Analyzing data from nearly 150,000 children with prenatal antidepressant exposure in two healthcare databases, a recent study finds no association between prenatal exposure to antidepressants and risk for neurodevelopmental disorders.  

 In a recent commentary, Dr. Lee Cohen, notes that over the last 15-20 years, we have collected an enormous amount of data on the use of antidepressants during pregnancy.  Data from multiple studies and meta-analyses have demonstrated no increased risk of major malformations in children exposed to antidepressants during pregnancy, including the SSRIs, SNRIs, tricyclic antidepressants and bupropion.    “However,” he notes, “for so many clinicians and for patients, the missing piece in the risk-benefit equation has been the issue of long-term neurodevelopmental sequelae in children whose mothers used antidepressants during pregnancy.” A new study — the largest to date — tackles that “missing piece”, examining the risk of specific neurodevelopmental disorders in children exposed to antidepressants during pregnancy.  

This cohort study extracted health care utilization data from pregnant individuals who were either publicly insured (Medicaid Analytic eXtract; MAX 2000-2014) or privately insured (IBM MarketScan Research Database; MarketScan 2003-2015).  A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until diagnosis of a neurodevelopmental disorder, insurance disenrollment, death, or the end of the study (maximum 14 years). 

Antidepressant exposure was defined as the dispensation of an antidepressant medication between gestational week 19 until delivery.  This period of exposure was selected because this is when synaptogenesis occurs, and it has been shown that exposures occurring during this window are important in terms of future risk for neurodevelopmental disorders.  In children, neurodevelopmental disorders were identified using a validated claims-based algorithm that has demonstrated high positive predictive values across a broad range of neurodevelopmental disorders.  

No Increased Risk of Neurodevelopmental Disorders in Antidepressant Exposed Children

Among the approximately 3 million pregnancies included in the analysis, there were 145,702 antidepressant-exposed and 3,032,745 unexposed pregnancies.  The mean age was younger among the women in the MAX database (26.2 years in exposed and 24.3 in unexposed) compared to the MarketScan database (32.7 and 31.9 years).  

The unadjusted analysis suggested an approximate doubling of risk for neurodevelopmental disorders in antidepressant-exposed children; however, after adjusting for potential confounding variables, no association was observed in the fully adjusted analyses. 

Furthermore, when the researchers controlled for genetic and familial environmental factors by comparing antidepressant-exposed and unexposed siblings, there was no difference in risk observed in the two groups.  Comparing exposed to unexposed siblings, hazard ratios were calculated for the following groups of disorders:

  • Any neurodevelopmental disorder:  0.97 (95% CI, 0.88-1.06) 
  • Autism spectrum disorder: 0.86 (95% CI, 0.60-1.23) 
  • Attention-deficit/hyperactivity disorder: 0.94 (95% CI, 0.81-1.08) 
  •  Specific learning disorders: 0.77 (95% CI, 0.42-1.39) 
  • Developmental speech/language disorder: 1.01 (95% CI, 0.88-1.16) 
  • Developmental coordination disorder: 0.79 (95% CI, 0.54-1.17) 
  • Intellectual disability: 1.00 (95% CI, 0.45-2.22) 
  • Behavioral disorders: 0.95 (95% CI, 0.80-1.12) 

This is the largest study to date examining neurodevelopmental outcomes in children exposed to antidepressants during pregnancy.  The results of this study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children.  There are, however, other factors more common in women who take antidepressants during pregnancy that may increase the risk of having a child with a neurodevelopmental disorder.  

Reassuring News, But Some Other Things to Think About

This is very reassuring and clinically useful information.  While we can speak with confidence regarding the risk of major malformations associated with many different types of antidepressants, it has been much more challenging to provide patients with high quality data regarding risk for neurodevelopmental outcomes. This study helps to close that gap in the information we provide to our pregnant patients.  

Concerns regarding the effects of fetal exposure to antidepressants is appropriate given that about 15% of women experience depression during pregnancy.  In the United States, approximately 7% of women use antidepressants during pregnancy.  Previous research regarding risk for neurodevelopmental disorders has been mixed.  While earlier reports suggested a link between SSRI exposure and increased risk for autism spectrum disorder, larger studies controlling for potential confounding variables did not support this association.  Smaller studies sometimes demonstrated a link between prenatal antidepressant exposure and other neurodevelopmental disorders.  These studies were often too small to reliably control for important confounding variables, including genetic factors, indication for use, exposures to alcohol and tobacco, BMI, and overall health. 

This study, like many others of its kind, shows us the importance of considering potential confounding variables.  Outside of a randomized controlled trial, we cannot assume that the women who choose to use antidepressants during pregnancy are identical to the women who do not use antidepressants.  In the current study, the researchers observed a twofold increase in risk for neurodevelopmental disorders in risk for neurodevelopmental disorders.  After adjusting for potential confounding factors, they observed that the unexposed and antidepressant-exposed groups had the same risk for neurodevelopmental disorder.  

While we can rest easier with regard to the risks associated with antidepressant exposure, we should not ignore these confounding variables.  These factors may contribute to risk for neurodevelopmental disorders and appear to be more common in women with depression during pregnancy, especially in women who take antidepressants during pregnancy.  Given the strong crude associations between antidepressant exposure and risk for neurodevelopmental disorder,  the authors note that antidepressant exposure in pregnancy may be an important marker signaling the need of early screening and possibly intervention.  Future studies are needed to better understand what these factors are and how we can best mitigate risk for neurodevelopmental disorders in children.

Ruta Nonacs, MD PhD

Suarez EA, Bateman BT, Hernández-Díaz S, Straub L, Wisner KL, Gray KJ, Pennell PB, Lester B, McDougle CJ, Zhu Y, Mogun H, Huybrechts KF. Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children. JAMA Intern Med. 2022 Oct 3. doi: 10.1001/jamainternmed.2022.4268. 

Nonacs RM, Cohen LS. Challenges in Determining Outcomes of Prenatal Exposure to Antidepressants.  J Clin Psychiatry. 2020 May 12.  Free Article 

 

 

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