Published online December 1, 2004
PEDIATRICS Vol. 114 No. 6 December 2004, pp. 1739-1740 (doi:10.1542/peds.2004-1626)
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Findings From Selective Serotonin Reuptake Inhibitor–Exposed Neonates Should Be Interpreted With Caution

Jonathan D. Norton, MS
Department of Biostatistics

Linda L. M. Worley, MD
Departments of Psychiatry and Obstetrics and Gynecology

Curtis L. Lowery, MD
Department of Obstetrics and Gynecology
University of Arkansas for Medical Sciences
Little Rock, AR 72212

To the Editor.—

After reading the noteworthy Zeskind and Stephens1 study of the effects of in utero exposure to selective serotonin reuptake inhibitors (SSRIs) on neonates, it is likely that many obstetricians will consider whether to alter treatment of their depressed patients. We hope that readers will consider what we deem to be significant methodologic problems with the study.

The most important limitation of the study was the nature of the control group. The neonates in the control group were not born to depressed mothers, so it is not possible to determine which apparent effects of exposure to SSRIs were actually effects of maternal depression during and after pregnancy.

Furthermore, while attempting to replicate the statistical results of Zeskind and Stephens, we found that the P values in their table 3, which show the behavioral differences between the exposed and nonexposed groups, were the result of 1-sided hypothesis tests. This is tantamount to assuming that for each measure there is only 1 potential direction of effect from exposure to SSRIs. In other words, one would have to hold that it is inconceivable for SSRI-exposed infants to be less tremulous that nonexposed infants, to have fewer bouts of rapid-eye-movement sleep, etc. Arguably, these assumptions are not appropriate, and the P values should be doubled. Table 1 shows the published and 2-sided P values from the authors' table 3. We take the P values from the right side of the original table, which were adjusted for the difference in gestational age.


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  		TABLE 1. Two-Sided P Values From Zeskind and Stephens' Table 3

 
The 3 remaining significant effects (at the .05 level) are differences in sleep and behavioral states that may or may not adversely affect development. The authors appropriately cited a longer-term study2 of SSRI-exposed children that showed no effects on mental and psychomotor development. (Tricyclic-exposed children in the study actually had higher verbal comprehension scores.)

Finally, it is important to consider the substantial risks of discontinuing antidepressants during pregnancy. Einarson et al3 studied 37 pregnant patients who discontinued taking an antidepressant and/or benzodiazepine and found that these risks included suicidal ideation (11 of 37 patients), hospitalization for suicidality (4 patients), and depression-driven therapeutic abortion (1 patient). In light of these and other findings, it may not be reasonable to discontinue antidepressant treatment to avoid alterations in neonate behavior that may have no developmental significance.

REFERENCES

  1. Zeskind PS, Stephens LE. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics. 2004;113 :368 –375[Abstract/Free Full Text]
  2. 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[Abstract/Free Full Text]
  3. Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling. J Psychiatry Neurosci. 2001;26 :44 –48[ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics



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E. L. Moses-Kolko, D. Bogen, J. Perel, A. Bregar, K. Uhl, B. Levin, and K. L. Wisner
Neonatal Signs After Late In Utero Exposure to Serotonin Reuptake Inhibitors: Literature Review and Implications for Clinical Applications
JAMA, May 18, 2005; 293(19): 2372 - 2383.
[Abstract] [Full Text] [PDF]

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