Journal Article Annotations
2017, 4th Quarter

Women’s Mental Health

Annotation by Jacquelin Esque, MD
January 2018

Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium

PUBLICATION #1 — Women’s Mental Health

Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium

Huybrechts KF, Bröms G, Christensen LB, et al

Abstract: JAMA Psychiatry 2017 Dec 13 (Epub ahead of print)

Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety.

Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants.

Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017.

Exposures: Methylphenidate and amphetamines dispensed during the first trimester.

Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations.

Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for 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: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64).

Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.

On PubMed: AMA Psychiatry 2017 Dec 13 (Epub ahead of print)

Annotation

Type of study: Cohort study

The finding: This was a cohort study evaluating risks of congenital malformations in pregnant women exposed to stimulants in the first trimester. Authors looked at data from US Medicaid beneficiaries (1,813,894 pregnancies) and conducted validation analyses using data from the Nordic Health registries (2,560,069 pregnancies). The authors reported a 28% increase in risk of cardiac malformations associated with intrauterine exposure to methylphenidate when looking at pooled data from the US and Nordic countries (RR 1.28 (95% CI, 1.00-1.64). The authors did not find a significantly increased risk for all congenital malformations with methamphetamine use and did not find any significantly increased risks for congenital malformations or specifically cardiac malformations for amphetamine use.

Strength and weaknesses: Strengths include that this study evaluated data from 6 different countries. Exposure and outcome data was independently and prospectively collected preventing recall bias. Surveillance bias was thought to be limited as noted that there was no increased risk for malformations in infants exposed to amphetamines. Authors accounted for possibility of nonadherence to prescribed stimulants by increasing specificity of the exposure definition, requiring medication to be dispensed to women twice during the time window and noted that this did not change findings.

Limitations include that both data sets looked only at live births, which may result in underestimation of relative risk due to selection bias. There was also the possibility that residual confounding by factors associated with ADHD severity could have contributed to the finding of increase risk of malformations in the methylphenidate group. It is additionally noted that when looking at the central finding that methylphenidate was associated with increased risk for cardiovascular malformations in the pooled data, the value for z is 1.93 which is less than the 1.96 formally required for statistical significance and the lower limit of the confidence interval was 1.0, indicating borderline statistical significance.

Relevance: Recently there has been an increase in stimulant medication use in adults for ADHD symptoms. Previous data regarding these medications in early pregnancy is limited. Although the statistical and clinical significance of the small increase in risk of cardiac malformations in infants exposed to methylphenidate is questionable, this study provides information that can be useful when discussing risks and benefits of different treatments for ADHD in pregnant women and young women of reproductive age.