Anti-psychotic medication use during pregnancy not associated with attention-deficit/hyperactivity disorder, autism spectrum disorder or small for gestational age in children

1. Children of mothers who were exposed to anti-psychotics during pregnancy, compared to those never exposed, did not have an increased risk of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), or small for gestational age (SGA), but had a mildly increased rate of pre-term birth.

2. Siblings of children with mothers exposed to anti-psychotics during pregnancy, compared to those never exposed to anti-psychotics, had similar rates of ADHD, ASD, preterm birth, and SGA.

Evidence Rating Level: 2 (Good)

Study Rundown: The safety of anti-psychotics during pregnancy has not been sufficiently investigated yet. Some studies connect their use to autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), preterm birth, and birth of an infant that is small for gestational age (SGA), but were confounded with anti-depressant use, had insufficient follow-up time to diagnose ADHD (recommended to have 6 years), and did not feature sibling-matching to account for genetics. This study assesses the safety of anti-psychotics in pregnancy while addressing these concerns. Data on ASD, ADHD, preterm, and SGA birth rates for mothers during pregnancy, before pregnancy, or never exposed to anti-psychotics were collected through the Hong Kong Clinical Data Analysis Reporting System (CDARS). 0.17% of 411,251 were exposed to anti-psychotics. Children exposed during pregnancy, compared to never exposed, did not have an increased risk of ADHD, ASD, or SGA, but were more commonly pre-term. All outcomes (ADHD, ASD, pre-term, and SGA rates) were similar for children of mothers who were exposed previously, but discontinued before pregnancy, compared to those exposed during pregnancy. Mothers previously exposed to anti-psychotics who stopped prior to pregnancy, compared to those who were never exposed, had higher rates of ADHD, pre-term birth, and SGA infants, but not ASD. In a sibling-matching analysis, siblings of children with mothers exposed to anti-psychotics, compared to those not exposed, were similar for ADHD, ASD, preterm birth, and being born SGA. A strength of this study is that it features a large database of population-based health information, necessary to create a sufficient sample of mothers taking antipsychotics during pregnancy. However, a limitation is this database does not capture private medical practitioners; though the number of children with neurodevelopmental disorders who never contact the public sector is low, it could somewhat underestimate this number. There is a low risk of recall bias in this study’s classification of drug exposure as the database included prescribing and dispensing records, which were used to determine anti-psychotic exposure.  However, this study does not account for adherence, which is known to be poor for anti-psychotics, suggesting some exposure misclassification bias. A sensitivity analysis was performed that found similar results when assuming only the persons refilling their prescriptions regularly had taken them. Confounders like genetics were assessed through a sibling-matching analysis, though this analysis was underpowered due to the limited sample size.

Click to read the study in JAMA Internal Medicine

Click to read an accompanying editorial in JAMA Internal Medicine

Relevant Reading: The Safety of Second-Generation Antipsychotics During Pregnancy: A Clinically Focused Review

In-Depth [retrospective cohort]: The neurodevelopmental disorder (ASD or ADHD), preterm (< 37 weeks) and SGA (>2 standard deviations below mean size for gestational age) status of all live births by females aged 15 – 50 in Hong Kong were collected in the CDARS. Mothers exposed to anti-depressants during pregnancy were excluded. Mothers were classified as having been exposed to an anti-psychotic listed in the British National Formulary during pregnancy (gestationally exposed), as having discontinued anti-psychotic use before pregnancy (previous/past exposed), and as having never used anti-psychotics (non-exposed). These groups were subdivided into those with and without psychiatric conditions. Of 411,251 infants, 0.17% were pre-natally exposed to anti-psychotics, 13.03% were pre-term, 2.69% were SGA, and 3.82% were diagnosed with ASD. Of the subgroup of 333,749 available records that assessed ADHD at least 6-years post-birth, 8.23% were diagnosed with ADHD. Gestationally exposed, compared to non-exposed, children had a nearly equal risk of ADHD (hazard ratio (HR) = 1.16, 95% CI = 0.83-1.61) ASD (HR = 1.06, 95% CI = 0.70-1.60), and SGA birth (HR = 1.36, 95% CI = 0.86-2.14), but an increased risk of pre-term birth (HR = 1.40, 95% CI, 1.13-1.75). There was no difference in the risk of any outcome between the gestationally and past exposure group, including ADHD (HR = 0.99; 95% CI = 0.60-1.61), ASD (HR = 1.10; 95% CI = 0.58-2.08), preterm birth (OR = 0.93; 95% CI = 0.70-1.24), and SGA (OR = 0.21; 95% CI = 0.66-2.20). There was an increased risk in the children of mothers previously exposed to anti-psychotics, compared to never exposed mothers, of ADHD (HR = 2.72; 95% CI = 2.16-3.44), preterm birth (OR = 1.47; 95% CI = 1.23-1.75), and being SGA (OR = 1.88; 95% CI = 1.36-2.59), but not ASD (HR = 1.35; 95% CI = 0.92-1.98). These risks were not associated with any trimester specifically. Of 40,756 mothers with 85,257 infants assessed for ASD, 215 were gestationally exposed to anti-psychotics, of which 14.88% were pre-term, 1.86% were SGA, and 2.79% developed ASD compared to 10.90%, 1.88%, and 1.92% of the unexposed children, respectively. Of 23,308 mothers with 48,275 children assessed for ADHD, 11.25% of the 160 children gestationally exposed to anti- psychotics developed ADHD compared to 3.96% of the unexposed children. The risk did not change in siblings of children from mothers exposed to anti-psychotics, compared to those not exposed, for ADHD (HR = 0.41; 95% CI = 0.04-4.93), ASD (HR = 0.90; 95% CI = 0.40-2.01), preterm birth (OR = 1.25; 95% CI = 0.85-1.82), or SGA (OR = 0.86; 95% CI = 0.32-2.31).

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