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 do not suggest a major teratogenic risk from the use of fluvoxamine. However, the above studies lack the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed because of the timing of the questionnaires. Selective serotonin reuptake inhibitor (SSRI) antidepressants, including fluvoxamine, have been associated with several developmental toxicities, including spontaneous abortions (SABs), low birth weight, prematurity, 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
Fluvoxamine is an antidepressant used in the treatment of obsessive-compulsive disorder. The mechanism of action is unknown, but the drug is an SSRI resulting in the potentiation of serotonin activity in the brain. The chemical structure of fluvoxamine is unrelated to other antidepressants.
All 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.
No evidence of teratogenicity was observed in reproductive studies with rats and rabbits administered oral doses approximately twice the maximum human daily dose based on BSA (MHDD) (2). Increased pup mortality at birth and decreased postnatal pup weight were seen, however, when rats were dosed at 2 and 4 times the MHDD, respectively, throughout pregnancy and weaning. These effects may have been partially due to maternal toxicity, but a direct toxic effect on the fetuses and pups could not be excluded (2).
No reports describing the transfer across the human placenta have been located. The molecular weight (about 434 for the maleate salt) is low enough that passage to the fetus should be expected.
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 (3). Multiple drug therapy occurred in about two-thirds of the mothers. Fluvoxamine was used in 67 pregnancies. The outcomes of these pregnancies were 9 elective abortions (EABs) (1 with defect—see below), 6 SABs, 2 stillbirths, 47 normal newborns (includes 2 premature infants), 2 infants with neonatal disorders (withdrawal, cyanosis), and 2 infants with congenital defects. The three cases of defects (all exposed in the 1st trimester or longer and to multiple agents) were multicystic left kidney, right megaureter with neonatal renal insufficiency; and hydrocephaly; right diaphragmatic hernia; and agenesis of the corpus callosum (EAB) (3).
A 1998 noninterventional ,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 (4). Data were obtained by questionnaires sent to the prescribing physicians one 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. Fluvoxamine was taken during the 1st trimester in 21 pregnancies. The outcomes of these pregnancies included one ectopic pregnancy, five SABs, two EABs, nine normal full-term newborns, one premature delivery (twins), and three lost to follow-up. One of the EABs was for a genetic abnormality (47,XXX) (4).
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) (5). 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 from women who had exposures to nonteratogenic agents. The pregnancy outcomes were determined, in most cases, 6–9 months after delivery. No significant differences were measured in the number of live births, SABs or EABs, 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] 0.43–2.62). 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 (5). All of the 267 women in the study group had taken an antidepressant during embryogenesis (6).
The effect of SSRIs on birth outcomes and postnatal neurodevelopment of children exposed prenatally was reported in 2003 (7). 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, respectively. Twenty-eight (90%) subjects nursed their infants, 17 of who took SSRIs (10 sertraline, 4 paroxetine, and 3 fluoxetine) compared with 11 (85%) controls, three 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 (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) (7).
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 (8). 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 any of the individual or combined studies (8).
In a 2006 report, a 33-year-old woman with severe psychotic depression was treated with fluvoxamine 200 mg/day and quetiapine 400 mg/day (9). After appropriate counseling, she continued this therapy and conceived and, after a normal pregnancy, delivered a healthy 2600-g, 49-cm-long female infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The infant was developing normally at 3 months (9).
A 2003 prospective study evaluated the pregnancy outcomes of 138 women treated with SSRI antidepressants during gestation (10). 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 was specified) (10). 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 (11).
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 (12). 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 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 (12).
A significant increase in the risk of low birth weight (<10th percentile) and respiratory distress after prenatal exposure to SSRIs was reported in 2006 (13). 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 (13).
A meta-analysis of clinical trials (1990–2005) with SSRIs was reported in 2006 (14). 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 ratios (ORs) 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 (14).
A brief 2005 report described significant associations between the use of SSRIs in the 1st trimester and congenital defects (15). 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) (15). An expanded report from this group was published in 2007 (see reference 22 below).
A 2006 report using the database (1995–2003) of the Swedish Medical Birth Registry examined the relationship between maternal use of antidepressants and major malformations and cardiac defects (16). There was no significant increase in the risk of major malformations with any antidepressant. The strongest effect among cardiac anomalies 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 (16). In 2007, the analysis of the Registry database was expanded to include the years 1995–2004 (17). There were 6481 women (6555 infants) who had reported the use of SSRIs in early pregnancy. The number using a single SSRI (i.e., no other SSRI or non-SSRI antidepressant) during the 1st trimester was 2579 citalopram, 1807 sertraline, 908 paroxetine, 860 fluoxetine, 66 escitalopram, and 36 fluvoxamine. Only paroxetine was significantly associated with cardiovascular effects (20 cases; OR 1.63, 95% CI 1.05–2.53). Paroxetine also had the strongest association with VSDs-ASDs, but did not reach significance (13 cases; relative risk [RR] 1.81, 95% CI 0.96–3.09). When the analysis was repeated after excluding women with body mass index >26, born outside of Sweden, or with reported subfertility (N = 405) , only paroxetine was significantly associated with any cardiac defect (13 cases, RR 2.62, 95% CI 1.40–4.50) and with VSDs-ASDs (8 cases, RR 3.07, 95% CI 1.32–6.04). The RR remained significant after also excluding women who took neuroleptics, sedatives, hypnotics, folic acid, nonsteroidal anti-inflammatory agents, or anticonvulsants (N = 340). Analysis of the combined SSRI group, excluding paroxetine, revealed no associations with cardiac defects or VSDs-ASDs. The study also found no association with omphalocele or craniostenosis (17).
A 2007 study evaluated the association between 1st trimester exposure to paroxetine and cardiac defects by quantifying the dose–response relationship (18). 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) (18).
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 (19). 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 (shown 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 than in 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 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 than in 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 (19).
A 2007 review conducted a literature search to determine the risk of major congenital malformations after 1st trimester exposure to SSRIs and SNRIs (20). 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 (20).
A case–control study, published in 2006, was conducted to test the hypothesis that exposure to SSRIs in late pregnancy was associated with PPHN (21). 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 (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% (21).
Two large case–control studies assessing associations between SSRIs and major birth defects were published in 2007 (22,23). The findings related to SSRIs as a group, as well as to four specific agents: citalopram, fluoxetine, paroxetine, and sertraline. The studies found increased risks for some birth defects, but the absolute risk appeared to be small. An accompanying editorial discussed the findings and limitations of these and other related studies (24). 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 (25). 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 52 fluvoxamine cases, the other cases were 113 bupropion, 184 citalopram, 21 escitalopram, 61 fluoxetine, 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 (OR 0.9, 95% CI 0.5–1.61). There were two major anomalies in the fluvoxamine group: atrial septal defect and an umbilical hernia. There were no major defects in the pregnancies exposed to bupropion, escitalopram, or trazodone (25).
BREASTFEEDING SUMMARY
Fluvoxamine is excreted into human milk. A 23-year-old, 70-kg woman in her 12th postpartum week was treated for postnatal depression with fluvoxamine, 100 mg twice daily (2.86 mg/kg/day) (26). Two weeks after the start of therapy, single milk and plasma samples were obtained 5 hours after a dose and concentrations of 0.09 and 0.31 mcg/mL, respectively, were measured. It was estimated that the infant was ingesting about 0.5% of the mother’s daily dose (26).
In a brief 1997 communication, plasma and breast milk samples were obtained from a breastfeeding mother 3 hours after her morning fluvoxamine dose (100 mg/day; 1.43 mg/kg/day) (27). The concentrations in the plasma and milk were 0.17 and 0.05 mcg/mL, respectively, a milk:plasma ratio of 0.29. The estimated infant dose was slightly less than 0.0075 mg/kg/day (0.5% of the mother’s daily dose). The nursing infant had been exposed to the drug in milk for about 3–4 weeks when breastfeeding was discontinued. No adverse effects from the exposure were noted on infant assessments conducted up to 21 months of age (27).
A 2000 case report described a 31-year-old breastfeeding woman, 3 months postpartum, on a stable dose (100 mg twice daily) of fluvoxamine (28). Serum and foremilk samples were collected every hour for 12 hours after a dose. The mean milk:serum ratio was 1.32. The estimated dose ingested by the nursing infant was 48 mcg/kg/day or 1.58% of the weight-adjusted maternal dose. No adverse effects or unusual behavior was noted in the nursing infant (28). Foremilk samples in women ingesting SSRI agents have been shown to contain much less drug than hindmilk because of the higher fat content of hindmilk and the lipid solubility of these drugs (see Paroxetine and Sertraline). Therefore, because only foremilk was collected from each breast, the milk:serum ratio and the actual dose ingested by the infant were probably higher.
In a second 2000 communication, a 26-year-old woman was started on fluvoxamine for severe obsessive-compulsive disorder symptoms at 19 days postpartum (29). About 8 weeks later, while on a dose of 25 mg three times daily, six breast milk (2–4 ounces) samples were collected (before each dose and before each feeding) over a 24-hour period. Blood samples were obtained from the mother and infant at the same time; 10 hours after a dose and 2–3 hours after the last feeding, respectively. Milk concentrations of fluvoxamine were 24–40 ng/mL over the collection period. Maternal and infant serum concentrations were 20 ng/mL and 9 ng/mL, respectively. The authors speculated that the atypically high infant serum concentration (45% of the mother’s level) may have been related to the infant’s hepatic function. The estimated maximum dose ingested by the nursing infant was 6 mcg/kg/day, or about 0.62% of the weight-adjusted maternal dose. No adverse effects or interference with normal developmental milestones up to 4 months of age was observed in the nursing infant (29).
In a 2006 case described in the Fetal Summary, a woman took fluvoxamine 200 mg/day and quetiapine 400 mg/day throughout a normal pregnancy (9). She continued this therapy while attempting to breastfeed her healthy female infant. Because of insufficient milk production, formula supplementation was required. The infant was developing normally and meeting all milestones at 3 months of age (9).
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 (30). However, because the long-term effects of exposure to SSRI antidepressants in breast milk on the infant’s neurobehavioral development are unknown, 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 fluvoxamine as a drug whose effect on a nursing infant is unknown, but may be of concern (31).
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