Correspondence

Selective Serotonin-Reuptake Inhibitors and Persistent Pulmonary Hypertension of the Newborn

N Engl J Med 2006; 354:2188-2190May 18, 2006

Article

To the Editor:

Several publications have recently reported an association between maternal treatment with selective serotonin-reuptake inhibitors (SSRIs) late in pregnancy and adverse outcomes in infants. These outcomes have included persistent pulmonary hypertension of the newborn (PPHN), as reported by Chambers et al. (Feb. 9 issue),1 and the neonatal abstinence syndrome, a condition found in infants born with drug dependency.2 Also, the Food and Drug Administration recently published a public health advisory concerning increased rates of congenital defects (and, specifically, heart defects) after the use of the SSRI paroxetine early in pregnancy.3 However, little information is available on the frequency of SSRI treatment during pregnancy.4

We have obtained such data from the National Birth Defects Prevention Study, a population-based, case–control study of congenital anomalies conducted in eight states (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, and Texas).5 Mothers of liveborn infants without birth defects (controls) were randomly selected at each site. Among 4094 control mothers who delivered their infants from October 1997 to December 2002 and completed an hour-long interview on exposures during pregnancy, 113 reported the use of SSRIs within three months before conception and through the end of pregnancy (2.8 percent), including 95 who used SSRIs during pregnancy (2.3 percent). These findings were similar to those regarding the frequency of use of SSRIs during pregnancy in the study by Chambers et al. among the matched controls (2.9 percent).1

Figure 1Figure 1The Use of SSRIs and Other Antidepressant Drugs among 4094 Women from Three Months before Conception through the End of Pregnancy. shows the prevalence of the use of SSRIs (and, specifically, of fluoxetine, sertraline, and paroxetine) and the use of any prescription antidepressant within three months before conception and through the end of pregnancy. The use of the drugs decreased after the first month of pregnancy: of the 76 women who used an SSRI in the first month of pregnancy, 23 discontinued treatment by the second month (30.3 percent). Between 1997 and 2002, there was no significant change in the reported use of SSRIs during pregnancy (1.5 percent of pregnancies in 1997 and 1998, 2.8 percent in 1999 and 2000, and 2.3 percent in 2001 and 2002); the reported use of any prescription antidepressant followed a similar pattern (2.0 percent, 3.3 percent, and 2.6 percent, respectively). Of 151 specific reports of antidepressant use by 140 control mothers before and during pregnancy, most involved SSRIs (77.5 percent), with bupropion (a norepinephrine- and dopamine-reuptake inhibitor) the second most commonly used agent (10.6 percent) and tricyclic antidepressants the third most commonly used class of agents (5.3 percent).

Approximately 4 million live births occur in the United States each year, and about 92,000 of these infants are prenatally exposed to SSRIs. Given the concern that has been expressed,1-3 more research on the fetal effects of maternal treatment with SSRIs during pregnancy is needed to enable pregnant women and their health care providers to make informed decisions about the management of depression.

Jennita Reefhuis, Ph.D.
Sonja A. Rasmussen, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333
nzr5@cdc.gov

Jan M. Friedman, M.D., Ph.D.
University of British Columbia, Vancouver, BC V6T 1Z4, Canada

5 References

1. 1

   Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-587
   Full Text | Web of Science | Medline

2. 2

   Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006;160:173-176
   CrossRef | Web of Science | Medline

3. 3

   FDA public health advisory: paroxetine. Washington, D.C.: Center for Drug Evaluation and Research, Food and Drug Administration, December 2005. (Accessed April 19, 2006, at http://www.fda.gov/cder/drug/advisory/paroxetine200512.htm.)
   

4. 4

   Mills JL. Depressing observations on the use of selective serotonin-reuptake inhibitors during pregnancy. N Engl J Med 2006;354:636-638
   Full Text | Web of Science | Medline

5. 5

   Yoon PW, Rasmussen SA, Lynberg MC, et al. The National Birth Defects Prevention Study. Public Health Rep 2001;116:Suppl 1:32-40
   CrossRef | Web of Science | Medline

To the Editor:

We have some concerns with regard to the study by Chambers et al., which concluded that the use of SSRIs in late pregnancy is associated with PPHN. Infants with malformations were excluded from the control group but not from the group with PPHN (cases), except for some cardiac malformations, which leaves a possibility of selection bias with regard to exposure. It is worth noting that none of the controls had been exposed to paroxetine, an SSRI associated with cardiac malformations.1

Information on medical history and concomitant medication (except for nonsteroidal antiinflammatory drugs) was not reported. The authors suggest that confounding by indication was unlikely because non-SSRI antidepressants were not associated with PPHN and because SSRIs were associated with an increased risk of PPHN only when exposure occurred in the second half of pregnancy. However, confounding by indication cannot be excluded since women who require SSRI therapy to term may have had more severe psychiatric illnesses than those who discontinued therapy early. Thus, mothers of case patients could have been more severely ill, with more associated complications and use of medications. These issues warrant consideration in the interpretation of the study results.

Pär Hallberg, M.D., Ph.D.
Viveca Odlind, M.D., Ph.D.
Medical Products Agency, 75103 Uppsala, Sweden
par.hallberg@mpa.se

Viktoria Sjöblom, Ph.D.
Uppsala University Hospital, 75185 Uppsala, Sweden

1 References

1. 1

   FDA public health advisory: paroxetine. Washington, D.C.: Center for Drug Evaluation and Research, Food and Drug Administration, December 2005. (Accessed May 1, 2006, at http://www.fda.gov/cder/drug/advisory/paroxetine200512.htm.)
   

Author/Editor Response

Dr. Reefhuis and colleagues provide data regarding the prevalence of SSRI exposure that are similar to those we identified among controls (as listed in Table 2 of our article) and also provide important data on the use of SSRIs by women during specific months immediately before and during pregnancy.

We appreciate the questions raised by Dr. Hallberg and colleagues regarding possible alternative explanations for our findings on the use of SSRIs in late pregnancy and PPHN. They suggest that given the putative association of cardiac defects with first-trimester exposure to paroxetine, the inclusion of infants with certain heart defects in the case group could have biased the findings by including more users of paroxetine in this group, thereby creating a spurious association with PPHN. However, none of the four infants with late exposure to paroxetine in the case group had cardiac defects. Dr. Hallberg and colleagues also suggest that confounding by indication cannot be ruled out as an explanation for our findings because women who continued taking an SSRI late in pregnancy might be expected to have more severe underlying disease. However, as can be extrapolated from Table 2 in the article, five mothers in the control group and no mothers in the case group used a non-SSRI antidepressant late in pregnancy, indicating no increased risk for PPHN if the antidepressant was not an SSRI. These data argue against confounding by indication as an alternative explanation if exposure to antidepressants in general in late pregnancy represents more severe underlying disease.

Christina Chambers, Ph.D., M.P.H.
University of California, San Diego, La Jolla, CA 92050
chchambers@ucsd.edu

Sonia Hernandez-Diaz, M.D., Dr.P.H.
Allen A. Mitchell, M.D.
Slone Epidemiology Center at Boston University, Boston, MA 02215

Citing Articles (12)

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   Gal Dubnov-Raz, Harri Hemilä, Yael Vurembrand, Jacob Kuint, Ayala Maayan-Metzger. (2011) Maternal use of selective serotonin reuptake inhibitors during pregnancy and neonatal bone density. Early Human Development
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   Cynthia M. Nijenhuis, Peter G.J. ter Horst, Nienke van Rein, Bob Wilffert, Lolkje T.W. de Jong-van den Berg. (2011) Disturbed development of the enteric nervous system after in utero exposure of selective serotonin reuptake inhibitors and tricyclic antidepressants. British Journal of Clinical Pharmacologyno-no
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   Adolfo Correa, Russell S. Kirby. (2010) An expanded public health role for birth defects surveillance. Birth Defects Research Part A: Clinical and Molecular Teratology 88:12, 1004-1007
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   Katherine L. Wisner. (2010) SSRI treatment during pregnancy: are we asking the right questions?. Depression and Anxiety 27:8, 695-698
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   M. E. Cogswell, R. H. Bitsko, M. Anderka, A. R. Caton, M. L. Feldkamp, S. M. H. Sherlock, R. E. Meyer, T. Ramadhani, J. M. Robbins, G. M. Shaw, T. J. Mathews, M. Royle, J. Reefhuis, . (2009) Control Selection and Participation in an Ongoing, Population-based, Case-Control Study of Birth Defects: The National Birth Defects Prevention Study. American Journal of Epidemiology 170:8, 975-985
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   Sura Alwan, Jan M. Friedman. (2009) Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy. CNS Drugs 23:6, 493-509
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   Marian K. Bakker, Pieternel Kölling, Paul B. van den Berg, Hermien E. K. de Walle, Lolkje T. W. de Jong van den Berg. (2008) Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands. British Journal of Clinical Pharmacology 65:4, 600-606
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   Susan E. Andrade, Marsha A. Raebel, Jeffrey Brown, Kimberly Lane, James Livingston, Denise Boudreau, Sharon J. Rolnick, Douglas Roblin, David H. Smith, Mary E. Willy, Judy A. Staffa, Richard Platt. (2008) Use of antidepressant medications during pregnancy: a multisite study. American Journal of Obstetrics and Gynecology 198:2, 194.e1-194.e5
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   François Dubé, Pascal Amireault. (2007) Local serotonergic signaling in mammalian follicles, oocytes and early embryos. Life Sciences 81:25-26, 1627-1637
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    Alwan, Sura, Reefhuis, Jennita, Rasmussen, Sonja A., Olney, Richard S., Friedman, Jan M., . (2007) Use of Selective Serotonin-Reuptake Inhibitors in Pregnancy and the Risk of Birth Defects. New England Journal of Medicine 356:26, 2684-2692
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    William O. Cooper, Mary E. Willy, Stephen J. Pont, Wayne A. Ray. (2007) Increasing use of antidepressants in pregnancy. American Journal of Obstetrics and Gynecology 196:6, 544.e1-544.e5
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    (2006) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 15:11, i-xii
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