More Evidence SSRIs in Pregnancy Boost Birth Defect Risk

Megan Brooks

June 28, 2011

June 28, 2011 — A study from Finland provides more evidence that exposure to selective serotonin reuptake inhibitors (SSRIs) in the first trimester of pregnancy increases the risk for major congenital anomalies, particularly cardiac defects.

In the study, use of fluoxetine in early pregnancy was associated with about a 2-fold increased risk for isolated ventricular septal defects, whereas paroxetine was associated with more than a 4-fold increased risk for right ventricular outflow tract defects.

Heli Malm, MD, PhD, from the Teratology Information Service, Helsinki University Central Hospital, Finland, and colleagues note the absolute risk for these specific cardiac anomalies is small — 0.5% and 0.2%, respectively, "but should guide clinicians not to consider fluoxetine or paroxetine the first option" when prescribing an SSRI to women planning pregnancy.

Reached for independent comment, Christina Chambers, PhD, MPH, from the University of California, San Diego, who has also studied potential risks of SSRI use in pregnancy, said this paper confirms results of "several other papers showing small increased risks for selected specific birth defects, although not all previous studies have shown a risk."

The study is published in the July issue of Obstetrics and Gynecology.

For the study, Dr. Malm and colleagues analyzed Finnish nationwide birth registry data covering 11 years (1996 – 2006). The cohort included 635,583 offspring, of whom 6976 (1.1%) had first-trimester exposure to SSRIs.

Overall, major congenital anomalies were not more common in SSRI-exposed offspring compared with unexposed offspring (adjusted odds ratio [OR], 1.08; 95% confidence interval [CI], 0.96 – 1.22).

For individual SSRIs, fluoxetine and paroxetine were associated with an increased risk for overall major congenital anomalies in the crude analysis, but the risk did not remain statistically significant after adjusting for confounding factors.

Table. Overall Major Congenital Anomalies in SSRI-Exposed Offspring

Exposed Offspring Crude OR (95% CI) Adjusted OR (95% CI)
Any SSRI (n = 6976) 1.24 (1.10 – 1.39) 1.08 (0.96 – 1.22)
Citalopram (n = 2799) 1.18 (0.98 – 1.43) 1.04 (0.86 – 1.25)
Fluoxetine (n = 1818) 1.30 (1.04 – 1.62) 1.16 (0.93 – 1.45)
Paroxetine (n = 968) 1.39 (1.03 – 1.86) 1.22 (0.91 – 1.64)
Sertraline (n = 869) 1.17 (0.84 – 1.64) 1.00 (0.71 – 1.39)
Escitalopram (n = 441) 1.09 (0.67 – 1.77) 0.84 (0.52 – 1.37)
Fluvoxamine (n = 240) 0.81 (0.38 – 1.73) 0.71 (0.34 – 1.51)

CI = confidence interval; OR = odds ratio; SSRI = selective serotonin reuptake inhibitor

True Association

SSRI-exposed infants were at greater risk for major cardiovascular anomalies in the crude analysis (OR, 1.29), but the risk did not remain significant after adjusting for confounders (adjusted OR, 1.09; 95% CI, 0.90 – 1.32).

For individual SSRIs, exposure to fluoxetine in early pregnancy was significantly associated with an increased risk for overall cardiovascular anomalies in the crude analysis (OR, 1.58; 95% CI, 1.14 – 2.19) and the adjusted analysis (adjusted OR, 1.40; 95% CI, 1.01 – 1.95).

In particular, fluoxetine was associated with an increased risk for isolated septal defects, even when excluding offspring needed care in the neonatal care unit (adjusted OR, 2.47; 95% CI, 1.50 – 4.07). This finding suggests a "true association between fluoxetine and ventricular septal defects," the study authors write.

Early in utero exposure to paroxetine was associated with an increased risk for right ventricular outflow tract defects, but this was seen in only 3 cases with a wide CI (adjusted OR, 4.68; 95% CI, 1.48 – 14.74). However, the fact that 2 other studies found a similar association "gives additional strength to our findings," the study authors say (Alwan et al. N Engl J Med. 2007;356:2684-2692 and Louik et al. N Engl J Med. 2007;356:2675-2683).

There was also a statistically significant association between citalopram and neural tube defects (adjusted OR, 2.46; 95% CI, 1.20 – 5.07). Two previous case-control studies have also suggested this link.

Dr. Malm and colleagues also observed that fetal alcohol spectrum disorders were nearly 10 times more common in SSRI-exposed offspring than in unexposed offspring (OR, 9.6; 95% CI, 4.6 – 20.0). Therefore, they advise that "special attention" be given to alcohol use in pregnancy women using SSRIs.

Chance Findings?

The researchers caution that they performed a "large number of comparisons" and "it is possible that some of the observed associations reflect variation by chance. Some of the associations were based on small numbers and could reflect random associations," they add.

Still, they believe fluoxetine or paroxetine should probably not be a first option in women planning to become pregnant.

Dr. Chambers made the point that "no epidemiologic study can prove that there is a risk, but if there is one, it appears to be very low."

Dr. Chambers' 1996 report in the New England Journal of Medicine was the first to raise a red flag about adverse birth outcomes in pregnant women taking fluoxetine (Chambers et al. N Engl J Med. 1996;335:1010-1015). Since then several other reports have been published about the potential risks of SSRIs in pregnancy.

One of the more recent ones was a report published in BMJ in September, 2009 and reported by Medscape Medical News at that time.

This large, population-based cohort study linked SSRI use in early pregnancy with about a 2-fold increased risk for septal heart malformations in offspring. The risk with individual SSRIs varied and again the absolute risk was small.

Dr. Malm and colleagues note in their report that depression affects up to 20% of pregnant women and use of SSRIs during pregnancy is becoming more common. Direct teratogenicity for any of the SSRIs has not been established, they note.

The currently available evidence points to fluoxetine and paroxetine as the individual SSRIs "seriously suspected to cause marginally increased risk for congenital cardiovascular anomalies," they write. The current study supports this link.

The study was funded by the Social Insurance Institution in Finland, the Finnish Medicines Agency, and the National Institute for Health and Welfare. The study authors have disclosed no relevant financial relationships.

Obstet Gynecol. 2011;118:111-120. Text

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