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. Several recent studies have suggested that exposure to SSRIs at the time of delivery may be associated with poor perinatal outcomes (Casper 2003, Laine 2003, Simon 2002, Zeskind and Stephens 2004) and prompted the FDA to include warnings in the packaging inserts regarding the use of certain antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and venlafaxine (Effexor), during pregnancy. These studies have been reviewed previously on the CWMH website (Newsletters Fall 2004 and Spring 2005).

In a new population-based study from Finland, outcomes were assessed in a group of 1782 women exposed to SSRIs during pregnancy (Malm 2005). These data were collected by linking several national databases: the Medical Birth Register, the Drug Reimbursement Register, the Register of Congenital Malformations, and the Register of Induced Abortions. The Medical Birth Register data are considered to be a complete record of all births and newborns in Finland. The registry collects data from all hospitals and obstetric providers and includes maternal demographic and medical data and neonatal outcomes data from all infants born after 22 weeks of gestation. The Drug Reimbursement Register contains data on all reimbursed prescription drug purchases.

Cases were defined as women who had made at least one purchase of an SSRI drug during the period of one month before conception and the day of delivery. Only singleton pregnancies were included in the study. Mother-infant pairs where either the mother or newborn had a chronic medical illness were excluded. 1,782 cases were identified. Controls were women with no reimbursed drug purchases during the same period and were matched with cases by age, parity, geographic area, and social status.

A total of 1,398 women purchased an SSRI drug either one month before conception or during the first trimester; malformations were no more common in this group than in non-exposed controls. Comparing women with SSRI purchases during the 2nd and 3rd trimesters to women who used SSRIs only during the first trimester and to the control group of women with no exposure, there were no observed differences in risk of preterm birth (< 37 weeks), birth before 32 weeks of gestation, or low birth weight. Low Apgar scores (< 7) were more common after third trimester exposure; however, this finding was not statistically significant after controlling for confounding variables. Treatment in a special or intensive care unit was more common in the offspring of women exposed to SSRIs in the third trimester (15.7%) than in women exposed only during the first trimester (11.2%).

This study has confirmed previous studies in that it indicates no increase in risk of major malformation in children exposed to SSRIs in utero. The greatest strengths of this study are the inclusion of a large number of pregnant women and its reliance upon carefully collected data. By including data from the Register of Induced Abortions, it was also possible to add pregnancy terminations due to fetal malformation to this analysis. One limitation, however, is that while medication may be prescribed and/or purchased, compliance is not assured; consequently, exposure and timing of exposure cannot be confirmed.

Like several previous studies (Chambers 1986, Casper 2003, Pearson 2001, Cohen 2000), Malm and colleagues have demonstrated increased rates of admission to the special care nursery among SSRI-exposed infants. While this may be an indication of SSRI-induced adverse events, these data must be intrerpreted carefully. One of the most significant shortcomings of these studies is that they do not use blinded raters to make assessments of neonatal outcomes. Observations of newborn behavior and symptoms made by unblinded physicians may introduce 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 Dr. Kimberly 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.

While this and other studies have suggested adverse events in newborns exposed to SSRIs in utero, clearly further research is essential. 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

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.

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.

Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol. 2005 Dec;106(6):1289-96. Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry. 2002 Dec;159(12):2055-61.

Zeskind PS, Stephens LE. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics. 2004 Feb;113(2):368-75.

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