METHODS

Study population and data collection

This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa),10,11 linked to records in the Medical Birth Registry of Norway (MBRN), 12 the Norwegian Prescription Database (NorPD),13 and the Norwegian Patient Registry (NPR)14 via the maternal personal identification number and pregnancy sequence. MoBa is a nation-wide, prospective population-based pregnancy study conducted by the Norwegian Institute of Public Health.10,11 Participants were recruited in 1999-2008 through a postal invitation in connection with a publicly offered routine ultrasound at 17-18 weeks of gestation. Prenatal data were gathered via two self-administered questionnaires at week 17 (Q1) and 30 (Q3). Postnatal follow-up questionnaires on maternal and child health were sent to mothers from child age 6 months to adolescence. Follow-up of children started in 1999 and is still ongoing. Prospective fathers also completed one prenatal questionnaire at week 17. The current study is based on version 9 of the quality-assured data files released for research. The cohort now includes 114500 children, 95200 mothers and 77300 fathers.10 The participation rate for all invited pregnancies was 41%.11 This study followed the STROBE reporting guideline for cohort studies.
The MBRN is a nationwide registry based on compulsory notification of all live births, stillbirths and induced abortions.12The NorPD collects data on all prescribed medications dispensed from community pharmacies irrespective of reimbursement since 2004. The NPR contains records on admission to hospitals and specialist healthcare since 2008. The data include date of admission and discharge, primary and secondary diagnosis, and cover all government-owned hospitals and outpatient clinics, and all private health clinics that receive governmental reimbursement. Diagnostic codes in the NPR follow the International Classification of Diseases, version 10 (ICD-10). Figure S1 outlines the exclusion criteria to achieve the i) final ADHD diagnosis sample, with complete registry-based outcome data for all MoBa children, and the ii) final ADHD symptom sample, including MoBa children with maternal-reported data at age 5 years.

Self-reported clinical depression and anxiety

We included pregnancies within women reporting depression and/or anxiety during gestation.15,16 In MoBa Q1 and Q3 women were presented with a list of concurrent illnesses, and could report whether they were having “depression” or “anxiety” or “other mental disorders” (hereafter, clinical depression/anxiety) in pregnancy, and likewise in the time prior to pregnancy. To further tease apart the role of underlying maternal psychiatric disease from that of drug treatment in pregnancy, we additionally included women (discontinuers) with no self-reported clinical depression/anxiety in pregnancy, but who reported using antidepressant solely in the six month period prior to pregnancy.
The study measured severity of maternal symptoms of depression and anxiety at week 17 and 30 via the short versions of The Hopkins Symptom Checklist-25, i.e. the 5-item (SCL-5) scale.17,18 More information is outlined in the Supplement.

SSRI and SNRI exposure

In MoBa Q1 and Q3 women reported the name of the medication taken and timing of use in four-week intervals according to indication (Q1 for week 0-13+ and also 6 months before pregnancy; Q3 for week 13-29+).19 Drug classification was based on the Anatomical Therapeutic Chemical (ATC) Classification System.20
In a sub-sample of women enrolled in MoBa since 2004, NorPD was used as complementary source of exposure data. Available data in NorPD include ATC codes of individual antidepressants dispensed, dispensing dates, and the amount dispensed. We measured any antidepressant prescriptions filled within the period from pregnancy start to delivery, in accordance to prior research.21 More detail about exposure definition in NorPD is given in the Supplement.
Gestational exposure to each individual antidepressant was defined as exposure to a drug belonging to the ATC group N06A. SSRIs (sertraline, fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine) and SNRIs (venlafaxine, duloxetine) were grouped together (SSRI/SNRI) because of their pharmacological properties.
Because symptoms of depression/anxiety were measured at week 17 and 30, and reflected disease severity in the prior two weeks, we defined the following points of exposure in the timing analysis, as described in prior work:8,22 early (weeks 1-16), mid (weeks 17-28) and late (> week 29) pregnancy. Length of SSRI/SNRI use was defined according to how many 4-week intervals, out of the eight possible throughout pregnancy, were checked. These were grouped into “1-8 weeks”, “9-20 weeks” or “> 20 weeks”. In addition, we defined an ever exposure group during gestation. Women were classified as exposed if they reported use of SSRI/SNRI during these periods. Two mutually exclusive comparison groups were defined: i) Non-medicated: women with self-reported clinical depression/anxiety in pregnancy but non-medicated; ii) Discontinuers: women who reported use of any antidepressant only in the six months period prior to pregnancy, who did not report depression/anxiety in pregnancy.

ADHD diagnosis

A diagnosis of ADHD in the offspring (hereafter, ADHD) was defined as i) at least one primary or secondary diagnosis in the NPR based on the ICD-10 codes F90 (hyperkinetic disorder), in the period 2008-2015; or ii) one or more dispensed ADHD medication licensed in Norway (i.e., methylphenidate, atomoxetine, racemic amphetamine, dexamphetamine, and lisdexamphetamine) in NorPD between 2004-2016.23 The ICD-10 codes diagnosis of hyperkinetic disorder requires the combination of both inattentive and hyperactive symptoms.24 The majority of MoBa children were born in 2004 or later and thus outcome data since birth were available for most of the children in this study (Figure S2).

ADHD symptoms

Child ADHD symptoms by age 5 years were mother-reported via completion of the widely-used, validated Conners Parent Rating Scale-Revised (CPRS-R).25 MoBa included 12 selected CPRS-R items measuring the ‘inattention’ and ‘hyperactivity/impulsivity’ domains. Mothers were asked to rate whether each item reflected their child’s behavior in the last six months. The CPRS-R items and related scoring have been previously published.22 Mean CPRS-R score was calculated and standardized, and higher z-scores indicated greater ADHD symptoms. In the current study the internal CPRS-R consistency was 0.90.

Measured confounders and other postnatal factors

We identified a sufficient set of confounders with the aid of directed acyclic graphs.26 These were pre-pregnancy maternal Body Mass Index (BMI), parity, education and gross yearly income, marital status, folic acid, smoking and alcohol use in early pregnancy, paternal age, and an obstetric comorbidity index,27 as described in detail in the Supplement; co-medication in early pregnancy with opioid analgesics, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepine/z-hypnotics, and antipsychotics; severity of maternal depressive and anxiety symptoms in pregnancy via the SCL-5, and Life Time History of Major Depression (LTH of MD), as measured in Q1 via five key depressive symptoms closely corresponding to the DSM-III-R criteria for lifetime major depression.28 We included maternal and paternal filled prescriptions for ADHD medication as proxy of familial risk of ADHD. In separate models, we included other maternal psychiatric, paternal, child and postnatal factors (see Supplement and Table S1). More details on covariates are given in the Supplement.

Data analysis

To estimate associations with ever SSRI/SNRI exposure as ever in gestation and by duration, we fit crude and weighted analyses using inverse probability of treatment weighting (IPTW), based on the propensity score.29 Logistic regression models were first fit to estimate the probability of ‘SSRI/SNRI exposure’ as ever and in the duration windows (1-8, 9-20, more than 20 weeks), relative to non-medicated or discontinuers, given the set of sufficient confounders. To estimate associations by timing of exposure, we fit marginal structural models (MSM)30 with two time points to account for i) time-varying SSRI/SNRI exposure; ii) time-varying confounders (i.e, SCL-5 in pregnancy and co-medications) which are affected by prior SSRI/SNRI treatment, as illustrated in prior work.8,22 We estimated the probability of SSRI/SNRI treatment using a pooled logistic regression in which the outcome was current treatment with an SSRI/SNRI in mid or late pregnancy, and covariates were maternal baseline, time-varying and time-fixed confounders, and SSRI/SNRI in early pregnancy. We then derived stabilized IPTW for each pregnancy at each time point.
To estimate standardized mean differences in symptoms and hazard ratio (HR) for ADHD, we respectively fit crude and weighted generalized linear and Cox regression models with robust standard errors. In the Cox regressions, we used child age as time scale and a quadratic term for year of birth to address left-truncation for children born before 2004; the follow-up period for all live-born children started at birth and ended on the date of ADHD diagnosis, date of first drug prescription for ADHD, or 31 December 2016, whichever came first. The current study did not have information about dates of potential emigration or death, but only whether these events had occurred (91 children (1.4%) had emigrated). Because the proportionality hazard assumption was not met, we split the follow-up time at child age 7 and 9 years (Figures S3-S4), estimating period-specific HRs. All statistical analyses were performed by using Stata MP 16. Data are presented crude and weighted hazard ratios (wHR), and as standardized means scores with 95% CI. Power analysis is outlined in Table S2.