Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The limited animal and human data suggest that sertraline is not a major teratogen. Two large case–control studies did find increased risks for some birth defects, but the absolute risk appears to be small (1,2). However, selective serotonin reuptake inhibitor (SSRI) antidepressants, including sertraline, have been associated with several developmental toxicities, including spontaneous abortions, low birth weight, preterm delivery, neonatal serotonin syndrome, neonatal behavioral syndrome (withdrawal), possible sustained abnormal neurobehavior beyond the neonatal period, respiratory distress, and persistent pulmonary hypertension of the newborn (PPHN).
FETAL RISK SUMMARY
Although the mechanism of action of the antidepressant, sertraline, is unknown, it is an SSRI similar to other drugs in this class. 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 (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) 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 (3). 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 based on BSA (MRHD), did not reveal evidence of teratogenicity. Delayed ossification of rat and rabbit fetuses, however, occurred at doses during organogenesis that were half and four times the MRHD, respectively. When female rats received a dose equal to the MRHD during the last third of gestation and throughout lactation, an increased 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 half the MRHD (4).
Consistent with the molecular weight of the free base (about 307), sertraline crosses the human placenta. A 2003 study of the placental transfer of antidepressants found cord blood:maternal serum ratios for sertraline and its metabolite that were 0.14–0.66 and 0.14–0.77, respectively (5). The dose-to-delivery interval was 7–35 hours, with the highest ratio for the parent drug and metabolite occurring at 24 hours.
A 24-year-old woman was treated before and during the first few weeks of gestation with sertraline for depression and bulimia (K. Murray and D. Jackson, personal communication, 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 from sertraline-exposed pregnancies were reported to the FDA as of December 1995 (F. Rosa, personal communication, 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 (6). The patient was treated 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 Breastfeeding Summary below) (6).
A brief 1995 report described a case of a 32-year-old woman who took sertraline 200 mg/day throughout pregnancy (7). 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 breastfed 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. 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 (7).
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed ≥1 of 34 newly marketed drugs by general practitioners in England (8). 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. The congenital malformations were one case each of congenital laryngeal stridor and a duplication cyst (gastrointestinal) (8).
A prospective, multicenter, controlled cohort study published in 1998 evaluated the pregnancy outcomes of 267 women exposed to ≥1 SSRI antidepressants during the 1st trimester: fluvoxamine (N = 26); paroxetine (N = 97); and sertraline (N = 147) (9). The women were combined into a study group without differentiation as to the drug they had consumed. A randomly selected control group (N = 267) was formed comprising women who had exposures to nonteratogenic agents. In most cases, the pregnancy outcomes were determined 6–9 months after delivery. No significant differences were observed 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 (RR) for major anomalies was 1.06 (ns). No clustering of defects was apparent. The outcomes of women who took an antidepressant throughout gestation were similar to those who took an antidepressant only during the 1st trimester (9). All of the women in the study group had taken an antidepressant during embryogenesis (10).
A 1999 abstract detailed the prospectively ascertained outcomes of 112 pregnant women taking sertraline compared with 191 controls (11). The rate of major congenital defects did not differ significantly between subjects and controls (3.8% vs. 1.9%). Infants exposed to sertraline in the 3rd trimester were more likely to be premature, to have neonatal transition difficulty, or to be admitted to a special care nursery. A dose–response relation was noted for the latter two complications (11).
The effect of SSRIs on birth outcomes and postnatal neurodevelopment of children exposed prenatally was reported in 2003 (12). Thirty-one children (mean age 12.9 months) exposed during pregnancy to SSRIs (15 sertraline, 8 paroxetine, 7 fluoxetine, and 1 fluvoxamine) were compared with 13 children (mean age 17.7 months) of mothers with depression who elected not to take medications during pregnancy. All of the mothers had healthy lifestyles. The timing of the exposures was 71% in the 1st trimester, 74% in the 3rd trimester, and 45% throughout. The average duration of breastfeeding in the subjects and controls was 6.4 and 8.5 months. Twenty-eight (90%) subjects nursed their infants, 17 of whom took an SSRI (10 sertraline, 4 paroxetine, and 3 fluoxetine) compared with 11 (85%) controls, 3 of whom took sertraline. There were no significant differences between the groups in terms of gestational age at birth, premature births, birth weight and length or, at follow-up, in sex distribution or gain in weight and length. Seven (23%) of the exposed infants were admitted to a neonatal intensive care unit (six respiratory distress, four meconium aspiration, and one cardiac murmur) compared with none of the controls (ns). Follow-up examinations were conducted by a pediatric neurologist, a psychologist, and a dysmorphologist who were blinded to the mother’s mediations status. The mean Apgar scores at 1 and 5 minutes were lower in the exposed group than in controls, 7.0 vs. 8.2, and 8.4 vs. 9.0, respectively. There was one major defect in each group: small asymptomatic ventricular septal defect (exposed) and bilateral lacrimal duct stenosis that required surgery (control). The test outcomes for mental development were similar in the groups, but significant differences in the subjects included a slight delay in psychomotor development and lower behavior motor quality (tremulousness and fine motor movements) (12).
A 2004 prospective study examined the effect of four SSRIs (citalopram, fluoxetine, paroxetine, and sertraline) on newborn neurobehavior, including behavioral state, sleep organization, motor activity, heart rate variability, tremulousness, and startles (13). Seventeen SSRI-exposed, healthy, full-birth-weight newborns and 17 nonexposed, matched controls were studied. A wide range of disrupted neurobehavioral outcomes were shown in the subject infants. After adjustment for gestational age, the exposed infants were found to differ significantly from controls in terms of tremulousness, behavioral states, and sleep organization. The effects observed on motor activity, startles, and heart rate variability were not significant after adjustment (13).
A 2003 prospective study evaluated the pregnancy outcomes of 138 women treated with SSRI antidepressants during gestation (14). Women using each agent were 73 fluoxetine, 36 sertraline, 19 paroxetine, 7 citalopram, and 3 fluvoxamine. Most (62%) took an SSRI throughout pregnancy and 95% were taking an SSRI at delivery. Birth complications were observed in 28 infants, including preterm birth (9 cases), meconium aspiration, nuchal cord, floppy at birth, and low birth weight. Four infants (2.9%) had low birth weight, all exposed to fluoxetine (40–80 mg/day) throughout pregnancy, including two of the three infants of mothers taking 80 mg/day. One infant had Hirschsprung disease, a major defect, and another had cavum septi pellucidi (neither the size of the cavum nor the SSRI agents were specified) (14). The clinical significance of the cavum septi pellucidi is doubtful as it is nearly always present at birth but resolves in the first several months (15).
A 2005 meta-analysis of seven prospective comparative cohort studies involving 1774 patients was conducted to quantify the relationship between seven newer antidepressants and major malformations (16). The antidepressants were bupropion, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, and trazodone. There was no statistical increase in the risk of major birth defects above the baseline of 1%–3% in the general population for the individual or combined studies (16).
The database of the World Health Organization (WHO) was used in a 2005 report on neonatal SSRI withdrawal syndrome (17). Ninety-three suspected cases with either neonatal convulsions or withdrawal syndrome were identified in the WHO database. The agents were 64 paroxetine, 14 fluoxetine, 9 sertraline, and 7 citalopram. The analysis suggested that paroxetine might have an increased risk of convulsions or withdrawal compared with other SSRIs (17).
Evidence for the neonatal behavioral syndrome that is associated with in utero exposure to SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) (collectively referred to as serotonin reuptake inhibitors [SRIs]) in late pregnancy was reviewed in a 2005 reference (18). The report followed a recent agreement by the FDA and manufacturers for a class labeling change about the neonatal syndrome. Analysis of case reports, case series, and cohort studies revealed that late exposure to SRIs carried an overall risk ratio of 3.0 (95% confidence interval [CI] 2.0–4.4) for the syndrome compared with early exposure. The case reports (N = 18) and case series (N = 131) involved 97 cases of paroxetine, 18 of fluoxetine, 16 of sertraline, 12 of citalopram, 4 of venlafaxine, and 2 of fluvoxamine. There were nine cohort studies analyzed. The typical neonatal syndrome consisted of CNS, motor, respiratory, and gastrointestinal signs that were mild and usually resolved within 2 weeks. Only one of 313 quantifiable cases involved a severe syndrome consisting of seizures, dehydration, excessive weight loss, hyperpyrexia, and intubation. There were no neonatal deaths attributable to the syndrome (18).
Possible sustained neurobehavioral outcomes beyond the neonatal period were reported in 2005 (19). Based on the previous findings that prenatally exposed newborns had reduced pain responses, biobehavioral responses to acute pain (heel lance) were prospectively studied in 2-month-old infants. The responses included facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity (derived from respiratory activity and heart rate variability). Three groups of infants were formed: 11 infants with prenatal SSRI exposure alone (2 fluoxetine and 9 paroxetine); 30 infants with prenatal and postnatal (from breast milk) SSRI exposure (6 fluoxetine, 20 paroxetine, and 4 sertraline); and 22 nonexposed controls (mothers not depressed). The exposure during breastfeeding was considered to be very low. Heel lance-induced facial action increased in all three groups but was significantly lowered (blunted) in the first group. Heart rate was significantly lower in the exposed infants during recovery. Moreover, exposed infants had a greater return of parasympathetic cardiac modulation, whereas controls had a sustained sympathetic response. The findings were consistent with the patterns of pain reactivity observed in exposed newborns and suggested sustained neurobehavioral outcomes (19).
A significant increase in the risk of low birth weight (<10th percentile) and respiratory distress after prenatal exposure to SSRIs was reported in 2006 (20). The population-based study, representing all live births (N = 119,547) during a 39-month period in British Columbia, Canada, compared pregnancy outcomes of depressed mothers treated with SSRIs with outcomes in depressed mothers not treated with medication and in nonexposed controls. The severity of depression in the depressed groups was accounted for by propensity score matching (20).
A 30% incidence of SSRI-induced neonatal abstinence syndrome was found in a 2006 cohort study (21). Sixty neonates with prolonged in utero exposure to SSRIs were compared with nonexposed controls. The agents used were paroxetine (62%), fluoxetine (20%), citalopram (13%), venlafaxine (3%), and sertraline (2%). Assessment was conducted by the Finnegan score. Ten of the infants had mild and eight had severe symptoms of the syndrome. The maximum mean score in infants with severe symptoms occurred within 2 days of birth, but some occurred as long as 4 days after birth. Because of the small numbers, a dose–response study could only be conducted with paroxetine. Infants exposed to mean maternal doses that were <19 mg/day had no symptoms, <23 mg/day had mild symptoms, and 27 mg/day had severe symptoms (21).
A meta-analysis of clinical trials (1990–2005) with SSRIs was reported in 2006 (22). The SSRI agents included were citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. The specific outcomes analyzed were major, minor, and cardiac malformations, and spontaneous abortions. The odds ratio (OR) with 95% CI (in parentheses) for the four outcomes were 1.394 (0.906–2.145), 0.97 (0.13–6.93), 1.193 (0.531–2.677), and 1.70 (1.28–2.25), respectively. Only the risk of spontaneous abortions was significantly increased (22).
A brief 2005 report described significant associations between the use of SSRIs in the 1st trimester and congenital defects (23). The data were collected by the CDC-sponsored National Birth Defects Prevention Study in an on-going case–control study of birth defect risk factors. Case infants (N = 5357) with major birth defects were compared with 3366 normal controls. A positive association was found with omphalocele (N = 161; OR 3.0, 95% CI 1.4–6.1). Paroxetine, which accounted for 36% of all SSRI exposures, had the strongest association with the defect (OR 6.3, 95% CI 2.0–19.6). The study also found a significant association between the use of any SSRI and craniosynostosis (N= 372; OR 1.8, 95% CI 1.0–3.2) (23). An expanded report from this group was published in 2007 (1).
In 1999, the Swedish Medical Birth Registry compared the use of antidepressants in early pregnancy and delivery outcomes for the years 1995–1997 (24). There were no significant differences for birth defects, infant survival, or risk of low birth weight (<2500 g) among singletons between those exposed to any depressant, SSRIs only, or non-SSRIs only, but a shorter gestational duration (<37 weeks) was observed for any antidepressant exposure (OR 1.43, 95% CI 1.14–1.80) (24). A second Registry report, published in 2006 and covering the years 1995–2003, analyzed the relationship between antidepressants and major malformations or cardiac defects (25). There was no significant increase in the risk of major malformations with any antidepressant. The strongest effect among cardiac defects was with ventricular or atrial septum defects (VSDs-ASDs). Significant increases were found with paroxetine (OR 2.22, 95% CI 1.39–3.55) and clomipramine (OR 1.87, 95% CI 1.16–2.99 (25). In 2007, the analysis was expanded to include the years 1995–2004 (26). There were 6481 women (6555 infants) who had reported the use of SSRIs in early pregnancy. The number of women using a single SSRI during the 1st trimester was 2579 citalopram, 1807 sertraline, 908 paroxetine, 860 fluoxetine, 66 escitalopram, and 36 fluvoxamine. After adjustment, only paroxetine was significantly associated with an increased risk of cardiac defects (N = 13, RR 2.62, 95% CI 1.40–4.50) or VSDs-ASDs (N = 8, RR 3.07, 95% CI 1.32–6.04). Analysis of the combined SSRI group, excluding paroxetine, revealed no associations with these defects. The study found no association with omphalocele or craniostenosis (26).
A 2007 study evaluated the association between 1st trimester exposure to paroxetine and cardiac defects by quantifying the dose–response relationship (27). A population-based pregnancy registry was used by linking three administrative databases so that it included all pregnancies in Quebec between 1997 and 2003. There were 101 infants with major congenital defects, 24 involving the heart, among the 1403 women using only one type of antidepressant during the 1st trimester. The use of paroxetine or other SSRIs did not significantly increase the risk of major defects or cardiac defects compared with non-SSRI antidepressants. However, a paroxetine dose >25 mg/day during the 1st trimester was significantly associated with an increased risk of major defects (OR 2.23, 95% CI 1.19–4.17) and of cardiac defects (OR 3.07, 95% CI 1.00–9.42) (27).
A 2007 retrospective cohort study examined the effects of exposure to SSRIs or venlafaxine in the 3rd trimester on 21 premature and 55 term newborns (28). The randomly selected unexposed control group consisted of 90 neonates of mothers not taking antidepressants, psychotropic agents, or benzodiazepines at the time of delivery. There were significantly more premature infants among the subjects (27.6%) than in controls (8.9%), but the groups were not matched. The antidepressants, and number of subjects and daily doses (in parentheses) in the exposed group were paroxetine (46; 5–40 mg), fluoxetine (10; 10–40 mg), venlafaxine (9; 74–150 mg), citalopram (6; 10–30 mg), sertraline (3; 125–150 mg), and fluvoxamine (2; 50–150 mg). The behavioral signs that were significantly increased in exposed compared with nonexposed infants were CNS: abnormal movements, shaking, spasms, agitation, hypotonia, hypertonia, irritability, and insomnia; respiratory system: indrawing, apnea/bradycardia, and tachypnea; and other: vomiting, tachycardia, and jaundice. In exposed infants, CNS (63.2%) and respiratory system (40.8%) signs were most common, appearing during the first day of life and lasting for a median duration of 3 days. All of the exposed premature infants exhibited behavioral signs compared with 69.1% of exposed term infants. The duration of hospitalization was significantly longer in exposed premature compared with nonexposed premature infants, 14.5 days vs. 3.7 days, respectively. In 75% of the term and premature infants, the signs resolved within 3 and 5 days, respectively. There were six infants in each group with congenital malformations, but the drugs involved were not specified (28).
A 2007 review conducted a literature search to determine the risk of major congenital malformations after 1st trimester exposure to SSRIs and SNRIs (29). Fifteen controlled studies were analyzed. The data were adequate to suggest that citalopram, fluoxetine, sertraline, and venlafaxine were not associated with an increased risk of congenital defects.In contrast, the analysis did suggest an increased risk with paroxetine. The data were inadequate to determine the risk for the other SSRIs and SNRIs (29).
A case–control study, published in 2006, was conducted to test the hypothesis that exposure to SSRIs in late pregnancy was associated with PPHN (30). A total of 1213 women were enrolled in the study, 377 cases whose infants had PPHN and 836 matched controls and their infants. Mothers were interviewed by nurses who were blinded to the hypothesis. Fourteen case infants had been exposed to an SSRI after the 20th week of gestation compared with six control infants (OR 6.1, 95% CI 2.2–16.8). The numbers were too small to analyze the effects of dose, SSRI used, or reduction of the length of exposure before delivery. No increased risk of PPHN was found with the use of SSRIs before the 20th week or with the use of non-SSRI antidepressants at any time during pregnancy. If the relationship was causal, the absolute risk was estimated to be about 1% (30).
Two large case–control studies assessing associations between SSRIs and major birth defects were published in 2007 (1,2). The findings related to SSRIs as a group, as well as to four specific agents: citalopram, fluoxetine, paroxetine, and sertraline. An accompanying editorial discussed the findings and limitations of these and other related studies (31). Details of the studies and the editorial are described in the paroxetine review (see Paroxetine).
A prospective cohort study evaluated a large group of pregnancies exposed to antidepressants in the 1st trimester to determine if there was an association with major malformations (32). The patient population came from the Motherisk database and involved 928 cases that met their criteria. The 928 matched (for age, smoking, and alcohol use) controls were pregnancies not exposed to antidepressants or known teratogens. In addition to the 61 sertraline cases, the other cases were 113 bupropion, 184 citalopram, 21 escitalopram, 61 fluoxetine, 52 fluvoxamine, 68 mirtazapine, 39 nefazodone, 148 paroxetine, 17 trazodone, and 154 venlafaxine. In the antidepressant group, there were 24 (2.5%) major defects compared with 25 (2.6%) in controls (odds ratio 0.9, 95% CI 0.5–1.61). There was one major anomaly, a hiatus hernia, in the sertraline group. There were no major defects in the pregnancies exposed to bupropion, escitalopram, or trazodone (32).
BREASTFEEDING SUMMARY
Eight reports describing the use of sertraline during lactation have been located (6,33–39). 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 exclusively breastfeeding her term infant (6). Milk levels (over a 24-hour period) were obtained at 3 weeks, and maternal and infant serum levels were measured at 3 and 7 weeks. Milk levels were 8.8–43 ng/mL, with the highest concentrations at 5 and 9 hours postdose. Maternal serum levels at 3 and 7 weeks were 48 and 47 ng/mL, respectively, but were undetectable in the infant. At the 3-week sampling, serum levels of nortriptyline in the mother and child were 120 ng/mL and undetectable, respectively. The infant was doing well at 3 months of age with normal weight gain and development (6).
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 breastfeeding (33). She stopped nursing after 11 days. No adverse effects were noted in the healthy infant either during or after breastfeeding.
Four lactating women were treated for postpartum depression with sertraline 50 mg/day (N = 2) or 100 mg/day (N = 2) (34). Whole blood 5-hydroxytryptamine (serotonin; 5-HT) levels in the mothers and infants were determined before and after 9–12 weeks of therapy. Sertraline and desmethylsertraline plasma levels were also measured at the time of postexposure sampling. One infant in each dose group was fully breastfed and the other two infants were breastfed 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 <2.5 and 5 ng/mL, respectively, compared with maternal plasma levels 10.3–48.2 and 19.7–64.5 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 (34).
Milk samples were collected from 12 women after a sertraline dose at 4–6 hours for 24 hours (35). Additionally, maternal (24 hours after a dose) and infant serum levels (2–4 hours after nursing) were also determined in 11 mother–infant pairs. All of the subjects had been taking a fixed dose (25–200 mg/day) for 14–21 days. Sertraline (range 17–173 ng/mL) and the relatively inactive metabolite, desmethylsertraline (range 22–294 ng/mL), were present in all milk samples. The first 10–20 mL of milk (foremilk) had approximately one-half of the drug concentrations of sertraline and metabolite as did the hindmilk. The mean milk:serum ratios for the parent drug and metabolite were 2.3 and 1.4, respectively. In maternal serum (doses 25–150 mg/day), the concentrations of sertraline and metabolite ranged from 9 to 92 and from 15 to 212 ng/mL, respectively. In contrast, only three infants had measurable serum sertraline levels (2.7–3.0 ng/mL), whereas six had measurable metabolite levels (1.6–10.0 ng/mL). The calculated sertraline and metabolite doses received by the infants from milk were 0.019–0.124 and 0.023–0.181 mg/day, respectively (35).
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 (36). 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 (36).
In another 1998 study, serum levels of sertraline and desmethylsertraline were measured in nine nursing mother:infant pairs (37). The maternal serum levels were 12–134 and 28–285 ng/mL, respectively. In six infants, the serum concentration of sertraline was below the quantification limit (<2 ng/mL), undetectable 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 (37).
The effect of sertraline on 5-HT reuptake in nursing infants was studied in 14 mother–infant pairs in a 2001 report (38). Preexposure levels of 5-HT were drawn from the infants at a mean age of 17.3 weeks, whereas postexposure levels were drawn at a mean age of 26.3 weeks. The mean maternal plasma levels of sertraline and the metabolite, desmethylsertraline, were 30.7 ng/mL and 45.3 ng/mL, respectively. In the mothers, sertraline (25–200 mg/day) caused marked declines (70%–96%) in whole blood 5-HT levels. In contrast, 5-HT levels in whole blood of the nursing infants were not affected (preexposure 223.7 vs. postexposure 227.0 ng/mL). Infant plasma levels of sertraline and the metabolite were undetectable. The results suggested that treatment of the mother with sertraline would not affect peripheral or central 5-HT transport in their nursing infants (38).
A 2004 study was conducted in 25 women (nursing 26 infants) to quantify the concentration of the SSRI or SNRI in their breast milk (39). The antidepressants taken by the women were citalopram (nine), paroxetine (six), sertraline (six), fluoxetine (one), and venlafaxine (three). The maternal mean dose of sertraline was 64 mg/day (50–100 mg/day). The mean milk concentration was 151 nmol/L (97–230 nmol/L), resulting in a theoretical maximum infant dose that was 0.9% of the mother’s weight-adjusted dose. Sertraline was not detected in the serum of the infants. There was no evidence of adverse effects in the breastfeeding infants (39).
A 1999 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 (40). 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 breastfeeding 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. However, the long elimination half-lives of all SSRIs and their weakly basic properties, which are conducive to ion trapping in the relatively acidic milk, probably will lessen the effectiveness of this strategy. The American Academy of Pediatrics classifies sertraline as a drug for which the effect on nursing infants is unknown but may be of concern (41).
A 2010 study using human and animal models found that drugs that disturb serotonin balance such as SSRIs and SNRIs can impair lactation (42). The authors concluded that mothers taking these drugs may need additional support to achieve breastfeeding goals.
References
1.Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, for the National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684–92.
2.Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675–83.
3.Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis: site-specific malformations following exposure to serotonin uptake inhibitors. Teratology 1992;46:367–78.
4.Product information. Zoloft. Pfizer, 2000.
5.Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry 2003;160:993–6.
6.Altshuler LL, Burt VK, McMullen M, Hendrick V. Breastfeeding and sertraline: a 24-hour analysis. J Clin Psychiatry 1995;56:243–5.
7.Kent LSW, Laidlaw JDD. Suspected congenital sertraline dependence. Br J Psychiatry 1995;167:412–3.
8.Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
9.Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond K, Matsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. A prospective controlled multicenter study. JAMA 1998;279:609–10.
10.Koren G. In reply. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873–4.
11.Chambers CD, Dick LM, Felix RJ, Johnson KA, Jones KL. Pregnancy outcome in women who use sertraline (abstract). Teratology 1999;59:376.
12.Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003;142:402–8.
13.Zeskind PS, Stephens LE. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 2004;113:368–75.
14.Hendrick V, Smith LM, Suri R, Hwang S, Haynes D, Altshuler L. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol 2003;188:812–5.
15.DeMyer W. Brain. Midline caves. In: Buyse ML, ed. Birth Defects Encyclopedia. Cambridge, MA: Blackwell Scientific Publications, 1990:238.
16.Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005;14:823–7.
17.Sanz EJ, De-las-Cuevas C, Kiuru A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005;365:482–7.
18.Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors. JAMA 2005;293:2372–83.
19.Oberlander TF, Grunau RE, Fitzgerald C, Papsdorf M, Rurak D, Riggs W. Pain reactivity in 2-month-old infants after prenatal and postnatal selective serotonin reuptake inhibitor medication exposure. Pediatrics 2005;115:411–25.
20.Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006;63:898–906.
21.Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adoles Med 2006;160:173–6.
22.Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials. Reprod Toxicol 2006;22:571–5.
23.Alwan S, Reefhuis J, Rasmussen S, Olney R, Friedman JM. Maternal use of selective serotonin reuptake inhibitors and risk for birth defects (abstract). Birth Defects Res (Part A) 2005;73:291.
24.Ericson A, Kallen B, Wiholm BE. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503–8.
25.Kallen B, Olausson PO. Antidepressant drugs during pregnancy and infant congenital heart defect. Reprod Toxicol 2006;21:221–2.
26.Kallen BAJ, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79:301–8.
27.Berard A, Ramos E, Rey E, Blais L, St.-Andre M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007;80:18–27.
28.Ferreira E, Carceller AM, Agogue C, Martin BZ, St-Andre M, Francoeur D, Berard A. Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates. Pediatrics 2007; 119:52–9.
29.Bellantuono C, Migliarese G, Gentile S. Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review. Hum Psychopharmacol Clin Exp 2007;22:121–8.
30.Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579–87.
31.Greene MF. Teratogenicity of SSRIs—Serious concern or much ado about little? N Engl J Med 2007;356:2732–3
32.Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry 2009;54:242–6.
33.Ratan DA, Friedman T. Antidepressants in pregnancy and breast-feeding. Br J Psychiatry 1995;167:824.
34.Epperson CN, Anerson GM, McDougle CJ. Sertraline and breast-feeding. N Engl J Med 1997;336:1189–90.
35.Stowe ZN, Owens MJ, Landry JC, Kilts CD, Ely T, Llewellyn A, Nemeroff CB. Sertraline and desmethylsertraline in human breast milk and nursing infants. Am J Psychiatry 1997;154:1255–60.
36.Kristensen JH, Ilett KF, Dusci LJ, Hackett LP, Yapp P, Wojnar-Horton RE, Roberts MJ, Paech M. Distribution and excretion of sertraline and N-desmethylsertraline in human milk. Br J Clin Pharmacol 1998;45:453–7.
37.Wisner KL, Perel JM, Blumer J. Serum sertraline and N-desmethylsertraline levels in breastfeeding mother–infant pairs. Am J Psychiatry 1998;155:690–2.
38.Epperson N, Czarkowski KA, Ward-O’Brien D, Weiss E, Gueorguieva R, Jatlow P, Anderson GM. Maternal sertraline treatment and serotonin transport in breast-feeding mother–infant pairs. Am J Psychiatry 2001;158:1631–7.
39.Berle JO, Steen VM, Aamo TO, Breilid H, Zahlsen K, Spigset O. Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome P450 genotypes. J Clin Psychiatry 2004;65:1228–34.
40.Edwards JG, Anerson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999; 57:507–33.
41.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.
42.Marshall AM, Nommsen-Rivers LA, Hernandez LI, Dewey KG, Chantry CJ, Gregerson KA, Horseman ND. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrin Metab 2010;95:837–46.