Associations Between ADHD Medication Use in Pregnancy and Severe Malformations Based on Prenatal and Postnatal Diagnoses

Abstract

Objective: Attention-deficit/hyperactivity disorder (ADHD) medications are increasingly used in pregnancy. Studies on the pregnancy safety of these medications that are restricted to live births may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The present study addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations. Methods: A nationwide registry-based study was conducted of 364,012 singleton pregnancies in Denmark from November 1, 2007, to February 1, 2014. Exposures to ADHD medication were obtained from redeemed prescriptions from the Danish Health Services Prescription Database. Outcome data included prenatally diagnosed malformations from the Danish Fetal Medicine Database and postnatally diagnosed malformations from the Danish National Patient Registry. The primary outcome was major malformations overall, and secondary outcomes were malformations of the central nervous system and cardiac malformations. The comparison group was pregnancies with no redeemed prescriptions for ADHD medication. We defined severe cardiac malformations (SCM) as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, postnatal death, or cardiac surgery within 1 year of birth. Results: The prevalence of first-trimester exposure to ADHD medication increased during the study period from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of the exposures being to methylphenidate. There were 5.1% malformations overall and 2.1% cardiac malformations among the exposed compared to 4.6% and 1.0%, respectively, among the unexposed. For methylphenidate, 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 (number needed to harm [NNH] = 92), with septum defects in 10 out of 12 cases. The PR for ventricular septal defect was 2.74 (95% CI, 1.03-7.28) and for SCM, 2.59 (95% CI, 0.98-6.90). Conclusions: Exposure to methylphenidate was not associated with an increased risk of malformations overall in data that included information from both prenatal and postnatal diagnoses of major malformations. There was an increased risk of cardiac malformations with NNH of 92 based on 12 cases among the exposed. More data are needed on other types of ADHD medication.

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations

“…The current study took advantage of a collaboration within the InPreSS consortium, which aims at pooling data from the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) and the US to increase statistical precision in pregnancy safety studies. Our study overlaps with previous studies using Swedish and Danish data 7,12,13 to some extent, but with its multicountry approach is significantly larger. Nevertheless, it was still limited by imprecise risk estimates.…”

“…Data on the potential teratogenicity of in utero exposure to atomoxetine, a selective norepinephrine reuptake inhibitor also used to treat ADHD, 9,10 are very limited. 11 Two studies 7,12 that reported on atomoxetine as one ADHD medication of several in a variable defined by exposure to any ADHD medication raised no concerns, and likewise for a recent study 13 that reported separately on atomoxetine and the risk of major malformations in general. In studies of rabbits and rats, 14 high doses of atomoxetine (25-100 mg/kg/d compared to the recommended dose in humans of 1.2-1.8 mg/kg/d) have been associated with reduced fetal and postnatal viability in rodents, particularly with increased frequency of cardiovascular malformations and incomplete ossification of bones.…”

Fifteen years' experience with methylphenidate for attention-deficit disorder during pregnancy: Effects on birth weight, Apgar score and congenital malformation rates

“…(2018) suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to MPD [19]. Kolding et al found that exposure to MPD was associated with an increased risk of cardiac malformations in particular ventricular septal defects [15]. The possible association with gastroschisis, omphalocele and transverse limb deficiency has to be investigated further [14].…”

“…ADHD medication use in early pregnancy may be associated with an increased risk for birth defects such as gastroschisis, omphalocele, and transverse limb deficiency [14]. ADHD medication such as MPD also seemed to be associated with an small but elevated risk of cardiac malformations when taken in first trimester [15,16]. On the other hand several large studies showed no major malformations when MPD was taken by pregnant patients [17][18][19].…”

Risk of Major Malformations in Infants After First-Trimester Exposure to Stimulants

“…These analyses found no differences in overall risk of major malformations after exposure to mixed amphetamine salts or methylphenidate. [10][11][12] Spontaneous abortion (miscarriage) has also been associated with in utero exposure to methylphenidate. 7,13,14 Considering obstetrical and neonatal complications, stimulants have been associated with increased risk of hypertensive disorders, 15 preeclampsia, 16 placental abruption, 16 small for gestational age fetal growth, 16 preterm birth, 10,16,17 and requirement for neonatal intensive care unit level of care.…”