Neurodevelopmental Outcomes in Children with Exposure to Prescription Stimulants During Pregnancy

Because the use of prescription stimulants for the treatment of ADHD in reproductive-aged women appears to be increasing, additional research on the reproductive safety of ADHD medications is needed so that we can inform women and their health care providers about any potential risks associated with ADHD medication exposure during pregnancy. While we have a growing body of literature investigating the risk of major malformations in infants with prenatal exposure to commonly used stimulant medications, we have less information on the long-term effects of prenatal exposure to ADHD medications. A new study from Suarez and colleagues provides valuable information on the use of prescription stimulants during pregnancy and risk for adverse neurodevelopmental outcomes in children. 

This cohort study analyzed health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals. Exposures were defined as the dispensing of amphetamine/dextroamphetamine or methylphenidate during the second half of pregnancy. Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were identified in the medical record using validated algorithms. Children were monitored from birth until diagnosis of a neurodevelopmental disorder, disenrollment, death, or end of the study. 

The publicly insured cohort included 4693 amphetamine/dextroamphetamine-exposed, 786 methylphenidate-exposed, and 2,496,771 stimulant-unexposed pregnancies, with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 2372 amphetamine/dextroamphetamine-exposed, 337 methylphenidate-exposed, and 1,773,501 stimulant-unexposed pregnancies with a mean (SD) age of 31.6 (4.6) years.

Amphetamine/Dextroamphetamine Exposures

In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes being considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any of the outcomes studied (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). 

Methylphenidate Exposures

After adjustment for potential confounders, methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but was not associated with other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). However, the association between methylphenidate and ADHD did not persist in sensitivity analyses conducted with stricter control for confounding by maternal diagnosis of ADHD.

Clinical Implications

This is the largest study to date exploring the effects of prenatal exposure to prescription stimulants on the neurodevelopment of exposed children. The cohort study included 7,065 pregnancies exposed to amphetamine/dextroamphetamine and 1,123 pregnancies exposed to methylphenidate in the second half of pregnancy. In this large and carefully crafted study, neither medication was associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, or other neurodevelopmental disorders in children.

The findings of this study are similar to a smaller study from Bang Madsen and colleagues that analyzed data from a Danish cohort. Outcomes in 898 children exposed to ADHD medications (mostly methylphenidate, n=703) were compared to outcomes in a control group of 1,270 children whose mothers discontinued ADHD medication prior to pregnancy. After adjusting for potential confounding variables, the researchers observed no increased risk of any developmental disorders in the exposed compared to unexposed offspring (adjusted hazards ratio 0.97, 95% CI 0.81 to 1.17). 

For women with mild to moderate attention-deficit/hyperactivity disorder (ADHD) symptoms, we often recommend discontinuing stimulant medications and switching to a non-pharmacologic intervention. However, we have observed that a significant number of women experience a marked decrease in their level of functioning, as well as symptoms of depression and anxiety. In these women, we may consider maintaining pharmacologic treatment. The findings of the current study are reassuring.

Ruta Nonacs, MD PhD

References
Suarez EA, Bateman BT, Hernandez-Diaz S, Straub L, McDougle CJ, Wisner KL, Gray KJ, Pennell PB, Lester B, Zhu Y, Mogun H, Huybrechts KF. Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children. JAMA Psychiatry. 2024 Jan 24:e235073.