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Original Investigation
August 5, 2020

Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects

Author Affiliations
  • 1Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia
  • 2Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  • 3United States Public Health Service, Atlanta, Georgia
  • 4Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida
  • 5Slone Epidemiology Center at Boston University, Boston, Massachusetts
JAMA Psychiatry. 2020;77(12):1246-1255. doi:10.1001/jamapsychiatry.2020.2453
Key Points

Question  Which antidepressants used by pregnant women are associated with specific birth defects and do associations between antidepressants and specific birth defects remain after partially accounting for the underlying condition?

Findings  In this case-control study of 30 630 mothers of infants with birth defects and 11 478 control mothers, there were previous and new associations between individual selective serotonin reuptake inhibitors, venlafaxine, and bupropion and specific birth defects. Many selective serotonin reuptake inhibitor and birth defect (particularly heart defect) associations attenuated after partially accounting for the underlying condition; most venlafaxine associations remained.

Meaning  Venlafaxine was associated with more birth defects than other antidepressants, which needs confirmation; studies to assess birth defect risk among women taking antidepressants should account for the underlying condition.


Importance  Antidepressants are commonly used during pregnancy, but limited information is available about individual antidepressants and specific birth defect risks.

Objective  To examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions.

Design, Setting, and Participants  The population-based, multicenter case-control National Birth Defects Prevention Study (October 1997–December 2011) included cases with selected birth defects who were identified from surveillance systems; controls were randomly sampled live-born infants without major birth defects. Mothers of cases and controls participated in an interview after the expected delivery date. The data were analyzed after the completion of the National Birth Defects Prevent Study’s data collection.

Exposures  Self-reported antidepressant exposure was coded to indicate monotherapy exposure to antidepressants.

Main Outcomes and Measures  We used multivariable logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations between maternal antidepressant use and birth defects. We compared early pregnancy antidepressant-exposed women with those without antidepressant exposure and, to partially account for confounding by underlying maternal conditions, those exposed to antidepressants outside of the birth defect development critical period.

Results  This study included 30 630 case mothers of infants with birth defects and 11 478 control mothers (aged 12–53 years). Early pregnancy antidepressant use was reported by 1562 case mothers (5.1%) and 467 control mothers (4.1%), for whom elevated aORs were observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD) (eg, fluoxetine and anomalous pulmonary venous return: aOR, 2.56; 95% CI, 1.10-5.93; this association was attenuated after partially accounting for underlying conditions: aOR, 1.89; 95% CI, 0.56-6.42). This pattern was observed for many SSRI-CHD combinations. Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (eg, citalopram and diaphragmatic hernia: aOR, 5.11; 95% CI, 1.29-20.24). Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for underlying conditions (eg, anencephaly and craniorachischisis: aOR, 9.14; 95% CI, 1.91-43.83).

Conclusions and Relevance  We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

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    1 Comment for this article
    Treatment comparisons should include psychological treatment
    Daniel M. Campagne, Ph.D. | Universidad Nacional de Educación a Distancia, Dept. of Personality, Evaluation and Psychological Treatment, Madrid, Spain
    The article shows a trend in psychiatry to always try and treat depression in pregnancy with antidepressants, ignoring proven and non-harmful alternatives such as psychological treatment. Authors recognize that antidepressant use in pregnancy is possibly harmful for the child, although “attenuated” after “partially accounting for the underlying condition”. Authors did not consider existing non-harmful alternatives, just antidepressant medication.
    Using antidepressants in pregnancy implies that all concerned knowingly accept an increased risk of pregnancy loss, congenital malformations, neonatal adaptation syndrome, persistent pulmonary hypertension of the newborn, autism spectrum disorder, and other long-term affective and health risks. Some propose that 1-3% of
    congenital problems is “normal” in the general population and should offer no special cause for concern (Robinson, 2015). Every treatment choice implies triage, and what works for most goes (Suri et al, 2014). But not when non-harmful alternatives are available. Then Primum Non Nocere should prevail. Pregnancy mishaps also occur because of other causes, and most negative effects of antidepressants will be small, but that does not liberate the physician from avoiding harm. Nor does it liberate the pregnant woman from concern over drug treatment or non-treatment’s nocive effects. She should be offered valid alternative options. Depression in pregnancy harms both, and that should not be ignored.
    Study design on this subject often lacks rigor, also in this study. Research comparing treating pregnant women with antidepressants, or not treating them at all should include control groups on alternatives such as early screening methods, non-medication and psychological treatments (O’Connor et al, 2016). Without it any comparison is incomplete and not valid as clinical data. Also, consequences as to maternal effects and fetal effects are phenomena in different universes and, as such, incomparable and without any “benefit-risk ratio” (Koren, Nordeng, 2012). Avoidable negative effects on offspring can hardly be “compensated” by beneficial effects on maternal depression. Significant identified negative effects should not be valued as “normal” with statistics. Genetic and cell-level malformations by antidepressants are being studied. Animal-model studies with common antidepressants such as citalopram identified some of these mechanisms, whilst human research already observed other antidepressants’ effects in placental cells or in fetal brain matter (Jha et al, 2016). Many adequate studies on pre-pregnancy and antenatal antidepressant use measured significant negative effects. SSRI and SNRIs are most represented here. This does not mean that all studies conclude against their use in pregnancy. But validity depends – importantly – on comparisons with alternative treatments. Quite unjustified, their use - though available at comparable cost and endorsed by leading authorities – is often restricted to minor or moderate depression, thus perpetuating the “drugs-yes, drugs-no dilemma” for major depression. The disquieting suggestion that antidepressant use in pregnancy is “relatively safe” is no exception (Akioyamen, 2016). In 1968, Ayd recommended what should be consensus by now: “Hence, one of the commandments of governing rational psychopharmacotherapy should be ‘Thou shalt not prescribe psychoactive drugs during the first trimester except when absolutely necessary.’” Psychological treatment should be considered from pre-pregnancy onwards, whenever depression is a clinical probability.