Posted by admin on September 3rd, 1995 — in newsletter
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Non-narcotic Analgesics and Pregnancy
Vol 4#1, September 1995
Eugene Pergament, MD, PhD; Amy Schechtman, MS; Ursula Smith
The non-narcotic analgesics, aspirin (acetylsalicylic acid), acetaminophen and ibuprofen, are among the most common over-the-counter drugs used during pregnancy (Collins, 1981). The Collaborative Perinatal Project (Heinonen et al., 1977) reports that of the 50,000 women in the study, approximately 30% used non-narcotic analgesics during the first trimester of gestation. Over 60% of the study participants used analgesics some time during their pregnancies. Furthermore, because these medications are self-administered, the potential exists for inappropriately extending their use and increasing their doses with medical implications for both mother and fetus (Peterson et al., 1985). This RISK||NEWSLETTER will focus on the effects of acetylsalicylic acid, acetaminophen and ibuprofen when used during pregnancy.
MECHANISMS OF ACTION
All three agents are prostaglandin synthestase inhibitors. The pathway that is affected involves the enzyme which catalyzes the conversion of arachidonic acid to the cyclic endoperoxide, prostaglandin G2. The enzyme, cyclo-oxygenase, either is inactivated or inhibited by aspirin, acetaminophen and ibuprofen. Prostaglandin G2 is a precursor for the larger family of prostaglandins responsible for vascular and uterine regulation (Barton et al., 1991). Prostaglandins are also important in the regulation of systemic and pulmonary vessels and the ductus arteriosus (Needs, 1985). Acetylsalicylic acid, acetaminophen and ibuprofen are known to cross the placenta and acetylsalicylic acid has been shown to remain longer in the neonatal system than in the adult system.
ACETYLSALICYLIC ACID (ASA)
The effects of ASA on a pregnancy have been disputed in the literature. In a large prospective study of 50,000 women who were treated with ASA, 14,000 during the first four lunar months of pregnancy, there was no evidence of increased risk for congenital anomalies in exposed infants, compared to those infants who were not exposed (Sloan et al., 1976). ASA use during pregnancy had no significant effect upon mean birth weight, neonatal death or the rate of stillbirths (Collins et al., 1981). Available data indicate that the risk of birth defects was not increased substantially when women took doses of ASA during their first trimester considered to be common occasional use (650-1300mg/day) (Teris, 1994). In the studies that have observed an increase in the frequency of birth defects, no specific, nor reproducible, pattern of anomalies has been described.
Two British studies showed salicylates could be a teratogen. In these studies, more than 1,200 mothers of children with birth defects were analyzed for salicylate use during pregnancy. A significant number of mothers had taken salicylates (Collins et al., 1981). An increase in oral clefts among exposed infants was seen in a study of almost 600 Finnish women whose consumption of aspirin was 3X that of controls (Collins et al., 1981). In another study, an increase in frequency of gastroschisis was associated with first trimester use of ASA (Werler et al., 1992). It is generally accepted that in women who take ASA during pregnancy, gestation length might be increased. Near-term use (within one week of deliver) has been associated with an increased risk of intracranial hemorrhage in infants that are premature or low-birthweight (Briggs, 1994). Analgesic use late in pregnancy may complicate delivery and adversely effect the neonate and is therefore not recommended.
In larger doses, for example those used in the treatment of rheumatic diseases (up to 5000 - 6000 g/day), ASA has been associated with a number of congenital birth defects including neural tube defects, facial clefts and skeletal malformations (Teris, 1994). An association between high doses of ASA and the premature closure of the ductus arteriosus has been suggested (Levin et al., 1978). This closure might result in neonatal pulmonary hypertension and hypoxemia (Barton et al., 1991). Other studies showed no association between children with congenital heart defects and occasional maternal use during pregnancy (Werler et al., 1989). If maternal high doses cause premature closure of the patent ductus arteriosus, it occurs infrequently. Chronic use of ASA during pregnancy is thought to increase the risk of stillbirth, anemia, prepartum hemorrhage and preeclamptic toxemia (Needs, 1985).
It has been suggested that the use of ASA in low doses (40-150 mg/day) throughout pregnancy or in the second and third trimesters may guard against preeclampsia, intrauterine growth retardation and maternal immunologic conditions associated with fetal loss such as lupus (Barton et al., 1991). More recently, however, a multinational study involving more than 9,000 women who were treated with very low doses of ASA (60 mg/day) showed no protection against an increase in preeclampsia or intrauterine growth retardation (CLASP, 1994). Thirty-eight percent of the study sample did not receive ASA treatment until after the 20th week of gestation. When studied separately, those women who received ASA treatment prior to 20 weeks did show a reduction in preeclampsia (Reprotox, 1995). Studies on this treatment have involved thousands of women and no adverse effects on their offspring have been observed (Teris, 1994).
ACETAMINOPHEN
Acetaminophen was used as an analgesic beginning in 1893, six years before the introduction of ASA (Peterson, 1985). If used in therapeutic doses for short amounts of time, there is no known teratogenic effect associated with acetaminophen. Generally, acetaminophen has a less “noteworthy” role as a prostaglandin synthesis inhibitor (Peterson, 1985). Routinely used during all phases of pregnancy, it is safe as a short-term analgesic.
Werler and her colleagues found a nonsignificant elevation of gastroschisis associated with first trimester use (1991); the prenatal exposures to acetaminophen in seventy-six infants with gastroschisis were studied. The Collaborative Perinatal Project studied the maternal use of acetaminophen during the first trimester and anytime in gestation in almost 1,000 women; no increase in frequency of congenital abnormalities was seen (Heinonen, 1977). A retrospective study on congenital heart defects found no association with the use of acetaminophen (Zierler et al., 1985). Aselton et al., (1985) studied 687 women with first trimester exposure to acetaminophen and found no increase in the rate of congenital abnormalities.
When maternal toxic levels of acetominophen are reached, various adverse effects have been noted including facial cleft, spina bifida, and pyloric stenosis (Briggs, 1994).
IBUPROFEN
The effects of ibuprofen during pregnancy have not been delineated as thoroughly as acetaminophen or ASA. There is a “none to minimal” risk of congenital anomalies associated with its use during pregnancy (Teris, 1994). The frequency of birth defects was not increased among the children of women who were treated in the first trimester (Aselton, 1985), or at various doses during pregnancy (Barry, 1984). Use of ibuprofen has been reported in over 100 human pregnancies without evidence of a syndrome of congenital anomalies.
Similar to the other prostaglandin inhibitors, high doses of ibuprofen during the third trimester may be a factor in the premature closure of the ductus arteriosus. Hendricks et al., (1990) studied a group of 309 women with preterm labor who received ibuprofen and found a relationship with premature closure of the ductus arteriosus. This potential toxicity is the basis for the recommendation against its use in the third trimester. One case report described a woman who had taken large doses of ibuprofen during the second and third trimesters; constriction of the ductus arteriosus was observed in the fetus. A causal relationship was not assessed due to confounding factors in the case (Baker, 1993).
SUMMARY
The non-narcotic analgesics discussed above belong to a class of drugs termed prostaglandin synthetase inhibitors. These agents inhibit cyclo-oxygenase, an enzyme which catalyzes the conversion of arachidonic acid to endoperoxide, a precursor of the prostaglandins. Vasoconstriction, uterine activity, uteroplacental blood flow and platelet aggregation are regulated by the prostaglandins.
Acetylsalicylic acid, acetaminophen and ibuprofen are common drugs taken during pregnancy. Self-administration has the potential for incorrect dosages or prolonged use. Women should be aware that any medication, even over-the-counter drugs, taken during pregnancy has the potential for disrupting the development of the fetus. Due to the association of ASA and ibuprofen with premature closure of the ductus arteriosus, their use is usually not recommended during the third trimester. When these agents are used as tocolytic treatment in the third trimester, weekly or biweekly ultrasounds may be useful to monitor for this condition (Wiggens et al., 1990). Acetaminophen is considered safe during pregnancy.
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Posted by admin on September 2nd, 1995 — in newsletter
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Benzodiazepines and Pregnancy
Vol 4#2 September 1995
Eugene Pergament, MD, PhD; Amy Schechtman MS; Aimee Wonderlick
It is estimated that 30 to 40% of pregnant women are treated with medications for anxiety during their pregnancy (McElhatton, 1994). The medications used for this purpose are often benzodiazepines, one of the most widely prescribed classes of drugs in the world. Benzodiazepines are used as anxiolytics, anti-convulsants, muscle relaxants, and sedatives. In addition to treating anxiety during pregnancy, they may also be used during normal deliveries, caesarean sections, and to treat eclampsia and preeclampsia (McElhatton, 1994). Benzodiazepines may also be abused by those addicted to drugs.
While many new benzodiazepines have been introduced in recent years, few studies have been conducted concerning their use during human pregnancy. Most of the information on benzodiazepine use during pregnancy is based on diazepam. Although initial studies suggested an association between first trimester use of diazepam and specific congenital anomalies, more recent reports have not supported these claims. Substantial evidence exists demonstrating that newborns of mothers treated with benzodiazepines near term or during delivery show classic drug withdrawal symptoms. This issue of RISK||NEWSLETTER will review the use of benzodiazepines during pregnancy.
RISK OF CONGENITAL MALFORMATIONS
Beginning in 1975, concern was raised over an association between first trimester use of diazepam and oral clefts in newborns (Saxen, 1974; Aarskog, 1975). In a retrospective study of 278 malformed children, Safra and Oakley (1975) found that pregnant women taking diazepam had a relative risk of four for having an infant with cleft lip (with or without cleft palate). These results have been criticized because the study introduced a possible source of recall bias by using a questionnaire to determine matenal exposure to diazepam. In addition, the study did not control for multiple drug use.
Later studies (Rosenberg et al., 1983; Shiono and Mills, 1984) found that first trimester use of diazepam posed no increased risk for oral clefts. Included in these studies was that of Czeizel (1988) which analyzed data obtained from the Hungarian Congenital Malformation Register. Information was collected on benzodiazepine (diazepam, nitrazepam, and chlordiazepoxide) use in four different studies using four different methods (both retrospective and prospective). The studies included over 350 exposed pregnant women and there was no indication that the use of benzodiazepines alone or with other drugs was associated with an increase in facial clefts or any other specific birth defects.
The possible teratogenicity of benzodiazepines was raised again when Laegrid et al. (1989) reported eight infants with birth defects whose mothers had taken diazepam or oxazepam while pregnant. Most of the abnormalities involved either facial defects or neurological problems. This study was criticized because photographs of the affected children revealed a physical appearance similar to that seen in Zellweger syndrome, an autosomal recessive condition. The blood samples from these women were analyzed for benzodiazepines only, so it was possible that the women were exposed to other drugs. It is also important to note that three of the mothers in the study denied using any drugs during pregnancy.
In order to address the issue of the potential teratogenicity of benzodiazepines in a systematic manner and to avoid the criticisms of earlier studies, Pastuszak et al., (in Schardein, 1995) conducted a prospective study of pregnancy outcome following first-trimester exposure. The subjects and controls consisted of women who were seen through the Motherisk Program in Toronto. Pregnancy outcomes of 137 women who sought counseling after first-trimester exposure to benzodiazepines were compared to 137 women who sought counseling after exposure to drugs that are known to be safe during pregnancy. The most commonly used benzodiazepines in this study were diazepam, lorazepam, and alprozolam. A trained interviewer obtained information on pregnancy outcome over the phone; pregnancy outcome reports were confirmed by a written report sent to the clinic by the child’s physician. No statistical difference in the rates of major birth defects were observed between the two groups. There were no cases of cleft lip and/or palate, and in fact, only one infant in the benzodiazepine exposed group had a congenital anomaly.
RISK OF NEONATAL WITHDRAWAL
The occurrence of withdrawal symptoms in infants of mothers exposed to benzodiazepines during pregnancy has been well documented (Cree et al., 1973; Gillberg, 1977; Haram, 1977). Neonatal withdrawal was most likely to occur when mothers were taking chronic doses of benzodiazepines near term or during delivery. Symptoms included hypotonia, respiratory distress, impaired temperature regulation, hyperactivity, and irritability. Signs of withdrawal were present at birth or appeared weeks later and continued for long periods of time (Besunder and Blumer, in Schardein, 1995). Elimination of benzodiazepines in the infant is slow, and it is thought that increased blood concentrations along with an immature blood-brain barrier may make newborns more sensitive to the drugs than adults (Pastuszak, in Schardein 1995). In addition to diazepam, withdrawal symptoms have also been observed in the infants of women who took clobazam, chlordiazepoxide, and lorazepam during pregnancy (Devreker et al., 1987; Stirrat et al., 1974; McBride et al., 1979).
Besunder and Blumer (1995) recommend that treatment of withdrawal should be initiated if the symptoms are causing poor feeding and weight gain or interfering with normal caretaker interactions. Initially, diazepam should be administered intravenously until symptoms have been controlled for one week, at which time the daily dosage should be weaned over three to four weeks. Schneiderman (in Schardein 1995) also recommended that pregnant women taking chronic doses of benzodiazepines attempt to achieve abstinence by gradual reducing their daily dose over a six to eight week period. Diazepam can be substituted for some of the shorter-acting benzodiazepines during detoxification in order to stabilize fluctuating blood levels of the medications. If abstinence cannot be reached through either outpatient or inpatient regimens, pregnant women should be given the lowest possible dose of benzodiazepines.
NEUROBEHAVIORAL EFFECTS
It has not been established that prolonged exposure in utero results in neurobehavioral disturbances, as suggested in certain reports. Laegrid et al., (1992) described 17 children whose mothers had psychiatric illnesses and were taking benzodiazepines during pregnancy. Compared to infants of mentally healthy mothers, the benzodiazepine-exposed infants showed delayed gross motor development at 6 and 10 months, but normal development by 18 months. Fine motor functions were impaired at all study periods. However, all major developmental milestones were achieved at the appropriate ages. Effects on long-term development were not evaluated.
Bergman et al., (1992) examined benzodiazepine use during pregnancy in deliveries registered with Medicaid between 1980 and 1983. Eighty women were identified who had been given 10 or more prescriptions for benzodiazepines and thus were assumed to be chronic users. Forty (50%) of these women were exposed throughout their entire pregnancy. In addition, 30% of the women reported drug dependence during pregnancy, 14% reported alcohol dependence, and over 50% had a chronic illness such as liver cirrhosis or hepatitis. Follow-up was obtained on 64 children and 14 were found to have some signs of developmental delay. However, given the medical and social history of their mothers, environmental factors cannot be ruled out as significant contributors to their failure to develop normally.
SUMMARY
Studies concerning the teratogenicity of benzodiazepines have produced conflicting results. Recent studies, however, have not provided substantive evidence that in utero exposure to benzodiazepines causes an increase in any specific malformation or pattern of malformations. Early studies that reported an association with adverse outcomes were criticized because of recall bias and possible multiple drug use.
Infants of mothers taking chronic doses of benzodiazepines near term are at risk for developing withdrawal symptoms postnatally. For this reason, women should discontinue use well before delivery. If abstinence is not possible, the lowest possible dose should be used and one of the shorter acting benzodiazepines should be considered (McElhatton, 1994).
Many women who are taking benzodiazepines may have psychiatric illnesses, epilepsy, or be dependent on other drugs or alcohol. Maternal illness or drug abuse is likely to create an environment that is not optimal for normal infant development, both prenatally and postnatally. Each of these conditions are risk factors during pregnancy and, therefore, it is difficult to discern negative clinical effects due specifically to benzodiazepines, especially in relation to neurobehavioral dysfunctioning.
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