Study design, population, and settings
The data used in this study were obtained from the Japan Environment and Children’s Study (JECS), an ongoing cohort study that began in January 2011 to determine the effect of environmental factors on children’s health. In the JECS, pregnant women were recruited between January 2011 and March 2014. The eligibility criteria for participants were: 1) residing in the study area at the time of recruitment, 2) expected delivery after August 1, 2011, and 3) capable of comprehending the Japanese language and completing the self-administered questionnaire. This study was registered in the UMIN Clinical Trials Registry (number: UMIN000030786). Details of the JECS project have been described previously [13, 14]. The JECS protocol was reviewed and approved by the Institutional Review Board on Epidemiological Studies of the Ministry of the Environment (ethical number: No. 100910001) as well as by the Ethics Committees of all participating institutions. The JECS was conducted in accordance with the Helsinki Declaration and other nationally valid regulations and guidelines. Written informed content was obtained from each participant.
The present study was based on the “jecs-an-20180131” dataset released in March 2018 containing information on 98,255 mothers who had a singleton pregnancy. Specifically, we focused on questionnaire data regarding developmental screening as self-described by mothers when their child was 12 months old. The screening tool was the Ages and Stages Questionnaire, third edition (ASQ-3) [15]. Maternal medical information, additional pregnancy details, and medical history were collected from subject medical record transcriptions for adoption as other covariates.
Data collection
Information on socioeconomic status, smoking habit of the mother and partner, and maternal alcohol consumption was collected during the second/third trimester of pregnancy (T2) by means of self-reported questionnaires. Details on a parental history of neurodevelopmental disorders, epilepsy, and mental disease were also collected from T2 questionnaires as described by the mother and partner. Maternal anthropometric data before and during pregnancy, complications and medication during pregnancy related to HDP, diabetes mellitus/gestational diabetes mellitus (DM/GDM), and neonatal information was gathered from medical record transcriptions. Prepregnancy BMI was calculated according to WHO standards as body weight (kg)/height (m)2 and categorized as underweight (BMI < 18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), and obese (BMI 30+).
Outcomes
The main outcomes of interest were ASQ-3 domain scores. The ASQ-3 is a parent-reported initial level developmental screening instrument for children aged 12 months with 30 items in five domains: communication, gross motor, fine motor, problem solving, and personal-social. Each item describes a skill, ability, or behavior to which the parent responds “yes” (10 points), “sometimes” (5), or “not yet” (0). Parents sometimes omit items when they are unsure of how to respond or because they have concerns about their child’s performance of the item. ASQ-3 scores were not calculated if there were three or more omitted items in a given domain. In the case of one or two omitted items, an adjusted total domain score was calculated by adding the averaged item score either once for one omission or twice for two omissions. The score calculated for each domain was categorized as normal development (above cut-off) or referral zone (score less than two standard deviations below the mean) [15].
Participants with established risk factors of developmental delay, such as neonatal asphyxia, and physical abnormality at birth including infection, respiratory distress, congenital abnormality, hearing disability, and chromosomal abnormalities, were excluded (Fig. 1). Infants with no ASQ-3 abnormalities were adopted as normal development.
Exposure
GWG in this study was subdivided as below, within, or above the reference values of the 2009 IOM guidelines widely used throughout the world. The IOM guideline ranges for total GWG based on prepregnancy BMI are as follows: 12.7-18.1 kg for underweight women, 11.3-15.9 kg for women of normal weight, 6.8-11.3 kg for overweight women, and 5.0-9.1 kg for obese women (Supplemental table S1).
Covariates
The covariates in our models were selected a priori based on previous literature and biologic plausibility [16-20]. We estimated the effects of GWG after adjusting for demographic data including maternal age, prepregnancy BMI, parental smoking habit, maternal drinking habit, maternal highest level of education, annual household income, parental history of neurodevelopmental disorders, epilepsy, and mental disease, as well as obstetric and medical variables such as parity, means of pregnancy, use of folic acid supplements, complications during pregnancy (including DM/GDM, HDP, and intrauterine growth restriction), means of delivery, birth weight, gender, method of feeding, and neonatal jaundice. Parental medical history of neurodevelopmental disorders included attention deficit and hyperactivity disorder, learning disability, autism, Asperger’s syndrome, pervasive developmental disorder, and others. Mental disease included depression, schizophrenia, and anxiety disorder.
Statistical analysis
Differences in maternal age, prepregnancy BMI, GWG, gestational weeks, and birth weight between subjects with normal development and developmental delay were assessed by the Mann-Whitney U test. We categorized all continuous and ordinal variables, such as maternal age (< 35 or 35+ years), prepregnancy BMI, GWG (below, within, or above), annual household income (< 4,000,000, 4,000,000-7,999,999, or 8,000,000+ JPY), gestational weeks (< 37, 37+ weeks), and birth weight (< 1,500, 1,500-2499, 2,500+ g). Fisher’s exact tests or chi-square tests were performed to compare covariates between groups stratified by category as well as by the presence of developmental delay. Additionally, differences in the scores of each domain among the three GWG groups were assessed by one-way repeated measures of analysis of variance (ANOVA) followed by post hoc (Bonferroni) testing. We employed logistic regression models to calculate adjusted ORs (ORs) and their 95% confidence intervals (CIs). Spearman’s rank correlation coefficient was used to check for multicollinearity of covariates. The variable of gestational weeks was excluded from the covariates because it was multicollinear with birth weight. Hosmer-Lemeshow testing was used to assess the goodness-of-fit of the models. We also analyzed the subjects without registered fathers to evaluate for possible selection bias.
All statistical analyses were performed using SPSS statistical software version 27 (SPSS Inc., Chicago, Illinois). All tests were two-tailed, and P-value of less than 0.05 were considered to indicate statistical significance.