Association of Maternal Use of Triptans During Pregnancy With Risk of Attention-Deficit/Hyperactivity Disorder in Offspring

Key Points Question Is prenatal exposure to triptans associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring? Findings This population-based cohort study of 10 167 children found no associations between prenatal exposure to triptans and ADHD diagnosis or ADHD symptoms among offspring. Meaning These findings suggest that there is no increased risk of ADHD in offspring associated with prenatal exposure to triptans.


Additional information about exposure
Women could report use of medications during pregnancy in two prenatal (Q1 and Q3) and one post-partum questionnaire (Q4). In each questionnaire, women were provided with a list of different illnesses and health problems, and asked to indicate if they had the problem/illness. On the same line, they could write the name of any medication used, and indicate when it was used. Q1 covered the period six months before pregnancy and gestational week (GW) 0-4, 5-8, 9-12, and 13+. Q3 covered GW 13-16, 17-20, 21-24, 25-28, and 29+. Q4 covered the last part of pregnancy. The questionnaires are available at the Norwegian Institute of Public Health webpage: https://www.fhi.no/en/studies/moba/for-forskere-artikler/questionnaires-from-moba/. 1

Additonal information about statistical analyses
Multiple imputation by chained equations was used to impute missing data in covariates, with 30 imputations. 2,3 Imputation models were fitted separately for the ADHD diagnosis sample and ADHD symptoms sample, and included all covariates that were included in the weights, exposure variables and outcome variables. Treatment weights were estimated and outcome models fit in each imputed dataset, then estimates were combined. 4 In the imputation model for ADHD diagnosis we included the hazard function, as recommended. 5 In the main analysis, non-overlapping regions of the propensity scores of exposed and unexposed were trimmed by excluding individuals with a propensity score outside of the common range, to avoid extrapolation. 6 The number of individuals that were trimmed differed for each imputed dataset, but was fewer than 1% of the total ADHD diagnosis sample and fewer than 2% of the ADHD symptoms sample.
For the probabilistic bias analysis, we used trapezoidal distributions for sensitivity and specificity with 20 000 simulations. Sensitivity and specificity was assumed the same for cases and non-cases (non-differential misclassification). We were not able to identify studies reporting sensitivity and specificity for self-reported triptan use compared to interview or medication diary as gold standard. One study examined the validity of prescribed pain medication, mostly NSAIDs, and found sensitivity between 0.29-0.34 and specificity between 0.98-0.99. 7 Recall time was longer in that study compared to this study, and we expect triptans to have higher sensitivity than NSAIDs because the indication for use is very specific. Another study reported sensitivity of 0.63 for occasional or short-term use of analgesics or antipyretics. 8 Based on this, we defined several scenarios for the parameters of sensitivity and specificity (e.g. optimistic, realistic and pessimistic).

Additonal results from sensitivity analyses
When we restricted the ADHD symptoms analysis to children with no missing items on the Conner's Parent Rating Scale (CPRS), results were similar to the main analysis (eTable 8).
Estimates based on trimmed and untrimmed weights were similar (eFigure 6 and 7).
Results from complete case analysis showed similarities and differences to the main analysis (eFigure 8 and 9). For ADHD symptoms, crude estimates were similar, but for the weighted estimates triptan exposed children had significantly lower scores than children whose mothers had migraine during pregnancy in the complete case analysis. However, the difference was small and not likely to be of clinical relevance. eTable 1. Items from the Conners' Parent Rating Scale-Revised, Short Form (CPRS-R(S)) 9,10 Included in Q5y

Item Question
How much of a problem has this been the last month? Fidgets with hands or feet, squirms in seat 4

Response
Messy or disorganised at home or in the kindergarten 5 Only attends if it is something he/she is very interested in 6 Distractibility or attention span a problem 7 Avoids, expresses reluctance about, or has difficulties engaging in tasks that require sustained mental effort (such as activities in kindergarten or helping out at home) 8 Gets distracted when given instructions to do something 9 Has trouble concentrating in kindergarten 10 Leaves seat in kindergarten or in other situations in which remaining seated is expected 11 Does not follow through on instructions and fails to finish tasks such as putting away shoes/tidying toys (not due to oppositional behaviour or failure to understand instructions) 12 Easily frustrated in efforts eTable 2. Overview of Covariates