietary calcium carbonate before mating and during organogenesis. Dietary calcium was not found to have adverse effects of the offspring. Severe hypercalcemia, a potentially life-threatening condition, was reported in a pregnant woman with excessive ingestion of absorbable calcium antacid. She was treated and the child was delivered a month later with an uncomplicated neonatal course (Kleinman et al., 1991). Even with toxic levels of calcium carbonate in the mother, teratogenic effects were not seen in the fetus. Therefore, calcium carbonate is unlikely to significantly increase the risk for birth defects.
Magnesium Hydroxide
In one study, magnesium hydroxide was administered to 27 pregnant women in the third trimester without adverse effects (Rudnicki et al., 1991). Although limited information is available, this data does not support an association between magnesium hydroxide and birth defects.
Histamine-2 Receptor Blockers (H2RA)
Histamine-2 Receptor Blockers (H2RA) treat the discomfort of heartburn and acid indigestion by blocking histamine, which decreases acid secretion. They are also commonly used during pregnancy, and they are available both over the counter and by prescription at higher doses. The majority of reproductive information for H2RAs regards cimetidine and ranitidine.
Cimetidine (Tagament)
Cimetidine has weak antiandrogenic effects in animals and antiandrogenic effects in humans, causing impotence and oligospermia (Sawyer et al., 1981). While no studies have examined these possible antiandrogenic effects in human pregnancy, two studies found that cimetidine adversely affects male androgenization and neuroendrocrine programming in rats (Anand and Van Theil, 1982; Parker et al., 1984). It is theoretically possible that use in pregnant women may adversely affect adult sexual behavior and development of male progeny. Other animal studies showed no difference in masculinity between those animals taking cimetidine from their controls (Hoie et al., 1994; Shapiro and Bitar, 1991; Shapiro et al., 1988; Walker et al., 1987). It remains unclear what significance, if any, these findings may have on human exposures.
A prospective study of 10 women exposed to cimetidine in the first trimester reported 2 therapeutic abortions and 8 normal births (Koren and Zemlickis, 1991). A retrospective study of 460 newborns exposed to cimetidine in the first trimester found no increase in major birth defects, but slightly more heart defects were observed than expected (Briggs et al., 1998). Other studies have not shown an increase in heart defects. The manufacturer reported three newborns with congenital birth defects (congenital heart defect, clubfoot, and mental retardation, respectively) after in utero exposure to cimetidine. No pattern was seen in these infants and the defects were not attributed to the use of cimetidine (Briggs et al., 1998). While limited, this data does not suggest an association between cimetidine and birth defects.
Cimetidine is also used at term to prevent maternal Mendelson’s syndrome. There are several reports of women exposed late in pregnancy, without reported teratogenic effects in the newborns (e.g., Carazza et al., 1982). Glade et al. (1980) reports transient neonatal liver toxicity in a newborn exposed to cimetidine at term. This has not been reported in any subsequent studies.
Famotidine (Pepcid)
Animal studies have shown no adverse effects when given famotidine at doses as high as 2,000 mg/kg/day, much higher than the recommended human dose (Shibata et al., 1983; Burek et al., 1985). There is little information in the medical literature on the effects of famotidine in human pregnancy. In a retrospective study of 33 newborns exposed to famotidine in the first trimester, 2 major birth defects were seen; there was no pattern to these defects(Briggs et al., 1998). The number of exposures is too small to make a risk assessment. Famotidine does not have antiandrogenic effects.
Nizatidine (Axid)
Nizatidine was given orally to rats and rabbits at doses as high as 1500mg/kg/day and no teratogenic effects were seen (Morton , 1987). In contrast, the manufacturer reports animal studies with congenital malformations at doses of 20mg/kg and 50mg/kg. These malformations included cardiac defects, neural tube defects and cutaneous edema (Briggs et al., 1998). There is no human epidemiologic data on the effects of nizatidine during pregnancy, and its risk is therefore undetermined. One case report of a woman exposed to nizatidine in the second trimester shows that she delivered a healthy infant (Briggs et al., 1998). Unlike cimetidine, nizatidine is not an androgen antagonist (Neubauer et al., 1990).
Ranitidine (Zantac)
Animal studies on ranitidine have not shown an increased risk for malformations. A prospective study of 13 women exposed to ranitidine during the first trimester reported 10 normal births, 2 spontaneous abortions and one infant born with a hemangioma on the right upper eyelid (Koren and Zemlickis, 1991). A retrospective study of 516 newborns exposed to ranitidine in the first trimester reported no increase in malformations nor pattern to those noted (Briggs et al., 1998).
Most data on ranitidine is regarding use near delivery to prevent Mendelson’s syndrome. There have not been reports of adverse effects in newborns exposed to ranitidine near delivery (summarized in Briggs et al., 1998). While limited, the data does not support an association between the drug and congenital defects. Antiandrogenic effects have not been seen with the use of ranitidine (Parker et al.,1984).
Proton Pump Inhibitors (PPIs)
Proton pump inhibitors decrease the stomach’s production of acid more completely than the H2RA’s by stopping the stomach’s acid pump, which is the final step of acid secretion. PPIs are a relatively new class of GERD treatment, and as such, less information is available.
Lansoprazole (Prevacid)
Animal studies on lansoprazole in rabbits and rats did not find evidence that lansoprazole impairs fertility or teratogenicity at 16 to 80 times the human doses, respectively (Schardein et al., 1990; Briggs et al., 1998). There have been no reports on the effects of lansoprazole use during human pregnancy, and as such its risk is undetermined.
Omeprazole (Prilosec)
Animals given up to 345 times the recommended human dose of omeprazole did not show teratogenic effects, although there was a slight increase in miscarriage and fetal mortality (Briggs et al., 1990). A case report of a woman who used omeprazole in three pregnancies, including one in the first trimester, showed that she delivered three healthy infants (Harper et al., 1995). Several case reports exist of adverse outcomes after omeprazole use. The FDA has received 11 voluntary reports of birth defects following pregnancy exposure to omeprazole use, including four cases of anencephaly and one case of hydranencephaly after use in the second trimester (Briggs et al., 1998). Tsirigotis et al. (1995) describes a woman who ingested 20mg of omeprazole daily during two consecutive pregnancies and subsequently terminated them because of anencephaly and clubfoot, respectively. While these case reports of anencephaly suggest a pattern of defects, without background information on these pregnancies, the potential confounding factors inherent in case reports make it difficult to attribute the cause to omeprazole.
In a recent prospective cohort study of 113 women exposed to omeprazole, 101 throughout organogenesis (89%) and 15% throughout pregnancy, no association was found between in utero exposure and malformations, birth weight, gestational age at delivery, preterm deliveries, or neonatal complications (Lalkin et al., 1998). Although the case reports may be concerning, the lack of teratogenicity in animals and the recent prospective human studies show that omeprazole is unlikely to significantly increase the risk for birth defects.
Prokinetic Agents
Prokinetic agents hasten emptying of the stomach contents, resulting in less acid secretion available for reflux. Some agents also increase the “tone” of the lower esophageal sphincter, making it more difficult to open.
Cisapride (Propulsid)
Animal studies in rats show impaired fertility at 25 times the human dose. At 12 to 100 times the human dose in rats and rabbits, respectively, an increase in IUGR and neonatal death was noted (Briggs et al., 1998). In a prospective study, 129 pregnant women were exposed to cisapride, including 88 during organogenesis. There were no differences in birthweight, gestational age at delivery, and rates of livebirths, spontaneous abortions, fetal distress, and major or minor malformations among those exposed to the drug and those used in the control group. This suggests that cisapride is not likely to pose a significant teratogenic risk (Bailey et al., 1997).
Metoclopramide (Reglan)
Manufacturer’s information on mice, rats, and rabbits given doses up to 250 times the human dose, showed no evidence of fetal harm (Briggs et al., 1998). In a retrospective study of 192 newborns exposed to metoclopramide in the first trimester, 10 (5.2%) major birth defects were seen (Briggs et al., 1998). In a study by Nageotte et al. (1996) 80 women with hyperemesis used metoclopramide during pregnancy. Three women who used metoclopromide in the second trimester delivered infants with birth defects; there was no pattern to the defects, making it even less likely that metoclopramide was a causal factor. Five case reports of women exposed to metoclopramide in early pregnancy did not show teratogenic effects (Briggs et al., 1998).
Summary
Little empiric data is available on most GERD treatments in pregnancy, despite their frequent exposure. The lack of human studies on GERD medications in pregnancy makes it difficult to provide an accurate teratogenic risk assessment. As with any medication, the lowest possible dose should be taken to relieve discomfort. Pregnant women with GERD should speak to their doctors about the best treatment for their GERD, and consider weighing the need for treatment with the options and information available on use during pregnancy.
References
Anand S, VanThiel D (1982) Science 18(4571):493-4
Bailey B et al. (1997) Dig Dis Sci 42(9):1848-52.
Baron TH, Richter JE (1992) GastroenterologyClin NA 21(4):777-91.
Briggs GG et al. (1998) Drugs in Pregnancy and Lactation, 5th ed. Baltimore:Williams & Wilkins.
Burek JD et al. (1985) Digestion 32(Sup1): 7-14.
Colomina MT et al. (1994) Pharmacology & Toxicology 74(4-5):236-9.
Corazza GR et al. (1982) Clin Trials J 19:91-3.
Domingo JL et al. (1989) Life Sciences 45(3):243-7.
Koren G, Zemlickis D (1991) Am J Perinat 8(1):37-8.
Glade G et al. (1980) Am J of Dis Child 34(1):87-8.
Gomez M et al. (1990) Vet Hum Toxicol 32(6):545-8.
Harper MA et al. (1995) Am J Obstet Gynecol
173(3 Pt 1):863-4.
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Hoie EB et al. (1994) J Pharm Sciences 83(1):107-9.
Kleinman GE et al. (1991) Obstet Gyn 78(3Pt2):496-9.
Lalkin A et al. (1998) Am J Obstet Gynecol 179(3 Pt 1):727-30.
Morton DM (1987) Scand J Gasteroent 22(S 136):1-8.
Neubauer BL et al. (1990) Tox AppPharm 102:219-32.
Parker S et al. (1984) Neuro Tox & Terat. 6(4):313-8.
Parker S et al (1994) Gastroenterology 86(4):675-80.
Rudnicki M et al (1991) Acta Obstet Gyn Scand 70(6):445-50.
Sawyer D et al. (1981) Am JHospPharm 38(2):188-97.
Shackelford ME et al. (1993) Food & Chemical Toxicology 31(12):953-61.
Schardein JL et al. (1990) Yakuri To Chiryo 18(S10):119-29.
Shapiro BH, Bitar MS (1991) Tox Letters. 55(1):85-98.
Shapiro BH et al. (1988) Tox Letters 44(3):315-29.
Shibata M et al. (1983) Oyo Yakuri 26: 489-497, 543-578, 831-840.
Tsirigotis M et al. (1995) Human Repro 10(8):2177-8.
Walker TF et al. (1987) Fund Appl Tox. 8(2):188-97.
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Posted by admin on June 1st, 1999 — in newsletter
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Update: Benzodiazepines in Pregnancy
Vol. 7., No. 4 June 1999
Kelly Ormond, MS, CGC and Eugene Pergament, MD, PhD
Benzodiazepines (BZDs) are frequently prescribed during pregnancy to treat anxiety or panic disorder. As a class, the BZDs are central nervous system depressants that have anxiolytic, sedative, hypnotic, muscle relaxant and occasionally anti-epileptic properties. They are well absorbed in the body and cross the placenta easily (Kanto, 1982); elimination half-lives for the BZDs range significantly (8-48 hours), with active metabolites often remaining in the body for longer periods of time (Gilman, 1990).
Initial concern regarding BZD exposure in pregnancy arose because they act upon GABA receptors; GABA is an amino acid neurotransmitter that may be related to palatal development (Kellogg, 1988). Early studies on Valium (diazepam), a commonly prescribed BZD, showed an increased risk for oral clefting in both animals (Zimmerman, 1984) and in retrospective and case-control studies in humans (Saxon and Saxen, 1975; Safra and Oakley, 1975). This has, however, been contradicted by several recent prospective and case-controlled studies and a meta-analysis that all uniformly found no association between diazepam use and clefting (Altshuler et al., 1996; Bracken, 1986; Czeizel, 1988; Ornoy et al., 1998; Pastuszak et al., 1994; Rosenberg et al., 1983; Shiono and Mills, 1984). In recent years, several prospective studies have addressed the potential teratogenicity of multiple BZDs. The association between BZDs and clefting, and birth defects in general, remains unclear, and it will be reviewed in more detail in this RISK//NEWSLETTER. BZDs were reviewed in the September, 1995 (RISK//NEWSLETTER 4(2)); this newsletter serves as an adjunct to that issue.
General studies on BZDs
Many of the studies on BZD exposure in pregnancy have lumped various drugs into a single analysis, making it difficult to determine if specific medications pose teratogenic risk in pregnancy. McElhatton (1994) provides an excellent review of many of the studies on BZDs. While there have been mixed findings, these studies do not suggest an overall increase in malformations after in utero exposure to BZDs. Pastuszak et al. (1994) prospectively ascertained 137 women exposed to BZDs, primarily diazepam (N=43) and lorazepam (N=33) and found no differences from control groups in frequency of malformations or miscarriage, birth weight, gestational age or measures of the Denver developmental scale at various ages. Johnson et al. (1995) presented an abstract reporting 272 women exposed to alprazolam, lorazepam and clonazepam; of the 186 liveborns, 15 had malformations, including four cardiac defects and six inguinal hernias, which the authors speculated may be secondary to the muscle relaxant properties of BZDs. In a separate abstract, Godet et al. (1995) reported on 187 malformed infants exposed to BZDs; while no anomaly was more frequent in this group as compared to a control group of over 10,000 malformed infants, associations between lorazepam and anal atresia and between bromazepam and urinary anomalies were noted, but there was no association between clefting and any BZD. Most recently, Ornoy et al. (1998) prospectively reported 460 pregnancies exposed to BZDs in the first trimester and found no increase in birth weight, gestational age or malformations, but more cardiac defects were present in the exposed versus control group; a slight increase in miscarriage and induced abortions was also observed.
Aside from the concerns regarding malformations after in utero exposure to BZDs, there are reports of transient neonatal withdrawal symptoms and even of a possible syndrome of BZD exposure after significant maternal exposure (Laegrid et al., 1989; Bergman et al., 1992). Laegrid et al. (1989) described facial dysmorphology similar to fetal alcohol syndrome, involving impaired growth, hypotonia, developmental and motor delays and transient neonatal withdrawal after significant maternal BZD exposures. Other studies have failed to support this association, suggesting that perhaps chronic use at high dosages is required to produce this syndrome. There has also been controversy about whether an autosomal recessive condition (Zellweger syndrome) explains some of the physical and developmental features noted. The confounding effect of other maternal drug use in Laegrid’s studies has also been raised. Most recently, the Michigan Medicaid study (Bergman et al., 1992) looked at 80 women who filled over 10 benzodiazepine prescriptions during a pregnancy and saw no increase in malformations among those exposed in utero. Concurrent maternal alcohol and substance exposure in pregnancy significantly biases all of the above studies. While no long term studies have been performed to assess neurodevelopment in exposed children, the potential exists for neurobehavioral teratogenicity after exposure to BZDs, and this has been noted in animal studies (Schardein, 1993).
Reproductive Data on Specific BZDs
Alprazolam (Xanax)
Several human studies exist on alprazolam exposure in pregnancy. Postmarketing research of 411 women with first trimester exposure to alprazolam did not suggest an increased frequency of malformations (St. Clair et al., 1992). Separate prospective studies of 133 and 149 women, respectively, found no increased risk of malformations nor any pattern to the malformations described (Johnson et al., 1995; Ornoy, 1998). Neonatal withdrawal symptoms have been noted after exposure to alprazolam in late pregnancy (Barry and St.Clair, 1987) and breast-feeding (Anderson and McGuire, 1989). Alprazolam has a relatively short half-life (<12 hours) compared to other BZDs.
Chlordiazepoxide (Librium)
Data on chlordiazepoxide exposure in pregnancy has been contradictory. 175 pregnancies exposed to chlordiazepoxide showed an increased frequency of malformations (Milkovich, 1974). In contrast, two studies of 257 and 136 women using Librium in the first trimester found no increase in malformations (Hartz, 1975; Crombie, 1975). This was supported by a large retrospective study of 788 women (Rosa, cited in Briggs, 1998) that also showed no increase in malformations, but there was a slight increase in cardiac anomalies (10 vs. 7 expected). A case-control study of infants with cardiac defects also showed a slight association with chlordiazepoxide exposure (Rothman et al., 1979), but it is unclear what to make of this association. Animal studies involving rats and mice show no increase in malformations at doses lower than the maternal toxicity levels; however, there is some evidence of low birth weight and behavioral changes at doses 2-7X the human dose. Withdrawal symptoms have been noted after exposure to chlordiazepoxide near term (Briggs, 1998).
Clonazepam (Klonopin)
Clonazepam has not been shown to increase malformations in rats or rabbits. A single retrospective study of 19 women exposed in the first trimester showed 3 malformations (including 2 heart defects); because of the small study size, the implications of this finding are unclear (Briggs, 1998). Prospective studies of 60 and 69 women each found a slight increase in malformations, but given the small number of women in each study, it remains difficult to determine causality from these studies (Johnson et al., 1995; Ornoy, 1998). One complicating factor is that clonazepam is also used to treat seizure disorder and therefore, an increase in malformations may be due to epilepsy rather than medication use. A case control study of anti-epileptic medications, including clonazepam, did not show an association with malformed infants and clonazepam use during pregnancy (Czeizel, 1992). Clonazepam has a relatively long half-life (20-40 hours) compared to other BZDs (McElhatton, 1994), and withdrawal symptoms have been observed after exposure late in pregnancy (Fisher et al., 1985).
Clorazepate (Tranxene)
While clorazepate crosses the placenta in a limited amount, it’s metabolite nordiazepam is related to diazepam and crosses the placenta easily. Clorazepate is not teratogenic in mice, rats or rabbits, but there are no human studies available. There is a single case report of multiple malformations in an infant whose mother took clorazepate during the first trimester; the relevance of this is unknown (Patel, 1980). As such, clorazepate has an undetermined risk during pregnancy.
Diazepam (Valium)
Most reproductive studies on BZDs involve diazepam, and its reproductive risks are well reviewed (McElhatton, 1994). As previously discussed, several early case controlled studies on diazepam showed an increased risk of oral clefts, with relative risks of approximately 3-4 times the baseline risks (Aarskog, 1975; Safra and Oakley, 1975; Saxen, 1974). These early studies were criticized for their study design and other confounding factors. Studies since that time have contradicted these results, showing no increase in clefting (Rosenberg et al., 1983; Shiono and Mills, 1984; Czeizel, 1988). Prospective studies of 43 and 89 women exposed to diazepam did not show any increased risk for malformations, specifically for oral clefts (Pastuszak et al., 1994; Ornoy et al., 1998). Thus, it appears that if there is a risk of oral clefting after exposure to diazepam, it is likely to be a insignificant.
Flurazepam (Dalmane)
Human studies on flurazepam are limited to a retrospective study following 73 women exposed in the first trimester (Briggs, 1998). No increase in malformations was seen. Animal studies have not shown an increased risk for malformations (McElhatton, 1994). However, because of the paucity of information on flurazepam in pregnancy, its risks remain undetermined.
Lorazepam (Ativan)
Lorazepam crosses the placenta more slowly than diazepam, and also has a short half life (12-16 hours). Lorazepam is not considered teratogenic in mice or rats, but human reproductive data is limited. Small prospective studies (N=30; N=112) have not shown an increase or pattern to the malformations observed in women exposed to lorazepam in the first trimester (Johnson et al., 1995; Ornoy, 1998). Much of the human information has reviewed use around labor, and shows an increase in respiratory distress, decreased APGARS, problems with temperature regulation and poor feeding (McElhatton, 1994).
Oxazepam (Serax)
Oxazepam is a metabolite of diazepam. It has not been shown to increase malformations in rats, rabbits or mice (Owens et al, 1970; Miller and Becker, 1973). No malformations were noted in 89 women exposed to oxazepam in a prospective study (Ornoy, 1998). Oxazepam was, however, one of the benzodiazepines that Laegrid (1987) associated with “fetal benzodiazepine syndrome” and neonatal withdrawal.
Triazolam (Halcion)
Data on triazolam is limited to manufacturers data and a retrospective study on 138 women exposed in the first trimester; neither showed any significant increase in malformations or pattern to these malformations (Briggs, 1998), although withdrawal symptoms have been noted (Barry and St. Clair, 1987; Sakai et al. 1996).
Virtually no data is available on Halazepam (Paxipam) or Prazepam (Centrex). Animal studies on these medications do not show an increase in malformations at non-toxic levels. As such, these medications have an undetermined risk for use during pregnancy.
Summary
Use of benzodiazepines, specifically diazepam, was previously thought to be associated with an increased frequency of cleft lip and/or palate; this finding has not been supported by the majority of recent studies. Although the balance of evidence from human studies of the benzodiazepines (chiefly, diazepam) does not show first trimester usage to be teratogenic, animal studies have shown an increase in abnormal behavioral patterns after in utero exposures at levels comparable to the usual human doses. At this point, there is still no conclusive data regarding the possible behavioral teratogenicity of benzodiazepine use during pregnancy. Withdrawal symptoms can occur after fetal exposure late in pregnancy.
References:
Aarskog; Lancet 2:29, 1975.
Altshuler et al. Am J Psychiatry 153:597-8, 1996.
Anderson & McGuire. Ann Pharmacother 23:614, 1989.
Barry and St.Clair. Lancet i:1436-7, 1987.
Bergman U et al. Lancet 340:694-696, 1992.
Bracken MB. NEJM 314: 1120, 1986.
Briggs G et al. Drugs in Pregnancy & Lactation 5th ed, Williams & Wilkins, Baltimore, 1998.
Crombie DL et al. NEJM 291:1268-71, 1975.
Czeizel A. Reprod Toxicol 1(3):183, 1988.
Czeizel A et al. Eur J Epidemiol 8:122-7, 1992.
Fisher JB et al. Obstet Gynecol 66:345-55, 1985.
Gilman AG et al., eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics 8th ed., NY, Macmillan, 1990.
Godet et al.. abstract at OTIS meetings, 6/1995.
Hartz SC et al.. NEJM 292: 726-8, 1975.
Johnson K et al. Teratology 53(1):170, 1995.
Kanto JH. Drugs 23: 354-80, 1982.
Kellogg CK. Prog Brain Res 73: 207-28, 1988.
Laegrid L et al. J Peds 114:126-31, 1989.
McElhatton PR. Reprod Toxicol 8(6):461, 1994.
Milkovich et al. NEJM 291:1268-71, 1974.
Miller R, Becker B.Tox App Pharm 25:453, 1973.
Ornoy A et al. Reprod Toxicol 12(5):511-5, 1998.
Owen G et al. Tox Appl Pharm 16:556-70, 1970.
Pastuszak A et al. in Maternal-Fetal Toxicology, ed by G Koren, 2nd ed., Marcel-Decker, New York, 1994, p 77-88.
Patel DA, Patel AR. JAMA 244: 135-6, 1980.
Rosenberg L. et al. NEJM 390: 1282-5, 1983.
Rothman K et al. Am J Epidem 109:433-439, 1979.
Saxen I, Saxen L. Lancet 2:498, 1975.
Safren MJ, Oakley GP. Lancet 2:478, 1975.
Sakai T, Matsuda H, Watanabe. Eur J Pediatr 155: 1065-6, 1996.
Schardein JL (ed). Chemically Induced Birth Defects 2nd ed., Marcel-Dekker, NY; 1993. pp 209-213.
Shiono PH and Mills JM. NEJM 311: 919, 1984.
St Clair SM, Schirmer RG. ObGyn 80:843, 1992.
Zimmerman EF and Wee EL. Current Topics in Developmental Biology 19: 37-63, 1984.
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Posted by admin on March 1st, 1999 — in newsletter
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Update: Prozac (fluoxetine) and other selective serotonin re-uptake inhibitors (SSRIs)
Kelly Ormond, MS, CGC and Eugene Pergament, MD, PhD
March 1999
Inquiries regarding antidepressant medications, particularly the selective serotonin re-uptake inhibitors (SSRI’s), are amongst the most common calls to the Illinois Teratogen Information Service. Estimates suggest that approximately 10% of women meet diagnostic criteria for clinical depression during pregnancy, with a higher percentage clinically depressed postpartum (Ohara, 1990). 1995 drug monitoring data suggest that Prozac (fluoxetine) is the 9th most commonly prescribed prescription medication, with Zoloft (sertraline) and Paxil (paroxetine) being 13th and 33rd, respectively (Leiken and Paloucek, 1998). It is appropriate, then, that concerns regarding inadvertent or planned exposures during pregnancy and/or lactation to such SSRIs are common in women of reproductive age. This newsletter will, therefore, review the most up-to-date information regarding common SSRIs. It should replace the information presented in the RISK//NEWSLETTER 4(3), 12/95.
Prozac (fluoxetine)
Over the past several years, fluoxetine has become one of the most well-studied prescription medications during pregnancy. It is commonly prescribed for depression, obesity, eating disorders, obsessive compulsive disorder, panic disorder, premenstrual syndrome and alcohol abuse (Gram, 1994). Clinically, fluoxetine produces fewer side effects than many other antidepressants, such as the tricyclic antidepressants, perhaps accounting for its frequent usage (Gram, 1994). Fluoxetine has a long half-life (averaging 2-3 days; norfluoxetine half-life, 7-9 days), and its metabolites are likely to remain in the body for several weeks after discontinuation; this is important to consider when counseling women about potential reproductive risks based on the time of exposure.Fluoxetine is known to cross the placenta and enter the breast milk. Animal studies have generally not found an increased risk for malformations, at up to 11 times the human dose, but a single study did note an increase in skin hematomas after in-utero exposure to fluoxetine (Stanford, 1993); this has not been noted in humans.
Human data on fluoxetine exposure in pregnancy is reviewed in the table below. From these studies, totaling over 530 retrospective reports and 1250 prospective reports, it appears that there is no significant increased risk for major malformations associated with first trimester exposure to fluoxetine, nor has a pattern been noted to the malformations that occurred. Chambers et al. (1996) noted an increase in 3 or more minor malformations; they suggested that the significance of this finding could predict an increased association of major malformations when multiple minor malformations were present. Other studies have not addressed this finding, however.
There is some controversy over whether fluoxetine exposure in the third trimester increases the rate of neonatal complications. Chambers et al. (1996) found a slight increase in NICU admissions (RR 2.6; 95% CI 2.2-6.9) and transient jitteriness, respiratory distress and feeding problems (RR 8.7; 95% CI 2.9-26.6) as compared to control infants. In response to the initial presentation of this in abstract form, Goldstein (1995) analyzed outcomes in 112 pregnancies exposed to fluoxetine in the third trimester. There was no increase in neonatal complications above that expected. Two case reports of neonatal toxicity have been published, detailing transient neonatal hypertonicity and jitteriness after maternal exposure to 20 mg and 60 mg/day, respectively (Spencer 1993; Mhanna et al., 1997). Since symptoms of jitteriness and hypertonicity were also reported with adult serotonin toxicity (Leiken and Paloucek, 1998), it is possible that they were related to in utero exposure. However, at this time, the magnitude of risk for exposed infants cannot be determined.
Zoloft (sertraline)
Initial animal studies on the reproductive toxicology of sertraline showed no increase in malformations at doses up to 20 times the human dose, but did show findings consistent with maternal toxicity (Roerig/Pfizer). Fifteen case reports of various abnormalities exist and were reported to the FDA; there was reportedly no pattern to these malformations (Rosa, 1994). Kulin et al. (1998) prospectively followed 150 women exposed to sertraline in the first trimester and found no increase in miscarriage, major malformations, stillbirth or prematurity. While this data is limited, when considered in combination with the information on fluoxetine, it appears that sertraline is unlikely to pose a significant risk for malformations when used in the first trimester. A single report describes neonatal toxicity after exposure to 200 mg sertraline daily in the third trimester (Kent and Laidlaw, 1995). A report of a woman on 150 mg sertraline daily without adverse neonatal effects suggests that these findings may occur only at the highest maternal doses (Ratan and Friedman, 1995).
Paxil (paroxetine)
Animal studies of paroxetine have not shown an increase in malformations at up to 50 times the usual human dose (Baldwin et al. 1989; Smithkline Beecham, 1996.). Human studies consist of a case series of three exposed infants (McElhatton et al., 1996), postmarketing data following 63 women exposed in the first trimester (Inman et al., 1993), and a prospective cohort study examining outcomes in 98 women exposed in the first trimester (Kulin et al., 1998). None of these studies showed an increase in malformations, nor were miscarriage, stillbirth or prematurity increased in the Kulin et al. report (1998). While this data is limited, when considered in combination with the information on fluoxetine, it appears that paroxetine is unlikely to pose a significant risk for malformations when used in the first trimester. A single report of transient neonatal toxicity (jitteriness and hypertonia) was reported in an infant whose mother consumed 30 mg paroxetine from six months of pregnancy (Dahl et al., 1997).
Luvox (fluvoxamine)
There is little information available on the reproductive effects of fluvoxamine in animals or humans. Animals studies at twice the human dose did not show adverse effects, but the manufacturer states that at doses 4 times the human dose, mortality and growth were affected. McElhatton et al. (1996) reported 2 out of 66 exposed pregnancies resulted in malformations; both of these mothers reported other medication exposures. Kulin et al. (1998) prospectively monitored 26 women exposed to fluvoxamine, and found no increase in malformations, miscarriage, stillbirth or prematurity. While this data is limited, when considered in combination with the information on fluoxetine, it appears that fluvoxamine is unlikely to pose a significant risk for malformations when used in the first trimester.
Neurobehavioral data
Studies have only recently begun to address the long-term effects of exposure to psychotropic agents in utero. As all psychotropic medications affect maternal neurotransmitters, there remains the theoretical possibility of similar effects on a developing fetal brain, which in turn might result in subtle behavioral or learning deficiencies. Animal studies on rats have shown that in utero exposure to fluoxetine resulted in auto-radiographically visible alterations in the biochemical systems of the brain, particularly the serotonin systems (summarized in Carrera-Vera and Battaglia, 1998). Two other studies did not detect alterations in the behavior of prenatally exposed rats, however (Hoyt, 1989; Vorhees, 1994). The implications of such findings on human exposure and neurodevelopment remain unclear.
Human studies are limited to a single study which assessed the developmental parameters of 55 children exposed to fluoxetine as compared to 80 exposed to tricyclic antidepressants and 84 control infants. At a mean age of three years old (range 18-86 months), no significant differences were noted between global IQ or language scores in the groups (Nulman et al., 1997). While this suggests there is not a significant risk for severe neurological impairment, the more subtle developmental issues have not been well addressed. Compounding issues, e.g., the potential role of maternal depression on neurodevelopment and difficulty in obtaining long-term follow up, will likely make this a complex question to answer in the future (Loebstein and Koren, 1997).
Breastfeeding data
Several studies document the presence of fluoxetine (Isenberg 1990; Burch and Wells, 1992; Taddio et al., 1996), sertraline (Altshuler et al., 1995; Stowe et al., 1997), paroxetine (Spigset et al., 1996) and fluvoxamine (Wright et al., 1991) in human breast-milk. Outside of a single abstract finding decreased weight gain after breastmilk exposure to fluoxetine (Chambers et al., 1998), no data exists providing short or long-term follow up after exposure in breastmilk. As with any medication used while breast-feeding, the physiologic and psychologic benefits of breast-feeding must be weighed against the benefits of treatment for the mother and potential risks to a newborn exposed to the medication. The American Academy of Pediatrics considers the effects of all antidepressants to be “unknown but of possible concern (1994).”
Summary
Fluoxetine is well studied in humans and does not appear to increase the risk for malformations when used in the first trimester of pregnancy. Less data is available on other SSRIs, but it does not suggest a significant increase in malformations with these other medications. Based on a single study and a handful of case reports, controversy exists about whether fluoxetine and other SSRIs increase the chance of neonatal complications, specifically those similar to serotonin overdose (jitteriness, hypertonicity) when used in the third trimester. Virtually no human research has addressed the long-term effects of exposure to psychotropic medications in utero, and therefore the potential for neurobehavioral effects remains undetermined but theoretically possible. As with any medication it is important that patients work with their health care providers to weigh the benefits of medication use versus the likely low risks of exposure in pregnancy or lactation.
Resources: Contact ITIS for a copy of a patient-oriented FACT SHEET on Fluoxetine, or at http://orpheus.ucsd.edu/otis/index.html
References
Addis A, Koren G (1997) Teratology 55:37.Altshuler LL et al. (1995) J Clin Psychiatry 56:243-5.
AAP (1994) Peds 93:137-50.
Baldwin J et al. (1989) Acta psychiatr scand 80:37-9.
Burch KJ, Wells BG (1992) Peds 89:676-7.
Byrd RA et al. (1989) Teratology 39:444.
Cabrera-Vera T, Battaglia G (1998) JPET 286:1474-81
Chambers CD et al. (1993) Teratology 47(5):386.
Chambers CD et al. (1996) NEJM 335:1010-5.
Chambers CD et al (1998) Teratology 57:188.
Dahl et al. (1997) Br J Psychiatry 171:391-2.
Goldstein (1995) J Clin Psych 15:417-20.
Goldstein (1997) Obstet Gynecol 89:713-8.
Gram LF (1994) NEJM 331:1354-1361.
Hoyt J et al. (1989) Teratol 39:459.
Inman W et al. (1993) Pharm Drug Safety 2:393-422.
Isenberg KE (1990) J Clin Psychiatry 51:169.
Kent L, Laidlaw J (1995) Br J Psychiatry 167:412-3.
Kulin et al., (1998) JAMA 279:609-10.
Leppig KA et al. (1987) J Prediatr 110:531-7.
Leiken J, Paloucek (1998) Poisoning & Toxicology Compendium with Symptoms Index.
Loebstein R, Koren G (1997) J Psy Neurosc 22:192-6.
McElhatton PR et al. (1996) Reproduc Tox 10:285-94. Mhanna et al (1997) Peds 100:158-159.
Nulman I and Koren G (1996) Teratol 53:304-8.
Nulman I et al.(1997) NEJM 336:258
Ohara MW et al. (1990) J Abnorm Psychol 99:3-15.
Pastuszak A et. al (1993) JAMA 269(17):2246-2248.
Ratan D, Friedman T (1995) Br J Psychiatry 167:824.
Rosa F (1994) Reproduc Tox 8:444-5.
Spencer MJ (1993) Peds 92:721-2.
Spigset O et al. (1996) J Clin Psychiatry 57:39.
Stanford MS, Patton JH (1993) Pharm Biochem Behav 45:959-62.
Stowe et al. (1997) Am J Psychiatry 154:1255-60.
Taddio et al. (1996) J Clin Pharm 36:42-7.
Vorhees et al. (1994) Fund Appl Tox 23:194-205.
Wright et al. (1991) Br J Clin Pharm 31:209.
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Posted by admin on December 3rd, 1998 — in newsletter
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Over the Counter Cold Medications in Pregnancy
Vol 7(2) December 1998
Rachel Koehn, BA; Kelly Ormond, MS, CGC; Eugene Pergament, MD, PhD
Cold season is upon us, and many pregnant women will have concerns about the teratogenic risk of over-the-counter cold medications. Most data on cold medication use during pregnancy comes from large, retrospective studies; little prospective data is available despite the common use of these medications in pregnancy. Many cold medications contain a combination of an antihistamine, a decongestant (sympathomimetic), an expectorant and/or an analgesic. This combination of medications makes determining the teratogenic risk of a specific agent more difficult. Rather than consuming a cold medication that treats all possible symptoms, pregnant women may want to limit medications to treat specific symptoms of nasal congestion, allergic rhinitis and/or malaise.
This RISK//NEWSLETTER will review the most common components of over-the-counter cold medications: antihistamines, sympathomimetics, expectorants and analgesics. We will also address less traditional cold treatments such as echinacea, zinc and vitamin C. The accompanying table lists the ingredients present in several common over-the-counter cold remedies.
Antihistamines
The most common antihistamines in cold medications are chlorpheniramine, diphenhydramine, brompheniramine and clemastine. In the Kaiser-Permanente Prospective Study of Asthma During Pregnancy, there was no relationship between first trimester exposure to antihistamines and major malformations (Schatz et al., 1997).
Prospective study of 269 women with first trimester exposure to chlorpheniramine did not find any increase in malformations (Schatz et al, 1997). This finding is supported by two retrospective studies of 1070 and 61 women with first trimester exposure to chlorpheniramine (Heinonen et al., 1977; Briggs et al., 1994). Therefore, chlorpheniramine exposure in pregnancy does not appear to increase the risk for malformations above the general population frequency.
Most studies of diphenhydramine use during pregnancy have not found a significantly increased risk for malformations. Saxen (1974) examined 599 children with oral clefts and 590 controls and found a significant association between first trimester use and oral clefting. This finding has not been confirmed by retrospective studies which examined more than 2300 pregnancies exposed in the first trimester (Heinonen et al., 1977; Aselton et al., 1985; Briggs et al., 1994). As such, the risk for malformations, including clefts, is likely to be low. High doses of diphenhydramine (>50mg) may lead to “oxytocin-like” properties. Because of this, high doses of diphenhydramine should not be used late in pregnancy to avoid the theoretical risk of pre-term labor.
The Collaborative Perinatal Project found a slight increase in malformations, specifically syndactyly, associated with first trimester exposure to brompheniramine (Heinonen et al., 1977). This study was too small (N=65 women), however, to draw causal conclusions about the risk of brompheniramine in pregnancy. Additionally, a larger retrospective study (N=270 women) did not find an association between exposure and an increased risk for malformations (Aselton et al., 1985).
Studies on clemastine are limited to a retrospective study of 1,617 women; no increased risk for malformations was noted (Briggs et al., 1994). Based on this, clemastine exposure does not appear to increase the risk for malformations above the general population frequency.
Decongestants (Sympathomimetics)
The most common decongestants include psuedoephedrine, phenylpropanolamine, phenylephrine, oxmetazoline and xylometazoline. As a group, decongestants (or sympathomimetics) mimic epinephrine and result in vasoconstriction; they also can produce maternal hypertension (Horowitz et al., 1980). Theoretically, this could impair blood flow to the fetus, leading to IUGR and/or fetal vasoconstriction. Several studies show an increased risk for gastroschisis after sympathomimetic exposure. Werler et al. (1992) reported that first trimester exposure to pseudoephedrine, but not to phenylpropanolamine, was more common among children born with gastroschisis (RR=3.2, 95% CI 1.3-7.7). Torfs et al. (1996) found the reverse, with significant associations between gastroschisis and exposure to all decongestants, particularly with phenylpropanolamine (OR 10.0; CI 1.2-85.6). A recent prospective study of 453 women using decongestants during the first trimester did not find a significantly increased risk for malformations, including gastroschisis (Schatz et al., 1997). However, due to the biological plausibility of vasoconstricting agents and gastroschisis, it has been suggested that use of decongestants in pregnancy be minimized.
Pseudoephedrine has been well studied in pregnancy. Schatz et al (1997) prospectively followed 714 women exposed to pseudoephedrine and found no increased risk for malformations. Retrospective studies of 940 women support this finding (Briggs et al., 1994), making it unlikely that first trimester exposure to pseudoephedrine poses an increased risk for malformations. Because pseudoephedrine has both alpha and beta agonist properties, single doses do not significantly alter blood flow velocities (Smith et al., 1990); pseudoephedrine, therefore, has the lowest theoretical risk of inducing maternal hypertension.
Phenylpropanolamine is a commonly used decongestant. The Collaborative Perinatal Project reported an association between first trimester exposure to phenylpropanolamine and an increased risk for minor malformations (N=726), but no pattern of malformations was observed, making a causal association unlikely (Heinonen et al., 1977). Another retrospective study of 82 women exposed to phenylpropanolamine in the first trimester found no increased risk for minor or major malformations (Aselton et al., 1985). Based on these results, the risk of malformations associated with phenylpropanolamine is considered low.
Two case-control studies involving approximately 700 women reported that first trimester use of phenylephrine was more common among children born with congenital heart disease (Rothman et al, 1979; Zierler & Rothman, 1985). The relationship between other exposures and maternal disease could not be ruled out as causes of the increased incidence of congenital heart disease in these women. The Collaborative Perinatal Project found a slight increase in the incidence of minor anomalies, mostly eye and ear malformations, in 1249 women exposed during the first trimester (Heinonen et al., 1977). Further studies are needed to clarify these associations.
Xylometazoline and oxymetazoline are decongestants found in nasal sprays. 5-10% of a medication delivered via nasal spray reaches maternal circulation; fetal exposure is, therefore, low. Because nasal congestion is common during pregnancy, women may use more than the recommended amount of nasal spray. Prospective data on 197 women exposed to intranasal oxymetazoline did not indicate an increased risk for malformations (Schatz et al 1997); a retrospective study on 207 women exposed to xylometazoline had similar negative findings (Aselton et al., 1985). Based on this, combined with the low exposure level, the risk of adverse outcome after exposure to nasal spray is thought to be minimal.
In summary, there is no clear association between decongestant exposure during pregnancy and an increased risk for malformations. However, because of the theoretical risk of decongestant use leading to maternal/fetal vasoconstriction, they should be used conservatively during pregnancy.
Expectorants
An increased incidence of inguinal hernias was noted in a retrospective study of 197 women with first trimester exposure to guaifenesin (Heinonen et al., 1977). Other retrospective studies have not, however, found an increased incidence of malformations associated with guaifenesin exposure during the first trimester (Aselton et al., 1985; Briggs et al., 1994). Overall, the teratogenic risk of guaifenesin is thought to be low.
Dextromethorphan is the focus of a recent controversy, following a report that dextromethorphan induced miscarriage and malformations, such as open neural tube defects, in chick embryos injected with dextromethorphan (Andaloro et al., 1998). The results from this study remain controversial because it is unclear how relevant these observations are to human exposures. Retrospective data on dextromethorphan use during human pregnancy, totaling 300 women exposed in the first trimester, have not found any increase in malformations (Heinonen et al., 1977; Aselton et al, 1985).
There is no evidence that either of these two expectorants significantly increases the risk for birth defects in human pregnancy when taken therapeutically during the first trimester.
Analgesics
The most commonly used analgesics in cold medications are aspirin, acetaminophen and ibuprofen. These medications do not appear to increase the risk for birth defects when taken therapeutically in the first trimester of pregnancy. However, aspirin and non-steroidal anti-inflammatories are not recommended in the third trimester because their prostaglandin inhibition properties may lead to an increased risk of intracranial hemorrhage and premature closure of the ductus arteriosis in infants, especially in premature or low-birthweight infants.
Non-traditional Cold Treatments
For centuries, homeopathic remedies including echinachea have been used to treat cold symptoms. Because of echinachea’s natural properties, many consumers assume that it is “safer” than other pharmacologic agents. However, little epidemiologic data exists on the use of any homeopathic remedy during gestation. Gallo et al. (1998) presented an abstract reviewing 66 women exposed to echinachea during the first trimester and compared them to disease matched controls. No increased risk for birth defects, miscarriage or low birth weight was noted. However, because this study involved a small number of women, the risks associated with using echinachea during pregnancy remain unclear.
Many patients consume large quantities of vitamin C to lessen cold symptoms, often at significantly higher levels than the recommended daily allowance (RDA 60 - 70 mg for pregnant women). Vitamin C is water soluble, and while deficiency leads to scurvy, excessive doses are usually not associated with clinical symptoms (Goodman and Gilman, 1996). While vitamin C exposure at or near the RDA has not been associated with adverse outcome, there is little data on possible risks associated with high doses. It also appears that Vitamin C is concentrated in the fetus at levels higher than those seen in the mother. In animals, some offspring exposed to high doses of vitamin C showed symptoms of scurvy (Cochrane, 1965). Human reports are limited to two infants who developed scurvy after exposure to greater than 400 mg/day (Cochrane, 1965) and a woman with an anencephalic infant after taking multiple vitamins at elevated doses (Averback, 1976).
In recent years, cold preparations and cough drops containing zinc (usually 13mg) have been marketed to reduce the severity of cold symptoms. The RDA of zinc is 12-15 mg per day. Animal studies showed an increased risk for malformations, particularly skeletal defects, with extremely high exposures to zinc during gestation; these findings may be related to maternal toxicity from elevated zinc levels.
In humans, the question whether zinc levels play a role in the occurrence of neural tube defects is unresolved. Two reports showed elevated zinc levels in the blood or amniotic fluid, respectively, in a total of 24 infants with anencephaly or spina bifida (Zimmerman, 1984; Parkinson et al, 1982). Another study found elevated maternal serum zinc levels in 69 women carrying a pregnancy with a neural tube defect as compared to 592 control pregnancies (McMichael et al, 1994). In contrast, other studies have shown decreased levels of maternal serum zinc in women who had a pregnancy affected with a neural tube defect (Cadver et al 1980; Hinks et al 1980). Finally, it appears that maternal zinc levels are related proportionately to infant birth weight and head circumference (Neggars et al 1990; Goldenberg et al 1995).
Miscellaneous Cold Remedies
Menthol is a common ingredient of many throat lozenges and sprays. There are no human studies on the use of menthol during pregnancy, so its risk is undetermined. The concentration of menthol in throat lozenges and sprays is low, and because of this the risk for malformations is believed to be small. Camphor (VapoRub) is also used to treat cold symptoms. Retrospective studies have not shown any developmental toxicity associated with in utero camphor exposures (Heinonen et al, 1975). Topical exposure generally delivers a low level of medication, therefore the risk to the fetus is thought to be small.
Summary:
Over-the-counter cold medications contain many different ingredients, most of which are not associated with an increased risk for birth defects. There is some theoretical risk of vasoconstriction with decongestant use in pregnancy, and for that reason, use should be minimized. During pregnancy, cold medications that specifically address a pregnant woman’s symptoms should be used to minimize theoretical risks in pregnancy.
References
Andaloro VJ et al. (1998) Ped Res 43:1-7.
Aselton et al. (1985) Obstet Gynecol 65:451-5.
Averbach P (1976) Can Med Assoc J 114:995.
Briggs GG, Freeman RK & Sumner JY: Drugs in Pregnancy and Lactation, Williams & Wilkins, 1998.
Cochrane WA (1965) Can Med Assoc J 93:893-9.
Gallo M et al . (1998) Teratology 57:283.
Goodman and Gilman (1996) pp.1547-53.
Goldenberg et al (1995) JAMA 274:463-8.
Heinonen OP et al: Birth Defects and Drugs in Pregnancy, Littleton Publishing Sciences Group, 1977.
Horowitz JD et al. (1980) Lancet 1: 60-1.
McMichael AJ et al (1994) Med J Aust 161:478-82.
Neggars et al (1990) Am J Clin Nutr 51:678-84.
Parkinson et al (1982) J Obstet Gynecol 1:207.
Rothman KJ et al. (1979) Am J Epidemiol 109:433-39.
Saxen I (1974) Lancet 1: 407-8.
Schatz M et al. (1997) J All Clin Immun 100:301-6.
Smith C et al. (1990) Obstet Gynecol 76:803-6.
Torfs CP et al. (1996) Teratology 54:84-92.
Werler M et al. (1992) Teratology 45:361-7.
Zierler S and Rothman KJ (1985) N Engl J Med 313: 347-52.
Zimmerman AW (1984) Neurology 34:844-9.
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Posted by admin on December 2nd, 1998 — in newsletter
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Travel and Pregnancy
VOL 6 #3, DECEMBER 1998
Eugene Pergament, MD, PhD; Kelly Ormond, MS; Kristin DeMarco
It is not uncommon for a pregnant woman to plan international travel for business or recreation. Several issues relating to travel during pregnancy are clinically significant as the maintenance of maternal and fetal health may require specific considerations. This RISK//NEWSLETTER will address several of the concerns which frequently arise as a pregnant woman considers international travel, including airline flight, immunizations, malarial infection and antimalarial agents.
General Travel Concerns
The American College of Obstetricians and Gynecologists (ACOG) considers the second trimester the best time to travel (ACOG Technical Bulletin, 1994). During this period, a woman’s body has adjusted to pregnancy, and movement is not yet limited. Also, the second trimester is considered safer because the risk for miscarriage is lower than during the first trimester. After the sixth month of pregnancy, there is an increased risk of premature labor and other complications.
There are several general medical concerns which should be addressed before a pregnant woman travels. First, a woman should have a thorough consultation with her obstetrician. Careful assessment of a woman’s obstetrical and medical history should be performed so that both the physician and the patient are aware of potential complications (Rose, 1997). Tubal pregnancy, multifetal pregnancy and placental abnormalities should be ruled out. The quality and availability of medical and obstetric care in the regions on the itinerary should be assessed. United States embassies and consulates maintain lists of English-speaking physicians and can provide referrals. Also, the International Association for Medical Assistance to Travelers (IAMAT) can provide travelers with a listing of qualified English-speaking physicians overseas at (519) 836-0102. The specifics of travel health insurance policies can vary; travelers should compare policies and be familiar with their exclusions (e.g., miscarriage, delivery) prior to purchase(Rose, 1997).
Airline Travel
Domestic and foreign airlines restrict travel for pregnant women after 36 and 35 weeks gestation, respectively (Barry, 1989). When a pregnant woman prepares to board an airplane, initial concern may arise when the woman encounters a security metal detector at the airport. These devices generally produce a magnetic field through which a person passes (Barry, 1997). There is no evidence to suggest that magnetic fields are harmful to a fetus.
Most commercial jetliners maintain cabin pressures at those found 5000-8000 feet (1524-2438 meters) above sea level. This results in a decrease in oxygen intake from 20% to 15% oxygen (Scholten, 1976). The change in fetal oxygenization is less, because fetal hemoglobin maintains a greater degree of oxygen saturation due to its oxygen-dissociation curve (Barry, 1989). Overall, the cabin pressures maintained in modern jet aircraft do not appear to be harmful to a fetus.
Cosmic radiation is increased during flight at altitudes maintained by modern commercial jets. Generally, radiation at levels lower than 5 rads during a pregnancy has not been associated with increased fetal risk. Since the monthly exposure limit for pregnant flight attendants is 50 millirads, it is unlikely that a traveler would exceed this limit (Rose, 1997). Therefore, the radiation exposure from commercial flying is unlikely to pose a risk to the fetus.
Pregnant women should also maintain hydration and frequent stretching and other activity to decrease the risk of dehydration and deep vein thrombosis while flying (Barry, 1989).
Immunizations
Many foreign countries do not have strict requirements for immunizations prior to entry. Vaccine recommendations are often obtained from consultation with travel-advisory groups. Ideally, a woman should receive immunizations prior to pregnancy. If immunization is indicated during pregnancy, the risk of exposure and risks to the mother and to the fetus from the disease must be weighed against potential risks of immunization (Barry, 1989).
It is important to consider the type of immunizing agent used for a particular vaccination. There are five types currently used: live vaccines, killed or inactivated vaccines, immune globulins, recombinant agents, and toxoids (ACOG, 1991). Overall, there is no evidence that vaccines in use today have harmful effects on the fetus. The concern regarding immunization during pregnancy involves the theoretical risk to the fetus of a live vaccine. Because live viral and bacterial vaccines are capable of replicating, there is concern that they could infect the mother, and therefore the fetus, potentially causing birth defects. Consequently, it is recommended that live viral or bacterial vaccines be avoided during pregnancy, especially during the first trimester during organogenesis. However, if a woman is at substantial risk of acquiring a particular infection, the risks and benefits of vaccination should be weighed. The ACOG Technical Bulletin Number 160 (October, 1991) serves as an excellent reference, as it presents the current recommendations of the Immunization Practices and Advisory Committee (ACIP) for immunization of pregnant women.
In the United States, most women of childbearing age are immune to measles, mumps, rubella, tetanus, diphtheria and poliomyelitis through vaccination or natural infection (ACOG, 1991). Travelers may need to consider other vaccinations depending on their destination. Yellow fever, typhoid fever, cholera, meningococcal meningitis and/or hepatitis A vaccines may be recommended.
Yellow fever vaccine is a live virus vaccine, so there is a theoretical risk associated with its use during pregnancy. In one study, out of 41 infants born to women who had been immunized with this vaccine during the first trimester, one infant had serological evidence of intrauterine infection but did not show any adverse fetal effects (Tsai et al., 1993). In addition, a large study of yellow fever vaccination in women of childbearing age did not suggest any increased risk for adverse fetal outcome (Nasidi et al., 1993). In general, if travel is unavoidable to regions where yellow fever is endemic, the vaccination is not contraindicated because of the significant morbidity and mortality associated with yellow fever infection.
Cholera, typhoid, and meningococcus are all killed or inactivated vaccines. In pregnant women who are at significant risk of exposure to these infections, these vaccinations are not contraindicated; however, avoidance of first trimester exposure is preferable (ACOG, 1991). Hepatitis A vaccine is available as either a standard immune globulin or an inactivated virus, while hepatitis B is often a recombinant vaccine. Because viral hepatitis can be exacerbated by pregnancy, vaccination for hepatitis A and/or B can be considered for international travelers at risk for acquiring this infection (Rose, 1997).
Malarial Infection
Malarial infection presents a major health concern worldwide. Infection is caused by various species of the parasite plasmodium, and is transmitted through the bite of the female mosquito. Malarial infection is a concern to individuals traveling to tropical areas.
Pregnancy increases susceptibility to malarial infection. Parasitemia is inversely related to parity, with an average 2-fold increase in prevalence in primigravidas compared to multigravidas (Nosten et al., 1991; Mutabingwa, 1994). Clinical manifestations in symptomatic pregnant women can be similar or more severe than in nonpregnant individuals, and include anemia, hypoglycemia, pulmonary edema, fever and headache which may mimic a viral illness. Maternal mortality rates can reach 10% (Weekly Epidemiological Record, 1996).
Placental infection influences perinatal outcome. The average prevalence of placental malaria in primigravidas is 30-40%, while the prevalence in multigravidas is approximately half this rate (Silver, 1997). Overall, obstetrical complications including abortion, stillbirth, and premature deliver are reported to be increased in infected women, with fetal loss rates ranging from 9% to 50% (McGregor, 1984; Sholapurkar et al, 1988). Congenital malaria is relatively rare; however, it can occur even in asymptomatic mothers (Bia, 1992). Prenatal or perinatal transmission to children occurs in up to 7.4% of non-immune mothers (Hulbert, 1992). Congenital malaria is characterized by fever, anemia, splenomegaly in most cases, with jaundice, hepatomegaly and hyperbilirubinemia occurring occasionally.
Anti-malarial Agents
For pregnant women traveling to regions endemic with malaria, chemoprophylaxis with anti-malarial agents is a preventative option. In most regions, plasmodium is sensitive to chloroquine (Aralen), a quinine derivative with anti-malarial properties. Numerous studies suggest that chloroquine is the drug of choice for the prophylaxis and treatment of sensitive malaria species during pregnancy (Rose, 1997). Concern was raised over a case report of a woman who had taken large doses of chloroquine in multiple pregnancies and then had one child with hemihypertrophy and two others with bilateral eye and ear abnormalities (Hart et al., 1964). However, no increase in congenital anomalies was reported in 18 patients taking large doses of chloroquine for treatment of lupus (Parke, 1988; Levy et al., 1991) or in a series of 169 women treated for malaria (Wolfe and Cordero, 1985). The Centers for Disease Control and Prevention does not consider pregnancy a contraindication for prophylactic doses of chloroquine (CDC, 1990).
Mefloquine (Larium) is a quinolone derivative that is considered the prophylaxis of choice for travel to areas with chloroquine-resistant P. falciparum. In rats and mice, mefloquine exposure was teratogenic only at maternally toxic doses (Minor et al., 1976). In small numbers of human pregnancies, mefloquine has been administered with no increase in adverse outcomes (Collignon et al., 1989; Karbwang et al., 1990; Nosten et al., 1990; Balacco et al., 1992; Nosten et al., 1994). Studies of 218 and 85 mefloquine-exposed pregnancies respectively did not show an increase in adverse outcomes (Elefant et al., 1991; Harinasuta et al., 1990). There is limited information about the effects of mefloquine use specifically in the first trimester.
Other anti-malarials are composed of pyrimethamine in combination with other agents. Pyrimethamine is a folic acid antagonist, and animal studies have found that it induces multiple malformations (Thiersch, 1954; Sullivan et al., 1971; Schvartsman, 1979; Misawa et al., 1982), including an association between vascular abnormalities and pyrimethamine exposure (Tangapregassom et al., 1985). Based on these animal studies and its action on folic acid, there are theoretical concerns about the use of pyrimethamine during the first trimester of pregnancy. Human studies have not, however, found an increase in abnormalities as a result of prenatal pyrimethamine exposure (Morley et al., 1964; Bruce-Chwatt, 1983; Main et al., 1983; Heinonen et al., 1977).
Pyrimethamine is combined with sulfadoxine or dapsone in the anti-malarials Fansidar and Daraprim, respectively. These anti-malarials are marketed for prophylaxis of chloroquine-resistant strains of malaria. Use of sulfonamides and related drugs during pregnancy has raised theoretical concern because sulfonamides can bind plasma proteins and displace bilirubin. Exposure of a late-term fetus may increase the risk for development of kernicterus as a result of this. Adverse reactions not related to pregnancy have been reported after use of these drugs (MMWR, 1985; Selby et al., 1985; Millar et al., 1986; Millikan et al, 1990). Overall, these drugs are not recommended during pregnancy unless they offer a clear therapeutic benefit over quinine derivatives.
Other anti-malarial agents include chloroguanide (proguanil, Paludrine), halofantrine (Halfan), and primaquine. There is little experience with use of these drugs during human pregnancy; consequently, the risks associated with prenatal exposure to these agents are undetermined.
A traveler can obtain information on the sensitivity of predominant malaria strains in a particular region through the CDC Malaria Hotline at (404) 332-4555.
Protection against insect bites is an important preventative measure, not only against malaria, but other insect-transmitted diseases as well. Diethyltoluamide (DEET) is an insect repellant used in many repellant products. Topical exposure to DEET results in systematic absorption of levels ranging from 6% to 8% of the dose applied (Snodgrass et al, 1982; Selim et al 1995). Animal studies have reported conflicting results regarding its teratogenic potential. There are very limited studies on the human reproductive effects of DEET; consequently, limited use by pregnant women may be advisable. Ways to minimize exposure include using an insecticide with a lower percentage of DEET, and spraying it on clothing rather than directly on skin.
Permethrin is a synthetic pyrethroid insecticide that is often used to treat clothing or netting. Pyrethroids in general do not appear mutagenic (Miyamato, 1976); however, human reproductive effects have not been studied. In light of these unknown risks, practical considerations for preventing insect bites can also be made. Travelers can place netting around sleeping areas and reduce skin exposure by wearing long-sleeved shirts and pants.
Summary
Overall, travel during pregnancy requires advance preparation and precaution. A patient should have a thorough consultation with her obstetrician before traveling. Airline travel does not present any known risks to pregnancy. Immunization with live viral or bacterial vaccines pose theoretical risks; however, these vaccines are not contraindicated when a woman is at high risk of exposure to the infectious agent. Prevention of malarial infection is an important concern as maternal malaria is associated with poor maternal and perinatal outcome. There are a variety of anti-malarial agents available for chemoprophylaxis, some of which, however, have undetermined risks in human pregnancy. As with any medication, the risks associated with a particular medication should be carefully weighed against its benefits.
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Posted by admin on October 1st, 1998 — in newsletter
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Cancer, Chemotherapy, and Pregnancy
Volume 7 #1 -October 1998
Kerry Marsh, BA; Kelly Ormond, MS, CGC; Eugene Pergament, MD, PhD
In the United States, there are approximately 3500 cases of cancer-complicated pregnancies per year. The most common cancers that occur during pregnancy are cervical, breast, melanoma, thyroid, leukemia, lymphoma and colorectal (Sorosky et al., 1997). In part, the recent increase in cancer-complicated pregnancies may be due to the increased frequency of delayed childbearing. A diagnosis of cancer during pregnancy causes significant conflict for both the physician and the patient when attempting to optimize maternal and fetal well being. The risks and benefits of possible surgery, radiation and chemotherapy and the timing of treatment must be considered. This RISK//NEWSLETTER will present information on the reproductive risks in persons who received cancer treatment prior to pregnancy, the effects of maternal chemotherapy exposure during pregnancy and the pregnancy risks of occupational exposure to chemotherapy. We will not address radiation therapy during pregnancy.
PREGNANCY IN CANCER SURVIVORS
As the survival from childhood and young adult cancers improves, the question about pregnancy outcome subsequent to chemotherapy and/or radiation therapy has become more frequent. Because of the obvious mutagenicity of these agents, there is theoretical concern that prior cancer treatment may alter fertility or increase the risk for birth defects, childhood cancer, chromosome abnormalities (e.g. aneuploidy) and single gene mutations. Most studies, which typically examine outcomes in patients treated between 1960 and the early 1980’s, have also considered patient’s gender, as male and female gametogenesis are different.
Early studies suggested that the offspring of cancer survivors had an increased risk for low birth weight, perinatal mortality and other adverse outcomes (Green et al., 1982; Li et al., 1987; Byrne et al., 1988; Hawkins and Smith, 1989). These outcomes were more commonly seen in women who received abdominal radiation therapy, and Smith and Hawkins (1989) postulated that these outcomes were related to possible changes in the uterine elasticity or vasculature secondary to radiation therapy.
Many studies have addressed whether birth defects or aneuploidy are increased in offspring of cancer survivors. Nygaard et al. (1991) and Kenney et al. (1996) examined birth outcomes in 48 and 140 offspring of acute lymphoblastic leukemia (ALL) survivors, respectively; neither found an increase in birth defects. More recently, Green et al. (1997) expanded on their earlier studies (1991) to document the outcome of 280 pregnancies to cancer survivors; no increase in birth defects was noted. Finally, Byrne et al. (1987; 1998) found no increase in birth defects, chromosome abnormalities or single gene disorders in 2198 offspring of survivors versus their sibling controls; this was true even when mutagenic and non-mutagenic treatments were considered separately. None of the above studies found differences in outcomes between male and female cancer survivors.
Finally, studies have examined whether childhood cancer is increased in the offspring of survivors. Mulvihill et al. (1987) examined 2308 offspring of survivors and did not find a significantly increased risk for childhood cancers as compared to sibling controls. Neither Nygaard et al. (1991) nor Green et al. (1997) noted any cases of childhood cancer in 48 and 143 offspring of survivors, respectively. Obviously the presence of a dominantly inherited cancer syndrome within a family can increase the frequency of childhood cancer, and must be considered when providing these risks to family members (Green et al., 1997).
In summary, offspring of cancer survivors do not appear to be at increased risk for birth defects, chromosomal abnormalities or single gene disorders. While the cancer treatment itself does not increase the risk of childhood cancer in offspring, the implications of an inherited cancer syndrome should be addressed in counseling.
CHEMOTHERAPY IN PREGNANCY
Chemotherapeutic agents have been used since the early 1950s (Schardein, 1993). Breast cancer, ovarian cancer, leukemia and lymphomas are commonly treated with chemotherapy (Doll et al., 1988). There are, however, no large prospective studies of chemotherapy use during pregnancy. Physicians must, therefore, rely primarily on case reports and retrospective studies, both subject to confounding factors, when formulating a treatment regimen for the pregnant woman with cancer. Additionally, the physician must consider the gestational age of the pregnancy, the stage of the cancer, and the emotional, religious, social and moral concerns of the individual prospective parents.
All chemotherapeutic agents are potentially teratogenic and mutagenic because they act on rapidly dividing cells. The potential exists for fetal malformations, intrauterine growth restriction, spontaneous abortion, stillbirth or premature delivery when a woman is exposed to chemotherapeutic agents prior to, or during, pregnancy. Possible outcomes depend on the particular treatment, its timing and duration, and the ability of the drug to cross the placenta. Most chemotherapeutic agents do cross the placenta. While the greatest risk for birth defects occurs with first trimester exposure, second and third trimester exposures may result in transient bone marrow suppression, pancytopenia, intrauterine growth restriction (Aviles et al., 1991), low birth weight and prematurity (Zemlickis et al., 1992). It has been suggested that chemotherapy be avoided for three weeks prior to delivery (Sokorsky, 1997), in order to allow the mother to recover from treatment-related bone marrow suppression. In addition, the fetus can better metabolize these agents with the assistance of the maternal system, avoiding the persistence of high levels of drugs in the neonatal circulation.
Most information about chemotherapy in pregnancy is derived from case reports or limited studies of different treatment regimens for pregnant women with specific types of cancer. Case reports are inherently biased towards reporting abnormal outcomes. Reports of outcomes after chemotherapy differ slightly, however, because many of these reports focused primarily on the cancer diagnosis in pregnancy rather than the specific treatment regimen. Also, many of these reports are from the 1960s and 1970s, when lower doses of single agent chemotherapy were commonly used; it is difficult to extrapolate to current doses (Reichman and Green, 1994). Finally, the introduction of combination chemotherapy complicates the assessment of teratogenic risk, because one must also consider the possibility of synergism. Chemotherapy may also be used in combination with radiation therapy, making it difficult to determine which portion of the treatment has teratogenic effects.
In a small number of case control studies, most of which are organized by type of cancer rather than by treatment, the biggest problem is variation in methodology. Specifically, while children exposed in utero to chemotherapy are examined for malformations, these examinations are not standardized, making accurate risk assessment difficult.
COMMON CHEMOTHERAPEUTIC AGENTS AND THEIR EFFECTS
Chemotherapeutic agents are classified by their mechanism of action corresponding to different stages of the cell cycle. We will discuss common alkylating agents, antimetabolites, vinca alkyloids and anthracycline antibiotics.
Alkylating agents:
The alkylating agents are cell cycle nonspecific (Zemlickis et al., 1996). They work during most cell cycle stages by denaturing DNA and inhibiting cell division and normal biological activity (Hardman et al., 1996).
Busulfan (Myleran)
Busulfan is commonly used to treat chronic myeloid leukemia (CML) (Hardman et al., 1996), and may be used either alone or in combination with 6-mercaptopurine, prednisone and radiation therapy (Aviles et al., 1991; Schardein, 1993). There are at least 38 cases in the literature of pregnancies exposed to busulfan (Briggs et al., 1994). Six cases of birth defects have been reported after busulfan exposure during pregnancy; there was no specified pattern to the anomalies. In the first case, a woman was treated with busulfan and 6-mercaptopurine throughout the majority of her pregnancy. The infant had severe growth retardation, cleft palate, microphthalmia, hypoplastic ovaries, bilateral corneal clouding, and poorly developed external genitalia (Diamond et al., 1960). Another infant, exposed throughout the pregnancy developed pyloric stenosis (Gililland and Weinstein, 1983). Two abortuses were reported following busulfan exposures, one with unspecified multiple abnormalities (deRezende et al., 1965) and one with myeloschisis (Abramovici et al., 1978). The remaining two cases cannot be directly correlated to the busulfan exposure either because the exposure occurred later in the pregnancy or the abnormality had a genetic basis (Boros and Reynolds, 1977; Saraux and Lefrancois, 1977). There have been over 30 normal offspring born following in utero exposure to busulfan (Summarized in Nicholson, 1968).
Chlorambucil (Leukeran)
Chlorambucil is used to treat chronic lymphocytic leukemia (CLL), Hodgkin’s’s disease and non-Hodgkin’s lymphoma (Hardman et al., 1996). More recently, it has been used to treat rheumatic disease and systemic lupus erythematosus because of its immunosuppressive properties (Ramsey-Goldman and Schilling, 1997). Four birth defects have been reported following first trimester exposure to chlorambucil. Two fetuses exposed at 5-11 weeks and 7-20 weeks respectively, had kidney and ureter agenesis. A third fetus, exposed at weeks 3-4, had a retinal defect (Rugh and Skaredoff, 1965; Shotten and Monie, 1963; Steege and Caldwell, 1980). Finally, a fetus exposed in the tenth week had a congenital heart defect (Thompson and Conklin, 1983). Several normal pregnancies have been reported after exposure to chlorambucil (summarized in Schardein, 1993; Ramsey-Goldman and Schilling, 1997; Jacobs et al., 1981; David et al., 1993).
Cyclophosphamide (Cytosan, Neosar)
Cyclophosphamide is used in the treatment of ALL, CLL, Hodgkin’s disease, non-Hodgkin’s lymphoma, neuroblastoma, Wilms’ tumor, soft-tissue sarcomas, cancers of the breast, ovary, lung, and cervix, (Hardman et al., 1996) and connective tissue disorders such as systemic lupus erythematosus (Clements, 1991). Cyclophosphamide is commonly used in combination chemotherapy regimens (see Combination Chemotherapy Section). Five cases of birth defects have been reported in conjunction with first trimester exposure to cyclophosphamide. The first case, an infant exposed from weeks 4-11, had four toes on each foot, a flattened nasal bridge, palatal grooves, a small skin tag on the anterior mid-abdomen, a slightly hypoplastic middle phalanx of the fifth finger and bilateral inguinal hernia sacs (Greenberg and Tanaka, 1964). In a second case, a woman exposed to cyclophosphamide and radiation terminated a male fetus with no toes and a single left coronary artery (Toledo et al., 1971). Another first trimester exposure resulted in a growth-retarded infant with imperforate anus and a rectovaginal fistula (Murray et al., 1984). Kirshon et al. (1988) reported exposure on days 15 and 46 in an infant with bilateral radial ray defects, cleft palate, low-set ears and multiple eye anomalies. Reynoso et al. (1987) described an exposed fetus with club hand, esophageal atresia and abnormal inferior vena cava. Additionally, reports exist of neonatal immunosuppression following in utero exposure (Khurshid and Saleem, 1978; Okun et al., 1979, Pizzuto et al., 1980, Zuazu, 1991) and a child who developed papillary thyroid cancer and neuroblastoma (Zemlickis, 1993).
Mechlorethamine (Nitrogen Mustard, Mustargen)
Mechlorethamine, used to treat Hodgkin’s disease and non-Hodgkin’s lymphoma (Hardman et al., 1996), is most commonly used in combination chemotherapy. Two reports of first trimester exposure resulted in infants with birth defects, but the mothers were also exposed to other agents. One child had four toes on each foot, a malformed ear, bowed tibia and cerebral hemorrhage (Garrett, 1974). A second exposed fetus had small malpositioned kidneys (Menutti et al., 1975). A third malformed fetus was described with hydrocephaly and early infant death following first trimester exposure (Zemlickis, 1992). At least 10 other reports document normal pregnancy outcome following in utero exposure to mechlorethamine (summarized in Briggs et al., 1994; Schardein, 1993) with an increased number if combination chemotherapy cases were included.
Antibiotics:
Antibiotics used in chemotherapy covalently bind to DNA, causing cytotoxicity (Hardman et al., 1996). The most commonly used antibiotics include doxorubicin, mitomycin, catinomycin and bleomycin. The antibiotics are most often used in combination chemotherapy (see section on combination chemotherapy). None of these agents has been associated with an increased risk of birth defects when used during the first trimester (summarized in Schardein, 1993). However, one case of bleomycin exposure in combination with two other drugs, 7 to 10 days before delivery, resulted in transient neonatal leukopenia and neutropenia in a premature infant (Raffles et al., 1989).
Antimetabolites:
The antimetabolites are comprised of analogues of folic acid, purines and pyrimidines. Antimetabolites interfere with the function of these components, resulting in deficiencies or substitutions of the above (Hardman et al., 1996).
Amniopterin
Amniopterin is a folic acid antagonist and abortifacient. A known human teratogen , it is no longer used in cancer treatment. The amniopterin syndrome is characterized by central nervous system abnormalities, including spina bifida, mental retardation, hydrocephalus and anencephaly. Other abnormalities include synostosis of the lambdoid sutures, partial or absent ossification of bones, micrognathia, high arched palate, short extremities, syndactyly of fingers, absent digits, clubfoot, large anterior and posterior fontanelles, wide depressed bridge of the nose and wide-set eyes. Cardiac abnormalities such as dextrocardia have also been reported (Powell and Ekert, 1971). There are a total of 17 reported cases of malformations following exposure to amniopterin during the first trimester (summarized in Schardein, 1993). About half of the cases resulted in a liveborn with the remainder resulting in miscarriage or stillbirth.
Methotrexate (Amethopterin)
Methotrexate, closely related to aminopterin, also acts as a folic acid antagonist and abortifacient (Hardman et al., 1996). Methotrexate is commonly used to treat ALL, cancers of the breast, head, neck and lungs (Hardman et al., 1996) and rheumatic disease (Songstridey and Furst, 1990). There are four documented cases of malformations consistent with aminopterin syndrome following exposure to methotrexate in utero (Milunsky et al., 1968; Powell and Ekert, 1971; Diniz et al., 1978, Buckley et al., 1997). Additionally, an ultrasound study by Van den Hof et al .(1990) reported 2 out of 14 fetuses exposed to folic acid antagonists during the first rimester had neural tube defects. Severe myelosuppression has been reported in two infants exposed to methotrexate and other chemotherapeutic agents in utero (Tokuda et al., 1994). There have been over 20 reports of normal pregnancies following fetal methotrexate exposure (summarized in Schardein, 1993). Kozlowski et al. (1990) described 10 pregnancies exposed to low-dose weekly methotrexate for rheumatic disease, resulting in 3 spontaneous abortions, 2 elective abortions and 5 normal infants (mean follow-up: 11 years). Donnenfeld et al. (1994) reported three normal infants, two after first trimester in utero exposure to methotrexate and one after exposure during the third trimester.
5-Flourouracil (Adrucil, Efudex, 5-FU)
5-FU is a pyrimidine antagonist that interferes with DNA and RNA synthesis (Hardman et al., 1996). It is commonly used to treat cancer of the breast, colon, stomach, pancreas, ovary, head, neck and bladder (Hardman et al., 1996) and topically to treat human papillomavirus infections (Van Le et al., 1991). There is one case report of a therapeutically aborted fetus exposed to 5-FU from 11-12 weeks gestation. The fetus had bilateral radial aplasia with absent thumbs and fingers (two on one hand and one on the other), hypoplasia of the lungs, aorta, thymus and bile ducts and aplasia of the esophagus, duodenum and ureters (Stevens et al., 1980). Another fetus exposed to 5-FU during the third trimester was structurally normal but had cyanosis and jerking of extremities during the neonatal period (Stadler and Knowles, 1971). A small but healthy neonate was born following a five month exposure to high dose 5-FU during the second and third trimesters (Dreicer and Love, 1991). There have been at least 4 other normal pregnancies reported following in utero exposure to 5-FU (summarized in Schardein, 1993). A study investigating the effects of topical 5-FU noted four normal infants and one infant with 47,XXX (Van Le et al., 1991).
Cytarabine (Cytosar, AraC, Cytosine arabinoside)
Cytarabine is a pyrimidine antagonist that impairs nucleic acid synthesis (Hardman et al., 1996). It is used in the treatment of AML and ALL (Hardman et al., 1996). There are two case reports of birth defects associated with cytarabine exposure during pregnancy. Wagner et al. (1980) reported an infant exposed to cytarabine early in pregnancy with bilateral microtia, atresia of the external auditory canals and abnormalities in three of four limbs. The second case involved a woman treated with cytarabine and thiogaunine who delivered an infant with distal limb defects including the thumbs and two digits on each foot (Schafer, 1981). Pancytopenia and low birth weight was observed in one infant exposed to cytarabine and several other chemotherapeutic drugs during the first trimester (Pizzuto et al., 1980). There are at least 15 case reports of normal infants and fetuses following in utero exposure to cytarabine, with increased numbers if combination chemotherapy cases were added (summarized in Schardein, 1993; Caligiuri and Mayer, 1989; Schafer, 1981; Taylor and Blom, 1980; Newcomb et al., 1978, Lilleyman et al., 1977).
Azathioprine (Imuran)
Azathioprine is a purine antagonist that metabolizes to 6-mercaptopurine (Hardman et al., 1996). It is most commonly used to treat leukemias, lupus, rheumatoid arthritis (Dameshek and Schwartz, 1960), inflammatory bowel disease (Present et al., 1989) and as an anti-rejection medication following transplantation (McKendry, 1991). There are three reports of birth defects associated with in utero exposure to azathioprine. One infant was born with unilateral polydactyly (Williamson and Karp, 1981). The second case was an infant with pulmonic stenosis who was not exposed during the first trimester (Nishimura and Tanimura, 1976). The final case, also exposed in the second trimester, described an infant with an atrial septal defect (Burleson et al., 1983). Because of the inconsistent nature of these anomalies it is unlikely that azathioprine use during pregnancy increases the risk for birth defects above the general population risk. Intrauterine growth retardation has been noted after in utero exposure to azathioprine, primarily in pregnancies of renal transplantation patients; the underlying disease may have contributed to this observation (Davidson and Lindheimer, 1982; Marushak et al., 1986). In a study by Cararach et al. (1993) examining the outcomes of 103 pregnancies in renal transplantation patients, 90% were exposed to azathioprine during gestation and no increase in birth defects were noted. No congenital anomalies were observed in 20 infants born to mothers treated with azathioprine during pregnancy following heart transplantation (Haagsma et al., 1989; Baxi and Rho, 1993; Wagoner et al., 1994). In addition, 14 normal infants were reported following first trimester exposure to azathioprine to treat inflammatory bowel disease (Alstead et al., 1990).
Vinca Alkaloids:
Vinka alkaloids inhibit spindle formation by binding to tubulin and preventing cell division during the M phase of cell division (Sorosky et al., 1997).
Vinblastine (Velban)
Vinblastine is commonly used in the treatment of Hodgkin’s disease, non-Hodgkin’s lymphoma and breast cancer. Of 10 case reports of fetuses exposed to vinblastine, there were no reported abnormalities (summarized in Schardein, 1993; Schapira and Chudley, 1983). There are two case reports of adverse outcomes following first trimester exposure: one spontaneous abortion and one infant with hydrocephalus (Schilsky et al., 1980). Vinblastine has been used in conjunction with other chemotherapeutic agents; reports of birth defects exist but these have been attributed to other agents.
Vincristine (Oncovin)
Vincristine is used to treat ALL, AML, Wilms’ tumor, Hodgkin’s disease and non-Hodgkin’s lymphoma (Hardman et al., 1996). Vincristine is also very commonly used in combination with other chemotherapeutics. No congenital malformations were noted in 14 infants born to mothers treated with only vincristine(summarized in Schardein, 1993). There have been at least 2 case reports of complications following exposure to vincristine in conjunction with other chemotherapeutic agents; it is possible that these complications were related to the other drugs (summarized in Gililland and Weinstein, 1983).
COMBINATION CHEMOTHERAPY
There are several combinations of chemotherapy that are commonly used to treat various types of cancer. The information is summarized below; overall, there does not appear to be an increased risk of birth defects associated with any particular combination therapy. Doll et al. (1989) noted that the rate of fetal malformation when more than one chemotherapeutic agen was used was similar to the rate observed with monotherapy.
CHOP= cyclophosphamide, doxorubicin, vincristine, prednisolone
CHOP-Bleo= same as above, plus bleomycin
COPP= cyclophosphamide, vincristine, prednisone, procarbazine
COP-Bleo= cyclophosphamide, vincristine, prednisone, bleomycin
CEOP-Bleo= cyclophosphamide, epidoxorubinicin, vincristine, prednisone, bleomycin
DATOP= daunorubicin, arabinosylcytosine, thioguanine, vincristine, prednisone
ABVD= adriamycin, bleomycin, vinblastine, decarbazine
AVTEP= doxorubicin, vincristine, teniposide, cyclophosphamide, prednisone
MOPP= mechlorethamine, vincristine, procarbazine, prednisone
Combination Chemotherapy Treatment and Pregnancy Outcomes Treatment Follow Up Reference
CHOP All normal Ward 1989, Aviles 1991, Zuazu et al 1991
CHOP-Bleo All normal Aviles, 1991
COPP 1 normal, 1 EAB Ward 1989, Zuazu et al. 1991
COP-Bleo Normal Ward 1989
CEOP-Bleo All normal Aviles 1991
DATOP 3 normal, 2 SAB(nml) Zuazu et al. 1991
ABVD All normal Aviles 1991
AVTEP Normal Ward 1989
MOPP 11 Normal, 1 SAB Ward 1989, Aviles 1991, Zuazu et al 1991
COUNSELING ISSUES
Following a cancer diagnosis early in pregnancy, a patient must cope with the shock of the diagnosis, her own mortality, and potential fears about the future of her unborn child. Regardless of treatment, it is important to assess the patient’s support system and make referrals when appropriate. Because cancer during pregnancy is relatively uncommon, it may be difficult to find anyone who has a similar experience. The National Cancer Information Service (1-800-4-CANCER) may be of assistance.
Both patient and physician must weigh the risks and benefits of delaying treatment until after the first trimester versus the prognosis of the cancer. If treatment cannot be delayed, termination of pregnancy may be an option for some women. Chorionic villus sampling and amniocentesis are not useful in detecting teratogenic effects of chemotherapeutic agents because there is no increased risk of chromosome abnormalities related to treatment. Targeted ultrasound may detect certain structural anomalies associated with first trimester exposure to chemotherapeutics.
OCCUPATIONAL EXPOSURE TO CHEMOTHERAPEUTIC AGENTS
Information on the reproductive effects of workplace exposure to chemotherapeutic agents is limited. A study by Selevan et al. (1985) observed an increased risk of fetal loss in nurses exposed to cyclophosphamide, doxorubicin and vincristine. However, because most nurses reported handling more than one agent, the individual effects of each drug could not be assessed. deWerk et al.. (1983), investigated the potential risks of inhaling chemotherapeutic agents. Most surveyed facilities had inadequate ventilation and did not use universal precautions when handing the medications. The authors found that 5-FU and cyclophosphamide could linger in the air and potentially be inhaled and systemically absorbed. Since there is little information regarding risks associated with occupational exposure to chemotherapueutics, it is prudent to minimize exposure in the pregnant worker. Ideally this means total avoidance, but other ways to decrease exposure include working in a hood, and using gloves, mask and other protective clothing.
SUMMARY
Most data suggests that cancer survivors are not at increased reproductive risk for offspring with structural malformations, aneuploidy or childhood cancers. While there are reports that provide specific risk estimates after first trimester exposure to chemotherapeutic agents (e.g. Schardein, 1993), the paucity of human data and the reporting biases inherent in case reports make the accuracy of these estimates suspect. Case reports of malformations and normal outcomes have been published. Studies of combination chemotherapy do not suggest an increased risk as compared to monotherapy. In any case of cancer diagnosed during prengancy, the risks and benefits of starting versus delaying treatment must be weighed. In those women where treatment is initiated in the first trimester, targeted ultrasound may be useful in detecting structural abnormalities. It has been recommended that chemotherapy be ceased three weeks prior to delivery in order to minimize neonatal complications.
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