In utero Exposure to β-2-adrenergic Receptor Agonists and ADHD/ASDs in Children Hong Liang MD, Ph.D Department of Epidemiology and Social Medicine Shanghai Institute of Planned Parenthood Research, China

Childhood neuropsychiatric disorders Attention-Deficit/Hyperactivity Disorder (ADHD) Persistent pattern of inattention and/or hyperactivity-impulsivity , 5% Autism spectrum disorders (ASDs) Persistent deficits in social communication and social interaction, 1‰ Environmental risk factors: maternal stress, lead and polychlorinated biphenyls, and prescribed drugs ( Acetaminophen)

β-2-adrenergic receptor agonist (β2AA) Mainstream medication for asthma treatment Poorly controlled asthma during pregnancy: increased risks of preeclampsia, preterm birth, low birth weight, and mortality. β2AA can cross the human placenta and stimulate beta-2- adrenergic receptor Maternal use of β2AA was reported to be associated with affected cognitive performance and motor development Few studies on the association between maternal β2AA use and ADHD/ASDs.

Objective To examine the association between prenatal exposure to β2AA and the risk of ADHD and ASDs in offspring

Data source Danish national register data Danish Civil Registration System (CRS) Danish Medical Birth Register Danish Integrated Database for Longitudinal Labour Market Danish National Prescription Registry Danish National Patient Registry Danish Psychiatric Central Register A unique personal identification ensures accurate linkage between all registers A cohort of 672,265 children were established between 1998 and 2007.

Study design and exposure window During pregnancy Cases 30 days before Conception Conception Birth Non-cases Follow-up period Outcome: ADHD, ASDs Exposure period Exposure: Maternal β2AA prescription

Danish Prescription Registry Exposure: maternal β2AA prescription The Antomical Therapeutic Chemical classification (ATC) codes: R03AC or R03CC Outcome: ADHD (ICD10 F90) ASDs (ICD10 F84.0, .1, .5, .8) Danish Prescription Registry Danish National Patient Registry Danish Psychiatric Central Register

Log-linear poisson regression was used to estimate incidence rate ratios (IRR) and 95% confidence interval (CI) of ADHD/ASDs. Covariates: sex, year of child birth, birth order, paternal age at child birth, maternal age at child birth, maternal education, maternal smoking during pregnancy, maternal socioeconomic status, and family history of psychiatric disorders. Danish Medical Birth Register Danish Integrated Database for Longitudinal Labour Market

Results In utero exposure to β2AA and the risk of ADHD In utero exposure to β2AA and the risk of ASDs Liang H, Chen J, Miao M, Christensen J, Dalsgaard S, Yuan W, et al. In utero exposure to beta-2-adrenergic receptor agonist and attention-deficit/hyperactivity disorder in children. Eur Child Adolesc Psychiatry. 2017. Su X, Yuan W, Chen J, Miao M, Olsen J, Pedersen LH, et al. Prenatal exposure to beta2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiology and drug safety. 2017;26(7):812-8.

1. Prenatal exposure to β2AA and ADHD The percentage of babies born to mothers with β2AA usage during pregnancy: 3.8% The incidence rate of ADHD: 20.5/10,000 person-years The median age at ADHD diagnosis: 8.1 -- Is β2AA usage associated with increased risk of ADHD?

β2AA usage was associated with a 1.30-fold increased risk of ADHD Table 1. Incidence rate ratios (IRRs) of ADHD in children following maternal β2AA Use β2AA usage was associated with a 1.30-fold increased risk of ADHD Is the association attributed to β2AA use or the underlying indication?

Definition of extended exposure window With indication but no drugs With indication and drugs During pregnancy Both Before pregnancy Non-cases Conception cases Birth 2-year Children born to mothers who had redeemed a β2AA prescription only during pregnancy are expected to have higher risk compared with only before pregnancy if β2AA did increase the risk of ADHD

Table 2. Incidence rate ratios (IRRs) of ADHD in children following maternal β2AA Use

Is the association attributed to β2AA Use ?

Is the association gender specific?

Table 4. Incidence rate ratios (IRRs) of ADHD following maternal β2AA Use stratified by child sex

Sensitivity analyses Stratified analyses Similar results were observed year of child birth parental history of psychiatric disorders Similar results were observed

2. Prenatal exposure to β2AA and ASDs The incidence rate of ASD: 12/10,000 person-years The median age at ASDs diagnosis: 7.0 years

Table 1. Association between maternal use of β2AA and the risk of ASDs in the offspring according to timing of drug use

Table 2. Association between maternal use of β2AA and the risk of ASDs among children of asthmatic mothers

Table 3. The association between maternal use of β2AA and the risk of ASDs stratified by sex

Summary Increased risk of ADHD and ASDs following in utero exposure to β2AA Maternal β2AA usage before pregnancy has similar risk No association was observed among children whose mother had a history of asthma The increased risk may be explained by the underlying disorders or associated pathological conditions, instead of the effect of β2AA

Strength Large sample size, including all singletone children born alive, with nearly complete follow-up adequate power less selection bias Re-define exposure Potential confounders control

Limitation The discrepancy between prescription and actual usage Children with ADHD/ASDs diagnosed outside the hospital system may not be recorded in the register

Team members Hong Liang, Maohua Miao, Jianping Chen & Wei Yuan, Key Lab of Reproductive Regulation of NPFPC, SIPPR, China. Jiong Li & Jorn Olsen, Department of Clinical Epidemiology, Aarhus University Hospital, Denmark. Jakob Christensen, Department of Neurology, Aarhus University Hospital, Denmark Lars Henning Pedersen, Department of Clinical Medicine, Obstetrics and Gynecology, Aarhus University, Denmark Soren Dalsgaard, National Center for register-based Research, Aarhus University, Denmark

Thank you!

Does the accompanied medication play any role in the association? Does dosage of β2AA usage matter?