Late Pregnancy Antiseizure Medication Exposure and Offspring Neurodevelopmental Risk: A Multi-Child Cohort Study.

Epidemiological studies have raised concerns about the risk of neurodevelopmental disorders (NDD) in children of patients with autoimmune or inflammatory disorders (AID). The pathophysiological pathways underlying this association are still unknown and little is known about the specific and distinct risk of each AID. To explore these questions, we investigated the association between the occurrences of several NDD in the offspring of mothers or fathers with different IDA. We conducted a meta-analysis—PROSPERO (CRD42020159250)—examining the risk of NDD in the offspring of mothers or fathers with AID. We performed specific analyses separately in fathers or mothers of NDD patients as well as subgroup analyses for each NDD and AID. We searched MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science Core Collection published until December 2021. From an initial pool of 2074 potentially relevant references, 14 studies were included, involving more than 1,400,000 AID and 10,000,000 control parents, 180,000 children with NDD and more than 14,000,000 control children. We found AID in mothers (Adjusted OR 1.27 [95% CI 1.03; 1.57] p = 0.02, [I2 = 65%, Tau2 = 0.03 p = 0.01] and adjusted OR 1.31 [95% CI 1.11; 1.55] p = 0.001, [I2 = 93%, Tau2 = 0.13 p = 0.001] and, although in a lesser extent, in fathers (adjusted OR 1.18 [95% CI 1.07; 1.30] p = 0.01, [I2 = 15.5%, Tau2 = 0.002 p = 0.47]) and adjusted OR 1.14 [95% CI 1.10; 1.17] p < 0.0001, [I2 = 0%, Tau2 = 0 p = 0.29]) to be associated with ASD and ADHD in the offspring. This difference in the strength of the association was found in the AID-specific analyses, suggesting that AID increase the risk of NDD by a shared mechanism but that a specific maternal route appears to represent an additional excess risk. Inflammatory bowel disease were not associated with an additional risk (neither in fathers nor in mothers) of NDD in offspring. Our results suggest that complex and multiple AID-specific pathophysiological mechanisms may underlie the association of AID and NDD in offspring. Further, comprehensive studies of the different AID and NDD are needed to draw definitive conclusions about the pathophysiological links between parental AID and NDD in children.

Neurodevelopmental Problems Not Linked to Antidepressant Exposure In Utero

Systematic Review and Meta-Analysis: Acetaminophen Use During Pregnancy and the Risk of Neurodevelopmental Disorders in Childhood.

BackgroundMaternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics).MethodsThis population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures.ResultsOverall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03–1.84), ID (2.09, 1.53–2.87) and ADHD (1.43, 1.16–1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID.ConclusionThe association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.

The global increase in maternal obesity has raised concerns regarding its potential impact on offspring neurodevelopment. This study investigated the association between maternal pre-pregnancy body mass index (BMI) and the risk of neurodevelopmental disorders in offspring using a large-scale national cohort in South Korea. We conducted a retrospective cohort study using data from the Korean National Health Information Database merged with the National Health Screening Program data. Maternal BMI, measured within three years prior to delivery, was categorized based on the Asia-Pacific guidelines. Neurodevelopmental disorders, including epilepsy, cerebral palsy, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder, were identified using diagnostic codes from the International Classification of Diseases, Tenth Revision (ICD-10) up to five years of age. Multivariable Poisson and Cox regression models were used to estimate the relative risks and hazard ratios, adjusting for neonatal and maternal covariates. This study analyzed a cohort of 2,285,943 live births in South Korea (January 1, 2014-December 31, 2021) to assess the association between maternal pre-pregnancy BMI and neurodevelopmental disorders in offspring. After excluding neonates lacking complete medical records or follow-up data, 779,091 neonates were included in the study. Maternal obesity (BMI ≥ 30.0) was independently associated with an elevated risk of epilepsy (adjusted hazard ratio 1.13; 95% CI, 1.08-1.18) and intellectual disability (aHR 1.37; 95% CI, 1.12-1.68), following adjustment for neonatal and maternal covariates. Maternal underweight status (BMI < 18.5) was not significantly associated with neurodevelopmental outcomes. Elevated maternal BMI prior to conception was independently associated with an increased risk of epilepsy and intellectual disability in offspring. The results underscore the importance of preconception weight management and support public health strategies to reduce neurodevelopmental disorders in children of mothers with overweight or obesity.

To assess the risk of a wide spectrum of neurodevelopmental disorders (NDDs) in offspring of mothers with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). This retrospective cohort study included 877233 singletons born between 2004 and 2008 in Taiwan. Children were followed up to 2015 for diagnoses of NDDs, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), developmental delay, intellectual disability, cerebral palsy, and epilepsy/infantile spasms using health insurance claims data. We performed Cox regression models to estimate the relative risks of NDDs associated with maternal diabetes. Covariates included parental age, year of birth, child sex, family income, urbanization level, hypertensive disorder, and preterm delivery status. In utero there were 338 (0.04%) children exposed to T1DM, 8749 (1.00%) to T2DM, and 90 200 (10.28%) to GDM. The effect of T1DM on NDDs was the largest, followed by T2DM, then GDM. T1DM was associated with an increased risk of developmental delay, intellectual disability, and epilepsy/intellectual spasms in offspring. T2DM was associated with an increased risk of ASD, ADHD, developmental delay, intellectual disability, cerebral palsy, and epilepsy/intellectual spasms. GDM was associated with an increased risk of ASD, ADHD, and developmental delay. Maternal diabetes during pregnancy, including T1DM, T2DM, and GDM, is associated with an increased risk of some NDDs in offspring.

Prenatal exposure to ambient air pollution has been implicated in adverse neurodevelopment, but evidence from large-scale, long-term studies in Asian populations remains limited. We examined the association between in utero exposure to multiple air pollutants and the risk of neurodevelopmental disorders (NDD) in offspring using a nationwide cohort in South Korea. We conducted a nationwide retrospective cohort study using linked administrative health and environmental data. A total of 1,436,685 children born between January 1, 2010, and December 31, 2014, were identified from the National Health Insurance Service database and followed up through December 31, 2023. Maternal exposure to nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), ozone (O3), and particulate matter ≤10 μm (PM10) was estimated by linking residential postal codes to fixed-site monitoring data. NDD diagnoses were identified from healthcare claims. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models adjusting for maternal sociodemographic, medical, obstetric, and neonatal covariates. During up to 13 years of follow-up, 140,971 children (9.8%) were diagnosed with an NDD. Prenatal exposure to NO2 showed the strongest association: each 0.01-ppm increase was associated with an 18% higher hazard of NDD (aHR 1.18, 95% CI 1.17-1.19; p < .001). SO2 exposure also demonstrated a small but statistically significant association (per 0.001-ppm increase: aHR 1.01, 95% CI 1.01-1.02; p = .008). These associations persisted across major NDD subtypes - including intellectual disabilities, developmental delays, and behavioral or emotional disorders - and remained robust in trimester-specific, stratified, and sensitivity analyses. Prenatal exposure to ambient air pollutants - particularly NO2 and SO2 - is associated with increased long-term risk of NDD in offspring. These findings highlight the neurodevelopmental vulnerability of the prenatal period and underscore the need for strengthened environmental policies to reduce maternal exposure to harmful pollutants.

Untreated depression may adversely affect pregnancy and offspring outcomes through several mechanisms; on the flip side, antidepressants used to treat depression may cross the placenta and affect the developing fetus and its brain. This article examines the research literature on gestational exposure to antidepressants and the risk of neurodevelopmental disorders (NDDs) in offspring. Two recent meta-analyses and 3 subsequently published observational studies, including 1 Asian study, are reviewed with especial focus on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Despite limitations of the literature, some conclusions can reasonably be drawn. In unadjusted analyses, which assist an understanding of real world risks, gestational exposure to antidepressant drugs is associated with an up to doubled risk of ASD and ADHD. However, in adjusted analyses, which assist an understanding of cause-effect relationships but not real world risks, the risks substantially attenuate and may lose statistical significance. The risks also lose statistical significance in analyses that address confounding by indication by comparing antidepressant-exposed and -unexposed pregnancies in women with psychiatric disorders. The likelihood of confounding by parental genes, parental environment, and parental health-related variables is suggested by findings that antidepressants remain significantly associated with NDDs when the exposure period is outside the pregnancy window (such as before or after but not during pregnancy) or when fathers are exposed to antidepressants during pregnancy. Finally, discordant sibling pair analyses suggest that whether or not a child develops an NDD is related to whether or not its sib has an NDD rather than whether or not the child was exposed to an antidepressant in utero. Discussion points are suggested for the shared decision-making process when counseling women about NDD risks associated with gestational exposure to antidepressant drugs. Take-home messages are summarized.

Benzodiazepine receptor agonists (BZRAs), including benzodiazepines and Z-drugs, are frequently prescribed during pregnancy but their long-term neurodevelopmental safety remains uncertain. To investigate whether prenatal BZRA exposure is associated with an increased long-term risk of neurodevelopmental disorders (LNDDs) in offspring. This nationwide, population-based cohort study used Korean National Health Insurance Service data on all live births from 2011 to 2014, followed until 2023. Prenatal BZRA exposure was defined as maternal prescriptions during pregnancy. Propensity score matching (1:10) was applied to balance covariates. Sensitivity analyses in the full cohort evaluated exposure intensity (0, 1-6, 7-29 and ≥30 cumulative days), drug class (benzodiazepines versus Z-drugs), trimester of exposure and discordant sibling comparisons with mother fixed effects. Among 1 553 505 eligible births, 5949 BZRA-exposed and 55 015 matched unexposed children were analysed. LNDD incidence was 13.9% in the exposed group versus 11.4% in the unexposed (odds ratio 1.25, 95% CI: 1.16, 1.35). In the full cohort, risks increased with exposure intensity: 1-6 days (odds ratio 1.16, 95% CI: 1.05-1.28), 7-29 days (odds ratio 1.19, 95% CI: 1.04-1.36) and ≥30 days (odds ratio 1.18, 95% CI: 1.01-1.38). By trimester, risks were higher with second- (odds ratio 1.30, 95% CI: 1.07-1.59) and third-trimester (odds ratio 1.27, 95% CI: 1.09-1.48) exposure. Class-specific analyses showed stronger associations for benzodiazepines only (odds ratio 1.19, 95% CI: 1.15-1.23) than for Z-drugs only (odds ratio 1.06, 95% CI: 1.04-1.08). In a discordant sibling analysis including 2572 children this association persisted (odds ratio 1.29, 95% CI: 1.05-1.60), indicating that neither familial nor genetic confounding fully explains the observed effects. Prenatal BZRA exposure was associated with increased long-term risks of LNDDs in offspring, with evidence of dose-response and class-specific effects, and persistence in sibling analyses.

The US Administration has moved to declare gestational exposure to acetaminophen (paracetamol) a risk factor for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children. This article examines the science on the subject. Studies suggest that about half of women use acetaminophen during pregnancy; nevertheless, there is no epidemic of neurodevelopmental disorders (NDDs) in offspring. Two large population-based studies, one Swedish and the other Japanese, found that maternal use of acetaminophen during pregnancy was associated with an increased risk of ASD, ADHD, and intellectual disability (ID) in children. However, the risks were very small in fully adjusted analyses; hazard ratios (HRs) were mostly in the 1.05-1.07 range. Importantly, maternal use of aspirin, other NSAIDs, opioids, or antimigraine drugs during pregnancy was also associated with an increased risk of ASD and ADHD (but not ID). Most importantly, in sibling analyses, gestational exposure to acetaminophen, aspirin, and other analgesic drug categories was not associated with an increased risk of NDDs. There are many key points. Acetaminophen has a safety profile that is better than that of alternative treatments. The magnitude of increase in absolute risk for NDDs is very small (eg, by 0.09% at age 10, for ASD). There are many unmeasured confounds that, evenif weak, could nullify the relationship between acetaminophen and NDDs. Sibling analyses suggest that shared genetic and shared environment risk factors (rather than acetaminophen exposure) may explain the NDD risk. Analyses of other analgesic drug groups suggest that pain and inflammation, rather than drug exposure, may also explain the NDD risk. Finally, for reasons that are explained, making acetaminophen unavailable during pregnancy does not mean that the NDD risk will reduce. These points need to be discussed with women in a shared decision-making process that is both equitable and free from guilting.

Evidence indicates that in utero exposure to chorioamnionitis might increase the risk of neurodevelopmental disorders in the offspring. However, findings on this topic have been inconsistent. To examine the association between chorioamnionitis and neurodevelopmental disorders in offspring. This was a retrospective population-based cohort study in Sweden. A total of 2,228,280 singleton live births and stillbirths between 1998 and 2019 were included in our study population. Data on maternal characteristics and neurodevelopmental disorders in offspring were obtained by individual record-linkages of nationwide Swedish registries. Chorioamnionitis was identified using the National Medical Birth Register. Inpatient and outpatient diagnoses were obtained for cerebral palsy, autism, attention deficit hyperactivity disorder, epilepsy, and intellectual disability. Multivariable Cox proportional hazards regression was used to estimate the association between chorioamnionitis and each neurodevelopmental disorder with adjusted hazard ratios and 95% confidence intervals. A causal mediation analysis of the relationship between chorioamnionitis and neurodevelopmental disorders with preterm delivery (<37 weeks) was performed. A total of 5770 (0.26%) offspring were exposed to chorioamnionitis during pregnancy. During the study's follow-up time there were 4752 (0.21%) cases of cerebral palsy, 17,897 (0.80 %) cases of epilepsy, 50,570 (2.27 %) cases of autism, 114,087 (5.12%) cases of attention deficit hyperactivity disorder, and 14,574 (0.65%) cases of intellectual disability. After adjusting for potential confounders, exposure to chorioamnionitis increased the hazard ratios of cerebral palsy (adjusted hazard ratio, 7.43; 95% confidence interval, 5.90-9.37), autism (adjusted hazard ratio, 1.43; 95% confidence interval, 1.21-1.68), attention deficit hyperactivity disorder (adjusted hazard ratio, 1.17; 95% confidence interval, 1.03-1.33), and intellectual disability (adjusted hazard ratio, 1.99; 95% confidence interval, 1.53-2.58), whereas chorioamnionitis was not significantly associated with higher rates of epilepsy in offspring. Mediation analysis revealed that these associations were mainly explained through preterm delivery; however, increased risk was also observed among term infants. Chorioamnionitis increases the risk of neurodevelopmental disorders, particularly cerebral palsy, autism, attention deficit hyperactivity disorder, and intellectual disability. These associations were mainly mediated through preterm delivery. Efforts for timely identification and appropriate interventions to treat infections during pregnancy will have sustained benefits in reducing the burden of neurologic complications in children at the population level.

Study question This study aims to evaluate whether ICSI intervention in male or female infertility will increase the risks of neurodevelopmental disorders in offspring or not. Summary answer ICSI increases the risks of autism spectrum disorder and delayed developments in offspring with female infertility but has no impact on male infertility. What is known already Damaged sperm has been proved to change epigenetics and increase the genome instability in early embryogenesis. It might also affect the offspring’s health, such as neurodevelopmental disorders. ICSI is the most common procedure in assisted reproductive technology. It is used not only in male infertility but also in female infertility. Several studies have advocated the potential risks of epigenetic alternation in embryos and neurodevelopmental disorders in the offspring. However, there is no conclusion to determine the risk of ICSI in the offspring’s health. Neurodevelopmental disorders are associated with epigenetic alterations such as ASD, ADHD, DD. Study design, size, duration Patients were collected between January 2008 and December 2016 in the national report of the ART database and the national population database in Taiwan. The inclusion criteria were singleton, infertility parents with fresh embryos transfer, and embryos without invasion procedure except for ICSI. The exclusion criteria were donated eggs or sperms. The follow-up time started from birth to December 2018. Participants/materials, setting, methods In total, 1,580,267 singletons were conducted in this study. They were divided into three groups: female infertility, male infertility, and spontaneous conception. Inverse probability of treatment weighting was used to lower the bias among the study groups. The covariate factors include maternal age, obstetrics risk factors, pregnancy complications, and parental psychiatric disorders. The offspring outcome includes ADHD, ASD, and DD. The result was analyzed with multivariate regression. The value of P &amp;lt; 0.05 is significant. Main results and the role of chance Offspring with male infertility showed to increase risk of ADHD (attention deficit and hyperactivity disorder) compared to spontaneous conception (Hazard ratio 1.76, 95% CI 1.03-3.02, p = 0.0389). There was no increased risks of ADHD, ASD (autism spectrum disorder), and DD (delayed developments) in offspring with female infertility compared to spontaneous conception. We further analyzed the impact of ICSI on offspring’s neurodevelopmental disorders. In singletons with male infertility, the risk of ADHD increased in offspring without ICSI intervention compared to spontaneous conception and male infertility with ICSI intervention (Hazard ratio 3.88, 95% CI 1.56-9.62, p = 0.0252) In newborns with female infertility, the risk of ASD and DD increased in offspring with ICSI intervention compared to spontaneous conception and female infertility without ICSI intervention. (ASD: hazard ratio 2.50, 95% CI 1.33-4.70, p = 0.0157; DD: hazard ratio 1.59, 95% CI 1.13-2.24, p = 0.0142) We also found the risks of neurodevelopmental disorders were higher in boys than girls. Preterm infants had increased risks of neurodevelopmental disorders than full-term infants. Limitations, reasons for caution This study had several limitations, such as the severity of sperm, the quality of embryos, and various laboratory conditions. However, we have tried to lower the potential cofactors such as maternal age, pregnancy complications, risk factors during pregnancy and labor, and psychiatric disorders in parents. Wider implications of the findings ICSI is widely used in female infertility to achieve pregnancy. However, our preliminary data shows that ICSI in female infertility increases the risk of neurodevelopmental disorders in offspring. This finding implies that we should pay attention on when using ICSI in female infertility couples. Trial registration number KMUHIRB-E(II)-20200217

ABSTRACTObjective:This meta-analysis aimed to investigate the risk of neurodevelopmental disorders in children conceived through assisted reproductive technology (ART), focusing on comparisons of neurodevelopment outcomes in children conceived using intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (IVF), as well as using frozen and fresh embryo transfers.Methods:A systematic literature search of PubMed, Web of Science, Scopus and Embase databases was done for studies focusing on singleton pregnancies, published in the last two decades (from year 2004 onwards to 31st May 2024) and reporting confounder-adjusted effect sizes. Pooled effect sizes were expressed as relative risk (RR) with 95% confidence intervals (CIs). Egger’s test and funnel plots were used to assess publication bias. The certainty of the pooled evidence was assessed using the GRADE approach.Results:Analysis of the 13 included studies showed that ICSI correlated with a higher incidence of autism spectrum disorder (ASD) in offspring compared to IVF ART (RR 1.36, 95% CI: 1.05, 1.75). However, the risks of attention-deficit/hyperactivity disorder (ADHD), intellectual disability, cerebral palsy and “any” developmental disorder were similar between the groups. There was no significant difference in neurodevelopmental outcomes, such as ASD, intellectual disability and cerebral palsy, in children conceived after frozen or fresh embryo transfer. The overall quality of evidence for these outcomes was judged to be “Low” according to the GRADE assessment criteria.Conclusion:Based on the low-quality evidence, children conceived through ICSI may be at higher risk of ASD compared to children conceived through IVF, while risks of other neurodevelopmental disorders appear similar. Frozen embryo transfer does not seem to increase the risk of neurodevelopmental disorders in offspring compared to fresh transfer.Registration: PROSPERO: CRD42024557480).

Parental occupational exposures might be associated with neurodevelopmental disorders (NDDs) in offspring. We aimed to conduct a systematic review and meta-analysis to summarize and synthesize the current literature and to estimate the pooled magnitude of the underlying association(s) between parental occupational exposures and subsequent risk of NDDs. In the meta-analysis of 20 included studies, significant associations were found between parental occupational exposure to pesticides or solvents and the risk of attention deficit hyperactivity disorder in offspring. Prenatal occupational exposure to pesticides was significantly associated with motor development or cognition disorders in children. Furthermore, some evidence showed that metals might have a role in the development of autism spectrum disorders. Further studies need to identify the level of parental occupational exposures that can be significantly associated with NDDs. Moreover, utilizing standardized outcome and exposure scales is recommended to incorporate paternal, maternal, and parental as well as both prenatal and postnatal exposure in future studies.

Objective: To summarize the available literature on in utero exposure to maternal rheumatoid arthritis (RA) and its influence on the risk of neurodevelopmental disorders (NDDs) in offspring. Method: We conducted a systematic literature review and assessed the internal validity of studies with the Newcastle Ottawa Scale tool. Results: Six studies were included. Three reported on autism spectrum disorders; one cohort study indicated a slightly elevated risk, and two case–control studies reported too few cases for risk assessment. Two large cohort studies reported elevated hazard ratios for epilepsy in offspring, in overlapping populations. One study on attention deficit hyperactivity disorder (ADHD) reported higher odds for maternal RA during pregnancy, among children with ADHD. Conclusion:Few studies were found specifically studying maternal RA during pregnancy and NDDs in offspring. The studies pointed towards a moderately higher risk of these outcomes; however, reporting bias appears to be a problem. Additional studies of appropriate design and power are needed.