Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The available animal and human experience indicates that fluoxetine is not a major teratogen. However, one animal study has shown that fluoxetine can produce changes, perhaps permanently, in the fetal brain. Moreover, the increased rate of three or minor anomalies found in one investigation may be evidence that the drug does adversely affect embryonic development. The other studies cited above lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Two large case–control studies did find increased risks for some birth defects, but the absolute risk appears to be small. However, selective serotonin reuptake inhibitor (SSRI) antidepressants, including fluoxetine, have been associated with several developmental toxicities, including spontaneous abortions (SABs), low birth weight, prematurity, neonatal serotonin syndrome, neonatal behavioral syndrome (withdrawal), possibly sustained abnormal neurobehavior beyond the neonatal period, respiratory distress, and persistent pulmonary hypertension of the newborn (PPHN).
FETAL RISK SUMMARY
Fluoxetine, an SSRI, is used for the treatment of depression. The chemical structure of fluoxetine is unrelated to other antidepressant agents.
All of the antidepressant agents in the SSRI class (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) 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.
Reproduction studies in rats and rabbits revealed no evidence of teratogenicity when using up to 1.5 and 3.6 times the maximum recommended human daily dose based on BSA (MRHDD), respectively, throughout organogenesis (2,3). In rats, however, doses of 1.5 times the MRHDD during gestation or 0.9 times the MRHDD during gestation and lactation were associated with an increase in stillbirths, a decrease in pup weight, and a decrease in pup survival during the first 7 days postpartum (2). The no-effect dose for pup mortality was 0.6 times the MRHDD (2). There was no evidence of developmental neurotoxicity in the surviving pups exposed to 1.5 times the MRHDD during gestation (2).
Using uterine rings from midterm (gestation day 14) and term pregnant rats, fluoxetine, and two other antidepressants (imipramine and nortriptyline), were shown to attenuate the activity of serotonin-induced spontaneous uterine contractions (4). Although a direct myometrial role could not be demonstrated for these monoamine reuptake inhibitors, the investigators discussed several other possible pathways that fluoxetine could induce preterm delivery (4).
Administration of fluoxetine to pregnant rats produced a down-regulation of fetal cortical 3H-imipramine binding sites that was still evident 90 days after birth (5). The clinical significance of this finding to the development of the human fetal brain is unknown.
In a study to determine if fluoxetine increased the bleeding risk in neonates, pregnant rats were administered fluoxetine (5.62 mg/kg/day) from day 7 of gestation until the delivery (6). The dose was approximately five times the maximum recommended human dose. Compared with controls, fluoxetine-exposed pups had a significantly higher frequency of skin hematomas. The mechanism was thought to be related to the inhibition of serotonin uptake by platelets (6).
Both fluoxetine and the active metabolite, norfluoxetine, cross the placenta and distribute within the embryo or fetus in rats (7). Consistent with the relatively low molecular weight (about 310 for the free base), fluoxetine and the metabolite desmethylfluoxetine (norfluoxetine) cross the human term placenta. In an in vitro experiment using a single placental cotyledon, the mean steady-state placental transfer for the two compounds was 8.7% and 9.1%, respectively (8). A 2003 study of the placental transfer of antidepressants found cord blood:maternal serum ratios for fluoxetine and its metabolite that ranged from 0.32 to 1.36 and 0.12 to 1.58, respectively (9). The dose-to-delivery interval was 9–37 hours, with the highest ratio for the parent drug and metabolite occurring at 26 hours. Moreover, two studies (cited below as references 19 and 20), have documented the human placental transfer of the antidepressant and its active metabolite at term.
During clinical trials with fluoxetine, a total of 17 pregnancies occurred during treatment, even though the women were required to use birth control, suggesting lack of compliance (3). No pregnancy complications or adverse fetal outcomes were observed.
A prospective evaluation of 128 women treated with a mean daily dose of 25.8 mg of fluoxetine during the 1st trimester was reported in 1993 (10). Two matched control groups were selected: one with exposure to tricyclic antidepressants (TCAs) and the other with exposure only to nonteratogens. No differences were found in the rates of major birth defects (2, 0, and 2, respectively) among the groups. An increased risk was observed, although not statistically significant, in the rate of SAB when the fluoxetine group was compared with those in the nonteratogen group, 14.8% vs. 7.8% (relative risk 1.9; 95% confidence interval [CI] 0.92–3.92). Because only 74 TCA 1st trimester exposures were available for matching, comparisons between the three groups were based on 74 women in each group. The rates of SAB from this analysis were 13.5% (fluoxetine), 12.2% (TCAs), and 6.8% (nonteratogens), again without reaching statistical significance (10).
A 1992 prospective multicenter study evaluated the effects of lithium exposure during the 1st trimester in 148 women (11). One of the pregnancies was terminated at 16 weeks’ gestation because of a fetus with a rare congenital heart defect—Ebstein’s anomaly. The fetus had been exposed to lithium, fluoxetine, trazodone, and L-thyroxine during the 1st trimester. The defect was probably caused by lithium exposure.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 142 newborns had been exposed to fluoxetine, 109 during the 1st trimester (F. Rosa, personal communication, FDA, 1994). Two (1.8%) major birth defects were observed (five expected), but details of the abnormalities were not available. No anomalies were observed in eight defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, hypospadias, brain defects, and eye defects) for which specific data were available. These data do not support an association between the drug and congenital defects.
A 1993 letter to the editor from representatives of the manufacturer summarized the postmarketing database for the antidepressant (12). Of the 1103 prospectively reported exposed pregnancies, 761 of which had potentially reached term, data were available for 544 (71%) outcomes, including 91 elective terminations. Among the remaining 453 pregnancies, there were 72 (15.9%) SABs; 2 (0.4%) stillbirths; and 20 (4.4%) infants with major malformations, 7 of which were identified in the postperinatal period. Details of the aborted fetuses and stillbirths were not given. The malformations observed in the perinatal period were abdominal wall defect (in one twin), atrial septal defect, constricted band syndrome, hepatoblastoma, bilateral hydroceles, gastrointestinal anomaly, intestinal blockage, macrostomia, stubbed and missing digits, trisomy 18, trisomy 21, and ureteral disorder (2 cases). The postperinatal cases included an arrhythmia, pyloric stenosis (2 cases), tracheal malacia (3 cases), and volvulus. Additional 28 cases of major malformations reported retrospectively to the manufacturer were mentioned, but no details were given other than the fact that the malformations lacked similarity and were not indicative of a pattern of anomalies (12).
A review that appeared in 1996 (before reference 14) examined the published data relating to the safety of fluoxetine use during gestation and lactation in both experimental animals and humans (13). Using previously published criteria for identifying human teratogens, the authors concluded that the use of fluoxetine during pregnancy did not result in an increased frequency of birth defects or effects on neurobehavior (13).
A prospective study published in 1996 compared the pregnancy outcomes of 228 women who took fluoxetine with 254 nonexposed controls (14). The rates of spontaneous abortion in the two groups were 10% (exposed) and 8.5% (controls), but 13.6% (23 of 169) among those who were enrolled in the study during the 1st trimester and who had 1st trimester exposure. No significant difference in the rates of major defects among liveborn infants from subjects and controls was observed and no anomaly patterns were evident in either group. A total of 250 infants (97 study and 153 controls) were examined (by a physician who was unaware of the infant’s drug exposure [15]) for minor anomalies and among those with three or more anomalies, 15 (15.5%) were exposed and 10 (6.5%) were not exposed (p = 0.03). In comparison with those infants who were exposed to fluoxetine during the 1st trimester or not exposed at all, late-exposed infants had a significant increase in perinatal complications, including prematurity (after excluding twins), rate of admission to special-care nurseries (after excluding preterm infants), poor neonatal adaptation, lower mean birth weight and shorter length in full-term infants, and a higher proportion of full-term infants with birth weights at ≤10th percentile. Moreover, two (2.7%) of the full-term infants who were exposed late had PPHN, a complication that is estimated to occur in the general population at a rate of 0.07%–0.10%. Although the authors concluded that the number of major structural anomalies and the rate of SABs were not significantly increased by fluoxetine exposure in this study, the increased rate of three or more minor anomalies, an unusual finding, is indicative that the drug does affect embryonic development and raises the concern of occult malformations, such as those involving brain development (14).
A 1993 case report described possible fluoxetine-induced toxicity in a term 3580-g male newborn (15). The infant’s 17-year-old mother had taken the antidepressant (20 mg/day) throughout most of her pregnancy for severe depression and suicidal ideation. The infant was initially alert and active with mild hypoglycemia (33 mg/dL). At 4 hours of age, marked acrocyanosis was noted and the infant became jittery. Tachypnea developed with a respiratory rate of 70. His condition continued to worsen with symptoms peaking at 36 hours. The symptoms included continuous crying, irritability, moderate to marked tremors, increased muscle tone, a hyperactive Moro reflex, and emesis. An extensive diagnostic workup, including a drug screen, was negative. The cord blood fluoxetine and norfluoxetine levels were 26 ng/mL and 54 ng/mL, respectively, both within a nontoxic range for adults. The infant was asymptomatic at 96 hours of age at which time the serum levels of the parent drug and metabolite were <25 ng/mL and 55 ng/mL, respectively. The toxicity was attributed to fluoxetine (15).
A case report in 1997 described a 3020-g male newborn who was delivered at term from a 34-year-old woman with obsessive-compulsive disorder treated with fluoxetine 60 mg/day (16). Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. The newborn was jittery and hypertonic with mild grunting, flaring, and retracting. Scattered petechiae on the face and trunk and a cephalohematoma were noted. A right, nondisplaced clavicular fracture was noted on chest X-ray. On the 2nd day of life, the serum fluoxetine and norfluoxetine concentrations were 129 ng/mL and 227 ng/mL, respectively, both in the normal adult range. The mother did not breastfeed the infant. Marked improvement in the jitteriness was observed by 2 weeks of age and by 5 months of age, the infant was considered normal. The symptoms, including the bruising and bleeding, were thought to have been caused by the antidepressant (16).
In a 1996 descriptive case series, the European Network of the Teratology Information Services (ENTIS) prospectively examined the outcomes of 689 pregnancies exposed to antidepressants (17). Multiple drug therapy occurred in about two-thirds of the mothers. Fluoxetine was used in 96 pregnancies. The outcomes of these pregnancies were 15 elective abortions, 13 SABs, 1 stillbirth, 60 normal newborns (includes 6 premature infants), 3 normal infants with neonatal disorder (asphyxia and bradycardia, periventricular bleeding; gastroesophageal regurgitation and bradycardia; and withdrawal symptoms), 2 infants with minor defects (angioma right eyebrow and pilonidal sinus), and 2 infants with congenital defects. The defects (all exposed in the 1st trimester or longer) were ventricular septal defect; and hypospadias (exposed to multiple other agents) (17).
Using data from the manufacturer’s prospective pregnancy registry, postnatal complications that had been reported in 112 pregnancies (115 infants) exposed to fluoxetine during the 3rd trimester were tabulated in a 1995 reference (18). Maternal doses were 10–80 mg/day, but were not reported in 20 pregnancies. Postnatal complications, unrelated to congenital malformations, were noted in 15 singleton term infants, including 2 infants with jitteriness and 3 with irritability. Irritability was also observed in one premature infant (gestational age not given). Except in one infant, the complications were considered mild and transitory. No relationship to the maternal dose was observed, but plasma drug levels were not measured in any of the infants (18).
A study published in 1997 described the outcomes among 796 pregnancies with confirmed 1st trimester exposure to fluoxetine that had been reported prospectively to the manufacturer’s worldwide fluoxetine pregnancy registry (19) (this is an update of the data presented in reference 12). Of the total number, 37 pregnancies were identified during clinical trials and 759 from spontaneous reports. SABs occurred in 110 (13.8%) cases and, for the remaining 686 pregnancies, malformations, deformations, and disruptions occurred in 34 (5.0%). No consistent pattern of defects was observed and only one minor malformation was reported. Moreover, no recurring patterns of malformations, increase in unusual defects, or adverse outcomes were observed in 89 infants from 426 retrospectively reported pregnancies. Based on these data, the authors concluded that it was unlikely that the drug was related to an increased risk of malformations (19).
The neurodevelopment of children ages 16–86 months, who had been exposed in utero for varying lengths of duration to fluoxetine (N = 55) or TCAs (N = 80), were described in 1997 (20). A control group (N= 84) of children not exposed to any agent known to adversely affect the fetus was used for comparison. Assessments of neurodevelopment were based on tests for global IQ and language development and were conducted in a blinded manner. No statistically significant differences were found between the three groups in terms of gestational age at birth, birth weight, and weight, height or head circumference at testing. The mean global IQ scores in the fluoxetine, tricyclic, and control groups were 117, 118, and 115, respectively (ns). Moreover, there were no significant differences in the language scores, or assessment of temperament, mood, arousability, activity level, distractibility, or behavior problems. In addition, no significant differences between the three groups were found with analysis of the data by comparing those exposed only during the 1st trimester to those exposed throughout pregnancy (20).
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 (21). 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. Fluoxetine was taken during the 1st trimester in 52 pregnancies. The outcomes of these pregnancies included 2 ectopic pregnancies, 6 SABs, 6 elective abortions, 11 cases lost to follow-up, 25 normal newborns (1 premature), and 2 infants with major malformations. The birth defects were spina bifida with hydrocephalus (the mother also took dothiepin, sodium valproate, and carbamazepine) and congenital hypothyroidism. In addition, one newborn with a normal chromosome pattern had a minor congenital anomaly (single palmar creases) (21).
Two reviews published in 1998 (22,23) and a meta-analytical review published in 2000 (24) concluded that fluoxetine was not associated with human teratogenicity.
In a 1998 case report, a 32-year-old woman with bipolar disorder took fluoxetine, buspirone, and carbamazepine (see Breastfeeding Summary for doses and further details) throughout gestation (25). At 42 weeks’ gestation she gave birth to a healthy 3940-g female infant. The mother continued her medications for 3 weeks while exclusively breastfeeding the infant. She reported seizure-like activity in her infant at 3 weeks, 4 months, and 5.5 months of age (25).
Five male infants exposed to citalopram (30 mg/day), paroxetine (10–40 mg/day), or fluoxetine (20 mg/day) during gestation exhibited withdrawal symptoms at or within a few days of birth and lasting up to 1 month (26). Symptoms included irritability, constant crying, shivering, increased tonus, eating and sleeping problems, and convulsions.
A 2002 prospective study compared two groups of mother–child pairs exposed to antidepressants throughout gestation (40 exposed to fluoxetine and 46 to tricyclics) with 36 nonexposed, not depressed controls (27). Offspring were studied between the ages of 15 and 71 months for effects of antidepressant exposure in terms of IQ, language, behavior, and temperament. Exposure to antidepressants did not adversely affect the measured parameters, but IQ was significantly and negatively associated with the duration of depression, and language was negatively associated with the number of depression episodes after delivery (27).
The effect of SSRIs on birth outcomes and postnatal neurodevelopment of children exposed prenatally was reported in 2003 (28). 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 who took SSRIs (10 sertraline, 4 paroxetine, and 3 fluoxetine) compared with 11 (85%) controls, 3 of who 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 (expressed at percentage). 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, psychologist, and a dysmorphologist who were blinded as 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); 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) (28).
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 (29). 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 (29).
A 2003 prospective study evaluated the pregnancy outcomes of 138 women treated with SSRI antidepressants during gestation (30). 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) (30). 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 (31).
In 2004, an expert panel of the National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CEHR) evaluated the developmental toxicity of fluoxetine (32). The panel concluded that fluoxetine, especially when used late in pregnancy, caused developmental toxicity that was characterized by an increased rate of poor neonatal adaptation, such as jitteriness, tachypnea, hypoglycemia, hypothermia, poor tone, respiratory distress, weak or absent cry, diminished pain reactivity, or desaturation with feeding (32). Other toxicities included low birth weight and decreased duration of gestation. The panel also concluded that fluoxetine can impair human fertility as demonstrated by reversible, impaired sexual function, specifically orgasm. The mechanism of these effects was unknown but could be related to the drug, disease, or to the pharmacological action of the drug (32).
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 (33). 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 (33).
The database of the World Health Organization (WHO) was used in a 2005 report on neonatal SSRI withdrawal syndrome (34). 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 (34).
Evidence for the neonatal behavioral syndrome that is associated with in utero exposure to SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) (collectively called serotonin reuptake inhibitors[SRIs]) in late pregnancy was reviewed in a 2005 reference (35). 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% 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 fluoxetine, 16 sertraline, 12 citalopram, 4 venlafaxine, and 2 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 1 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 (35).
Possible sustained neurobehavioral outcomes beyond the neonatal period were reported in 2005 (36). 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 (36).
A significant increase in the risk of low birth weight (<10th percentile) and respiratory distress after prenatal exposure to SSRIs was reported in 2006 (37). 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 (37).
A 30% incidence of SSRI-induced neonatal abstinence syndrome was found in a 2006 cohort study (38). 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 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 (38).
A meta-analysis of clinical trials (1990–2005) with SSRIs was reported in 2006 (39). The SSRI agents included were citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. The specific outcomes analyzed were major, minor, and cardiac malformations and SABs. The odds ratio (OR) with 95% CI 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 SABs was significantly increased (39).
A brief 2005 report described significant associations between the use of SSRIs in the 1st trimester and congenital defects (40). The data were collected by the CDC-sponsored National Birth Defects Prevention Study in an ongoing 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) (40). An expanded report from this group was published in 2007 (see reference 49 below).
In a multicenter, prospective controlled study, the pregnancy outcomes of three groups of women were evaluated: (a) paroxetine 330 (286 in the 1st trimester), (b) fluoxetine 230 (206 in the 1st trimester), and (c) 1141 exposures not known to cause birth defects (41). Compared with controls, there was a higher rate of congenital defects among those exposed to paroxetine in the 1st trimester, 5.1% vs. 2.6%, relative risk (RR) 1.92, 95% CI 1.01–3.65. There also was a higher rate for cardiovascular anomalies, 1.9% vs. 0.6%, RR 3.46, 95% CI 1.06–11.42. In addition, perinatal complications were more prevalent in both SSRI groups than in controls (41).
In 1999, the Swedish Medical Birth Registry compared the use of antidepressants in early pregnancy and delivery outcomes for the years 1995–1997 (42). 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) (42). A second Registry report, published in 2006 and covering the years 1995–2003, analyzed the relationship between antidepressants and major malformations or cardiac defects (43). 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 (44). In 2007, the analysis was expanded to include the years 1995–2004 (44). 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 (44).
A 2007 study evaluated the association between 1st trimester exposure to paroxetine and cardiac defects by quantifying the dose–response relationship (45). 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) (45).
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 (46). 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, as well as the 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 as follows: 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 1st 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 (46).
A 2007 review conducted a literature search to determine the risk of major congenital malformations after 1st trimester exposure to SSRIs and SNRIs (47). 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 (47).
A case–control study, published in 2006, was conducted to test the hypothesis that exposure to SSRIs in late pregnancy was associated with PPHN (48). The study concept evolved from a 1996 study (see above) in which two (2.7%) newborns exposed to fluoxetine late in pregnancy had PPHN (14). A total of 1213 women were enrolled in the study, consisting of 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 (adjusted OR 6.1, 95% CI 2.2–16.8). The numbers were too small to analyze the effects of dosage, 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 in pregnancy. If the relationship was causal, the absolute risk was estimated to be about 1% (48).
Two large case–control studies assessing associations between SSRIs and major birth defects were published in 2007 (49,50). 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 (51). Details of the studies and the editorial are described in the paroxetine review (see Paroxetine).
A 16-year-old primigravida with narcolepsy, cataplexy, and glutaric aciduria type II (an autosomal recessive disorder) was treated throughout pregnancy with modafinil 200 mg/day, fluoxetine 20 mg/day, L-carnitine, and riboflavin (52). Because the episodes of narcolepsy and cataplexy increased in frequency, a cesarean section was conducted at 38 weeks’ to deliver a 2.360-kg infant (sex not specified) with Apgar scores of 7, 8, and 9. No signs of withdrawal or abnormalities in vital signs or behavior were noted in the infant, who was discharged home with the mother after 3 days (52).
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 (53). 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 fluoxetine cases, the other cases were 113 bupropion, 184 citalopram, 21 escitalopram, 52 fluvoxamine, 68 mirtazapine, 39 nefazodone, 148 paroxetine, 61 sertraline, 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 were three major anomalies in the fluoxetine group: pulmonary valve stenosis, hypospadias, and ventricular septal defect. There were no major defects in the pregnancies exposed to bupropion, escitalopram, or trazodone (53).
BREASTFEEDING SUMMARY
Fluoxetine is excreted into breast milk. A 1990 case report described a woman, 3 months postpartum, who was started on fluoxetine, 20 mg every morning, for depression (54). No drug-related adverse effects were noted in the infant by the mother or the infant’s pediatrician. However, the woman’s husband, also a pediatrician, thought that the nursing infant showed increased irritability during the first 2 weeks of therapy. Two months after treatment had begun, plasma and milk samples were obtained from the mother (time in relationship to the dose was not specified). Plasma concentrations of the antidepressant and its active metabolite, norfluoxetine, were 100.5 and 194.5 ng/mL, respectively. Similar measurements in the milk were 28.8 and 41.6 ng/mL, respectively. The milk:plasma ratios for the parent compound and the metabolite were 0.29 and 0.21, respectively (54).
A 1992 report described a woman treated for postpartum depression with fluoxetine, 20 mg at bedtime, 10 weeks after delivery (55). The dosing time was chosen just before the infant’s longest period of sleep to lessen his exposure to the drug. After 53 days of therapy, milk and serum samples were collected 8 hours after the usual dose and 4 hours after a subsequent dose administered to approximate peak concentrations of fluoxetine. Serum concentrations of fluoxetine and the active metabolite at 4 hours were 135 and 149 ng/mL, respectively, and at 8 hours were 124 and 141 ng/mL, respectively. The variation in the milk samples was greater, with values at 4 hours of 67 and 52 ng/mL (hand-expressed foremilk), respectively, and at 8 hours of 17 and 13 ng/mL (hand-expressed hindmilk obtained after nursing), respectively. Assuming that the milk contained a steady concentration of 120 ng/mL of fluoxetine and norfluoxetine, and the infant was ingesting 150 mL/kg/day of milk, the maximum theoretical infant dose was 15–20 mcg/kg/day. No adverse effects were observed in the nursing infant’s behavior, feeding patterns, or growth during the treatment period (55).
A 1993 case study described colicky symptoms consisting of increased crying, irritability, decreased sleep, vomiting, and watery stools in a breastfed infant whose mother was taking fluoxetine, 20 mg/day (56). The mother had begun breastfeeding the infant immediately after birth and began taking fluoxetine 3 days later. The baby began to show symptoms at 6 days of age. The mother was enrolled in a study of infant crying at 3 weeks postpartum and, at 6 weeks, the infant was switched to a commercial formula for 3 weeks. The mother continued to pump her breasts during this time. She noted a marked change in the infant’s behavior shortly after the change to formula feeding. The milk concentrations of fluoxetine and norfluoxetine were 69 ng/mL and 90 ng/mL, respectively. After 3 weeks of bottle-feeding, feeding with the mother’s milk from a bottle was resumed; within 24 hours, the colic returned and she restarted feeding with the commercial formula. Drugs levels of fluoxetine and metabolite, determined by a commercial laboratory, in the infant’s serum on the 2nd day after the return to mother’s milk were 340 ng/mL and 208 ng/mL, respectively. The authors associated the symptoms of colic with the presence of fluoxetine in the mother’s milk (56).
The very high infant serum levels of fluoxetine and metabolite, similar to therapeutic range in adults, are difficult to explain based on the mother’s low dose. A 1996 review suggested that one possible explanation was laboratory error (57).
The presence of fluoxetine and its active metabolite, norfluoxetine, was measured in the breast milk of 10 women and in serum or urine of some of the 11 (one set of twins) nursing infants (median age 185 days) (58). The women had been taking fluoxetine at an unchanged dose for 7–14 days. The mean maternal dose of fluoxetine was 0.39 mg/kg/day (range 0.17–0.85 mg/kg/day). Milk concentrations of fluoxetine, over a 24-hour interval, were 17.4–293 ng/mL, whereas those for norfluoxetine were 23.4–379.1 ng/mL. In three women, the mean milk:plasma ratios for the two agents were 0.88 (range 0.52–1.51) and 0.82 (range 0.60–1.15), respectively. Peak milk concentrations of fluoxetine occurred within 6 hours in 8 women, more than 12 hours in 2, and undetermined in 1. A plasma sample obtained from one infant contained no measurable drug or metabolite (limit of detection for both <1 ng/mL). Fluoxetine was detected in four of five infant urine samples (1.7–17.4 ng/mL) and norfluoxetine was measured in two of the five samples (10.5 and 13.3 ng/mL). Based on an ingestion of 1000 mL of milk per day, the mean infant doses of fluoxetine and norfluoxetine were 0.077 mg/day and 0.084 mg/day, respectively, or about 10.8% of the weight-adjusted maternal dose. No adverse effects in the nursing infants, including alterations in sleeping, eating, or behavior patterns, were reported by the mothers (58).
In a 1998 case report, a 32-year-old woman with bipolar disorder took fluoxetine (20 mg/day), buspirone (45 mg/day), and carbamazepine (600 mg/day) throughout pregnancy and during the first 3 weeks postpartum (25). She reported seizure-like activity in the infant at 3 weeks, 4 months, and 5.5 months of age. Breast milk and infant serum were evaluated for the presence of fluoxetine and metabolite on postpartum days 13 and 21. On day 13, fluoxetine concentrations in breast milk were 45 ng/mL and 68 ng/mL (right and left breasts), whereas norfluoxetine levels were 68 and 57 ng/mL (right and left breasts). On day 21, the milk concentrations of the drug and metabolite were 38 and 28 ng/mL (mixed milk), respectively. The infant’s serum had no detectable fluoxetine on day 13, but the level was 61 ng/mL on day 21. Norfluoxetine concentrations in infant serum on day 13 and 21 were 58 and 57 ng/mL, respectively. Maternal serum samples were not obtained for fluoxetine analysis. Similar analyses were conducted for buspirone and carbamazepine (see Buspirone and Carbamazepine for results). A neurologic examination of the infant, which included electroencephalography, was within normal limits. The authors were unable to determine the cause of the seizure-like activity, if indeed it had occurred (none of the episodes had been observed by medical personnel) (25).
Serum and milk concentrations of fluoxetine (maternal dose 20–40 mg/day) and norfluoxetine in four breastfeeding women were reported in a 1998 study (59). Maternal fluoxetine serum concentrations ranged from 71 to 250 ng/mL, whereas the levels for the metabolite were 67–177 ng/mL. Hindmilk levels of fluoxetine and norfluoxetine (always higher than foremilk) were 37–132 ng/mL and 11–74 ng/mL, respectively. Neither the parent drug nor metabolite could be detected in the serum or urine samples from the nursing infants. No neurological abnormalities were detected in the infants and all had normal mental and psychomotor performance development up to 12–13 months of age, as assessed by the Bayley Scales of Infant Development (59).
In 14 breastfeeding women receiving a mean fluoxetine dose of 0.51 mg/kg/day, the mean milk:plasma ratios for the parent drug and metabolite were 0.68 and 0.56, respectively (60). The mean total infant dose (fluoxetine plus active metabolite) was estimated to be 6.81% (range 2.15%–12%) of the weight-adjusted maternal dose. In nine infants for which plasma samples were obtained, fluoxetine was detected in five (range 20–252 ng/mL) and norfluoxetine in seven (range 17–187 ng/mL). In eight cases, the antidepressant had also been taken during pregnancy and three of these infants had the highest plasma concentrations of fluoxetine. Two infants had colic, which had resolved in one infant before the study. Two other infants, with the highest plasma levels of fluoxetine, norfluoxetine, or both, exhibited symptoms of withdrawal consisting of uncontrollable crying, irritability, and poor feeding. In one case, however, maternal methadone use may have contributed to the symptoms (60).
An abstract of a study published in 1999 examined the effect of maternal fluoxetine therapy on the weight gain of nursing infants (61). A total of 64 women took the antidepressant during pregnancy and 26 continued the drug during breastfeeding. The other 38 women, who also breastfed their infants but who had discontinued the drug, were used as controls. Fluoxetine-exposed nursing infants had a growth curve significantly below the controls, averaging a deficit in weight gain of 392 g (95% CI –5, –780) in measurements taken between 2 weeks and 6 months of age. Although no adverse effects in the exposed nursing infants were reported by the mothers, the reduced growth was thought to be of possible clinical significance if infant weight gain was already of concern (61).
A 2001 case report described a woman who had been taking fluoxetine (40 mg/day) for 8 years, including throughout pregnancy (62). The infant was delivered at 37 weeks’ gestation with a birth weight of about 2.76 kg. The infant was drowsy in the immediate postpartum period but was able to nurse. On day 3 of life, the infant was difficult to arouse, stopped rooting, closed her mouth, nursed only for a few minutes, and began to moan and grunt. On day 11, signs and symptoms included fever (102°F) and continuous moaning with an expiratory grunt; in addition, the infant was drowsy and difficult to arouse and hypotonic. An examination for sepsis was negative. Breastfeeding was stopped. The mother’s serum fluoxetine and norfluoxetine levels were 453 and 422 ng/mL, respectively, whereas her milk levels were 114 and 124 ng/mL, respectively. The infant’s serum levels of fluoxetine and metabolite were <40 ng/mL and 142 ng/mL, respectively. Eight days after nursing was stopped, the infant’s serum levels were <40 ng/mL and 86 ng/mL, respectively. The infant recovered over the next 3 weeks (62).
A 2010 study using human and animal models found that drugs disturbing serotonin balance such as SSRIs and SNRIs can impair lactation (63). The authors concluded that mothers taking these drugs may need additional support to achieve breastfeeding goals.
Although some of the above reports described toxicity, the long-term effects on neurobehavior and development from exposure to this potent serotonin reuptake blocker during a period of rapid CNS development have not been adequately studied. Further, the reduced weight gain identified in one study may have clinical significance in some situations. As reported by the FDA, the manufacturer was advised to revise the labeling of fluoxetine to contain a recommendation against its use by nursing mothers (64). The current labeling contains this revision (2). In contrast, the authors of a 1996 review stated that they encouraged women to continue breastfeeding while taking the drug (13). Similarly, 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 (65). The American Academy of Pediatrics classifies the effects of fluoxetine on the nursing infant to be unknown but may be of concern (66).
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