Lisdexamfetamine in Early Pregnancy and Risk of Major Congenital Malformations

Background: Lisdexamfetamine (LDX) has been available in Europe to treat attention-deficit/hyperactivity disorder (ADHD) since 2013 and approved for adults since 2015 in Sweden and 2018 in Norway. Use of LDX has increased internationally in recent years but data on its safety in pregnancy are limited.

Objectives: To determine if use of LDX in first trimester is associated with an increased risk of major congenital malformations (MCM) compared to no ADHD medication use or methylphenidate (MPH).

Methods: This was a population-based cohort study including data from Norway (2016-2020) and Sweden (2014-2019). The main data sources were the national registers of births, prescribed drugs, and specialist healthcare. We included all pregnancies resulting in a live birth or stillbirth at 22-44 gestational weeks. Pregnancies with exposure to known teratogenic drugs, or where one or more infants were diagnosed with a chromosomal abnormality or genetic syndrome were excluded. LDX use in first trimester was defined as having filled one or more prescriptions from the first day of the last menstrual period (LMP) to LMP+97 days. We defined monotherapy of LDX or MPH as having no other ADHD drug prescription filled from LMP to LMP+97. Those with no ADHD medication use had not filled a prescription for any ADHD drug from LMP-90 days to LMP+97 days. The outcomes were any and cardiac MCM diagnosed in the first year of life and identified by ICD-10 codes aligned with the EUROCAT classification. To adjust for potential confounders, we estimated propensity scores models that included country, age, smoking, diabetes, hypertension, psychiatric conditions, co-medication, and more. We used log-binomial regression with propensity score fine-stratification weights to estimate adjusted risk ratios and 95% confidence intervals.

Results: We identified 837 pregnancies in which the mother used LDX in first trimester and 712 as monotherapy. They were compared with 944,322 pregnancies with no ADHD medication use and 2321 with MPH monotherapy. Among those with LDX use, 28 pregnancies had any MCM (3.34%) and 14 cardiac MCM (1.67%), versus 30,701 (3.25%) and 12,847 (1.36%), respectively, among those with no ADHD medication use. The corresponding adjusted RRs were 0.9 (95% CI 0.6-1.3) for any MCM and 1.0 (0.6-1.7) for cardiac MCM. For LDX versus MPH monotherapy, the adjusted RRs for were 0.8 (0.5-1.3) for any MCM (25 [3.51%] versus 105 [4.55%] cases) and 0.9 (0.5-1.7) for cardiac MCM (13 [1.82%] versus 49 [2.11%] cases).

Conclusions: LDX use in first trimester was not associated with an increased risk of MCM compared to no ADHD medication use or MPH monotherapy. While the number of LDX exposed pregnancies was < 1000, we can rule out a doubling of the risk of MCM.