Prenatal opioid exposure by likelihood of exposure and risk to prenatal development: Medicaid-covered births in Wisconsin, 2010-2019.

Prenatal opioid exposure is an established public health problem, in particular among Medicaid-covered births. Yet, existing prevalence rates are plausibly underestimated. We leverage extensive linked longitudinal administrative data for all Medicaid-covered live births in Wisconsin from 2010 to 2019 to estimate a range of prevalence rates using an innovative strategy that jointly accounts for both likelihood of exposure and potential risk to prenatal development. We find that 20.8% of infants may have been prenatally exposed to opioids, with 1.7% diagnosed with neonatal abstinence syndrome and an additional 1.2% having a high combined likelihood of exposure and potential risk to prenatal development, 2.6% a moderate combined likelihood and risk, and 15.3% a low or uncertain combined likelihood and risk. We assess improvements in prevalence estimates based on our nuanced classification relative to those of prior studies. Our strategy could be broadly used to quantify the scope of the opioid crisis for pregnant populations, target interventions, and promote child health and development.

Social determinants of respiratory health from birth: still of concern in the 21st century?

Respiratory symptoms are ubiquitous in children and, even though they may be the harbinger of poor long-term outcomes, are often trivialised. Adverse exposures pre-conception, antenatally and in early childhood have lifetime impacts on respiratory health. For the most part, lung function tracks from the pre-school years at least into late middle age, and airflow obstruction is associated not merely with poor respiratory outcomes but also early all-cause morbidity and mortality. Much would be preventable if social determinants of adverse outcomes were to be addressed. This review presents the perspectives of paediatricians from many different contexts, both high and low income, including Europe, the Americas, Australasia, India, Africa and China. It should be noted that there are islands of poverty within even the highest income settings and, conversely, opulent areas in even the most deprived countries. The heaviest burden of any adverse effects falls on those of the lowest socioeconomic status. Themes include passive exposure to tobacco smoke and indoor and outdoor pollution, across the entire developmental course, and lack of access even to simple affordable medications, let alone the new biologicals. Commonly, disease outcomes are worse in resource-poor areas. Both within and between countries there are avoidable gross disparities in outcomes. Climate change is also bearing down hardest on the poorest children. This review highlights the need for vigorous advocacy for children to improve lifelong health. It also highlights that there are ongoing culturally sensitive interventions to address social determinants of disease which are already benefiting children.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Neurodevelopmental assessment of normocephalic children born to Zika virus exposed and unexposed pregnant people.

BACKGROUND: Studies examining the association between in utero Zika virus (ZIKV) exposure and child neurodevelopmental outcomes have produced varied results. METHODS: We aimed to assess neurodevelopmental outcomes among normocephalic children born from pregnant people enrolled in the Zika in Pregnancy in Honduras (ZIPH) cohort study, July-December 2016. Enrollment occurred during the first prenatal visit. Exposure was defined as prenatal ZIKV IgM and/or ZIKV RNA result at enrollment. Normocephalic children, >6 months old, were selected for longitudinal follow-up using the Bayley Scales of Infant and Toddler Development (BSID-III) and the Ages & Stages Questionnaires: Social-Emotional (ASQ:SE-2). RESULTS: One hundred fifty-two children were assessed; after exclusion, 60 were exposed and 72 were unexposed to ZIKV during pregnancy. Twenty children in the exposed group and 21 children in the unexposed group had a composite score <85 in any of the BSID-III domains. Although exposed children had lower cognitive and language scores, differences were not statistically significant. For ASQ:SE-2 assessment, there were not statistically significant differences between groups. CONCLUSIONS: This study found no statistically significant differences in the neurodevelopment of normocephalic children between in utero ZIKV exposed and unexposed. Nevertheless, long-term monitoring of children with in utero ZIKV exposure is warranted. IMPACT: This study found no statistically significant differences in the neurodevelopment in normocephalic children with in utero Zika virus exposure compared to unexposed children, although the exposed group showed lower cognitive and language scores that persisted after adjustment by maternal age and education and after excluding children born preterm and low birth weight from the analysis. Children with prenatal Zika virus exposure, including those normocephalic and have no evidence of abnormalities at birth, should be monitored for neurodevelopmental delays. Follow-up is important to be able to detect developmental abnormalities that might not be detected earlier in life.

Assessment of Ante- and Postnatal Development of the Offspring of Male Rats Crossed in Delayed Periods after Treatment with Methotrexate in Low Doses.

We studied ante- and postnatal development of the offspring of intact female rats crossed with males injected with low doses of methotrexate 3 and 6 months before mating. The time of crossing corresponded to the manifestation of the cytostatic effect on spermatogonial stem cells. The offspring of methotrexate-treated males was characterized by increased preimplantation losses and fetal growth restriction in the antenatal period and inhibition of physical development, delayed formation of sensory-motor reflexes, and impaired learning abilities in the postnatal period.

Prenatal Alcohol Counseling Among American Indian and Alaska Native Women and Non-Hispanic White Women in the Pregnancy Risk Assessment Monitoring System.

OBJECTIVE: Universal screening and counseling are recommended for alcohol use during pregnancy, but no prior study has examined differences in prenatal counseling by race or ethnicity. We used Pregnancy Risk Assessment Monitoring System (PRAMS) data to assess differences in provision of counseling on prenatal alcohol use between American Indian/Alaska Native (AI/AN) and non-Hispanic White (NHW) women during prenatal care. METHODS: We analyzed data from 2014-2015 from the four PRAMS states with the highest number of births to AI/AN women: Alaska, New Mexico, Oklahoma, and Washington. We estimated the prevalence of prenatal alcohol use, associated risk factors, and prenatal alcohol prevention counseling for AI/AN (n = 1,805) and NHW (n = 5,641) women. We then conducted multivariable logistic regression modeling stratified by race to estimate factors associated with receipt of prenatal alcohol prevention counseling. All analyses were weighted and accounted for the complex sampling design of PRAMS. RESULTS: Results showed that AI/AN women were counseled on prenatal alcohol use more often than NHW women (77% vs. 67%, p < .05), although the likelihood of any prenatal alcohol use was the same in both groups. The likelihood of prenatal drinking increased with age, education, and income in both groups. Higher education levels were significantly associated with lower risk of prenatal alcohol counseling receipt among AI/AN women. Compared with those with less than a high school diploma, AI/AN women with a college degree or more had 39% reduced risk of receiving counseling (adjusted risk ratio [aRR] = 0.61; 95% confidence interval [CI]: 0.45-0.83). Among NHW women, living at 100% to 199% of the Federal Poverty Level was associated with lower risk (aRR = 0.88; 95% CI: 0.79-0.98) of counseling receipt compared with women living below the federal poverty line. Higher parity was significantly associated with lower risk of counseling for both groups of women. CONCLUSION: Although race was not associated with prenatal alcohol use, AI/AN women were more likely than NHW women to be counseled about prenatal alcohol exposure. Factors associated with counseling receipt differed between the two groups. These findings suggest that receipt of counseling is associated with sociodemographic characteristics, and that counseling is not universally provided. More efforts to provide universal counseling are warranted.

Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy.

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (ß = 0.31; 95% CI, -2.97 to 3.58), gross motor (ß = 0.82; 95% CI, -1.34 to 2.99), fine motor (ß = 0.36; 95% CI, -0.74 to 1.47), expressive language (ß = -1.00; 95% CI, -4.02 to 2.02), or receptive language (ß = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

Exposure to a mixture of non-persistent environmental chemicals and neonatal thyroid function in a cohort with improved exposure assessment.

BACKGROUND: In vitro and toxicological studies have shown that non-persistent environmental chemicals can perturb thyroid hormone homeostasis. Epidemiological studies with improved exposure assessment (i.e., repeated urine samples) are needed to evaluate effects of these compounds, individually or as a mixture, in humans. We studied the associations between prenatal exposure to non-persistent environmental chemicals and neonatal thyroid hormones. METHODS: The study population consisted of 442 mother-child pairs from the French SEPAGES mother-child cohort recruited between July 2014 and July 2017. For each participant, four parabens, five bisphenols, triclosan, triclocarban, benzophenone-3 as well as metabolites of phthalates and of di(isononyl)cyclohexane-1,2-dicarboxylate were assessed in two pools of repeated urine samples (median: 21 spot urines per pool), collected in the 2nd and 3rd trimesters of pregnancy, respectively. Thyroid stimulating hormone (TSH) and total thyroxine (T4) levels were determined in newborns from a heel-prick blood spot. Maternal iodine and selenium were assessed in urine and serum, respectively. Adjusted linear regression (uni-pollutant model) and Bayesian Kernel Machine Regression (BKMR, mixture model) were applied to study overall and sex-stratified associations between chemicals and hormone concentrations. RESULTS: Interaction with child sex was detected for several compounds. Triclosan, three parabens, and one phthalate metabolite (OH-MPHP) were negatively associated with T4 among girls in the uni-pollutant model. BKMR also suggested a negative association between the mixture and T4 in girls, whereas in boys the association was positive. The mixture was not linked to TSH levels, and for this hormone the uni-pollutant model revealed associations with only a few compounds. CONCLUSION: Our study, based on repeated urine samples to assess exposure, showed that prenatal exposure to some phenols and phthalates disturb thyroid hormone homeostasis at birth. Furthermore, both uni-pollutant and mixture models, suggested effect modification by child sex, while, to date underlying mechanisms for such sex-differences are not well understood.

Assessment of the Risk Evaluation and Mitigation Strategy (REMS) for Phentermine-Topiramate to Prevent Exposure During Pregnancy.

BACKGROUND: The U.S. Food and Drug Administration approved phentermine-topiramate for obesity in 2012 and required a Risk Evaluation and Mitigation Strategy (REMS) to prevent prenatal exposure. No such requirement was introduced for topiramate. OBJECTIVE: To evaluate the rate of prenatal exposure, contraceptive use, and pregnancy testing among patients with phentermine-topiramate compared with topiramate or other antiobesity medications (AOMs). DESIGN: Retrospective cohort study. SETTING: Nationwide health insurance claims database. PARTICIPANTS: Females aged 12 to 55 years with no infertility diagnosis or sterilization procedure. Patients with other indications for topiramate were excluded to identify a cohort that was likely treated for obesity. MEASUREMENTS: Patients initiated use of phentermine-topiramate, topiramate, or an AOM (liraglutide, lorcaserin, or bupropion-naltrexone). Pregnancy at treatment initiation, conception during treatment, contraceptive use, and pregnancy testing outcomes were ascertained. Measurable confounders were adjusted for, and extensive sensitivity analyses were done. RESULTS: A total of 156 280 treatment episodes were observed. Adjusted prevalence of pregnancy at treatment initiation was 0.9 versus 1.6 per 1000 episodes (prevalence ratio, 0.54 [95% CI, 0.31 to 0.95]) for phentermine-topiramate versus topiramate. The incidence rate of conception during treatment was 9.1 versus 15.0 per 1000 person-years (rate ratio, 0.61 [CI, 0.40 to 0.91]) for phentermine-topiramate versus topiramate. Both outcomes were similarly lower for phentermine-topiramate compared with AOM. Prenatal exposure was marginally lower in topiramate users compared with AOM users. Approximately 20% of patients in all cohorts had at least 50% of treatment days covered by contraceptives. Few patients had pregnancy tests before treatment (≤5%), but this was more common among phentermine-topiramate users. LIMITATIONS: Outcome misclassification; unmeasured confounding due to lack of prescriber data to account for possible clustering and spillover effects. CONCLUSION: Prenatal exposure seemed to be significantly lower among phentermine-topiramate users under the REMS. Pregnancy testing and contraceptive use appeared to be inadequate for all groups, which deserves attention to prevent the remaining potential exposures. PRIMARY FUNDING SOURCE: None.

Compliance with Prescribing and Dispensing Conditions for Valproate and Related Substances in Girls and Women of Childbearing Potential: A Survey of Community Pharmacists in France.

INTRODUCTION: Prenatal exposure to valproate and related substances is associated with a risk of malformations and/or neurodevelopmental disorders. In France, prescription and dispensing conditions of oral valproate forms are subject to risk minimization measures for girls and women of childbearing potential with the aim to limit pregnancy under this treatment. These risk minimization measures were issued in 2015 and were strengthened in 2018. OBJECTIVE: We aimed to evaluate compliance with prescription and dispensing conditions of valproate for oral administration: an annual prescription from a specialist and a signed risk acknowledgment form. METHODS: Two prospective observational surveys were carried out between 2018 and 2020 on a representative sample of French community pharmacies. Data were collected from female patients aged 2-49 years presenting to one of the participating pharmacies with a valproate prescription. RESULTS: In total, 1067 and 824 valproate prescriptions were analyzed in 2018 and 2020, respectively, the majority of which were for girls and women of childbearing potential (≥ 92%). The prescription and dispensing conditions for valproate were met in 42% of cases (95% confidence interval 39-45) in 2018 and in 47% of cases (95% confidence interval 43-50) in 2020. Compliance levels were higher for prescriptions from neurologists (≥ 60%) than from other prescribers (≤ 45%). CONCLUSIONS: In France, the implementation of specific risk minimization measures for girls and women of childbearing potential with respect to oral valproate forms and related substances requires a stronger involvement of stakeholders. Increased awareness and compliance among healthcare professionals regarding risk minimization measures could limit prenatal exposure to valproate.

Longitudinal and prospective assessment of prenatal maternal sleep quality and associations with newborn hippocampal and amygdala volume.

BACKGROUND: The rapid maturation of the fetal brain renders the fetus susceptible to prenatal environmental signals. Prenatal maternal sleep quality is known to have important health implications for newborns including risk for preterm birth, however, the effect on the fetal brain is poorly understood. METHOD: Participants included 94 pregnant participants and their newborns (53% female). Pregnant participants (Mage = 30; SDage= 5.29) reported on sleep quality three times throughout pregnancy. Newborn hippocampal and amygdala volumes were assessed using structural magnetic resonance imaging. Multilevel modeling was used to test the associations between trajectories of prenatal maternal sleep quality and newborn hippocampal and amygdala volume. RESULTS: The overall trajectory of prenatal maternal sleep quality was associated with hippocampal volume (left: b = 0.00003, p = 0.013; right: b = 0.00003, p = .008). Follow up analyses assessing timing of exposure indicate that poor sleep quality early in pregnancy was associated with larger hippocampal volume bilaterally (e.g., late gestation left: b = 0.002, p = 0.24; right: b = 0.004, p = .11). Prenatal sleep quality was not associated with amygdala volume. CONCLUSION: These findings highlight the implications of poor prenatal maternal sleep quality and its role in contributing to newborn hippocampal development.

Prenatal exposure to maternal social disadvantage and psychosocial stress and neonatal white matter connectivity at birth.

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social disadvantage and psychosocial stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social disadvantage, but not psychosocial stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical morbidities and prenatal drug exposure. In moderation analysis, psychosocial stress was associated with lower MD in the left inferior CB among the lower-to-higher socioeconomic status (SES) (INR ≥ 200%) group, but not the extremely low SES (INR < 200%) group. Increasing access to social welfare programs that reduce the burden of social disadvantage and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways.

Effects of maternal high-fat diet on the hypothalamic components related to food intake and energy expenditure in mice offspring.

Maternal exposure to a high-fat diet (HFD) during pregnancy and lactation has been related to changes in the hypothalamic circuits involved in the regulation of food intake. Furthermore, maternal HFD during the critical period of development can alter the offspring's metabolic programming with long-term repercussions. This study systematically reviewed the effects of HFD consumption during pre-pregnancy, pregnancy and/or lactation. The main outcomes evaluated were food intake, body weight and cellular or molecular aspects of peptides and hypothalamic receptors involved in the regulation of energy balance in mice. Two independent authors performed a search in the electronic databases Medline/PubMed, LILACS, Web of Science, EMBASE, SCOPUS and Sigle via Open Gray. The experimental studies of mice exposed to HFD during pregnancy and/or lactation that evaluated body composition, food intake, energy expenditure and hypothalamic components related to energy balance were included. Internal validity was assessed using the SYRCLE risk of bias. The Kappa index was measured to analyze the agreement between reviewers. The PRISMA statement was used to report this systematic review. Most studies demonstrated that there was a higher body weight, body fat deposits and food intake, as well as alterations in the expression of hypothalamic neuropeptides in offspring that consumed HFD. Therefore, the maternal diet can affect the phenotype and metabolism of the offspring, in addition to harming the hypothalamic circuits and favoring the orexigenic pathways.

Maternal Western-style diet reduces social engagement and increases idiosyncratic behavior in Japanese macaque offspring.

Recent evidence in humans and animals indicates an association between maternal obesity and offspring behavioral outcomes. In humans, increased maternal body mass index has been linked to an increased risk of children receiving a diagnosis of early-emerging neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and/or Autism Spectrum Disorder (ASD). However, a limited number of preclinical studies have examined associations between maternal Western-Style Diet (mWSD) exposure and offspring social behavior. To our knowledge, this is the first study to investigate relationships between mWSD exposure and social behavior in non-human primates. Since aberrant social behavior is a diagnostic criterion for several neurodevelopmental disorders, the current study focuses on examining the influence of maternal nutrition and metabolic state on offspring social behavior in Japanese macaques (Macaca fuscata). We found that mWSD offspring initiated less affiliative social behaviors as well as proximity to a peer. Using path analysis, we found that the association between mWSD consumption and reduced offspring social engagement was statistically mediated by increased maternal interleukin (IL)-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin in the third trimester. Together, these results suggest that NHP offspring exposed to mWSD exhibit behavioral phenotypes similar to what is described in some early-emerging neurodevelopmental disorders. These results provide evidence that mWSD exposure during gestation may be linked to increased risk of neurodevelopmental disorders and provides targets for prevention and intervention efforts.

Prescribed opioid analgesics in early pregnancy and the risk of congenital anomalies: a population-based cohort study.

BACKGROUND: Recent data suggest an increased risk of congenital anomalies with prenatal exposure to opioid analgesics. We sought to further quantify the risk of anomalies after opioid analgesic exposure during the first trimester in a population-based cohort study. METHODS: Using administrative health data from Ontario, we followed 599 579 gestational parent-infant pairs from singleton pregnancies without opioid use disorder. We identified opioid analgesics dispensed in the first trimester and congenital anomalies diagnosed during the first year of life. We estimated propensity score-adjusted risk ratios (RRs) between first trimester exposure (any opioid analgesic and specific agents) and congenital anomalies (any anomaly, organ system anomalies, major or minor anomalies and specific anomalies). RESULTS: The prevalence of congenital anomalies was 2.8% in exposed infants and 2.0% in unexposed infants. Relative to unexposed infants, we observed elevated risks among those who were exposed for some anomaly groups, including gastrointestinal anomalies (any opioid analgesic: adjusted RR 1.46, 95% confidence interval [CI] 1.15-1.85; codeine: adjusted RR 1.53, 95% CI 1.12-2.09; tramadol: adjusted RR 2.69, 95% CI 1.34-5.38) and several specific anomalies, including ankyloglossia (any opioid: adjusted RR 1.88, 95% CI 1.30-2.72; codeine: adjusted RR 2.14, 95% CI 1.35-3.40). These findings persisted in sensitivity analyses. INTERPRETATION: Although the absolute risk of congenital anomalies was low, our findings add to accumulating data that suggest a small increased risk of some organ system anomalies and specific anomalies with first trimester exposure to opioid analgesics. These findings further quantify the potential risks associated with prenatal exposure to opioid analgesics to inform treatment choices for pain in pregnancy.

Assessment of the association between prenatal exposure to multiple ambient pollutants and preterm birth: A prospective cohort study in Jinan, east China.

Air pollution has been documented with a series of adverse pregnancy outcomes, yet their reproductive and developmental toxicity on human beings has not been fully elucidated. Here, we analyzed the geographic distribution of Jinan and examined its contribution to air pollution. After adjusting demographic variables and environmental co-pollutants, we built statistical models based on 424 couples and checked different air pollutants on their pregnancy outcomes. We find that Jinan is tightly surrounded by mountains from 3 of 4 sides, geographically resulting in a typical basin texture that hinders the diffusion of ambient pollutants. Of 424 pregnant women enrolled in this study, 17 subjects were diagnosed with preterm birth. Using air quality index (AQI) as an integrated indicator of PM10, PM2.5, SO2, NO2, CO, and O3, we found that each interquartile range (IQR) increase in AQI was associated with 11% increased odds of preterm birth. Also, elevating PM2.5, PM10, SO2, and O3 led to different increased risk levels of preterm birth. By running the generalized additive model analyses, the association of AQI and preterm birth was further confirmed. In conclusion, based on samples in Jinan, east China, prenatal exposure to multiple ambient pollutants is associated with reduced gestational age and increased risk of preterm birth.

Moderation effect of economic status in the association between early life famine exposure and MAFLD in adulthood.

BACKGROUND & AIMS: The double burden of malnutrition (DBM) in China resulted in high prevalence of diet-related non-communicable diseases. The aim of this study was to analyse the moderation of economic status in the association between early famine exposure and metabolic dysfunction associated with fatty liver disease (MAFLD) in adulthood. METHODS: 10 190 participants in the SPECT-China study enrolled from 2014 to 2016 were included in this study. Participants with fetal famine exposure (birth year 1959-1962) or early-childhood famine exposure (birth year 1955-1958) formed the exposure group. The associations with MAFLD were assessed via regression analyses. RESULTS: In men, economic status could not moderate the association between early life famine and MAFLD after adjusting for age, excess alcohol drinking, current smokers, famine severity, waist circumference, diabetes, hypertension, and dyslipidemia (P for interaction = .52). However, in women and in the total population, economic status could moderate the association between early life famine and MAFLD after adjusting for the above confounders (P for interaction = .01). In the total population and in women, early life famine exposure was associated with MAFLD in both low economic status and high economic status. However, in men, early life famine exposure was not associated with MAFLD in low economic status, while in high economic status, early-childhood famine exposure was associated with MAFLD. CONCLUSIONS: Economic status could moderate the association between early life famine exposure and MAFLD in total population and in women.

Trajectories of Prescription Opioid Utilization During Pregnancy Among Prepregnancy Chronic Users and Risk of Neonatal Opioid Withdrawal Syndrome.

Little is known about the impact of dose, duration, and timing of prenatal prescription opioid exposure on the risk of neonatal opioid withdrawal syndrome (NOWS). Using a cohort of 18,869 prepregnancy chronic opioid users nested within the 2000-2014 Medicaid Analytic eXtract, we assessed average opioid dosage within biweekly gestational age intervals, created group-based trajectory models, and evaluated the association between trajectory groups and NOWS risk. Women were grouped into 6 distinct opioid use trajectories which, based on observed patterns, were categorized as 1) continuous very low-dose use, 2) continuous low-dose use, 3) initial moderate-dose use with a gradual decrease to very low-dose/no use, 4) initial high-dose use with a gradual decrease to very low-dose use, 5) continuous moderate-dose use, and 6) continuous high-dose use. Absolute risk of NOWS per 1,000 infants was 7.7 for group 1 (reference group), 28.8 for group 2 (relative risk (RR) = 3.7, 95% confidence interval (CI): 2.8, 5.0), 16.5 for group 3 (RR = 2.1, 95% CI: 1.5, 3.1), 64.9 for group 4 (RR = 8.4, 95% CI: 5.6, 12.6), 77.3 for group 5 (RR = 10.0, 95% CI: 7.5, 13.5), and 172.4 for group 6 (RR = 22.4, 95% CI: 16.1, 31.2). Trajectory models-which capture information on dose, duration, and timing of exposure-are useful for gaining insight into clinically relevant groupings to evaluate the risk of prenatal opioid exposure.

Assessment of embryo morphology following perinatal exposure to aspirin, ibuprofen and paracetamol using whole embryo culture system.

BACKGROUND: Recent evidence from a meta-analysis indicates that maternal prenatal exposure, single or repeated, to non-steroidal anti-inflammatory drugs (NSAIDs) or non-opioid painkillers, is associated with increased risk of cerebral palsy and cognitive-behavioral disorders in offspring. One potential route of action is interference with the neurulation process and hence early brain development. OBJECTIVE: To examine the effect of prenatal exposure to common NSAIDs and non-opioid drugs on neurulation using an in vitro whole embryo culture system. METHODS: Mouse embryos from in-bred Institute of Cancer Research albino strain mice were exteriorized on embryonic day 7.5 and cultured for 48 h in either 1 mL heat-inactivated rat serum + 0.1% dimethyl sulfoxide ("Control") or 1 mL of rat serum supplemented with six increasing concentrations of laboratory-grade aspirin, paracetamol, and ibuprofen ("Experimental"). After culture, embryo morphological and developmental parameters were documented using standardized scoring systems at each dosage concentration. The assessed concentration in rat serum culture ranged from 1.23 to 13.57 mg/mL for aspirin and 0.06-4.93 mg/mL for paracetamol and ibuprofen. The equivalent respective human dosages were 600-6600 mg and 30-2400 mg. RESULTS: Between-group comparisons ("Control" vs "Experimental") and post-hoc pair-wise tests, adjusted for multiple comparisons, indicating no statistically significant effect on crown-rump length (p > .21), head length (p > .28), somite number (p > .25), incidence of absent hindlimb buds (p > .18), yolk sac circulation score (p > .07) and posterior neuropore closure (p > .35) in the aspirin, paracetamol and ibuprofen experiments. All embryos had forelimb buds, closed anterior neuropores and none had neural tube defects. CONCLUSION: This study has demonstrated that there are no safety concerns regarding high-dose aspirin, ibuprofen, and paracetamol on mice's embryonic development.