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 InhibitorsA Prospective Controlled Multicenter Study. JAMA. 1998;279(8):609-610. doi:10.1001/jama.279.8.609
From The Motherisk Program, The Hospital for Sick Children, and the University of Toronto, Toronto, Ontario (Mss Kulin and Pastuszak and Dr Koren); Teratogen Information Service, Tampa, Fla (Ms Sage); Pregnancy Healthline at Pennsylvania Hospital, Philadelphia (Ms Schick-Boschetto); Connecticut Pregnancy Exposure Information Service, Farmington, Conn (Mss Spivey and Brochu); Pregnancy Riskline, Salt Lake City, Utah (Ms Feldkamp); Department of Pediatrics, University of Vermont, College of Medicine, Burlington (Ms Ormond); FRAME Program, London, Ontario (Drs Matsui and Rieder); Illinois Teratogen Information Service, Chicago, Ill (Ms Stein-Schechman); and Indiana Teratogen Information Service, Indianapolis, Ind (Ms Cook).
Context.— Although a large number of women of reproductive age use new selective
serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned,
no data exist on the safety of these agents for the human fetus.
Objective.— To assess fetal safety and risk of fluvoxamine, paroxetine, and sertraline.
Design.— A prospective, multicenter, controlled cohort study.
Setting.— Nine Teratology Information Service centers in the United States and
Patients.— All women who were counseled during pregnancy following exposure to
a new SSRI and followed up by the participating centers. Controls were randomly
selected from women counseled after exposure to nonteratogenic agents.
Main Outcome Measures.— Rates of major congenital malformations.
Results.— A total of 267 women exposed to an SSRI and 267 controls were studied.
Exposure to SSRIs was not associated with either increased risk for major
malformations (9/222 live births [4.1%] vs 9/235 live births [3.8%] in the
controls, relative risk, 1.06, 95% confidence interval, 0.43-2.62) or higher
rates of miscarriage, stillbirth, or prematurity. Mean (SD) birth weights
among SSRI users (3439  g) were similar to the controls (3445  g)
as were the gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks).
Conclusion.— The new SSRIs, fluvoxamine, paroxetine, and sertraline, do not appear
to increase the teratogenic risk when used in their recommended doses.
A DECADE after the introduction of the first selective serotonin reuptake
inhibitor (SSRI), fluoxetine, into clinical use, this class of antidepressants
is being used by millions of men and women worldwide. Because more than half
of all pregnancies are unplanned1 and an estimated
8% to 20% of all women suffer from depression,2
fetal safety is a primary concern. During the last decade, several studies
have reported on pregnancy outcome following first-trimester or whole-pregnancy
exposure to fluoxetine. Although there was no evidence of major malformations
or behavioral teratology,3- 5
women who took fluoxetine throughout pregnancy had more perinatal complications
and more minor malformations,4 possibly as
a result of risks associated with more severe depression.
During the last few years new SSRIs have been introduced into the market.6 Currently, while a large number of women of reproductive
age use newer SSRIs for depression and other indications (such as obsessive
compulsive disorder7), no human data on their
reproductive safety exist.
Animal teratology studies with fluvoxamine (up to 80 mg/kg per day),8 paroxetine (up to 43 mg/kg per day),9
and sertraline (up to 80 mg/kg per day)10 have
failed to show an increased risk of fetal dysmorphology or other perinatal
complications. Spontaneous reports to the manufacturers are sparse and include
both retrospective and prospective cases with no controls, precluding the
ability to estimate fetal risk.
We report on the first prospective, controlled, cohort study of pregnancy
outcome following fetal exposure to the new SSRIs.
This prospective cohort included all women who contacted 1 of 9 participating
Teratology Information Service centers regarding exposure to fluvoxamine,
paroxetine, and sertraline during the first trimester of pregnancy for depression.
Excluded were women who, in addition to being exposed to a new SSRI, were
also exposed to a known human teratogen or drugs of uncertain teratogenicity.
The group exposed to SSRIs was matched to controls who were randomly selected
from the total group of women counseled and followed by the Motherisk Program
after exposure to agents proven to be nonteratogenic (eg, dental x-rays, acetaminophen).
During the initial interview at the time of exposure, women were asked
about a variety of health-related issues including diagnosis; SSRI dose schedule
and length of therapy; other drug therapy; recreational drug use; cigarette
and alcohol consumption; past medical, obstetric, and genetic history; and
exposure to environmental toxins. After the expected date of confinement,
women were contacted and interviewed regarding the course of pregnancy, pregnancy
outcome, and neonatal health. In most cases, these interviews were conducted
6 to 9 months after delivery. Reports of major malformations were corroborated
with medical records.
The primary end point of interest was the rates of major malformations,
defined as structural or functional anomalies that have significant medical
or social consequences. The SSRI and control groups were compared on a variety
of baseline characteristics and pregnancy outcome values using the unpaired t test (for continuous variables) or the Fisher exact test
A total of 267 women met the study inclusion criteria (92 from Toronto,
Ontario; 66 from Tampa, Fla; 46 from Philadelphia, Pa; 32 from Farmington,
Conn; 11 from Salt Lake City, Utah; 7 from Burlington, Vt; 6 from London,
Ontario; 4 from Chicago, Ill; and 3 from Indianapolis, Ind). A total of 147
women used sertraline, 97 used paroxetine, and 26 used fluvoxamine. One woman
used both sertraline and fluoxetine, and 2 women used paroxetine and sertraline
in the first trimester. Of the 267 women exposed to an SSRI, 49 used the drug
throughout pregnancy. The majority of women took sertraline at a dosage of
50 mg/d (range, 25-250 mg/d), paroxetine at 30 mg/d (range, 10-60 mg/d), and
fluvoxamine at 50 mg/d (range, 25-200 mg/d).
Women exposed to an SSRI were significantly less likely to be primigravid
and significantly more likely to smoke cigarettes and to have had a previous
therapeutic abortion than the 267 control women (Table 1). These trends were homogeneous among the 3 SSRIs (data
Pregnancy outcome did not differ between the groups, with similar rates
of major malformations, spontaneous and elective abortions and stillbirth,
and similar mean birth weight and gestational age (Table 2). The relative risk for major malformations among SSRI-exposed
neonates was 1.06 (95% confidence interval, 0.43-2.62). Table 3 presents the major malformations in the study and control
groups. In addition, there were 3 cases with defined genetic syndromes (trisomy
21 and familial deafness in the SSRI group and Langer-Giedion syndrome among
Pregnancy outcome among women who took an SSRI throughout pregnancy
did not differ from those who took the drug only during the first trimester.
Among SSRI users, there were no differences in outcome measures between smokers
and nonsmokers (data not shown).
Because half of all pregnancies are unplanned,1
several months after the introduction of the new SSRIs into clinical use,
our centers were contacted by many women who found out they had conceived
while taking fluvoxamine, paroxetine, or sertraline. Moreover, other women
who have benefited from these drugs wished to find out, on planning pregnancy,
whether the new SSRIs are safe for their unborn fetuses.
Typically, women are excluded from premarketing clinical trials as it
is perceived to be medically unethical to test drugs during human pregnancy.
This results in a lack of fetal safety information on introduction of the
drug into the market, and the SSRIs are not an exception.
Our study confirms animal experiments by showing that when used in the
recommended doses, the new SSRIs do not appear to increase the risk of congenital
malformations. Our sample size was large enough to detect a relative risk
of 2.5 for major malformations with a power of 80% and an α of .05.
However, the almost identical rates (9/222 vs 9/235) between the SSRI and
control groups implies that thousands more cases in each group would not change
this result. Our results on all measured pregnancy outcomes are well within
those reported in the general population.11
Our study was not designed to address potential behavioral teratology
of SSRIs. A recent study with fluoxetine failed to find differences in IQ,
language, and behavior after fetal exposure to the drug.5
Recent findings of more minor malformations and perinatal complications among
infants exposed to fluoxetine throughout pregnancy are difficult to interpret
because the study did not control for depression.4
When controlled for depression with a group exposed to tricyclic antidepressants,
infants exposed to fluoxetine in utero do not appear to have more minor malformations3 or perinatal complications (I. Nulman, written communication,
October 1, 1997).
In summary, this study indicates that the new SSRIs, fluvoxamine, paroxetine,
and sertraline, do not appear to increase the teratogenic risk when used in
their recommended doses.