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Absolute Risk for Birth Defects With SSRIs Appears Small

  • Authors: News Author: Susan Jeffrey
    CME Author: Penny Murata, MD
  • CME Released: 6/28/2007; Reviewed and Renewed: 6/30/2008
  • Valid for credit through: 6/30/2009
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This article is intended for primary care clinicians, obstetricians, psychiatrists, and other specialists who care for pregnant women who might need treatment with selective serotonin reuptake inhibitors.

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  1. Report whether overall selective serotonin reuptake inhibitor use in pregnant women is associated with birth defects.
  2. Report whether use of a specific selective serotonin reuptake inhibitor in pregnant women is associated with birth defects.


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  • Susan Jeffrey

    Susan Jeffrey is the News Editor for Medscape Neurology & Neurosurgery and Medscape Psychiatry. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for and also wrote for; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians. She can be contacted at [email protected]


    Disclosure: Susan Jeffrey has disclosed no relevant financial relationships.

CME Author(s)

  • Penny Murata, MD

    Penny Murata is a freelancer for Medscape.


    Disclosure: Penny Murata, MD, has disclosed no relevant financial relationships.

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Absolute Risk for Birth Defects With SSRIs Appears Small

Authors: News Author: Susan Jeffrey CME Author: Penny Murata, MDFaculty and Disclosures

CME Released: 6/28/2007; Reviewed and Renewed: 6/30/2008

Valid for credit through: 6/30/2009


June 28, 2007 — Two studies examine the risk for birth defects associated with the use of selective serotonin reuptake inhibitors (SSRIs) and reveal that, although there appear to be risks for specific defects with the use of particular drugs, the absolute risk for defects is likely to be low.

The studies are published in the June 28 issue of The New England Journal of Medicine.

In an editorial accompanying the publications, Michael F. Greene, MD, from the division of maternal-fetal medicine at Massachusetts General Hospital, points out that "patients and physicians alike would prefer it if there were clear lines separating 'risk' and 'no risk' and if all studies gave consistent results pointing in the same direction."

"Unfortunately, this is often not the case, and the data to inform potential risks of SSRIs is no exception," Dr. Greene writes. "The 2 reports in this issue of the Journal, together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks."

Slone Epidemiology Center Birth Defects Study

In one study, researchers including first author Carol Louik, ScD, from the Slone Epidemiology Center at Boston University in Massachusetts, examined associations between first-trimester use of SSRIs and the risk for various defects in 9849 infants with defects and 5860 infants without such defects participating in the Slone Epidemiology Center Birth Defects Study.

About 10% of pregnant woman are affected by depression and are treated with antidepressants, Dr. Louik and colleagues write. Although not major teratogens, SSRIs do cause neonatal effects on the infant, including "SSRI neonatal withdrawal syndrome" and "SSRI abstinence syndrome," they note, and recent studies have suggested an increased risk for birth defects overall — specifically omphalocele, craniosynostosis, and congenital heart defects — with the use of these drugs.

Of note, the authors add, 1 study has associated the SSRI paroxetine with increased risk for omphalocele, and 3 studies linked this drug to congenital heart defects. (In response to these studies, GlaxoSmithKline agreed to a request by the US Food and Drug Administration to change the label to reflect these risks.)

In this study, Dr. Louik and colleagues analyzed defects that had been previously associated with SSRI use and report that overall use of these drugs was not associated with significantly increased risks for craniosynostosis, omphalocele, or heart defects overall.

Table 1. Risk for Birth Defects Associated With Overall SSRI Use*

Defect No. of Subjects No. Exposed Odds Ratio 95% CI
Craniosynostosis 115 2 0.8 0.2 - 3.5
Omphalocele 127 3 1.4 0.4 - 4.5
Heart Defects 3724 100 1.2 0.9 - 1.6

*SSRI indicates selective serotonin reuptake inhibitor; and CI, confidence interval.
Source: N Engl J Med. 2007;356:2675-2683.

However, when they examined the risk associated with individual SSRIs in relation to specific defects, they did see significant associations between sertraline and omphalocele and between use of paroxetine and septal defects as well as right ventricular outflow tract obstruction defects.

Table 2. Risk for Specific Defects With Specific SSRIs*

SSRI and Defect No. Exposed Odds Ratio 95% CI
Sertraline and omphalocele 3 5.7 1.6 - 20.7
Paroxetine and septal defects 13 2.0 1.2 - 4.0
Paroxetine and RV outflow tract obstruction 6 3.3 1.3 - 8.8

*SSRI indicates selective serotonin reuptake inhibitor; CI, confidence interval; and RV, right ventricular.
Source: N Engl J Med. 2007;356:2675-2683.

Risks were not "appreciably or significantly" increased in this study for other defects, other SSRIs, or other non-SSRI antidepressants, they note, although exploratory analyses involving 66 comparisons showed possible associations between paroxetine and sertraline and other specific defects.

The authors point out that because of the large number of comparisons made in their analysis, they cannot rule out that some of their findings may be the result of chance.

However, they conclude, "our findings do not show that there are significantly increased risks of craniosynostosis, omphalocele, or of heart defects associated with SSRI use overall. They suggest that individual SSRIs may confer increased risks for some specific defects, but it should be recognized that the specific defects implicated are rare and the absolute risks are small."

National Birth Defects Prevention Study

The researchers in the other study in the same issue of the journal include first author Sura Alwan, MSc, from the University of British Columbia in Vancouver, Canada, and senior author Jennita Reefhuis, PhD, from the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention in Atlanta, Georgia.

For this study, the researchers used data on 9622 infants with major birth defects and compared them with those of 4092 control infants without defects born between 1997 and 2002 participating in the National Birth Defects Prevention Study. Case patients were ascertained through surveillance systems in 8 US states, and control subjects were selected at random from those same areas.

Mothers completed standardized telephone interviews asking about their exposure to risk factors before and during pregnancy, including their use of medications. Exposure to SSRIs was defined as treatment with any SSRI from 1 month prior to 3 months after conception. Any birth defects were assigned to 26 categories and subcategories, the authors write.

No significant associations were seen between maternal use of SSRIs overall during early pregnancy and congenital heart defects, or most other categories or subcategories of birth defects, Alwan and colleagues write. "However, we observed associations between SSRI use and the occurrence of anencephaly, craniosynostosis, and omphalocele, defects that had not previously been associated with maternal SSRI use in pregnancy," they write.

Table 3. Risk for Specific Defects Associated With SSRI Use in Pregnancy*

Defect No. of Infants No. Exposed Adjusted Odds Ratio 95% CI
Anencephaly 214 9 2.4 1.1 - 5.1
Craniosynostosis 432 24 2.5 1.5 - 4.0
Omphalocele 181 11 2.8 1.3 - 5.7

*SSRI indicates selective serotonin reuptake inhibitor; and CI, confidence interval.
Source: N Engl J Med. 2007;356:2684-2692.

These authors also point out the limitations of the large number of comparisons carried out on these data.

"Our study did not show an increased risk of most birth defects, and SSRI exposure was present in only a small number of cases of certain defects," Alwan and colleagues conclude. "The absolute risks associated with SSRIs appear small in comparison with the baseline risks of birth defects that exist in every pregnancy."

They point out that maternal stress and depression during pregnancy have in themselves been shown to adversely affect reproductive outcomes, and discontinuation of antidepressant therapy in pregnant women who have serious depressive illness can have adverse effects on both mother and baby. "Thorough assessment of the potential risks and benefits of SSRI use is necessary to allow women of reproductive age to make informed decisions about such therapy," they conclude.

The Slone Epidemiology Center Birth Defects Study was supported in part by grants from the National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute. Additional support was provided by Aventis and Sanofi Pasteur. This data analysis was supported in part by a contract from GlaxoSmithKline, the maker of paroxetine (Paxil). Dr. Louik has disclosed receiving support from Sanofi Pasteur to identify rates of use of various vaccines in pregnancy. Disclosure information for Dr. Louik's coauthors appears in the original article.

The National Birth Defects Prevention Study is coordinated by the Centers for Disease Control and Prevention, Atlanta Georgia. One coauthor, Jan M. Friedman, MD, PhD, has disclosed receiving honoraria for consulting from 13 Research. The other authors have disclosed no relevant financial relationships.

The editorialist, Dr. Greene, has disclosed no relevant financial relationships.

N Engl J Med. 2007;356:2675-2692, 2732-2733.

Clinical Context

In the February 2007 issue of Birth Defects Research. Part B, Developmental and Reproductive Toxicology, Berard and colleagues reported the possible increased risk for congenital malformations, especially congenital heart defects, in women who used SSRIs during pregnancy. The effect of specific SSRI use during pregnancy on the fetus has also been investigated. An abstract by Cole and colleagues in a 2006 issue of Pharmacoepidemiology and Drug Safety noted an association between paroxetine and increased risk for congenital heart defects.

The 2 current multicenter, case-control studies evaluate the association between overall and specific SSRI use during pregnancy and birth defects in the offspring.

Study Highlights

  • Alwan and Colleagues
    • 9622 case infants with major birth defects and 4092 control infants were enrolled during 5 years.
    • Birth defects were analyzed if at least 200 mothers of affected infants were interviewed.
    • Exclusion criteria were chromosomal abnormalities and single-gene conditions.
    • 709 infants had multiple birth defects.
    • Mothers were interviewed by telephone between 6 weeks to 2 years following estimated delivery date.
    • 71.1% of case mothers and 68.6% of control mothers participated.
    • SSRI exposure was defined as reported use between 1 month prior and 3 months after conception.
    • 408 (3%) mothers used an SSRI before or during pregnancy.
    • Case mothers were more likely to be older than 35 years, have less than 12 years of education, have lower family income, smoke, have diabetes, have hypertension, and be obese.
    • Adjusted analysis took into account maternal confounders of ethnicity, obesity, smoking, and family income; infants of mothers with prepregnancy diabetes were excluded.
    • Overall SSRI use was associated with 3 birth defects: anencephaly in 9 exposed infants of 214; craniosynostosis in 24 exposed infants of 432; and omphalocele in 11 exposed infants of 181.
    • Fluoxetine was associated with craniosynostosis (10 exposed infants; adjusted odds ratio [aOR], 2.8; 95% confidence interval [CI], 1.3 - 6.1).
    • Sertraline was associated with anencephaly (4 exposed infants; aOR, 3.2; 95% CI, 1.1 - 9.3).
    • Paroxetine was associated with anencephaly (5 exposed infants; aOR, 5.1; 95% CI, 1.7 - 15.3), right ventricular outflow tract obstruction (7 exposed infants; aOR, 2.5; 95% CI, 1.0 - 6.0), omphalocele (6 exposed infants; aOR, 8.1; 95% CI, 3.1 - 20.8), and gastroschisis (5 exposed infants; aOR, 2.9; 95% CI, 1.0 - 8.4).
  • Louik and Colleagues
    • 9849 case infants with birth defects and 5860 control infants without birth defects were enrolled during 12 years.
    • Exclusion criteria were isolated minor defects, chromosomal abnormalities, syndromes, inherited disorders, and metabolic disorders.
    • Mothers were interviewed in person or by telephone up to 6 months after delivery.
    • SSRI exposure was defined as use between 28 days before last menstrual period through fourth month.
    • Control mothers had no antidepressant use between 56 days before last menstrual period and end of pregnancy.
    • Birth defects analysis included outcomes of omphalocele (127 infants), craniosynostosis (115), and congenital heart defects (3724, mostly with septal defects).
    • Overall SSRI use was not linked to omphalocele, craniosynostosis, or congenital heart defects.
    • Fluoxetine did not lead to increased risks.
    • Sertraline was linked with omphalocele (3 exposed infants; aOR, 5.7; 95% CI, 1.6 - 20.7) and septal defects (13 exposed infants; aOR, 2.0; 95% CI, 1.2 - 4.0).
    • Paroxetine was linked with right ventricular outflow tract obstruction defects (6 exposed infants; aOR, 3.3; 95% CI, 1.3 - 8.8).
    • Analysis of other birth defects showed additional links:
      • Sertraline and anal atresia (3 exposed infants; aOR, 4.4; 95% CI, 1.2 - 16.4).
      • Sertraline and limb-reduction defects (3 exposed infants; aOR, 3.9; 95% CI, 1.1 - 13.5).
      • Paroxetine and neural tube defects (4 exposed infants; aOR, 3.3; 95% CI, 1.1 - 10.4).
      • Paroxetine and clubfoot (10 exposed infants; aOR, 5.8; 95% CI, 2.6 - 12.8).
    • Non-SSRI antidepressants had a link to anal atresia (aOR, 2.2; 95% CI, 0.6 - 7.8) but no other birth defects.
  • Authors of both studies noted low number of subjects and low absolute risk for uncommon birth defects.

Pearls for Practice

  • Overall SSRI use in pregnant women is inconsistently linked to increased risk for craniosynostosis, omphalocele, and anencephaly but not cardiac abnormalities in their offspring.
  • Use of certain SSRIs in pregnant women might increase the risk for specific anomalies in offspring (sertraline: anencephaly, omphalocele, and septal defects; paroxetine: anencephaly, omphalocele, right ventricular outflow tract obstruction defects, and gastroschisis), but the absolute risk is small.

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