Posted by admin on December 2nd, 1995 — in newsletter
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Fluoxetine and Pregnancy
Vol 4#3, December 1995
Eugene Pergament, MD, Ph.D.; Amy Schechtman, MS, CGC; Stacy Owen, BA
Fluoxetine (Prozac) is a medication used in North America by millions of patients with major depression (Pastuszak et al., 1993). It is probably the most commonly prescribed anti-depressant. This medication is an oral anti-depressant which selectively inhibits serotonin reuptake by neurons, thus prolonging the action of this neurotransmitter. Not chemically related to the more traditional tricyclic anti-depressants, fluoxetine has enhanced specificity and potency. These properties are due to its specific effects on serotonin uptake and the long elimination half-life in vivo of fluoxetine (2-3 days) and its active metabolite, norfluoxetine (7-9 days) (Pohland et al., 1989). Moreover, one of the medical benefits of prescribing this medication rather than a tricyclic anti-depressant is that fluoxetine use results in fewer and milder dose-related side effects (Edwards et al., 1994).
A significant number of women of reproductive age suffer from depression, necessitating long-term therapy with psychotropic drugs. It is important therefore to consider the potential reproductive effects of fluoxetine. It is estimated that as many as 10% of pregnant women meet the criteria for major and minor depression and that even larger numbers are affected during the post-partum period (O’Hara et al., 1994). Manufacturers and health providers often suggest that women not be treated with psychotropic medications during gestation. This generalized recommendation fails to acknowledge the role that a psychotropic medication, such as fluoxetine, may play in maintaining the health and well-being of some affected women. It is important to consider that the discontinuation of therapy may endanger the health of women and the safety of their pregnancies.
Thus, the potential benefits of therapy to a woman must be considered in relation to any potential reproductive risks associated with the medication. This issue of RISK||NEWSLETTER will review the potential reproductive risks of fluoxetine use in pregnant women.
RISK FOR CONGENITAL MALFORMATIONS
Human studies and case reports provide no evidence to suggest that fluoxetine is teratogenic. A cohort study performed at four teratogen information services found that the incidence of congenital anomalies was not increased among infants born to 128 women who took fluoxetine during the first trimester of pregnancy (Pastuszak et al., 1993). The rate of major malformations in the infants exposed to fluoxetine during the first trimester was not statistically different from the rate reported in the unexposed control group (2% vs. 1.8%; p=.38) (Pastuszak et al., 1993). Similar findings have been reported in an abstract by Schick-Boschetto and Zuber (1992).
A separate abstract from the California Teratogen Information Service reported the pregnancy outcome of 107 women who had been exposed to fluoxetine during their pregnancies. Although a control group was not included in this study, there was no evidence of an increased incidence of birth defects among the infants born to the women in this cohort (chambers et al., 1992).
The frequency of congenital anomalies did not appear to be increased among the infants of 485 women voluntarily reporting to the manufacturer during pregnancies in which fluoxetine was prescribed. In this population, 13 malformations were reported, with an incidence of 3.4%. Among 28 infants with major congenital anomalies which were retrospectively reported to the manufacturer, no recurrent pattern of malformations were apparent (Goldstein and Marvel, 1993). The inconsistent pattern of anomalies does not suggest a causative relationship between fluoxetine and congenital malformations.
Data from animal studies also suggest that fluoxetine is unlikely to pose a substantial teratogenic risk. According to the manufacturer (Eli Lilly), the frequency of malformations was not increased among the offspring of rats administered 9-11 times the maximum dose of this medication generally prescribed for humans (Byrd et al., 1989).
A second animal study found an increased incidence of skin hematomas in the offspring of rats that were administered fluoxetine on a mg/kg basis in doses which were 17 times higher than those generally prescribed for humans (Stanford and Patton, 1993). This study suggests that exposure to fluoxetine in utero may affect the serotonergic aspects of vascular activity and cause exposed offspring to be highly susceptible to bruising and hematomas during the birth process. However, this study did not suggest that long term susceptibility to bleeding and bruising results from in utero exposure (Stanford and Patton, 1993). No reports of hematomas have been made in the offspring of women exposed to fluoxetine during pregnancy.
RISK FOR MISCARRIAGE
The rate of miscarriage was evaluated in the prospective study of 128 women treated with therapeutic doses of fluoxetine during the first trimester of pregnancy (Pastuszak et al., 1993). Two matched control groups were selected for this study: one with exposure to non-teratogens and one with exposure to tricyclic anti-depressants. There was a tendency for a higher percentage of miscarriages in the 128 fluoxetine patients in comparison to the non-exposed group, but it did not reach statistical significance (14.8% vs. 7.8%; RR 1.9%; 95% CI, 0.92-3.92). However, the sample size of this cohort had limited power to show statistical significance. In addition, women exposed to tricyclic anti-depressants tended to report higher rates of miscarriage when compared to the control group (13.5% fluoxetine group; 12.2% tricyclic antidepressant group; 6.8% control group). The authors suggest that additional studies are necessary to document this finding and to determine whether the reported tendency towards higher rates of miscarriage results from the psychotropic medications or the effects of a psychiatric condition (Pastuszak et al., 1993).
Data from the prospective study of Chambers et al., (1993) did not suggest an increased risk for miscarriage among women exposed to fluoxetine. However, the data suggested an association between maternal exposure to fluoxetine and large-for-gestational age infants. In this study, 39% of the infants born to women who had taken fluoxetine during pregnancy were above the 90th percentile in weight. No other studies have reported a similar association between maternal use of fluoxetine during pregnancy and infants who are born large-for-gestational age.
RISK FOR NEUROBEHAVIORAL EFFECTS
Fluoxetine alters neurotransmitters in the brain of a person who is exposed to this medication. Therefore, there is a theoretical risk that this medication could potentially affect brain development in an exposed fetus.
Most of the information that is available concerning this issue has come from animal studies. One study evaluated the behavioral effects of fluoxetine on the offspring of rats treated with doses as high as 12 mg/kg/day. At no dose was there evidence in the offspring of behavioral abnormalities attributed to the maternal fluoxetine treatment (Vorheers et al., 1994).
In contrast, at least one published study reported a short-term effect on the neurobehavior of rats exposed prenatally to fluoxetine (Montero, 1990). However, it has not been determined whether these findings in an animal model have relevance to human pregnancy.
There has been one case report of a neonate with transient central nervous system toxicity with measurable cord blood levels of fluoxetine and its metabolite norfluoxetine (Spencer, 1993). In this case the symptoms reportedly resolved four days after birth. in the future, long term studies will be required to rule out potential neurodevelopmental teratology of fluoxetine (Pastuszak et al., 1993).
RISK FROM BREASTFEEDING
It is known that fluoxetine is excreted into human breast milk. An estimate of total fluoxetine intake by a suckling infant is 15-20 ug/kg/day, which contributes a very low level of exposure (Birchland and Wells, 1992). Although the level of exposure in breast feeding infants is seemingly low, the concern about possible effects on neonates exposed to fluoxetine has been raised in case reports. One group reported a possible association between exposure to fluoxetine and colic in one infant (Lester et al., 1993). A second report of increased irritability in a suckling infant during the first two weeks of therapy has also been made (Isenberg, 1990). However, it is important to note that there were differences among those who observed these infants in regard to the infants’ symptoms and their association with fluoxetine exposure.
Serotonin is an inhibitor of suckling-induced oxytocin release. This effect has been intensified by exposure to fluoxetine in anesthetized rats (Moos, 1983). This finding raises the possibility that fluoxetine may hinder the nursing process. However, inhibition of oxytocin release was not consistent throughout the study by Moos (1993). Serotonin inhibition of oxytocin release was not observed among rats given fluoxetine but not anesthetized (Spencer, 1993).
Based on limited data, the American Academy of Pediatrics considers the effects of fluoxetine on a nursing infant to be undetermined. Concern about possible effects of this medication on exposed neonates has led the manufacturer to revise its label for fluoxetine and to recommend that it not be used by nursing mothers (Nightengale, 1994). Those women who use fluoxetine during lactation should be advised to be aware of any changes in their infants behavior (e.g., agitation, irritability, drowsiness, ect.), which may be associated with neonatal fluoxetine exposure.
SUMMARY
Based on human and animal studies, there is no evidence to suggest that the use of fluoxetine during pregnancy is associated with an increased risk for major congenital malformations. Concern regarding a relationship between an increased risk for miscarriage among women who have used fluoxetine or tricyclic anti-depressant has been raised. However, the results were not found to be statistically significant. Additional studies will be necessary to document this finding and to determine whether the reported tendency towards higher rates of miscarriage results from the psychotropic medications or the effects of a psychiatric conditions. No information is available concerning what effect, if any, fetal or neonatal exposure may have on neurobehavioral development.
Based on the available data, it can be concluded that there are potential benefits and risks to using fluoxetine during pregnancy and lactation. Thus, the use of fluoxetine should only be recommended if the benefit of anti-depressant therapy to the woman outweighs any potential reproductive risks.
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Posted by admin on December 1st, 1995 — in newsletter
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Paint and Pregnancy
Vol 4#4, December 1995
Eugene Pergament, MD, PhD; Amy Schechtman, MS, CGC; Elizabeth Chen, BS
Many pregnant women are exposed to paint under a variety of circumstances. Medical health providers are often questioned about the potential risks of paint exposure to the developing fetus. This issue of the RISK||NEWSLETTER addresses paint exposure during pregnancy under different circumstances: recreational use, occupational exposures, and household exposures.
CONSTITUENTS AND TYPES OF PAINT
A paint consists of pigment particles suspended in a liquid medium called, a “vehicle”. Pigments are almost always metal-based inorganic substances, including salts of lead, zinc, barium, magnesium, or aluminum. White or pastel paints usually contain titanium compounds that are replaced by other metals when a color change is desired (Gosselin et al., 1984). “Extenders”, also known as translucent pigments, are often added to improve the quality of paint appearance. Vehicles are derived from a variety of sources, such as natural oils and pure or synthetic resins. Examples of natural oils include soybean, castor, safflower, linseed and perilla. Copal, rosin, shellac, and manila are examples of resins derived from trees. Thinners, solvents (ethylene glycol and glycol ethers), rust inhibitors and biocides are often found in addition to the basic ingredients of paint (Scialli, 1989).
There are three broad categories of paint. Latex paints comprise the majority of those used for the household. They are commonly based on emulsions of polyvinyl acetate or acrylic resins, and can be thinned by water. Oil paints contain an alkyd resin or oil varnish. They are commonly thinned by mineral spirits, also known as petroleum distillates (Gosselin et al., 1984). Enamel paints are similar to oil paints, except with more vehicle and smaller particles (Scialli, 1989).
The potential for paint toxicity depends on which components are present in the paint. However, the degree of toxicity during pregnancy is difficult to predict, since there are no methods to quantify actual exposure. Limitations are due to the nature of inhalation and skin contact exposures. Dosage and duration are variable. Current data on potential teratogenicity of paint have been limited to abusive sniffing and occupational exposures (Scialli, 1989).
RECREATIONAL PAINT USE
Toluene, an aromatic organic solvent, is believed to be the agent that causes euphoria among those who sniff paint. Organic solvents (refer to RISK||NEWSLETTER Vol 3. No. 4) have been shown to increase the rate of miscarriage following high levels of exposure. Although there have not been many studies, available data suggest an association between paint abuse during pregnancy and an increased risk for birth defects.
Three children whose mothers sniffed paint were reported to have microcephaly, midface hypoplasia, short palpebral fissures, low-set ears, micrognathia, dysmorphic fingers, hypotonia, and hyperreflexia. The authors noted characteristic similarities to fetal alcohol and fetal hydantoin syndromes (Hersh et al., 1985). Five additional pregnant women who sniffed paint and presented with renal tubular acidosis were subsequently studied. Intrauterine growth retardation was seen in the infants of three women. One of these infants had deformed ears, ventricular septal defect, micrognathia, and fetal alcohol syndrome facies. Hydronephrosis was present in one of the infant who was not growth retarded. The other three infants were reported to be phenotypically normal (Goodwin, 1988).
Higher levels of exposure are expected with recreational paint use than with occupational or household uses. An increased risk for teratogenicity exists.
OCCUPATIONAL EXPOSURES
The effects of occupational exposure to paint are difficult to assess with respect to teratogenicity. The amount of paint inhalation and possible skin contact cannot be accurately epidemiologic studies on occupational paint exposure and effects on pregnancy.
A study from a Danish county of Funen collected information on reproductive histories from women, including 76 painters working in various occupations. The control group included shop assistants and vegetable warehouse workers whose exposure to chemicals was lower. The purpose of the study was to see if chemical exposures increased the likelihood of miscarriage. Upon controlling for gravidity, pregnancy order and age, self-reported miscarriages among painters were increased with an odds ratio of 2.9 (95% CI 1.0 to 8.8). However, when only hospital documented miscarriages were considered, the odds ratio became significant at 1.4 (95% CI 0.4 to 2.5). This discrepancy may have been due to recall bias (Heidam, 1984).
A separate study conducted in the same county looked for associations between parental occupational exposure to organic solvents and birth defects in children. A computerized registry was used to identify infants with central nervous system, intestinal and limb malformations and to obtain control cases with abnormalities not known to be due to teratogenic effects. None of the mothers were painters. Fathers who were painters showed a significant increased odds ratio (4.9, 95% CI 1.4 to 17.1) of having children with defects involving the central nervous system. Other paternal occupations with similar chemical exposures did not show a significant association. This correlation has been challenged, since multiple comparisons were made in this study. Therefore, the association may have been due to chance (Olsen, 1983).
Daniell and Vaughn (1988) looked for associations between paternal occupations and pregnancy outcomes in a U.S. retrospective cohort study. Fathers who worked as auto body painters were found to have significantly higher numbers of low birthweight infants born after 37 weeks (odds ratio 1.6, CI 1.1-2.4) than the control group. No other increased risk was noted. Since multiple comparisons were made in this study, it is possible that this association was also due to chance.
Precautions toward minimizing occupational exposures included wearing protective clothing and working in a well ventilated area.
Spray Paints
Spray paints can contain a variety of organic solvents (Paul, ed., 1993). As previously mentioned, high levels of exposure to organic solvents have been associated with a higher rate of miscarriage. The concern with spray paints is that due to the larger quantity of mist generated, the amount of solvent inhaled may be considerably greater. Spray painting in an occupational setting will more likely release more airborne solvent than spray painting around the home or for art projects. It is recommended that precautions be taken to minimize exposure and reduce any potential risk, e.g., keeping the painted area ventilated and wearing protective clothing.
Association with Childhood Cancer
In 1974, Fabia and Thuy reported a possible association between childhood cancer, especially leukemias, and paternal exposure in hydrocarbon-exposed occupations, including the paint industry. This study initiated a surge of interest on the topic. Many studies have been performed since 1974 on both maternal and paternal effects and risks for childhood cancer (Lindquist et al., 1987; VanSteensel-Moll et al., 1985; Lowengart et al., 1987; Zack et al., 1980; Kwa et al., 1980; Peters et al., 1981; Hakulinen et al., 1976; Hemminki et al., 1981; Sanders et al., 1981). Most of the studies focus on paternal exposures because only a small number of women work as architectural or industrial painters. Unfortunately, analysis of all the findings did not prove a causal relationship due to contradictory results. Although some studies have been criticized on methodological grounds, this issue of concern cannot be completely disregarded.
HOUSEHOLD EXPOSURES
There are no publications, which specifically assessed the effects of household painting on pregnancy. It is often assumed that exposures are lower and less frequent in the home than in the workplace. However, minimizing household exposures is still recommended since levels of paint, and thus solvents, are difficult to determine when present in the air.
Painting the Walls
Household paints are classified as interior or exterior paints, and can be latex or oil based. Most of the paints intended for use around the home are latex paints, which are thinned by water. organic solvents are sometimes added in small amounts to improve the overall quality of the paint. Glycol ethers are the most commonly added organic solvents in latex paints. Ethylene glycol ethers are toxic and are gradually being substituted by less toxic propylene glycol ethers. The concentration of organic solvents is significantly less in latex paints than oil paints, which makes latex the paint of choice if painting is necessary during pregnancy (Paul, ed., 1993).
Removing Old Paint
Caution should be taken when considering home renovations due to the possibility of lead exposure. Increased maternal blood lead levels have been associated with fetal toxicity and a variety of minor anomalies (Wong et al., 1992). Please refer to RISK||NEWSLETTER Vol.3 No.3 for more information on lead exposure during pregnancy. Homes built before 1977 were mostly painted with lead-based paint. Even though the Consumer Product Safety Commission (CPSC) in 1977 determined the maximum allowable lead content in household paints to be 0.06% (600 parts per million lead by dry weight), homes built after this date may still be a major source of lead exposure (ATSDR, 1988). A trained professional before removal should check all wall paint for lead.
Painting as a Hobby
Art paints contain two general types of pigments, organic and inorganic. Inorganic pigments contain various toxic elements such as lead, chromium, cadmium, cobalt, mercury, nickel and manganese. Flake white (white lead) and Naples yellow (antimony yellow) are the two lead-containing pigments used in oil paints that raise the most concern (Hersh et al., 1985).
Artists commonly use spray paints that can contain organic solvents. Care should be taken to minimize spraying of these products during pregnancy. Brush painting is recommended over spray or air-brush techniques to prevent mist generation and subsequent inhalation (Paul, ed., 1993).
Significant exposure to toxic chemicals can occur if artists mix their own paint. Use of premixed paint is suggested. In general, water colors, acrylic, and tempura paints are recommended over oil paints for projects (Paul, ed., 1993).
The Center for Safety in the Arts (212-227-6220) or Arts, Crafts, and Theater Safety (212-777-0062) can be contacted for more information regarding art hazards and ways to lessen exposure levels.
SUMMARY
Data are insufficient in quantity and quality to determine the safety of paint exposure during pregnancy. Questions will continue to be asked and therefore counseling skills are important in communicating the ambiguity of our present knowledge. Studies do not suggest an increased incidence of miscarriage or congenital anomalies in children born to men or women exposed to paint, but these possibilities cannot be excluded. Toxicity is likely to be dose-related as shown by the studies of paint abuse for recreational purposes.
In general, to reduce any potential risks to the developing fetus, it is advised that paint exposures be kept to a minimum. if an occupational exposure is unavoidable, protective clothing (including gloves and masks) and effective ventilation of the workplace will reduce the level of possible risk. Paint exposures around the home are likely to be less than those at the work site. However, it is still recommended that home painting projects be completed before conception. When the removal of old paint is anticipated, it is important not to do so until the paint is determined to be lead-free. Latex paints containing solvents such as ethylene glycol ethers and biocides should be avoided. Art hobbyists should take care in minimizing exposure to toxic constituents in paint products. In general, water colors, acrylic, and tempura paints are recommended over oil paints.
It is important to inform individuals that these recommendations are made without conclusive data. Paint has not been proven to be teratogenic. However, all precautions would serve as an additional safety measure and would most likely decrease any potential risk to the pregnancy and the fetus.
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