Drugs and Fetal Development: Focus, Paroxetine

Antidepressants are among the medications most commonly prescribed to young women; and, of those available, selective serotonin reuptake inhibitors (SSRIs) are among the most popular. It is estimated that as many as 2-3% of all women in their childbearing years may be on one of these drugs (Paxil, Prozac, Zoloft, and Lexapro). They were initially thought be very safe in pregnancy and began their distribution as FDA “Category C” compounds with no clear evidence of teratogenic effects (and no good studies) in pregnant women to prohibit their use. Since then, due to the ‘human experiment’ associated with widespread use, it has become apparent that these drugs may cause fetal malformations if taken early in pregnancy, a plethora of other short-term side-effects (apart from teratogenesis) if taken later in pregnancy, and the potential for long-term neurodevelopmental abnormalities in babies exposed throughout pregnancy. Today, let’s simply consider the teratogenic potential of Paxil (paroxetine), perhaps the most widely used SSRI, and recently reclassified by the FDA as a “category D” (drugs found to have harmful effects on the fetus).

The fetal heart is later to develop than the neural tube. In fact, the fetal heart only begins to partition into a structure that will eventually have four chambers about 28 days after conception (6 weeks gestational age), or about the same time the neural tube finishes closing. By day 32, the interventricular septum can be seen growing from the apex of the heart in the midline toward the center of the heart called the endocardial cushion. At the same time, the interatrial septum begins to undergo a more complex developmental process that eventually results in a large, valved hole between the right and left atria, called the foramen ovale, and fusion of the lower portion of the interatrial septum with the endocardial cushion. The foramen ovale, is positioned to allow the most well-oxygenated blood, coming into the heart from the ductus venosus, to bypass the right ventricle, enter the left atrium and then the left ventricle, and be pumped into the aorta, mostly to the fetal brain. The entire process is not entirely completed until about day 56 (10 weeks gestational age).

On October 4, 2005, the manufacturer of Paxil, GlaxoSmithKline, sent a letter to physicians warning that the drug might be linked to a higher rate of congenital malformations in babies exposed to the drug in first trimester. In an unpublished review of 3,500 pregnant women (taken from U.S. insurance claims and a Swedish national registry) taking antidepressants, 4% of those taking Paxil had babies with birth defects compared to 2% of those taking other antidepressants. The most common abnormalities were congenital heart defects, specifically, atrial septal and ventricular septal defects (ASDs and VSDs), and the rate for these was approximately twice that (2%) seen in the general population. As the result of these observations, the FDA released an advisory December 8, 2005, informing health care providers “to discuss the potential risk of birth defects with patients taking Paxil who plan to become pregnant or are in their first three months of pregnancy…should consider discontinuing Paxil…and not to prescribe Paxil in women who are in the first three months of pregnancy or are planning pregnancy, unless other treatment options are not appropriate.” Coincident with this release, Paxil was reclassified to a category D drug. Finally, November 30, 2006, the Obstetric Practice Committee of the American College of Obstetricians and Gynecologists announced support for the FDA recommendations and published that opinion in the December issue of Obstetrics and Gynecology.

In view of the known time course of development of the fetal heart, discontinuing Paxil early in first trimester might prevent some congenital heart defects. Of course, this needs to be balanced against the timing of discontinuation with regard to the actual gestational age, the risks of not treating the condition for which the drug was prescribed, and the risk of withdrawal symptoms that have been well-documented with SSRIs. Certainly, any woman who has been on Paxil in first trimester should be offered a fetal echocardiogram to assess the fetal heart as part of routine care. Although the evidence to implicate the other common SSRIs in congenital heart defects has not yet been established, these drugs can have effects later in pregnancy, resulting in neonatal complications, and these will be discussed in my next post…

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