Risk Factor: BM
Class: Central nervous system drugs / Antidepressants

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Fetal Risk Summary

Although the mechanism of action of the antidepressant sertraline is unknown, it is a selective serotonin reuptake inhibitor (SSRI) similar to other drugs in this class (see also Citalopram, Fluoxetine, Fluvoxamine, and Paroxetine). This effect of sertraline results in the potentiation of serotonin activity in the brain. The chemical structure of sertraline is unrelated to other antidepressants.

All the antidepressant agents in the SSRI class are thought to share a similar mechanism of action, although they have different chemical structures. These differences could be construed as evidence against any conclusion that they share similar effects on the embryo, fetus, or newborn. In the mouse embryo, however, craniofacial morphogenesis appears to be regulated, at least in part, by serotonin. Interference with serotonin regulation by chemically different inhibitors produces similar craniofacial defects (1). Regardless of the structural differences, therefore, some of the potential adverse effects on pregnancy outcome may also be similar.

Reproductive studies in rats and rabbits, conducted with doses up to approximately 4 times the maximum recommended human dose on a mg/m2 basis (MRHD) did not reveal evidence of teratogenicity (2). Delayed ossification of rat and rabbit fetuses, however, occurred at doses during organogenesis of 0.5 and 4 times the MRHD, respectively. When female rats were dosed at 1 times the MRHD during the last third of gestation and throughout lactation, an increase in the number of stillbirths, decreased pup survival, and decreased pup weights were observed. The decreased pup survival was shown to be due to in utero exposure to sertraline. The no effect dose for rat pup mortality was 0.5 times the MRHD (2).

No reports describing the transfer of sertraline across the human placenta have been located. The molecular weight (about 343 for the hydrochloride salt) is low enough, however, that passage to the fetus should be expected.

A 24-year-old woman (gravida 5, para 0, therapeutic abortion 4) was treated before and during the first few weeks of gestation with sertraline for depression and bulimia (personal communication, K. Murray and D. Jackson, Eugene, Oregon, 1994). Ultrasound revealed a single fetus with anencephaly and an abdominal wall defect. Chromosomal analysis performed after termination indicated that the fetus had trisomy 18 (47,XX,+18). Because trisomy 18 is a naturally occurring mutation, in the absence of any animal or other evidence for a causal relationship, it is doubtful that the drug therapy was related to the outcome of this pregnancy.

Fifteen diverse birth defects have been reported to the FDA as of December 1995 (personal communication, F. Rosa, FDA, 1996).

A 1995 report described the use of sertraline 100 mg/day and nortriptyline 125 mg/day in a woman with recurrent major depression (3). The patient ingested these drugs before and throughout gestation. Attempts to discontinue the agents in the 1st and 2nd trimesters were unsuccessful. She eventually gave birth at term to a healthy infant (sex and weight not specified) who, at age 3 months, was doing well and achieving the appropriate developmental milestones (see also Breast Feeding section below) (3).

A brief 1995 report described a case of a 32-year-old woman who took sertraline 200 mg/day throughout pregnancy (4). Lithium and thioridazine were also taken during the first 6 weeks of gestation. She continued the same dose of sertraline for 3 weeks after delivery of a healthy, full-term male infant. During this period, she breast-fed the infant who was feeding and developing normally. One day after she stopped sertraline, the infant developed agitation, restlessness, poor feeding, constant crying, insomnia, and enhanced startle reaction (4). The infant's symptoms continued for another 48 hours before gradually resolving over several days. Similar symptoms were not observed in the mother. Because the same types of symptoms have been observed in adults after discontinuing sertraline (1), the authors attributed them to withdrawal (4).

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (5). Data were obtained by questionnaires sent to the prescribing physicians 1 month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Sertraline was taken during the 1st trimester in 51 pregnancies. The outcomes of these pregnancies included 1 ectopic pregnancy, 2 spontaneous abortions, 11 elective abortions, 1 intrauterine death, 26 normal full term newborns, 2 infants with birth defects, and 8 pregnancies lost to follow-up (5). The congenital malformations were one case each of congenital laryngeal stridor and a duplication cyst (gastrointestinal).

A prospective, multicenter, controlled cohort study published in 1998 evaluated the pregnancy outcomes of 267 women exposed to one or more of three SSRI antidepressants during the 1st trimester: fluvoxamine (N=26), paroxetine (N=97), and sertraline (N=147) (6). The women were combined into a study group without differentiation as to the drug they had consumed. All of the women had contacted a teratogen information service about their use of the drugs during pregnancy. A randomly selected control group (N=267) was formed from women who had contacted one service after exposure to nonteratogenic agents. The pregnancy outcomes were determined, in most cases, 69 months after delivery. The study group was significantly more likely to smoke cigarettes and to have had a previous elective abortion but less likely to be a primigravid. Other characteristics, such as a previous spontaneous abortion, alcohol consumption, and maternal age at conception did not differ between the groups. As for pregnancy outcomes, no significant differences were measured in the number of live births, spontaneous or elective abortions, stillbirths, major malformations, birth weight, or gestational age at birth. Nine major malformations were observed in each group. The relative risk for major anomalies was 1.06 (95% confidence interval [CI] 0.432.62). No clustering of defects was apparent. In the study group, no differences were found in the pregnancy outcomes of smokers compared to nonsmokers. In addition, the outcomes of women who took an antidepressant throughout gestation were similar to those who took an antidepressant only during the 1st trimester (6). One of the investigators, in response to subsequent correspondence regarding the study (7,8), clarified that all of the 267 women in the study group had taken an antidepressant during embryogenesis (9). Other concerns relating to the outcomes and sample size were also addressed.

In 1999, the Swedish Medical Birth Registry published the results of a study on the use of antidepressants in early pregnancy and delivery outcome for the years 19951997 (10). During the period, 281,728 infants were registered, 531 of whom had been exposed in utero to SSRI antidepressants, 15 to SSRIs plus a non-SSRI antidepressant, and 423 to non-SSRI antidepressants. Of the 34 women who used sertraline, 32 used it alone and 2 used it in combination with another SSRI agent (citalopram and paroxetine). There were no significant differences in relative risk (RR=observed/expected) for birth defects between those exposed to any antidepressant (total 39; RR 1.13), SSRIs only (total 21; RR 1.12), and non-SSRIs only (total 18; RR 1.15) (specific defects were only given for those exposed to citalopram). Similarly, no significant differences in infant survival were observed among the groups. A shorter gestational duration (<37 weeks) was observed for exposure to any antidepressant (OR 1.43, 95% CI 1.141.80) but no difference between SSRI and non-SSRI antidepressants. Moreover, antidepressant exposure was not associated with an increased risk of low birth weight (defined as <2500 g) among singletons as the crude OR 1.32 (95% CI 0.961.80) decreased to 1.03 after adjustment for confounders (10).

In summary, the limited animal and human data do not support a major teratogenic risk from the use of sertraline during pregnancy. A 1999 review of SSRI antidepressants concluded that if therapy were required during pregnancy, the SSRIs were a good choice because of their side-effect profile and safety in overdose (11). However, the studies cited above lack the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed in one study because of the timing of the questionnaires. In addition, one study has demonstrated that at least one of these agents (see Fluoxetine) can induce long-term, perhaps permanent changes in the brain of in utero exposed rats. Therefore, even though the clinical significance of this is unknown, the potential for behavioral teratogenicity cannot be excluded and long-term studies of exposed infants are warranted.

Breast Feeding Summary

Four reports describing the use of sertraline during lactation have been located (3,12,13 and 14). In a 1995 case (described above), a woman with recurrent major depression consumed sertraline 100 mg/day and nortriptyline 125 mg/day throughout gestation and while breast feeding her term infant (3). After 3 weeks of breast feeding, milk levels (8 times during a 24-hour interval) and maternal and infant serum levels (12 hours after the dose) were measured. Serum sampling was repeated a second time after 7 weeks of exclusive breast feeding. Maternal serum levels at 3 and 7 weeks were 48 and 47 ng/mL, respectively, while the serum levels in her fully breast-fed infant were below the test sensitivity (<0.5 ng/mL) at both samplings. Milk concentrations during the 24-hour period ranged from 8.8 to 43 ng/mL, with the highest concentrations in the samples obtained at 5 and 9 hours after the dose. Milk levels of nortriptyline were not analyzed nor were metabolites of either drug. At the 3-week sampling, serum levels of nortriptyline in the mother and child were 120 ng/mL and not detectable (test sensitivity 10 ng/mL), respectively. These tests were not repeated at 7 weeks. The infant was doing well at 3 months of age with normal weight and development.

A brief 1995 correspondence described a 32-year-old woman who was treated with sertraline 150 mg/day during the second half of gestation and while breast feeding (12). She stopped breast feeding after 11 days. No adverse effects were noted in the normal healthy infant either during or after breast feeding. Of note, however, apparent withdrawal has been noted in an infant who was exposed throughout gestation and during 3 weeks of breast feeding to a maternal dose of 200 mg/day (see Reference 4 above).

In four lactating women being treated for postpartum depression with maximum doses of either 50 mg/day (N=2) or 100 mg/day (N=2), whole blood 5-hydroxytryptamine (serotonin) levels in the mothers and infants were determined before and after 912 weeks of therapy (13). Sertraline and desmethylsertraline plasma levels were also measured at the time of postexposure sampling. One infant in each dose group was fully breast-fed and the other two infants were breast-fed 3 or 4 times daily. The ages of the infants at the start of maternal treatment were 15 days, 26 days, 6 months, and 12 months. Sertraline and metabolite plasma levels in the infants were less than 2.5 ng/mL and 5 ng/mL, respectively, compared with maternal plasma levels ranging from 10.3 to 48.2 ng/mL and from 19.7 to 64.5 ng/mL, respectively. Little to no change was observed in the platelet (equivalent to whole-blood) levels of serotonin in the infants, in contrast to the marked decreases measured in the mothers. Although the authors could not exclude other possible pharmacologic effects in the infants, the lack of changes measured in serotonin levels was reassuring (13).

Milk samples were collected from 12 women after a sertraline dose at 46 hours for 24 hours (14). Additionally, maternal (24 hours after a dose) and infant serum levels (24 hours after nursing) were also determined in 11 mother-infant pairs. All of the subjects had been taking a fixed dose (25200 mg/day) for 14 to 21 days. Three of the women had been treated with the antidepressant during pregnancy. Therapy was started in the postpartum period in the remaining nine subjects. Sertraline (range 17173 ng/mL) and the relatively inactive metabolite, desmethylsertraline (range 22294 ng/mL), were present in all milk samples. The first 1020 mL of milk (foremilk) had approximately one-half of the drug concentrations of sertraline and metabolite as did the hindmilk. The mean milk:serum ratio for the parent drug was 2.3 1.3 and 1.4 0.8 for the metabolite. In maternal serum (doses 25150 mg/day), the concentrations of sertraline and metabolite ranged from 9 to 92 ng/mL and from 15 to 212 ng/mL, respectively. In contrast, only three infants had measurable serum sertraline levels (2.73.0 ng/mL) whereas six had measurable metabolite levels (1.610.0 ng/mL) (quantitative limit for both 1.0 ng/mL). The calculated sertraline and metabolite doses received by the infants from milk ranged from 0.019 to 0.124 mg/day and from 0.023 to 0.181 mg/day, respectively (14).

In a 1998 study, the mean milk:plasma ratios of sertraline and the metabolite in eight lactating women (mean dose 1.05 mg/kg/day) were 1.93 and 1.64, respectively (15). The estimated infant doses were 0.2% and 0.3%, respectively, of the weight-adjusted maternal dose. Neither sertraline nor desmethylsertraline was detected in the plasma samples obtained from four infants. No adverse effects from the drug exposure were noted in the infants. All had achieved normal development milestones (15).

In another 1998 study, serum levels of sertraline and desmethylsertraline were measured in nine nursing mother:infant pairs (16). The maternal serum levels ranged from 12 to 134 ng/mL and from 28 to 285 ng/mL, respectively. In six infants, the serum concentration of sertraline was below the quantification limit (<2 ng/mL), not detectable in one, and 3 ng/mL in another. The metabolite serum levels in these eight infants ranged from nonquantifiable to 24 ng/mL. In the ninth infant, however, the serum sertraline concentration was 64 ng/mL, 55% of the mother's serum level (117 ng/mL). The metabolite serum concentrations in the infant and mother were 68 and 117 ng/mL, respectively. The mother's dose in this case was 100 mg/day. The serum samples from the mother and infant were drawn 2 hours after a dose. Because the levels were so unusual, the investigators checked the values twice. Although they speculated as to possible cause(s), they were unable to determine why the levels in this particular case were so high (16).

A recent review of SSRI agents concluded that if there were compelling reasons to treat a mother for postpartum depression, a condition in which a rapid antidepressant effect is important, the benefits of therapy with SSRIs would most likely outweigh the risks (17). However, because the long-term effects of exposure to SSRI antidepressants in breast milk on the infant's neurobehavioral development are unknown (no such adverse effects have been identified to date but research is needed), stopping or reducing the frequency of breast feeding should be considered if therapy with these agents is required. Avoiding nursing around the time of peak maternal concentration (about 4 hours after a dose) may limit infant exposure. The American Academy of Pediatrics classifies antidepressants as drugs whose effect on a nursing infant is unknown but may be of concern (18). The mother should be provided all of this information so that she can actively participate in any decision.


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