Maternal smoking, consumption of alcohol, and caffeinated beverages during pregnancy and the risk of childhood brain tumors: a meta-analysis of observational studies.

BACKGROUND: We conducted this meta-analysis to investigate the potential association between maternal smoking, alcohol and caffeinated beverages consumption during pregnancy and the risk of childhood brain tumors (CBTs). METHODS: A thorough search was carried out on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Internet to identify pertinent articles. Fixed or random effects model was applied to meta-analyze the data. RESULTS: The results suggested a borderline statistically significant increased risk of CBTs associated with maternal smoking during pregnancy (OR 1.04, 95% CI 0.99-1.09). We found that passive smoking (OR 1.12, 95% CI 1.03-1.20), rather than active smoking (OR 1.00, 95% CI 0.93-1.07), led to an increased risk of CBTs. The results suggested a higher risk in 0-1 year old children (OR 1.21, 95% CI 0.94-1.56), followed by 0-4 years old children (OR 1.12, 95% CI 0.97-1.28) and 5-9 years old children (OR 1.11, 95% CI 0.95-1.29). This meta-analysis found no significant association between maternal alcohol consumption during pregnancy and CBTs risk (OR 1.00, 95% CI 0.80-1.24). An increased risk of CBTs was found to be associated with maternal consumption of caffeinated beverages (OR 1.16, 95% CI 1.07-1.26) during pregnancy, especially coffee (OR 1.18, 95% CI 1.00-1.38). CONCLUSIONS: Maternal passive smoking, consumption of caffeinated beverages during pregnancy should be considered as risk factors for CBTs, especially glioma. More prospective cohort studies are warranted to provide a higher level of evidence.

Risk of Adverse Neonatal Outcomes After Combined Prenatal Cannabis and Nicotine Exposure.

Importance: The prevalence of cannabis use in pregnancy is rising and is associated with adverse perinatal outcomes. In parallel, combined prenatal use of cannabis and nicotine is also increasing, but little is known about the combined impact of both substances on pregnancy and offspring outcomes compared with each substance alone. Objective: To assess the perinatal outcomes associated with combined cannabis and nicotine exposure compared with each substance alone during pregnancy. Design, Setting, and Participants: This retrospective population-based cohort study included linked hospital discharge data (obtained from the California Department of Health Care Access and Information) and vital statistics (obtained from the California Department of Public Health) from January 1, 2012, through December 31, 2019. Pregnant individuals with singleton gestations and gestational ages of 23 to 42 weeks were included. Data were analyzed from October 14, 2023, to March 4, 2024. Exposures: Cannabis-related diagnosis and prenatal nicotine product use were captured using codes from International Classification of Diseases, Ninth Revision, Clinical Modification, and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification. Main Outcome and Measures: The main outcomes were infant and neonatal death, infants small for gestational age, and preterm delivery. Results were analyzed by multivariable Poisson regression models. Results: A total of 3 129 259 pregnant individuals were included (mean [SD] maternal age 29.3 [6.0] years), of whom 23 007 (0.7%) had a cannabis-related diagnosis, 56 811 (1.8%) had a nicotine-use diagnosis, and 10 312 (0.3%) had both in pregnancy. Compared with nonusers, those with cannabis or nicotine use diagnoses alone had increased rates of infant (0.7% for both) and neonatal (0.3% for both) death, small for gestational age (14.3% and 13.7%, respectively), and preterm delivery (<37 weeks) (12.2% and 12.0%, respectively). Moreover, risks in those with both cannabis and nicotine use were higher for infant death (1.2%; adjusted risk ratio [ARR], 2.18 [95% CI, 1.82-2.62]), neonatal death (0.6%; ARR, 1.76 [95% CI, 1.36-2.28]), small for gestational age (18.0%; ARR, 1.94 [95% CI, 1.86-2.02]), and preterm delivery (17.5%; ARR, 1.83 [95% CI, 1.75-1.91]). Conclusions and Relevance: These findings suggest that co-occurring maternal use of cannabis and nicotine products in pregnancy is associated with an increased risk of infant and neonatal death and maternal and neonatal morbidity compared with use of either substance alone. Given the increasing prevalence of combined cannabis and nicotine use in pregnancy, these findings can help guide health care practitioners with preconception and prenatal counseling, especially regarding the benefits of cessation.

Association between passive smoking and dental caries status in children: A cross-sectional analytical study.

BACKGROUND: Several risk factors contribute to the development of dental caries in children, including sociodemographic, dietary, oral hygiene-related and other miscellaneous factors. Maternal smoking was highly associated with dental caries when compared to smoking by fathers or other household members. OBJECTIVES: The aim of the study was to determine the prevalence of dental caries and their association with exposure to environmental tobacco smoke (ETS) among 5- to 10-year-old students attending private and government schools. MATERIAL AND METHODS: A cross-sectional analytical study was conducted among schoolchildren. Data was collected from the primary caregivers using a pre-tested form to assess the ETS exposure under 5 domains based on history: antenatal exposure; exposure during the index period; exposure in the school neighborhood; exposure in restaurants/roadside stalls; and exposure in bus stops/railway stations. Dental caries was assessed based on the World Health Organization (WHO) guidelines from 1997. The association was reported using prevalence ratios (PRs) (95% confidence interval (CI)). RESULTS: Data was obtained from 211 schoolchildren attending government (39.8%) and private schools (60.2%). The overall prevalence (95% CI) of dental caries was 49.3% (42.5-56.1%). Among all the risk factors evaluated in the study, exposure to ETS was associated with a significantly increased risk of dental caries. The adjusted prevalence ratio (APR) of ETS exposure varied with the mother's educational status and high sugar exposure, although this was statistically insignificant. CONCLUSIONS: The prevalence of dental caries among schoolchildren aged 5 to 10 years in the city was moderate and similar to the national average. Among the risk factors assessed in the study, antenatal exposure to ETS was found to significantly increase the prevalence of dental caries by 41% after adjusting for other factors. Therefore, it is important to educate parents on the causal role of ETS exposure in dental caries.

'Joining the Dots: Linking Prenatal Drug Exposure to Childhood and Adolescence' - research protocol of a population cohort study.

INTRODUCTION: Prenatal drug exposure (PDE) is one of the most important causes of child harm, but comprehensive information about the long-term outcomes of the families is difficult to ascertain. The Joining the Dots cohort study uses linked population data to understand the relationship between services, therapeutic interventions and outcomes of children with PDE. METHODS AND ANALYSIS: Information from routinely collected administrative databases was linked for all births registered in New South Wales (NSW), Australia between 1 July 2001 and 31 December 2020 (n=1 834 550). Outcomes for seven mutually exclusive groups of children with varying prenatal exposure to maternal substances of addiction, including smoking, alcohol, prescription/illicit drugs and neonatal abstinence syndrome will be assessed. Key exposure measures include maternal drug use type, maternal social demographics or social determinants of health, and maternal physical and mental health comorbidities. Key outcome measures will include child mortality, academic standardised testing results, rehospitalisation and maternal survival. Data analysis will be conducted using Stata V.18.0. ETHICS AND DISSEMINATION: Approvals were obtained from the NSW Population and Health Services Research Ethics Committee (29 June 2020; 2019/ETH12716) and the Australian Capital Territory Health Human Research Ethics Committee (11 October 2021; 2021-1231, 2021-1232, 2021-1233); and the Aboriginal Health and Medical Research Council (5 July 2022; 1824/21), and all Australian educational sectors: Board of Studies (government schools), Australian Independent Schools and Catholic Education Commission (D2014/120797). Data were released to researchers in September 2022. Results will be presented in peer-reviewed academic journals and at international conferences. Collaborative efforts from similar datasets in other countries are welcome.

Neonatal outcomes in women with Multiple Sclerosis - Influence of disease activity: A Danish nationwide cohort study.

BACKGROUND: Maternal Multiple Sclerosis (MS) has been associated with an increased risk of adverse birth outcomes. We hypothesized that active disease during conception and pregnancy plays an important role in this context, which this study aims to address. METHODS: We used the Danish registers to conduct a nationwide cohort study. Information on maternal disease activity during pregnancy was retrieved using proxies from the linked registers (hospitalization, magnetic resonance imaging of the brain, and use of systemic corticosteroids during pregnancy). Neonates, exposed in utero to maternal disease activity constituted the exposed cohort and the unexposed cohort constituted neonates without in utero exposure to maternal disease activity. The examined outcomes were preterm birth, small for gestational age, low 5-minute Apgar score, and major congenital anomalies. In logistic regression models we estimated the odds ratios (OR) with adjustment for confounders such as maternal age, comorbidities, parity, smoking, calendar year of birth, and disease-modifying treatment. RESULTS: Among the study population of 2492 children of mothers with MS we identified 273 (11 %) neonates exposed to maternal disease activity during pregnancy, and 2219 (89 %) neonates without exposure to disease activity. The adjusted odds ratios (aOR) for preterm birth, small for gestational age, low 5-minute Apgar score, and major congenital anomalies among children born to women with disease activity during pregnancy were 0.92 (95 % confidence interval (95 % CI) 0.53-1.60), aOR 1.19 (95 % CI 0.62-2.26), aOR 2.57 (95 % CI 0.93-7.15) and aOR 0.93 (95 % CI 0.48-1.83), respectively. CONCLUSIONS: Women with MS having disease activity during pregnancy did not have a statistically significantly increased risk of adverse neonatal outcomes compared to women with MS without disease activity, which is overall reassuring results. We believe, that this will be useful knowledge for patients and clinicians in planning a pregnancy and preparing a birth plan.

Prenatal and postnatal exposure to antibiotics and risk of food allergy in the offspring: A nationwide birth cohort study in South Korea.

BACKGROUND: There are only preliminary studies examining the associations of postnatal antibiotic exposure with food allergy in childhood, and the effect of antibiotic exposure in utero has not been resolved. Thus, we aimed to investigate the effect of prenatal and postnatal antibiotic exposure on the risk of food allergy in childhood. METHODS: Using the nationwide birth cohort in South Korea, all 3,163,206 infants (pairing mother; n = 2,322,735) born in South Korea between 2010 and 2017 were included in the analysis. The primary outcome was the diagnosis of food allergy, and the observation period was between January 1, 2009, and December 31, 2020. We implemented four different designs for the study, which consisted of a full unmatched cohort, 1:1 propensity-matched cohort, sibling comparison cohort, and health screening cohort along with multiple subgroup analyses. RESULTS: During the follow-up period (median 6.92 years [IQR, 4.72-9.00]) of the 3,161,858 infants (52.6% male) in the birth cohort, 29,973 (1.9%) were diagnosed with food allergies. After a 1:1 propensity score matching, the use of antibiotics increased the risk of overall food allergy (prenatal [HR, 1.05; 95% CI, 1.04-1.09] and postnatal [HR, 1.05; 95% CI, 1.01-1.10] periods). The association was more significantly accentuated when antibiotic exposure was used in the short term, and the children were born preterm or with low birthweight; however, a trimester-specific effect was not observed. We observed more pronounced risks of food allergy in the health screening cohort (prenatal, 17%; postnatal, 15%), thus addressing the adverse effects of critical factors including maternal BMI, smoking status, and type of infant feeding. Similar trends were observed across all four differnt cohorts. CONCLUSION: This study reported a moderate association between early-life antibiotic use and subsequent food allergy during childhood throughout four different designs of analyses. This study suggests that clinicians need to consider the risks and benefits of antibiotics when administering antibiotics to individuals in the prenatal and postnatal periods.

Environmental Exposure to Pesticides and the Risk of Child Neurodevelopmental Disorders.

Background and Objectives: Neurodevelopment is a fragile brain process necessary for learning from the beginning of childhood to adulthood. During the procedure, several risks could affect it, including environmental factors such as neurotoxic chemicals or environmental pollutants and, within them, exposure to pesticides. Materials and Methods: This ecological descriptive study attempted to assess the association between environmental exposure to pesticides and neurodevelopmental disorders. This study was conducted on 4830 children diagnosed for 11 years in a total population of 119,897 children in three areas: high, medium, and low greenhouse concentrations. Results: Chromosomal abnormalities were the most common prenatal disorder (28.6%), while intrauterine physical factors were the least common (0.5%). Among perinatal diagnoses, gestational age less than 32 weeks was the most common (25%), while hyperbilirubinemia requiring exchange transfusion and birth complications was the least common (0.4%). Brain damage was the most common problem detected in postnatal diagnosis (36.7%), while unspecified postnatal abnormalities were the least common (3.1%). Conclusions: The areas with the highest greenhouse concentration had higher incidences of neurodevelopmental disorders, particularly in boys, and lower age of referral. Chromosomal abnormalities were prevalent for prenatal diagnoses, gestational age below thirty-two weeks for perinatal diagnoses, and brain damage for postnatal diagnoses. Future studies should analyze the connection between pesticide exposure and neurodevelopmental disorders using spatial point pattern analysis.

Behavioural disorders after prenatal exposure to anaesthesia for maternal surgery.

BACKGROUND: The association between prenatal exposure to general anaesthesia for maternal surgery during pregnancy and subsequent risk of disruptive or internalising behavioural disorder diagnosis in the child has not been well-defined. METHODS: A nationwide sample of pregnant women linked to their liveborn infants was evaluated using the Medicaid Analytic eXtract (MAX, 1999-2013). Multivariate matching was used to match each child prenatally exposed to general anaesthesia owing to maternal appendectomy or cholecystectomy during pregnancy with five unexposed children. The primary outcome was diagnosis of a disruptive or internalising behavioural disorder in children. Secondary outcomes included diagnoses for a range of other neuropsychiatric disorders. RESULTS: We matched 34,271 prenatally exposed children with 171,355 unexposed children in the database. Prenatally exposed children were more likely than unexposed children to receive a diagnosis of a disruptive or internalising behavioural disorder (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.23-1.40). For secondary outcomes, increased hazards of disruptive (HR, 1.32; 95% CI, 1.24-1.41) and internalising (HR, 1.36; 95% CI, 1.20-1.53) behavioural disorders were identified, and also increased hazards of attention-deficit/hyperactivity disorder (HR, 1.32; 95% CI, 1.22-1.43), behavioural disorders (HR, 1.28; 95% CI, 1.14-1.42), developmental speech or language disorders (HR, 1.16; 95% CI, 1.05-1.28), and autism (HR, 1.31; 95% CI, 1.05-1.64). CONCLUSIONS: Prenatal exposure to general anaesthesia is associated with a 31% increased risk for a subsequent diagnosis of a disruptive or internalising behavioural disorder in children. Caution is advised when making any clinical decisions regarding care of pregnant women, as avoidance of necessary surgery during pregnancy can have detrimental effects on mothers and their children.

The effect of maternal prenatal tobacco smoking on offspring academic achievement: A systematic review and meta-analysis.

BACKGROUND: Previous epidemiological studies examining the prospective association between maternal prenatal tobacco smoking and offspring academic achievement have reported conflicting results. Therefore, this systematic review and meta-analysis was conducted to examine the magnitude and consistency of association reported by those studies. METHODS: This systematic review and meta-analysis was guided by the PRISMA protocol. Relevant epidemiological studies on the topic were extracted from four main databases (PubMed/Medline, Embase, PsycINFO, and Scopus). The Newcastle-Ottawa Scale (NOS) was used to appraise the methodological quality of the included studies. We conducted a narrative assessment of the studies that did not report effect estimates. Inverse variance-weighted random effect meta-analysis was used to combine studies reporting effect sizes to estimate pooled adjusted odds ratio with 95% confidence intervals (95% CI). The review was prospectively registered in PROSPERO (CRD42022350901). RESULTS: Nineteen observational studies, published between 1973 and 2021 with a total of 1.25 million study participants were included in the final review. Of these, fifteen studies (79 %) reported reduced academic achievement in offspring exposed to maternal prenatal tobacco smoking. The eight primary studies (sample size = 723,877) included in the meta-analysis together suggested a 49 % higher risk of reduced academic achievement in offspring exposed to maternal prenatal tobacco smoking when compared to non-exposed offspring (Pooled odds ratio = 1.49, 95 % CI:1.17-1.91). CONCLUSION: Our review found a positive association between maternal prenatal tobacco smoking and offspring reduced academic achievement. However, variation in the adjustment of potential confounders and significant heterogeneity across included studies limited more conclusive inference. Mechanistic studies to identify causal pathways and specific academic impacts are needed to inform targeted developmental programs to assist child learning and academic performance.

In Utero Exposure to Alcohol and Tobacco and Electroencephalogram Power During Childhood.

Importance: Prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) are risk factors associated with adverse neurobehavioral and cognitive outcomes. Objective: To quantify long-term associations of PAE and PTE with brain activity in early and middle childhood via electroencephalography (EEG). Design, Setting, and Participants: This cohort study included participants enrolled in the Safe Passage Study (August 2007 to January 2015), from which a subset of 649 participants were followed up in the Environmental Influences on Child Health Outcomes Program. From September 2018 through November 2022, EEG recordings were obtained at ages 4, 5, 7, 9, or 11 years. Data were analyzed from November 2022 to November 2023. Exposures: Maternal self-reported consumptions of alcohol and tobacco during pregnancy were captured at the recruitment interview and at up to 3 visits during pregnancy (20-24, 28-32, and ≥34 weeks' gestation). Classifications of PAE (continuous drinking, quit-early drinking, and nondrinking) and PTE (continuous smoking, quit-early smoking, and nonsmoking) were previously obtained. Main Outcomes and Measures: EEG band powers (theta, alpha, beta, gamma) were extracted from the EEG recordings. Linear regression models were used to estimate the associations of PAE and PTE with EEG estimates. Results: The final sample included 649 participants (333 [51.3%] female) aged 4, 5, 7, 9, or 11 years. Children whose mothers were in the quit-early drinking cluster had increased alpha power (0.116 [95% CI, 0.023 to 0.209] µV2; P = .02) compared with individuals without PAE. The magnitude of this increase was approximately double for children exposed to continuous drinking (0.211 [95% CI, 0.005 to 0.417] µV2; P = .04). Children whose mothers were in the continuous smoking cluster had decreased beta power (-0.031 [95% CI, -0.059 to -0.003] µV2; P = .03) and gamma power (-0.020 [95% CI, -0.039 to -0.000] µV2; P = .04) compared with the nonsmoking cluster. In exploratory sex-stratified models, male participants in the quit-early PAE cluster had greater EEG power in the alpha band (0.159 [95% CI, 0.003 to 0.315] µV2; P = .04) compared with those with no PAE, and the difference was approximately double for male participants with continuous PAE (0.354 [95% CI, 0.041 to 0.667] µV2; P = .03). Male participants in the continuous PTE cluster had decreased beta (-0.048 [95% CI, -0.090 to - 0.007] µV2; P = .02) and gamma (-0.032 [95% CI, -0.061 - 0.002] µV2; P = .04) power compared with those with no PTE. Conclusions and Relevance: These findings suggest that even low levels of PAE and PTE were associated with long-term alterations of brain activity.

The causal impact of maternal smoking around birth on offspring ADHD: A two-sample Mendelian randomization study.

BACKGROUND: The previous literature highlights a relationship between maternal smoking around birth (MSAB) and offspring attention-deficit/hyperactivity disorder (ADHD). These studies have focused on the causal effects of MSAB on offspring ADHD. METHOD: A Mendelian randomization analysis was conducted using summary statistics. Data on MSAB were obtained from a recent study including 391,992 participants. ADHD data were obtained from six sources for 246,888 participants. The present study used five methods to examine the causal impact from outcomes on exposures. The inverse variance weighted (IVW) was the main method of analysis, while the other four methods were supplementary methods. RESULT: The IVW revealed that MSAB was a risk factor for offspring ADHD (OR: 2.54; 95 % confidence interval [CI]: 1.61-4.00, p = 6.04 × 10-5). Concerning ADHD in both sexes, MSAB was associated with females (OR = 3.96, 95 % CI: 1.99-7.90, p = 8.98 × 10-5) and males (OR = 3.74, 95 % CI: 1.74-5.72, p = 1.48 × 10-4). In different diagnosis periods for ADHD, MSAB increased the risk of childhood (OR = 3.63, 95 % CI: 2.25-5.87, p = 1.31 × 10-7), late-diagnosed (OR = 2.99, 95 % CI: 1.74-5.14, p = 7.33 × 10-5), and persistent (OR = 4.77, 95 % CI: 1.88-12.14, p = 1.03 × 10-3) ADHD. The final analysis did not reveal heterogeneity. CONCLUSIONS: A causal impact of MSAB on offspring ADHD was observed. These findings highlight the need for careful consideration of prenatal exposure (MSAB) during the assessment of offspring ADHD. Additionally, it can provide targeted guidance for prenatal interventions. Future studies should analyze the effects of different doses of maternal smoking on ADHD.

Investigating the associations between prenatal exposure to substances and intergenerational maltreatment and symptoms of psychopathology for adolescent girls from families with low income.

BACKGROUND: Adolescent girls whose families experience poverty are more vulnerable to psychopathology, and it is vital to investigate biopsychosocial factors contributing to mental health functioning. OBJECTIVE: To test associations between prenatal exposure to substances, intergenerational maltreatment, and adolescent mental health symptoms. PARTICIPANTS AND SETTING: Baseline data were used from a randomized controlled trial testing the efficacy of Interpersonal Psychotherapy (IPT-A) for depression among girls with and without maltreatment exposure. Adolescents (Aged 13-16; 63.5 % Black/African-American, 21.0 % White, 15.57 % other racial identity; 12.57 % Latina/x) were recruited from families experiencing financial adversity (income <200 % poverty threshold). METHODS: Adolescent maltreatment status was determined by using multiple sources (child protective service records, parental report, and adolescent report). Mothers reported on prenatal substance exposure, experiences of maltreatment in their own childhood, and rated adolescent internalizing and externalizing symptoms. Latent Class Analysis was used to determine common patterns of prenatal substance exposure (tobacco, alcohol, marijuana, and cocaine). Structural Equation Modeling was used to evaluate associations between maltreatment in two generations, prenatal exposure to substances, and adolescent mental health symptoms. RESULTS: Two profiles of prenatal substance exposure emerged: one typified by low substance exposure (92.8 %), and one with moderate to high substance exposure (7.2 %). Both prenatal substance exposure and maternal history of maltreatment were associated with adolescent maltreatment, which in turn, was associated with greater adolescent externalizing symptoms. Parental history of maltreatment was directly associated with greater adolescent internalizing symptoms. CONCLUSION: Prenatal exposure to substances and intergenerational maltreatment each confer risk for mental health symptoms in adolescent girls.

Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

Smoking during pregnancy and risk of multiple sclerosis in offspring and mother: A Danish nationwide register-based cohort study.

BACKGROUND: The association between intra-uterine exposure to maternal smoking and risk of multiple sclerosis (MS) has been little studied and with conflicting results. OBJECTIVE: To examine the risk of MS in offspring exposed intra-uterine to maternal smoking. In addition, to re-examine prior observations of an elevated risk of MS among smokers, assuming that self-reported smoking during pregnancy reflects the woman's general smoking habits. METHODS: The study cohort included all Danish women, pregnant in the period 1991-2018, (n = 789,299) and singletons from these pregnancies (n = 879,135). Nationwide information on maternal smoking during pregnancy and MS cases in the study cohort were obtained from the Medical Birth Register and the National Patient Register. Cox regression analysis was used to estimate hazard ratios (HRs) for the association between smoking and MS risk. RESULTS: Women who smoked during pregnancy had a 42% increased risk of developing MS compared with non-smoking women (HR = 1.42 (1.32-1.52), n = 1,296). The risk of MS among singletons of women who smoked during pregnancy was 38% higher than that among singletons born to non-smoking women (HR = 1.38 (1.08-1.76), n = 110). CONCLUSION: Our observations add further to the evidence implicating smoking in the development of MS and suggest that intra-uterine exposure to tobacco smoke may increase MS risk.

Intergenerational transmission of tobacco smoking: The role of the child's behavioral difficulties. Data from the Danish National Birth cohort (DNBC).

AIMS: This study explores the role of offspring behavioral difficulties in the intergeneration transmission of tobacco smoking. METHODS: This longitudinal cohort study is based on children born in Denmark in 1996-2003 participating in the Danish National Birth Cohort (DNBC), followed-up until 18years of age. We included mother-child pairs with complete data regarding the exposure (4 trajectories of maternal daily smoking quantity during pregnancy: low, intermediate/stable, intermediate/decreasing and high), outcome (offspring daily smoking status at 18 years) and mediator (offspring symptoms of hyperactivity-inattention at 11 years), that is 24,588 mother-child pairs. RESULTS: In our study population, during pregnancy respectively 86.2%, 6.80%, 4.08% and 2.97% mothers belonged to the low, intermediate/stable, intermediate/decreasing and high smoking trajectory groups. After controlling for covariates using propensity scores, the direct effect of maternal smoking in pregnancy on offspring smoking in adolescence was statistically significant, especially when the mother belonged to the intermediate/stable smoking trajectory group (ORIPW = 2.09, 95% CI: 1.70 - 2.61) or to the high smoking trajectory group (ORIPW = 2.08, 95% CI: 1.52 - 3.11) compared to the low smoking trajectory group. None of the indirect effects of maternal smoking in pregnancy were statistically significant, and neither were the proportions mediated. CONCLUSION: Maternal pregnancy smoking seems to have an influence on offspring smoking in early adulthood, which does not appear to be mediated by offspring behavioral difficulties. Women should be strongly encouraged to quit smoking in pregnancy to reduce both short and long-term health risks among their offspring.

Prenatal Exposure to PFAS, Associations with Preterm Birth and Modification by Maternal Estrogen Levels: The Maoming Birth Study.

BACKGROUND: Estrogens play a critical role in parturition, and poly- and perfluoroalkyl substances (PFAS), which have estrogenic effects, have been associated with preterm birth. However, the impact of estrogens on the association between PFAS and preterm birth is unknown. OBJECTIVE: The objective of this study is to investigate if estrogens modified the association between PFAS and preterm birth, using a nested case-control study design. METHODS: A total of 371 preterm births and 508 controls were selected from a birth cohort study in China between 2016 and 2018. Perfluorobutanoic acid (PFBA), perfluorohexanesulfonic acid (PFHxS) and its branched isomer, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and its branched isomer, and perfluorononanoic acid (PFNA) were quantified in maternal serum (mean gestational age of 32 wk). Estradiol and estriol were quantified in cord serum. Preterm birth was defined as live delivery at <37 gestational weeks. Causal mediation analysis was used to estimate the mediation and interaction effects of estrogen on the association between PFAS and preterm birth. Latent profile analysis was used to identify important estrogen profiles. Multiple linear regression was used to estimate associations between PFAS and preterm birth and interactions between PFAS and estrogens on preterm birth. RESULTS: Overall, higher odds ratios (ORs) of preterm birth were associated with each 1 ln-unit PFAS increase: PFBA [1.20, 95% confidence interval (CI): 1.14, 1.26], PFNA (1.30, 95% CI: 1.21, 1.39), PFOA (1.98, 95% CI: 1.54, 2.55), and PFOS (1.91, 95% CI: 1.76, 2.07) and its branched isomer (1.91, 95% CI: 1.90, 1.92). We detected statistically significant interactions between cord estradiol and PFAS on preterm birth, while no mediation effects of cord estrogen were observed. The ORs of PFOS (4.29, 95% CI: 1.31, 8.25), its branched isomer (6.71, 95% CI: 1.06, 11.91), and preterm birth were greater for participants with high cord estrogen levels than for participants with low cord estrogen levels. DISCUSSION: Our findings suggest that estrogen modified the association between maternal PFAS exposure and preterm birth. Further studies on maternal PFAS exposure and preterm birth, taking interaction effects of cord estrogens into account, are warranted. https://doi.org/10.1289/EHP11377.

Prenatal exposure to metal mixtures and lung function in children from the New Hampshire birth cohort study.

Prenatal exposure to metals/metalloids, even at common US population levels, may pose risks to fetal health, and affect children's lung function. Yet, the combined effects of simultaneous prenatal exposures on children's lung function remain largely unexplored. This study analyzed 11 metals (As speciation, Cd, Co, Cu, Mo, Ni, Pb, Sb, Se, Sn, Zn) in maternal urine during weeks 24-28 of gestation and evaluated lung function, including forced vital capacity (FVC) and forced expiratory volume in the first second of expiration (FEV1), in 316 US mother-child pairs at around age 7. We used Bayesian Kernel Machine Regression (BKMR), weighted quantile sum regression (WQSR), and multiple linear regression to examine the association between metal mixture exposure and children's lung function, adjusting for maternal smoking, child age, sex, and height. In BKMR models assessing combined exposure effects, limited evidence of metal non-linearity or interactions was found. Nevertheless, Co, As species, and Pb showed a negative association, while Mo exhibited a positive association with children's FVC and FEV1, with other metals held constant at their medians. The weighted index, from WQSR analysis assessing the cumulative impact of all metals, highlighted prenatal Mo with the highest positive weight, and Co, As, and Sb with the most substantial negative weights on children's FVC and FEV1. Urinary Co and Pb were negatively associated with FVC (ß = -0.09, 95% confidence interval (CI) (-0.18; -0.01) and ß = -0.07, 95% CI (-0.13; 0.00), respectively). Co was also negatively associated with FEV1 (ß = -0.09, 95% CI (-0.18; 0.00). There was a negative association between As and FVC, and a positive association between Mo and both FVC and FEV1, though with wide confidence intervals. Our findings suggest that prenatal trace element exposures may impact children's lung function, emphasizing the importance of reducing toxic exposures and maintaining adequate nutrient levels.

Prenatal Exposure to Toxic Metals and Neural Tube Defects: A Systematic Review of the Epidemiologic Evidence.

BACKGROUND: Neural tube defects (NTDs) affect >300,000 pregnancies worldwide annually. Few nongenetic factors, other than folate deficiency, have been identified that may provide intervenable solutions to reduce the burden of NTDs. Prenatal exposure to toxic metals [arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn) and lead (Pb)] may increase the risk of NTDs. Although a growing epidemiologic literature has examined associations, to our knowledge no systematic review has been conducted to date. OBJECTIVE: Through adaptation of the Navigation Guide systematic review methodology, we aimed to answer the question "does exposure to As, Cd, Hg, Mn, or Pb during gestation increase the risk of NTDs?" and to assess challenges to evaluating this question given the current evidence. METHODS: We selected available evidence on prenatal As, Cd, Hg, Mn, or Pb exposure and risk of specific NTDs (e.g., spina bifida, anencephaly) or all NTDs via a comprehensive search across MEDLINE, Embase, Web of Science, and TOXLINE databases and applied inclusion/exclusion criteria. We rated the quality and strength of the evidence for each metal. We applied a customized risk of bias protocol and evaluated the sufficiency of evidence of an effect of each metal on NTDs. RESULTS: We identified 30 studies that met our criteria. Risk of bias for confounding and selection was high in most studies, but low for missing data. We determined that, although the evidence was limited, the literature supported an association between prenatal exposure to Hg or Mn and increased risk of NTDs. For the remaining metals, the evidence was inadequate to establish or rule out an effect. CONCLUSION: The role of gestational As, Cd, or Pb exposure in the etiology of NTDs remains unclear and warrants further investigation in high-quality studies, with a particular focus on controlling confounding, mitigating selection bias, and improving exposure assessment. https://doi.org/10.1289/EHP11872.

The Association Between Prenatal Infection and Adolescent Behavior: Investigating Multiple Prenatal, Perinatal, and Childhood Second Hits.

OBJECTIVE: Exposure to infections during pregnancy may be a potential risk factor for later psychopathology, but large-scale epidemiological studies investigating associations between prenatal infection and long-term offspring behavioral problems in the general population are scarce. In our study, we aimed to investigate the following: (1) the association between prenatal infection and adolescent behavior, (2) putative underlying pathways (mediation), and (3) "second hits" interacting with prenatal infection to increase the risk of adolescent behavior problems (moderation). METHOD: Our study was embedded in a prospective Dutch pregnancy cohort (Generation R; n = 2,213 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. At age 13 to 16 years, we assessed total, internalizing, and externalizing problems, and autistic traits using the Child Behavioral Checklist and the Social Responsiveness Scale, respectively. We investigated maternal lifestyle and nutrition, perinatal factors (placental health and delivery outcomes), and child health (lifestyle, traumatic events, infections) as mediators and moderators. RESULTS: We observed associations of prenatal infection with adolescent total behavioral, internalizing, and externalizing problems. The association between prenatal infection and internalizing problems was moderated by higher levels of maternal psychopathology, alcohol and tobacco use, and a higher number of traumatic childhood events. We found no association between prenatal infection and autistic traits. Yet, children exposed to prenatal infections and maternal substance use, and/or traumatic childhood events, had a higher risk of autistic traits in adolescence. CONCLUSION: Prenatal infection may be a risk factor for later psychiatric problems as well as a disease primer making individuals susceptible to other hits later in life. STUDY PREREGISTRATION INFORMATION: Prenatal maternal infection and adverse neurodevelopment: a structural equation modelling approach to downstream environmental hits; https://osf.io/cp85a; cp85a. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants.