Risk Of Attention-deficit/hyperactivity Disorder In Offspring Research Articles

Gestational exposure to benzodiazepines or z-hypnotics and neurodevelopmental disorders in offspring: Systematic review and meta-analysis.

Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring. We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD. We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses. Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy.

Maternal asthma and asthma exacerbation during pregnancy and attention-deficit/hyperactivity disorder in offspring: a population-based cohort study.

The link between inflammatory disorders, such as asthma, and attention deficit hyperactivity disorder (ADHD) is attracting increasing attention but few studies have examined cross-generational associations. We sought to examine associations of maternal asthma and asthma exacerbation during pregnancy, as well as paternal asthma, with the risk of ADHD in children. This population-based cohort study used data from the Taiwan National Health Insurance Research Database from 2004 to 2017. Cox regression models compared the risk of ADHD in children of parents with and without asthma, adjusting for parental sociodemographic, physical, and mental health conditions, as well as the child's birth weight, and number of births. A sibling control approach was employed to compensate for unmeasured confounders of asthma exacerbation during pregnancy. In the fully adjusted models, maternal and paternal asthma were both significantly associated with an increased risk of ADHD in offspring, with hazard ratios (HRs) of 1.36 (1.31-1.40) and 1.10 (1.05-1.14), respectively. Acute asthma exacerbation during pregnancy was not associated with the risk of further offspring ADHD (adjusted HR 1.00, 95% CI: 0.75-1.34). Both maternal and paternal asthma are associated with an increased risk of ADHD in offspring. The risk was higher from maternal asthma. However, no such association was found with maternal asthma exacerbation during pregnancy of sibling comparison.

The association between maternal diabetes and the risk of attention deficit/hyperactivity disorder in offspring: Updated systematic review and meta-analysis.

IntroductionThe existing body of evidence on the association between maternal diabetes and attention deficit/hyperactivity disorder (ADHD) in offspring is inconsistent and inconclusive. Thus, we need to synthesise the available evidence to examine the association between maternal diabetes and risk of ADHD in offspring.ObjectivesThe aim of this meta-analysis was to examine the association between maternal diabetes and the risk of ADHD in offspring.MethodsWe conducted a comprehensive search across PubMed, MEDLINE, EMBASE, Scopus, CINAHL and PsychINFO databases from their inception to September 8th, 2023. The methodological quality of the included studies was evaluated using Joanna Briggs Institute (JBI) and Newcastle-Ottawa Scale (NOS). Between-study heterogeneity was assessed using I2 statistic and potential publication bias was checked using both funnel plot and Egger’s test. Randomeffect model was used to calculate the pooled effect estimates and subgroup, sensitivity, and meta-regression were further performed to support our findingsResultsTwenty observational studies (two cross-sectional, five case-control and thirteen cohort studies) were included in this systematic review and meta-analysis. Our meta-analysis indicated that intra-uterine exposure to any type of maternal diabetes was associated with an increased risk ADHD in offspring [RR=1.33: 95 % CI: 1.23–1.43, I2=79.9%]. When we stratified the analysis by maternal diabetes type, we found 17%, and 37% higher risk of ADHD in offspring exposed to maternal gestational [RR=1.17: 95 % CI: 1.07–1.29] and pre-existing diabetes [RR=1.37: 95 % CI: 1.27–1.48] compared to unexposed offspring respectively. Results of subgroup and sensitivity analysis further supported the robustness of our main finding.ConclusionsOur review suggested that exposure to maternal diabetes increased the risk of ADHD in offspring. These findings underscore the need for early screening and prompt interventions for exposed offspring.Disclosure of InterestNone Declared

Gestational thyroid hormone concentrations and risk of attention-deficit hyperactivity disorder in the Norwegian Mother, Father and Child Cohort Study.

Maternal thyroid function plays an important role in foetal brain development; however, little consensus exists regarding the relationship between normal variability in thyroid hormones and common neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD). We sought to examine the association between mid-pregnancy maternal thyroid function and risk of clinically diagnosed ADHD in offspring. We conducted a nested case-control study in the Norwegian Mother, Father and Child Cohort Study. Among children born 2003 or later, we randomly sampled singleton ADHD cases obtained through linkage with the Norwegian Patient Registry (n=298) and 554 controls. Concentrations of maternal triiodothyronine (T3), thyroxine (T4), T3-Uptake, thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab) were measured in maternal plasma, collected at approximately 17 weeks' gestation. Indices of free T4 (FT4i) and free T3 (FT3i) were calculated. We used multivariable adjusted logistic regression to calculate odds ratios and accounted for missing covariate data using multiple imputation. We used restricted cubic splines to assess non-linear trends and provide flexible representations. We examined effect measure modification by dietary iodine and selenium intake. In sensitivity analyses, we excluded women with clinically significant thyroid disorders (n=73). High maternal T3 was associated with increased risk of ADHD (5th vs 1st quintile odds ratio 2.27, 95% confidence interval 1.21, 4.26). For FT4i, both the lowest and highest quintiles were associated with an approximate 1.6-fold increase in risk of ADHD, with similar trends found for T4. The FT4i association was modified by dietary iodine intake such that the highest risk strata were confined to the low intake group. Both high and low concentrations of maternal thyroid hormones, although within population reference ranges, increase the risk of ADHD in offspring. Increased susceptibility may be found among women with low dietary intake of iodine and selenium.

In utero antidepressant exposure not associated with ADHD in the offspring: A case control sibling design.

Recent studies have reported an association between antidepressant (AD) use during pregnancy and the risk to develop attention-deficit/hyperactivity disorder (ADHD) in the offspring. However, the association might be confounded by risk factors in the pregnant parent. To control for unmeasured factors between pregnancies carried by the same parent, we set up a case-control sibling study using the University of Groningen prescription database IADB.nl. Children receiving medication for ADHD (cases) before the age of 16 years were matched to siblings not receiving such medication (controls). Exposure was defined as at least two prescriptions for any AD during pregnancy, i.e., the period of 39weeks before the birth date of the offspring. Secondary analyses were performed to assess the effects of the degree of exposure (the amount of Defined Daily Doses) and the type of AD exposed to. Univariate and multivariate logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI). In total, 2,833 children (1,304 cases and 1,529 controls) were included in the analysis. Exposure rate to ADs among cases and controls was 2.2% and 2.4%, respectively. After adjusting for the birth date of the child (as a proxy for the date of pregnancy), age of the pregnant parent at birth, use of psychostimulants, opioids, and antiepileptic drugs by the pregnant parent in the 15 months before birth of the child, an adjusted OR of 1.11 (95% CI 0.67-1.83) was found for the risk of ADHD in the offspring when exposed in utero to ADs. This indicates no increased risk of ADHD in offspring following in utero exposure to ADs. The secondary analyses revealed no statistically significant associations either. The present study provides further evidence that an association between in utero AD exposure and ADHD in offspring might not exist. This perceived association may be caused (at least partially) by confounding by indication. The extent to which depression in the pregnant parent could cause mental disorders such as ADHD in offspring, and the mechanisms involved, should be investigated in further studies.

Influence of Maternal Diabetes on the Risk of Neurodevelopmental Disorders in Offspring in the Prenatal and Postnatal Periods.

This study aimed to evaluate the influence of maternal diabetes in the risk of neurodevelopmental disorders in offspring in the prenatal and postnatal periods. This cohort study included singleton gestational diabetes mellitus (GDM) pregnancies >22 weeks' gestation with live newborns between 1991 and 2008. The control group was randomly selected and matched (1:2) for maternal age, weeks of gestation and birth year. Cox regression models estimated the effect of GDM on the risk of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and maternal type 2 diabetes mellitus (T2DM). Moreover, interaction between maternal T2DM and GDM-ADHD relationship was evaluated. Children (n=3,123) were included (1,073 GDM; 2,050 control group). The median follow-up was 18.2 years (interquartile range, 14.2 to 22.3) (n=323 with ADHD, n=36 with ASD, and n=275 from women who developed T2DM). GDM exposure was associated with ADHD (hazard ratio [HR]crude, 1.67; 95% confidence interval [CI], 1.33 to 2.07) (HRadjusted, 1.64; 95% CI, 1.31 to 2.05). This association remained significant regardless of the treatment (diet or insulin) and diagnosis after 26 weeks of gestation. Children of mothers who developed T2DM presented higher rates of ADHD (14.2 vs. 10%, P=0.029). However, no interaction was found when T2DM was included in the GDM and ADHD models (P>0.05). GDM was not associated with an increased risk of ASD (HRadjusted, 1.46; 95% CI, 0.74 to 2.84). Prenatal exposure to GDM increases the risk of ADHD in offspring, regardless of GDM treatment complexity. However, postnatal exposure to maternal T2DM was not related to the development of ADHD.

Circulating levels of maternal vitamin D and risk of ADHD in offspring: results from the Vitamin D Antenatal Asthma Reduction Trial.

Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the association between 25(OH)D during fetal development and risk of childhood ADHD. Maternal plasma 25(OH)D was measured at 10-18 and 32-38 weeks of gestation, with sufficiency defined as 25(OH)D ≥ 30 ng/ml. Offspring ADHD status between ages 6-9 years was measured by parent report of clinical ADHD diagnosis among 680 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial. Association between maternal 25(OH)D and child ADHD was assessed using logistic regression, adjusting for maternal age, race and ethnicity. Effect modification by offspring sex was also assessed. No associations between maternal 25(OH)D at 10-18 weeks of gestation and offspring ADHD were observed. In the third trimester, we observed associations between maternal vitamin D sufficiency and offspring ADHD [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.26-0.84], in addition to maternal 25(OH)D sufficiency category, comparing the deficient (OR 0.34, 95% CI 0.12-0.94), insufficient (OR 0.41, 95% CI 0.15-1.10) and sufficient (OR 0.20, 95% CI 0.08-0.54) categories against highly deficient 25(OH)D, respectively. Stratified analyses revealed a protective association for sufficient maternal 25(OH)D and child ADHD among males (OR 0.47, 95% CI 0.23-0.94); the synergy index for additive effect modification of risk was 1.78 (95% CI 0.62-5.08). Higher levels of maternal vitamin D in the third trimester are associated with lower risk of ADHD in offspring, with modest evidence for a stronger effect among male offspring. However, larger studies will be necessary to confirm these findings.

Parental Age and the Risk of ADHD in Offspring: A Systematic Review and Meta-Analysis.

Evidence has suggested that parental age at birth is a risk factor of offspring attention deficit/hyperactivity disorder (ADHD). We conducted a meta-analysis of observational studies investigating the association between parental age and offspring ADHD. We conducted a systematic search that followed the recommended guidelines for performing meta-analyses on PUBMED, EMBASE, and Web of Science up to 8 April 2021. We calculated pooled risk estimates from individual age with and without adjusting for possible confounding factors. Dose–response analysis for parental age and ADHD risk was performed. Eleven studies were selected in this meta-analysis, which included 111,101 cases and 4,417,148 participants. Compared with the reference points, the lowest parental age category was associated with an increased risk of ADHD in the offspring, with adjusted odds ratios (ORs) of 1.49 (95% confidence intervals (95%CI) 1.19–1.87) and 1.75 (95%CI 1.31–2.36) for the mother and father, respectively. The highest parental age was statistically insignificant, with adjusted ORs of 1.11 (95%CI 0.79–1.55) and 0.93 (95%CI 0.70–1.23) for mother and father separately. Dose–response analysis indicated a non-linear relationship of parental age with offspring ADHD, with the lowest ADHD risk at 31–35 years old. The results of this meta-analysis support an association between young parental age and the risk of ADHD. More high-quality studies are needed to establish whether the association with parental age is causal.

Sex differences in parent-offspring recurrence of attention-deficit/hyperactivity disorder.

BackgroundAttention‐deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison.MethodsIn a generation study linking data from several population‐based registries, all Norwegians born 1967–2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex.ResultsThe absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2–8.6 vs. RRpaternal 6.2, 6.0–6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5–21.7) vs. PDpaternal 14.8% (14.3–15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons.ConclusionsThe intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex‐ and diagnosis‐specific intergenerational recurrence risk in parents with ADHD.

Does exposure to organophosphate esters during pregnancy increase the risk of attention-deficit hyperactivity disorder in offspring?

Background. Elevated organophosphate esters (OPEs) during pregnancy has been associated with hyperactivity and attention problems in children. Such behaviors are often found in children with attention-deficit hyperactivity disorder (ADHD). However, no study has investigated OPEs in relation to clinically diagnosed ADHD.Aim. To evaluate associations between prenatal exposure to OPEs and ADHD diagnosis, in a case-cohort substudy of the Norwegian Mother, Father and Child Cohort.Methods. We identified 297 ADHD cases through the Norwegian patient registry and sampled a sub-cohort of 555 participants among the eligible population. Diphenyl phosphate (DPHP), di-n-butyl phosphate (DnBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in urine collected at 17 gestational weeks. Binary exposure indicators were created for DPHP (cutoff: sub-cohort median), DnBP (limit of quantification, LOQ), BBOEP and BDCIPP (limit of detection, LOD). We estimated ORs using logistic regression, adjusting for the season of urine collection, child sex, birth year, maternal depression, maternal ADHD, and phthalate metabolite concentrations. Missing covariates were multiply imputed and estimates were pooled using Rubin’s rules. Effect measure modification by child sex was investigated.Results. DPHP was detected in nearly all samples (98%>LOD), with a higher geometric mean among ADHD cases (0.70 ng/ml) as compared to the sub-cohort (0.52 ng/ml). DNBP was commonly detected as well (6%<LOD; 39% LOD-LOQ; 55%>LOQ), while BBOEP (51%>LOD) and BDCIPP (21%>LOD) were detected less frequently. Children whose mothers had above the median DPHP concentrations during pregnancy were more likely to be diagnosed with ADHD (aOR: 1.41 [95% CI: 1.00, 1.99]). Similar positive associations were observed for BDCIPP (1.47 [0.99, 2.17]), but near-null associations were observed for DnBP (0.93 [0.67,1.30]) and BBOEP (1.05 [0.75, 1.45]). We did not observe strong evidence of modification by child sex.Conclusions. DPHP and BDCIPP exposure during pregnancy may increase the risk of ADHD in offspring.

Maternal pre-pregnancy overweight/obesity and the risk of attention-deficit/hyperactivity disorder in offspring: a systematic review, meta-analysis and quasi-experimental family-based study.

BackgroundPrevious studies are inconclusive concerning the association between maternal pre-pregnancy overweight/obesity and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. We therefore conducted a systematic review and meta-analysis to clarify this association. To address the variation in confounding adjustment between studies, especially inadequate adjustment of unmeasured familial confounding in most studies, we further performed cousin and sibling comparisons in a nationwide population-based cohort in Sweden.MethodsWe searched PubMed, Embase and PsycINFO during 1975–2018. We used random-effects models to calculate pooled risk ratios (RRs) with 95% confidence interval. In the population-based study, Cox proportional hazard models were used to calculate the unadjusted hazard ratios (HRs) and HRs adjusted for all confounders identified in previous studies. Stratified Cox models were applied to data on full cousins and full siblings to further control for unmeasured familial confounding.ResultsEight cohorts with a total of 784 804 mother–child pairs were included in the meta-analysis. Maternal overweight [RRoverweight = 1.31 (1.25–1.38), I2 = 6.80%] and obesity [RRobesity = 1.92 (1.84–2.00), I2 = 0.00%] were both associated with an increased risk of ADHD in offspring. In the population-based cohort of 971 501 individuals born between 1992 and 2004, unadjusted Cox models revealed similar associations [HRoverweight = 1.30 (1.28–1.34), HRobesity = 1.92 (1.87–1.98)]. These associations gradually attenuated towards the null when adjusted for measured confounders [HRoverweight = 1.21 (1.19–1.25), HRobesity = 1.60 (1.55–1.65)], unmeasured factors shared by cousins [HRoverweight = 1.10 (0.98–1.23), HRobesity = 1.44 (1.22–1.70)] and unmeasured factors shared by siblings [HRoverweight = 1.01 (0.92–1.11), HRobesity = 1.10 (0.94–1.27)].ConclusionPre-pregnancy overweight/obesity is associated with an increased risk of ADHD in offspring. The observed association is largely due to unmeasured familial confounding.

Association Between Maternal Exposure to Magnetic Field Nonionizing Radiation During Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Offspring in a Longitudinal Birth Cohort

An association between maternal exposure to magnetic field (MF) nonionizing radiation during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) has been reported in both animal and human studies. To determine whether maternal exposure to high levels of MF nonionizing radiation is associated with an increased risk of ADHD in offspring by using more accurate measurements of MF nonionizing radiation levels and physician-diagnosed ADHD, rather than self-reports, and to determine whether the association differs for the subtypes of ADHD with or without immune-related comorbidities. A longitudinal birth cohort study was conducted at Kaiser Permanente Northern California among 1482 mother-child pairs whose mothers were participants of an existing birth cohort and whose level of exposure to MF nonionizing radiation was captured during pregnancy in 2 studies conducted from October 1, 1996, to October 31, 1998, and from May 1, 2006, to February 29, 2012. The offspring were followed up from May 1, 1997, to December 31, 2017. All participating women wore a monitoring meter for 24 hours during pregnancy to capture the level of exposure to MF nonionizing radiation from any sources. Physician-diagnosed ADHD and immune-related comorbidities of asthma or atopic dermatitis up to 20 years of age in offspring captured in the Kaiser Permanente Northern California electronic medical record from May 1, 1997, to December 31, 2017. Confounders were ascertained during in-person interviews during pregnancy. Among the 1454 mother-child pairs (548 white [37.7%], 110 African American [7.6%], 325 Hispanic [22.4%], 376 Asian or Pacific Islander [25.9%], and 95 other or unknown [6.5%]; mean [SD] maternal age, 31.4 [5.4] years]), 61 children (4.2%) had physician-diagnosed ADHD. Using Cox proportional hazards regression to account for follow-up time and confounders, compared with children whose mothers had a low level of exposure to MF nonionizing radiation during pregnancy, children whose mothers were exposed to higher levels of MF nonionizing radiation had more than twice the risk of ADHD (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.06-3.81). The association was stronger for ADHD that persisted into adolescence (≥12 years of age), with an aHR of 3.38 (95% CI, 1.43-8.02). When the subtypes of ADHD were examined, the association existed primarily for ADHD with immune-related comorbidities (asthma or atopic dermatitis), with an aHR of 4.57 (95% CI, 1.61-12.99) for all ADHD cases and an aHR of 8.27 (95% CI, 1.96-34.79) for persistent cases of ADHD. Consistent with the emerging literature, this study suggests that in utero exposure to high levels of MF nonionizing radiation was associated with an increased risk of ADHD, especially ADHD with immune-related comorbidity. The findings should spur more research to examine the biological association of in utero MF exposure with risk of ADHD in offspring, given that almost everyone is exposed to it.

Prenatal Exposure to Acetaminophen and the Risk of Attention-Deficit/Hyperactivity Disorder: A Nationwide Study in Taiwan.

Studies have suggested that a significant association exists between prenatal exposure to acetaminophen and the offspring's attention-deficit/hyperactivity disorder (ADHD) risk. However, this association has largely been unexplored among the Asian population, generally, and the Taiwanese population, specifically. In our study, 950 study pairs (children with ADHD [ICD-9-CM code: 314] and their mothers) and 3,800 control pairs (children without ADHD and their mothers) matched by demographic characteristics were identified between 1998 and 2008 from the Taiwan Longitudinal Health Insurance Database. Maternal use of acetaminophen was assessed in the first trimester, second trimester, and third trimester of pregnancy and over the period from 3 months before pregnancy to the date of last menstrual cycle. Logistic regression analysis with adjustments for demographic data, gestational infections, comorbid perinatal conditions, and maternal mental health disorders indicated that exposure to acetaminophen in the second trimester (odds ratio [OR] = 1.19; 95% CI, 1.00-1.40), both the first and second trimesters (OR = 1.28; 95% CI, 1.00-1.64), or in any trimester (OR = 1.20; 95% CI, 1.01-1.42) was associated with an increased risk of ADHD in offspring. Sensitivity analysis excluding gestational infections and maternal mental health disorders confirmed this association (OR = 1.33; 95% CI, 1.04-1.69). Prenatal exposure to acetaminophen was associated with an increased risk of ADHD in offspring, regardless of gestational infections and maternal mental health disorders. Additional studies are necessary to clarify the underlying mechanisms by which prenatal exposure to acetaminophen leads to neurodevelopmental risks.

Maternal serum C-reactive protein (CRP) and offspring attention deficit hyperactivity disorder (ADHD)

Exposure to infection and inflammation during the fetal period are associated with offspring neuropsychiatric disorders. Few previous studies have examined this association with ADHD with mixed findings. This study aims to examine the association between early gestational maternal C-reactive protein (CRP), prospectively assayed in stored maternal sera and the risk of ADHD in offspring. This study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case–control design. It includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD. A total of 1079 cases and equal number of controls were matched on date of birth, sex and place of birth. Maternal CRP levels were assessed using a latex immunoassay from archived maternal serum specimens, collected during the first and early second trimester of pregnancy. Elevated maternal CRP when analyzed as a continuous variable was not associated with offspring ADHD (OR 1.05, 95% CI 0.96–1.15). No significant associations were seen in the highest quintile of CRP (OR 1.18, 95% CI 0.88–1.58). The results were similar in both sexes as well as among ADHD cases with or without comorbid ASD or conduct disorder. In this first study examining CRP, a biomarker for inflammation, during early pregnancy in relation to offspring ADHD, we report no significant associations. The lack of any association, when considered with positive findings seen in ASD and schizophrenia, and negative findings in bipolar disorder suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.

Pre-eclampsia and the risk of attention-deficit/hyperactivity disorder in offspring: Findings from the ALSPAC birth cohort study

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent heterogeneous neurodevelopmental syndrome associated with various environmental factors. This study examined the association between maternal pre-eclampsia and offspring ADHD at 7- and 10-years. The study cohort consisted of more than 7200 children who participated in Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. ADHD was diagnosed using parent reported Development and Wellbeing Assessment (DAWBA). Log-binomial regression and Generalized Estimating Equation (GEE) models were used. The GEE analysis showed that pre-eclampsia was associated with increased risk of ADHD in offspring (adjusted risk ratio [RR] = 2.77; 95% confidence interval [CI] = 1.42–5.38). Similarly, the results of multivariable log-binomial regression analysis at each time point showed that pre-eclampsia was associated with an almost threefold increase risk of offspring ADHD. This study suggests that offspring of mothers with pre-eclampsia are at increased risk of ADHD, although residual and unmeasured confounding by environmental and genetic factors warrants further study. If our findings are replicated by others, early screening for ADHD and other developmental delays may be recommended in offspring of women with pre-eclampsia.

Maternal Gestational Diabetes Mellitus, Type 1 Diabetes, and Type 2 Diabetes During Pregnancy and Risk of ADHD in Offspring.

To examine the relative importance of maternal preexisting type 1 diabetes (T1D), preexisting type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) on risk of attention deficit/hyperactivity disorder (ADHD) in offspring. This retrospective birth cohort study included 333,182 singletons born in 1995-2012 within Kaiser Permanente Southern California hospitals. Children were prospectively followed through electronic medical records from age 4 years. Relative risks of ADHD associated with diabetes exposures in utero were estimated by hazard ratios (HRs) using Cox regression with adjustment for potential confounders. For GDM, timing of exposure was evaluated by gestational age at diagnosis and severity was assessed by the need for antidiabetes medication treatment during pregnancy. A total of 37,878 (11.4%) children were exposed to diabetes (522 exposed to T1D, 7,822 T2D, and 29,534 GDM). During a median of 4.9 years (interquartile range 2.2, 9.6) of follow-up after age 4 years, 17,415 (5.2%) children were diagnosed with ADHD. ADHD risk was not associated with GDM taken as a whole (P = 0.50) or with gestational age at GDM diagnosis (P = 0.16). However, the risk was significantly greater for the GDM requiring versus not requiring antidiabetes medications (P < 0.001). Compared with children unexposed to diabetes, the adjusted HRs for ADHD in children were 1.57 (95% CI 1.09-2.25) for exposure to T1D, 1.43 (1.29-1.60) for T2D, 1.26 (1.14-1.41) for GDM requiring antidiabetes medications, and 0.93 (0.86-1.01) for GDM not requiring medications. The hierarchy of risks suggests that severity of maternal diabetes (T1D vs. T2D vs. GDM requiring antidiabetes medications) influences the risk of ADHD in offspring of mothers with diabetes.

Parental socioeconomic position and risk of ADHD in offspring: a cohort study of 9648 individuals in Denmark 1976-2013.

The strength of the association between parental socioeconomic position (SEP) and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring is found to vary substantially, perhaps due to the negligence of possible changes in parental life course SEP. The present study investigated the association between parental SEP in adulthood and risk of ADHD diagnosis in offspring and whether parental childhood SEP modified this association. The study population included 9648 live-born singletons followed in the Psychiatric Central Register from birth in 1976-1996 until 2013. Cox regression was used to estimate hazard ratios for ADHD diagnosis according to parental SEP in adulthood. The results showed that low parental SEP in adulthood was associated with higher risk of ADHD diagnosis in offspring, also after adjustment for possible confounders. Thus, offspring of parents with low SEP in adulthood had 4.52 (95% CI 2.81-7.26) times higher hazard of ADHD diagnosis compared with offspring of parents with high SEP in adulthood. Further, parental childhood SEP was found to modify the observed association. Thus, offspring of parents with downward social mobility from childhood to adulthood and offspring of parents with stable low SEP experienced the highest risk of ADHD diagnosis, followed by offspring of parents with upward social mobility, compared with offspring of parents with stable high SEP. The results suggest that it is important to take into account the possibility of social mobility as changes in parental life course SEP from childhood to adulthood seem to influence the risk of ADHD diagnosis in offspring.

Prenatal Paternal Selective Serotonin Reuptake Inhibitors Use and Risk of ADHD in Offspring.

It has been shown that maternal prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) may be a risk factor for attention-deficit/hyperactivity disorder (ADHD) in offspring. Our goal was to examine whether paternal SSRI use before conception increases the risk of ADHD in offspring. On the basis of Danish national registers, we conducted a cohort study of 781 470 singletons born between 1996 and 2008 with follow-up throughout 2013. The children whose fathers used SSRIs during the last 3 months before conception were identified as the exposed. Cox regression was used to estimate the hazard ratio (HR) of ADHD. A total of 7216 children (0.92%) were born to fathers who had used SSRIs during the last 3 months before conception. There were 12 520 children diagnosed with ADHD. Compared with unexposed children, the exposed had a 26% increased risk of ADHD (HR = 1.26, 95% confidence interval [CI]: 1.06-1.51) after adjusting for potential confounders. When extending the exposure window to 1 year before conception, paternal use of SSRIs only during the period of 12 to 3 months before conception was associated with the HR of 1.35 (95% CI: 1.10-1.66), whereas paternal use of SSRIs only during the last 3 months before conception was associated with a similarly increased risk of ADHD (adjusted HR = 1.31, 95% CI: 0.95-1.82). The mildly increased risk of ADHD in offspring associated with paternal SSRI use before conception could probably be due to the underlying indications related to SSRI use.

Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study

Objective To assess the potential association between prenatal use of antidepressants and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring.Design Population based cohort study.Setting Data from the Hong Kong population...

Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases

BackgroundPrenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring. MethodsWe performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967–2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004–2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models. ResultsThe following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2–2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5–1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3–2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4–1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1–1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5–1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4–1.6 for male offspring]), none of the associations differed significantly by offspring sex. ConclusionsSeveral maternal somatic diseases with immune components were found to increase the risk of ADHD in offspring. The associations could involve several causal pathways, including common genetic predisposition and environmental factors, and increased insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD.