Women with attention-deficit/hyperactivity disorder (ADHD) often discontinue psychostimulant  medications during pregnancy, especially if they have milder symptoms.  While this approach makes sense in terms of limiting unnecessary exposures in women with what appears to be milder illness, we have often been surprised by clinical outcomes in this population, specifically when women who were previously high functioning experience significant psychiatric morbidity during pregnancy after discontinuation of stimulants.  Supporting these clinical observations is a new research study from our program which indicates that women who stop stimulant medications during pregnancy are more likely to experience significant impairment in family functioning and higher levels of depressive symptoms.

New Data on the Reproductive Safety of ADHD Medications

A Danish registry-based study including 364,012 singleton pregnancies adds to our information regarding the reproductive safety of stimulants.  Looking at pregnancies occurring between November 1, 2007, and February 1, 2014, researchers identified exposures to ADHD medications using redeemed prescriptions documented in the Danish Health Services Prescription Database. Major malformations were identified during pregnancy using  the Danish Fetal Medicine Database and after birth using the Danish National Patient Registry.  The comparison group consisted of pregnancies with no redeemed prescriptions for ADHD medication. 

The prevalence of first-trimester exposure to ADHD medications varied from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of these exposures being to methylphenidate. In the exposed group, 5.1% of the pregnancies were associated with major malformations, compared to 4.6% in the control group.  

With regard to cardiac malformations, 2.1% of the exposed pregnancies were associated with cardiac malformations compared to 1.0% in the unexposed group. For methylphenidate (473 exposures), the adjusted prevalence ratios (PRs) were 1.04 (95% confidence interval [CI], 0.70-1.55) for malformations overall and 1.65 (95% CI, 0.89-3.05) for any cardiac malformations.  Septal defects were identified in 10 out of 12 cases. The PR for ventricular septal defects was 2.74 (95% CI, 1.03-7.28).  The PR for severe cardiac malformations (SCM) — defined as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, or death or cardiac surgery within 1 year of birth — was 2.59 (95% CI, 0.98-6.90). (Note:  The confidence interval for SCM includes the number 1, which means that there is insufficient evidence to conclude that the two groups are statistically significantly different.)

Using information from both prenatal and postnatal diagnoses of major malformations, the current study from Kolding and colleagues observes that exposure to methylphenidate was not associated with an increased risk of malformations overall.  However, when the researchers focused on risk of cardiac malformations, they did observe a statistically significant increase in risk of ventricular septal defects with a  RR of 2.74 (95% CI, 1.03-7.28).

How Does this Study Compare to Previous Studies?

In 2017, Huybrechts and colleagues analyzed data from the 2000-2013 US Medicaid Analytic eXtract which included 2072 exposures to methylphenidate and 5571 exposures to amphetamines.   In the unadjusted analysis, researchers observed a small increase in risk of cardiovascular malformations in the methylphenidate-exposed group.  However, when the researchers controlled for potential confounding factors, including maternal psychiatric illness, the findings of increased risk were no longer observed.   The adjusted relative risks in pregnancies exposed to methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines; the adjusted relative risk was 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. 

This group also analyzed data from the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden).  They did not have adequate numbers of amphetamine-exposed pregnancies so this analysis focused only on exposures to amphetamines (n=1402).  The researchers calculated an adjusted relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations in the methylphenidate exposed infants, a finding which was not statistically significant.  When they combined the US and Nordic cohorts, they calculated a pooled relative risk of 1.28 (95% CI, 1.00-1.64) for cardiovascular malformations associated with methylphenidate exposure, a finding which was borderline statistically significant.  

Putting It All Together

Based on the findings of these large studies, it appears that prenatal exposure to methylphenidate or amphetamines is not associated with an  increase in the overall risk of major malformations.  However, both the older Huybrechts study and the newer Kolding study have observed an increase in risk of cardiovascular malformations — specifically ventricular septal defects in the Kolding study — in pregnancies exposed to methylphenidate.  While the Kolding study had only a small number of amphetamine exposures, the Huybrechts  study reported on over 5500 amphetamine exposures, documenting no increase in risk of cardiac malformations.   

For methylphenidate, there may or may not be a signal here; however, there is no cause for alarm.  Looking at the pooled data from the 2000-2013 US Medicaid Analytic eXtract and  the Nordic Health registries 2003-2013 (which overlaps with Danish cohort included in the Kolding study), Huybrechts and colleagues reported on the outcomes of 3,474 methylphenidate-exposed pregnancies and calculated a pooled estimate of relative risk of 1.28 (95% CI, 1.00-1.64) for cardiac malformations, a finding which was borderline statistically significant.  

It is important to note that many studies have shown small but statistically significant associations between exposures to a particular medication (for example, SSRIs, bupropion, ondansetron, acetaminophen) and increased risk for cardiac malformations.  In many of those studies, these associations disappear when researchers are able to control for potential confounding variables.    

Assuming the relative risk calculated in this study is correct, the risk for cardiac malformation in the methylphenidate-exposed children would be around 1.63%.  A very small increase in absolute risk.  Our primary goal is to maintain mental health stability and functioning during pregnancy, and these studies provide useful information to women taking stimulants who are pregnant or planning to conceive.  

Ruta Nonacs, MD PhD

Huybrechts KF, Bröms G, Christensen LB, Einarsdóttir K, et al.  Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium. JAMA Psychiatry. 2018 Feb 1;75(2):167-175.  

Kolding L, Ehrenstein V, Pedersen L, Sandager P, Petersen OB, Uldbjerg N, Pedersen LH.  Associations Between ADHD Medication Use in Pregnancy and Severe Malformations Based on Prenatal and Postnatal Diagnoses: A Danish Registry-Based Study.  J Clin Psychiatry. 2021 Jan 5;82(1):20m13458. Free article.

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