Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

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.

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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