FLUVOXAMINE

Fetal Risk Summary

Fluvoxamine is an antidepressant used in the treatment of obsessive-compulsive disorder. Its mechanism of action is unknown, but, similar to other drugs in this class (see also Citalopram, Fluoxetine, Paroxetine, and Sertraline), fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) resulting in 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 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 on a mg/m2 basis (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 maximum human daily dose, 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, however, that passage to the fetus should be expected.

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (3). 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 these 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 spontaneous abortions, two elective abortions, nine normal full term newborns, one premature delivery (twins), and three lost to follow-up (3). One of the elective abortions was for a genetic abnormality (47,XXX).

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) (4). The women were combined into a study group without differentiation as to the drug they had consumed. All of the women had contacted a teratogen information service about their use of the drugs during pregnancy. A randomly selected control group (N=267) was formed from women who had contacted one service after exposure to nonteratogenic agents. The pregnancy outcomes were determined, in most cases, 6 to 9 months after delivery. The study group was significantly more likely to smoke cigarettes and to have had a previous elective abortion but less likely to be a primigravid. Other characteristics, such as a previous spontaneous abortion, alcohol consumption, and maternal age at conception did not differ between the groups. As for pregnancy outcomes, no significant differences were measured in the number of live births, spontaneous or elective abortions, stillbirths, major malformations, birth weight, or gestational age at birth. Nine major malformations were observed in each group. The relative risk for major anomalies was 1.06 (95% Confidence Interval 0.43–2.62). No clustering of defects was apparent. In the study group, no differences were found in the pregnancy outcomes of smokers compared to nonsmokers. In addition, the outcomes of women who took an antidepressant throughout gestation were similar to those who took an antidepressant only during the 1st trimester (4). One of the investigators, in response to subsequent correspondence regarding the study (5,6), clarified that all of the 267 women in the study group had taken an antidepressant during embryogenesis (7). Other concerns relating to the outcomes and sample size were also addressed.

In summary, the limited animal and human data do not demonstrate a major teratogenic risk from the use of fluvoxamine during pregnancy. 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 (i.e., 1 month after delivery). Moreover, one study has demonstrated that at least one of these drugs (see Fluoxetine) can induce long-term, perhaps permanent, changes in the brain of in utero exposed rats. Therefore, even though the clinical significance of this is unknown, the potential for behavioral teratogenicity cannot be excluded and long-term studies of exposed infants are warranted.

Breast Feeding Summary

Fluvoxamine is excreted into human milk (8,9,10 and 11). 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) (8). 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 µg/mL, respectively, were measured. The authors estimated that the infant was ingesting about 0.5% of the mother's daily dose.

In a brief 1997 communication, plasma and breast milk samples were obtained from a breast feeding mother 3 hours after her morning fluvoxamine dose (100 mg/day; 1.43 mg/kg/day) (9). The concentrations in the plasma and milk were 0.17 and 0.05 µg/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) (9). The nursing infant had been exposed to the drug in milk for about 3 to 4 weeks when breast feeding was discontinued. No adverse effects from the exposure were noted on infant assessments conducted up to 21 months of age.

Another communication, published in 2000, described a 31-year-old breast feeding woman, 3 months postpartum, on a stable dose (100 mg twice daily) of fluvoxamine (10). Serum and fore milk 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 µg/kg/day or 1.58% of the weight-adjusted maternal dose. Fore milk samples in women ingesting SSRI agents have been shown to contain much less drug than hind milk because of the higher fat content of hind milk and the lipid solubility of these drugs (see Paroxetine and Sertraline). Therefore, because only fore milk was collected from each breast, the milk:serum ratio and the actual dose ingested by the infant were probably higher (10). No adverse effects or unusual behavior were noted in the nursing infant.

In a second 2000 communication, a 26-year-old woman was started on fluvoxamine for severe obsessive-compulsive disorder symptoms at 19 days postpartum (11). Approximately 8 weeks later, while on a dose of 25 mg three times daily, six breast milk (2 to 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 varied from 24 to 40 ng/mL over the collection period. Maternal and infant serum concentrations were 20 ng/mL and 9 ng/mL, respectively. The author's 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 µg/kg/day, or about 0.62% of the weight-adjusted maternal dose (11). No adverse effects or interference with normal developmental milestones up to 4 months of age were observed in the nursing infant.

A recent review of SSRI agents concluded that if there were compelling reasons to treat a mother for postpartum depression, a condition in which a rapid antidepressant effect is important, the benefits of therapy with SSRIs would most likely outweigh the risks (12). However, because the long-term effects of exposure to SSRI antidepressants in breast milk on the infant's neurobehavioral development are unknown (no such adverse effects have been identified to date but research is needed), stopping or reducing the frequency of breast feeding should be considered if therapy with these agents is required. Avoiding nursing around the time of peak maternal concentration (about 4 hours after a dose) may limit infant exposure. The American Academy of Pediatrics classifies antidepressants as drugs whose effect on a nursing infant is unknown but may be of concern (13). The mother should be provided all of this information so that she can actively participate in any decision.

References

1. 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.
2. Product information. Luvox. Solvay Pharmaceuticals, 1996.
3. 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.
4. 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.
5. Grush LR. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873.
6. Witlin AG. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873.
7. Koren G. In reply. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873–4.
8. Wright S, Dawling S, Ashford JJ. Excretion of fluvoxamine in breast milk. Br J Clin Pharmacol 1991;31:209.
9. Yoshida K, Smith B, Channi Kumar R. Fluvoxamine in breast-milk and infant development. Br J Clin Pharmacol 1997;44:209–13.
10. Hagg S, Granberg K, Carleborg L. Excretion of fluvoxamine into breast milk. Br J Clin Pharmacol 2000;49:286–8.
11. Arnold LM, Suckow RF, Lichtenstein PK. Fluvoxamine concentrations in breast milk and in maternal and infant sera. J Clin Psychopharmacol 2000;20:491–3.
12. Edwards JG, Anerson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57:507–33.
13. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.