You may not know it, but this year marks a milestone in the world of SSRI teratology research. Ten years ago, JAMA published the first controlled study of Prozac exposure in pregnancy (1). The results? Neither Prozac nor tricyclics caused more birth defects than controls, but both antidepressants caused more neonatal complications.

Ten years later, we are study-rich but answer-poor. The research has blossomed, but the findings are difficult to synthesize easily.

There is one thing that we can be fairly confident of, however. The SSRIs have consistently been shown not to cause a higher than expected rate of major birth defects, such as congenital heart defects, club feet, and the like. The generally accepted prevalence of such anomalies in the general population is 2- 4%, and all of the studies looking at SSRIs report comparable rates for neonates exposed to medications (2).

The really controversial topics, and the ones that you will be spending the most time discussing with your patients, are:

1. Neurobehavioral effects of SSRI exposure, especially over the long-term, and


2. The risk of pre-term birth and neonatal complications.

Some authorities recommend discontinuing SSRIs during the third trimester

The neurobehavioral story is easy to tell, since there is almost no data. There are basically two published studies that bear on this issue, both produced by the same Canadian researchers (3,4). Their 1997 New England Journal study compared children exposed in utero (first trimester only) to tricyclics, Prozac, or nothing (the control group). These kids were tested 1 to 7 years later, and there were no differences in behavioral problems, IQ, or any number of other relevant indices (3). These authors returned in 2002 with a similarly designed study, but this time looking at children who had been exposed throughout gestation (ie., all three trimesters). Again, there were no differences between the groups; the only factor that statistically predicted poor cognitive development was the severity of the mothers’ depression (4).

These studies are certainly a good start, but the numbers are low (a total of 241 exposed children), and the follow-up short. What will happen to these kids as adolescents and adults? Will they have high rates of psychiatric or substance abuse disorders? Will they become low achievers? Antisocial? At this point, nobody knows.

The better-researched issue is perinatal complications. Unwelcome information has accumulated over the years, beginning with the first Prozac study in 1993, and culminating in an influential paper published in the New England Journal in 1996 (5). This is the study many of you will remember that accused third trimester Prozac exposure of causing premature births, neonatal complications, and admissions to special-care nurseries. A flurry of letters to editors ensued, criticizing various aspects of the study’s methods, but a sober review of the literature in JAMA in 1998 largely refuted these. The main problem with all of these studies is that it is very hard to separate out possible teratogenic effects of depression from the effects of an antidepressant. For ethical reasons, it is impossible to obtain a control group of depressed but untreated pregnant women.

Since then, at least 7 well-designed studies of SSRI’s (or in one case, the SNRI Effexor) used in pregnancy have been published. And the results (other than the comforting finding of no birth defects) have been mixed at best, alarming at worst. Third trimester exposure to SSRI’s has been linked to unpleasantries such as low Apgar scores, high rates of special care nursery admissions, and neonatal symptoms of respiratory distress, jitteriness, and hypoglycemia. Other findings have included low birth weight and lower gestational age. Whether these problems represent neonatal SSRI toxicity or SSRI withdrawal is unknown.

To be fair, the studies have not been entirely consistent. Some report low birth weight but no higher incidence of neonatal complications, while others report precisely the reverse pattern. No study, however, reports that exposed babies fare better than unexposed controls. And nobody can walk away from an evening poring over this literature without a severe case of SSRI disillusionment, at least where pregnant women are concerned.

So, faced with some disturbing data, how should we counsel our patients? The truly reassuring thing that we can say is that SSRIs do not cause birth defects. Furthermore, fetal exposure to SSRIs up until delivery is likely very safe. The real risk-benefit discussion is what to do late in the third trimester. On the one hand, you can argue that women should take SSRIs with relatively short half-lives, such as Paxil and Celexa, so that they can be stopped a few weeks before the due date and be metabolized rapidly out of the system. On the other hand, short half-life agents cause worse discontinuation symptoms, and these can’t be good for a fetus, even if bathed cozily in utero. Prozac will avoid discontinuation symptoms, but will more likely be present in significant quantities during delivery.

Of course, the very notion of stopping an antidepressant in an at-risk patient is controversial. The danger of this maneuver depends on the patient’s history. Those with histories of very severe depressions will probably opt to accept the potential risks of transient perinatal complications, because a severe maternal depression will likely cause even more damage to the neonate in the long term.

There are no easy answers here, as is often the case in psychiatry. But that is one reason we find our profession so intriguing.

TCR VERDICT: Watch out for that Third Trimester!

<sub>1. Pastuszak A, Schick-Boschetto B, Zuber C, et. al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 1993; 269:2246-2248.
2. Hendrick V and Altshuler L. Management of major depression during pregnancy. Am J Psychiatry 2002, 159:1667- 1673.
3. Nulman I, Rovet J, Stewart DE, et. al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997; 336:258-262.
4. Nulman I, Rovet J, Stewart DE, et. al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study.. Am J Psychiatry 2002; 159:1889-1895.
5. Chambers CD, Johnson KA, Dick LM, et. al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335:1010-1015.</sub>