The increasing number of reproductive-age women taking antidepressants has raised concerns about the potential risks of using these medications during pregnancy. Literature accumulated over the last decade supports the use of certain selective serotonin reuptake inhibitors (SSRIs) and the older tricyclic antidepressants during pregnancy, indicating no increased risk of congenital malformation in children exposed to these medications during the first trimester of pregnancy. Still, questions remain regarding the purported risk for “toxicity” in newborns exposed to antidepressants around the time of labor and delivery. These concerns are not new. Twenty years ago, case reports suggested that maternal use of tricyclic antidepressants near the time of delivery was associated with problems in the newborn such as difficulty feeding, restlessness, or jitteriness.

Several recent studies have suggested that exposure to SSRIs at the time of delivery may be associated with poor perinatal outcomes. This concern was first raised by Chambers and colleagues who reported an association between third-trimester use of fluoxetine (Prozac) an increased risk of neonatal complications and higher rates of admission to the special care nursery (Chambers 1996). Several other studies have also shown increased rates of admission to the special care nursery among SSRI-exposed infants (Casper 2003, Pearson 2001, Cohen 2000). Nonetheless, the clinical relevance of admission to the special care nursery in non-blinded series is unclear (Cohen 2000).

Another study compared neonatal outcomes following in utero exposure to tricyclic antidepressants and SSRIs using a large database from a group-model HMO. In this study, there was an association between third-trimester exposure to SSRIs and lower Apgar scores, decreased gestational age, and lower birth weight; these differences were not observed among tricyclic-exposed newborns (Simon 2002). Several other studies also observed lower Apgar scores in SSRI-exposed infants (Casper 2003, Laine 2003, Kallen 2004); however, not all studies have demonstrated differences in APGAR scores between exposed and non-exposed infants (Suri 2004, Pearson 2001). It is reassuring to note that in these studies that demonstrated lower Apgar scores, the difference in Apgar scores between exposed and non-exposed infants was small (less than 1 point) and average Apgar scores in the exposed children remained high (above 7). Clinically a score of 7 or greater at 5 minutes suggests that the baby’s condition is good to excellent.

In a prospective, controlled, follow-up study (Laine 2003), neonatal outcomes were assessed in 20 mothers taking 20 to 40 mg of either citalopram or fluoxetine and in 20 controls not receiving any psychotropic medication. The newborns were assessed during the first 4 days of life and at 2 weeks and 2 months of age. In exposed infants, symptoms of “serotonergic overactivity” were observed more frequently than in non-exposed controls. The most prominent symptoms observed in the newborns included tremor, restlessness, and increased muscle tone. These symptoms resolved over the next 1 to 4 days, and there were no observed differences between the exposed and non-exposed infants at 2 weeks and 2 months. Similarly, Simon and colleagues reported that from 6 months on, significant differences between exposed and non-exposed groups were not evident, despite the differences noted at birth. Exposure to SSRI or tricyclic antidepressants was not associated with developmental delays through age 2.

Whether these symptoms represent a direct effect of exposure to antidepressant or a discontinuation syndrome is not clear. Investigators at the Motherisk Program at the University of Toronto reported that exposure to paroxetine (Paxil) late in pregnancy was associated with a significantly higher rate of transient neonatal complications among 55 paroxetine-exposed newborns, as compared to infants exposed to paroxetine early in pregnancy or to newborns with no paroxetine exposure (Costei 2003). Respiratory distress was the most commonly reported adverse event. The authors hypothesize that the unexpectedly high rate of symptoms in these newborns may be the neonatal equivalent of the discontinuation syndrome commonly seen in adults who develop a variety of somatic symptoms after rapidly stopping paroxetine.

One of the most significant shortcomings of these studies is that most did not use blind raters to make assessments of neonatal outcomes. Observations of newborn behavior and symptoms were made either by the physician or the mother. This runs the obvious risk of introducing a significant bias and may over-estimate the risk of adverse events in SSRI-exposed children. The decision to admit a newborn to a special care nursery may represent a reasonable precaution for an infant exposed to medication in utero and may not be an indication of a serious problem. In fact, the research from Pearson and colleagues at the Center for Women’s Mental Health suggests that the duration of stay in the special care nursery was much shorter for the SSRI-exposed children than for non-exposed children, suggesting that they may have been admitted only for prudent observation.

Other methodologic limitations in the few studies addressing this issue lie in failure to assess maternal mood during pregnancy or at the time of delivery. Ample evidence exists that depression and/or anxiety in the mother may contribute to poor neonatal outcomes, including premature delivery and low birth weight. Thus, it is important to evaluate the contribution of maternal mood in studies designed to describe the effect of prenatal and peripartum exposure to SSRIs on neonatal outcomes.

Summarily, it is possible that the findings from these studies signal a potential problem. Reassuringly, the reported adverse events appear to be relatively short-lived and rarely require any type of medical intervention. Furthermore, there is no indication of longer-term problems in children exposed to SSRIs during pregnancy (Laine 2003, Casper 2003, Simon 2002, Nulman 2002). Clearly further research is essential, but pending more controlled study, appropriate vigilance of exposed newborns after delivery is good clinical practice. It is unclear at this point if discontinuing or lowering the dosage of the mother’s antidepressant shortly before delivery will reduce the risk of neonatal toxicity; however, it is clear that this type of intervention may significantly increase the risk of recurrent depression in the mother. Given the adverse effects of maternal depression on the child, maintaining mood stability in the mother should remain a highest priority.

Ruta Nonacs, MD, PhD
Lee S. Cohen, MD

Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr. 2003 Apr;142(4):402-8.

Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine.N Engl J Med. 1996 Oct 3;335(14):1010-5.

Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS, Bouffard SM. Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry. 2000;48:996-1000.

Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine.Arch Pediatr Adolesc Med. 2002 Nov;156(11):1129-32.

Kallen B. Fluoxetine use in early pregnancy. Birth Defects Res B Dev Reprod Toxicol. 2004 Dec;71(6):395-6.

Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry. 2003 Jul;60(7):720-6.

Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002 Nov;159(11):1889-95.

Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry. 2002 Dec;159(12):2055-61.

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