In-utero Exposure Research Articles

In-utero exposure to tenofovir disoproxil fumarate pre-exposure prophylaxis and growth metrics in HIV unexposed breastfed infants in South Africa: a post hoc analysis of the CAP 016 PrEP in pregnancy RCT.

We evaluated growth metrics in HIV unexposed African breastfed infants in the first 18 months of life in association with in-utero exposure to Tenofovir Diphosphate Fumarate (TDF) containing pre-exposure prophylaxis (PrEP). We conducted a secondary data analysis of a TDF-PrEP randomized control trial (CAP016 RCT). Pregnant women without HIV were randomized to initiating TDF-PrEP in pregnancy (Immediate-PrEP-IP) or deferred initiation of TDF-PrEP at cessation of breastfeeding (Deferred-PrEP-DP). Infant weight (W), length (L), and head circumference (HC) were measured at birth and 6, 26, 50, and 74 weeks of age. Stored dried blood spot samples from pregnant women randomized to the IP arm were used to measure tenofovir-diphosphate (TFV-DP) levels. Age-stratified mean weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head circumference-for-age (HCAZ) Z-scores were compared between infants exposed to varying TFV-DP concentrations and infants in the DP arm. A total of 455 mother-infant pairs were included in the secondary analysis, 228 in the IP arm and 227 in the DP arm. WAZ, LAZ, WLZ, and HCAZ scores were comparable between infants in the Deferred-PrEP arm and Immediate-PrEP arm. In a mixed-effects linear regression model adjusting for maternal age, body mass index, socioeconomic and newborn characteristics, in-utero exposure to varying TFV-DP levels was not associated with WAZ (β = -0.52), LAZ (β = -0.46), WLZ (β = -0.43) and HCAZ (β = -0.11) scores over time. There was no evidence of an association between growth metrics in the first 18 months of life and in-utero exposure to TFV-DP among breastfed HIV unexposed infants.

IN UTERO EXPOSURE TO THE DUTCH HUNGER WINTER AND THE PACE OF BIOLOGICAL AGING

Abstract Adults with histories of early-life adversity experience younger age-of-onset for aging-related disease and shorter lifespan, suggesting an accelerated pace of biological aging. To test this hypothesis, we analyzed data from an established natural experiment: in-utero exposure to famine conditions induced by a Nazi blockade of the Southern Netherlands in Winter 1944-5. We analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N=951). DHWFS enrolled survivors of in-utero famine exposure, matched controls born in the same hospitals as the survivors immediately prior to and following the famine period, and siblings of these individuals. Blood samples were collected when the famine survivors were aged 58. We analyzed blood DNA methylation data to measure the GrimAge and PhenoAge 2nd-generation epigenetic clocks and the DunedinPACE 3rd-generation clock. We tested if famine survivors were biologically older and aging faster as compared to controls. We found that famine survivors had faster DunedinPACE pace of aging, as compared with controls, but similar PhenoAge and GrimAge biological ages. In sex-stratified analyses, we found stronger effects of famine exposure in women as compared with men, including for the GrimAge and PhenoAge clocks; among women, famine exposure was associated with faster DunedinPACE and older GrimAge and PhenoAge, whereas in men effect-sizes were near zero. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Sibling-difference analyses reproduced size and direction of effect estimates. Findings provide natural-experiment evidence for long-term effects of in-utero famine exposure on the pace biological aging.

CASUAL EFFECTS OF EARLY-LIFE ADVERSITY AND MID/LATE-LIFE BEHAVIORAL INTERVENTION ON THE PACE OF BIOLOGICAL AGING

Abstract Epigenetic clocks have taken gerontology by storm. With the advent of 2nd and 3rd generation epigenetic clocks, including GrimAge and DunedinPACE, the field now has genomic biomarkers of aging that exhibit strong and consistent associations with aging-related morbidity and mortality. But the causes of variation in these powerful indices of aging-related biological changes remain poorly understood. In this symposium, we present four studies at the vanguard of research to elucidate causal drivers of 2nd and 3rd generation epigenetic clocks drawn from four disciplines. From life-course epidemiology, we present a natural-experiment study of the long-term impact of in-utero famine exposure. From economics, we present a quasi-natural experiment study of long-term impacts of early-life exposure to the Great Depression. From psychology, we present results from a randomized controlled trial (RCT) of cognitive behavioral therapy (CBT) for insomnia in older adults. And from geroscience, we present results from an RCT of long-term calorie restriction in healthy, non-obese adults (CALERIE). These studies report novel and important findings that suggest early-life adversity acts to accelerate the pace of biological aging –and— that it may be possible to slow the pace of biological aging in mid- and later-life through behavioral intervention. They also illustrate study designs and methods that can help move the field forward as costs for measurement of epigenetic clocks fall, enabling their introduction into many more cohort and intervention studies.

Di-(2-ethylhexyl) phthalate exacerbates abnormalities of testicular development in F1 males via inhibition the Wnt/β-catenin signaling pathway

The theory of “Developmental Origins of Health and Disease (DOHaD)” espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bw•d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/β-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/β-catenin signaling pathway in DEHP-induced male reproductive disorders.

Polycyclic aromatic hydrocarbon (PAH) source identification and a maternal transfer case study in threatened killer whales (Orcinus orca) of British Columbia, Canada

The northeastern Pacific (NEP) Ocean spans the coast of British Columbia (Canada) and is impacted by anthropogenic activities including oil pipeline developments, maritime fossil fuel tanker traffic, industrial chemical effluents, agricultural and urban emissions in tandem with stormwater and wastewater discharges, and forest wildfires. Such events may expose surrounding marine environments to toxic polycyclic aromatic hydrocarbons (PAHs) and impact critical habitats of threatened killer whales (Orcinus orca). We analyzed skeletal muscle and liver samples from stranded Bigg’s killer whales and endangered Southern Resident killer whales (SRKWs) for PAH contamination using LRMS. C3-phenanthrenes/anthracenes (mean: 632 ng/g lw), C4-dibenzothiophenes (mean: 334 ng/g lw), and C4-phenanthrenes/anthracenes (mean: 248 ng/g lw) presented the highest concentrations across all tissue samples. Diagnostic ratios indicated petrogenic-sourced contamination for SRKWs and pyrogenic-sourced burdens for Bigg’s killer whales; differences between ecotypes may be attributed to habitat range, prey selection, and metabolism. A mother-fetus skeletal muscle pair provided evidence of PAH maternal transfer; low molecular weight compounds C3-fluorenes, dibenzothiophene, and naphthalene showed efficient and preferential exposure to the fetus. This indicates in-utero exposure of PAH-contamination to the fetus. Our results show that hydrocarbon-related anthropogenic activities are negatively impacting these top predators; preliminary data found here can be used to improve oil spill and other PAH pollution management and regulation efforts, and inform policy to conserve killer whale habitats in the NEP.

Effects of in-utero personal exposure to PM2.5 sources and components on birthweight

In-utero exposure to fine particulate matter (PM2.5) and specific sources and components of PM2.5 have been linked with lower birthweight. However, previous results have been mixed, likely due to heterogeneity in sources impacting PM2.5 and due to measurement error from using ambient data. Therefore, we investigated the effect of PM2.5 sources and their high-loading components on birthweight using data from 198 women in the 3rd trimester from the MADRES cohort 48-h personal PM2.5 exposure monitoring sub-study. The mass contributions of six major sources of personal PM2.5 exposure were estimated for 198 pregnant women in the 3rd trimester using the EPA Positive Matrix Factorization v5.0 model, along with their 17 high-loading chemical components using optical carbon and X-ray fluorescence approaches. Single- and multi-pollutant linear regressions evaluated the association between personal PM2.5 sources/components and birthweight, adjusting for gestational age, maternal age, race, infant sex, parity, diabetes status, temperature, maternal education, and smoking history. Participants were predominately Hispanic (81%), with a mean (SD) gestational age of 39.1 (1.5) weeks and age of 28.2 (6.0) years. Mean birthweight was 3295.8 g (484.1) and mean PM2.5 exposure was 21.3 (14.4) µg/m3. A 1 SD increase in the mass contribution of the fresh sea salt source was associated with a 99.2 g decrease in birthweight (95% CI − 197.7, − 0.6), and aged sea salt was associated with a 70.1 g decrease in birthweight (95% CI − 141.7, 1.4). Magnesium, sodium, and chlorine were associated with lower birthweight, which remained after adjusting for PM2.5 mass. This study found evidence that major sources of personal PM2.5 including fresh and aged sea salt were negatively associated with birthweight, with the strongest effect on birthweight from Na and Mg. The effect of crustal and fuel oil sources differed by infant sex with negative associations seen in boys compared to positive associations in girls.

Developmental impairment in children exposed during pregnancy to maternal SARS-COV2: A Brazilian cohort study

ObjectivesTo determine the effects of in-utero exposure to maternal SARS-CoV-2 infection on offspring's neurodevelopment during the first year of life. MethodsWe performed a prospective cohort of babies exposed to SARS-CoV-2 during pregnancy, and a control group (CG) of unexposed babies in a low-income area in Brazil. Children's neurodevelopment was assessed using the guide for Monitoring Child Development in the Integrated Management of Childhood Illness context for both groups (at 1,2,3,4,5,6, 9, and 12 months), and the Ages & Stages Questionnaire (ASQ-3) for the exposed group (EG) (at 4, 6 and 12 months). ResultsWe followed 137 children for 1 year, 69 in the COVID-19-EG, and 68 in the CG. All mothers were unvaccinated at the time of cohort inclusion, and maternal demographics were similar in the two groups. 20.3% of EG children and 5.9% of the CG received a diagnosis of neurodevelopmental delay within 12 months of life (P = 0.013, relative risk = 3.44; 95% confidence interval, 1.19- 9.95). For the EG, the prevalence of neurodevelopment impairment using Ages & Stages Questionnaire was 35.7% at 4 months, 7% at 6 months, and 32.1% at 12 months. ConclusionSARS-CoV-2 exposure was associated with neurodevelopmental impairment, and specific guidelines are needed for the follow-up of these high-risk children to mitigate the long-term effects on children's health.

In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood

BackgroundThere is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing. However, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. MethodsFor this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004–2014). A total of 41 women who were born after the PBB contamination incident (1973–1974) and were prenatally exposed to PBBs, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). ResultsWomen in our study were, on average, 27.5 (SD:5.3) years old and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (>1.0–3.0 ppb) and high (>3.0 ppb) exposure had higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) μg/mg creatinine. There were no meaningful differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. ConclusionHigher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation.

Health Impacts of Wildfire Smoke on Children and Adolescents: A Systematic Review and Meta-analysis.

Wildfire smoke is associated with human health, becoming an increasing public health concern. However, a comprehensive synthesis of the current evidence on the health impacts of ambient wildfire smoke on children and adolescents, an exceptionally vulnerable population, is lacking. We conduct a systematic review of peer-reviewed epidemiological studies on the association between wildfire smoke and health of children and adolescents. We searched for studies available in MEDLINE, EMBASE, and Scopus from database inception up to October 11, 2022. Of 4926 studies initially identified, 59 studies from 14 countries were ultimately eligible. Over 33.3% of the studies were conducted in the USA, and two focused on multi-countries. The exposure assessment of wildfire smoke was heterogenous, with wildfire-specific particulate matters with diameters ≤ 2.5µm (PM2.5, 22.0%) and all-source (22.0%) PM2.5 during wildfire period most frequently used. Over half of studies (50.6%) focused on respiratory-related morbidities/mortalities. Wildfire smoke exposure was consistently associated with enhanced risks of adverse health outcomes in children/adolescents. Meta-analysis results presented a pooled relative risk (RR) of 1.04 (95% confidence interval [CI], 0.96-1.12) for all-cause respiratory morbidity, 1.11 (95% Ci: 0.93-1.32) for asthma, 0.93 (95% CI, 0.85-1.03) for bronchitis, and 1.13 (95% CI, 1.05-1.23) for upper respiratory infection, whilst - 21.71g for birth weight (95% CI, - 32.92 to - 10.50) per 10µg/m3 increment in wildfire-specific PM2.5/all-source PM2.5 during wildfire event. The majority of studies found that wildfire smoke was associated with multiple adverse health outcomes among children and adolescents, with respiratory morbidities of significant concern. In-utero exposure to wildfire smoke may increase the risk of adverse birth outcomes and have long-term impacts on height. Higher maternal baseline exposure to wildfire smoke and poor family-level baseline birthweight respectively elevated risks in preterm birth and low birth weight associated with wildfire smoke. More studies in low- and middle-income countries and focusing on extremely young children are needed. Despite technological progress, wildfire smoke exposure measurements remain uncertain, demanding improved methodologies to have more precise assessment of wildfire smoke levels and thus quantify the corresponding health impacts and guide public mitigation actions.

Maternal serum neonicotinoids during early-mid pregnancy and congenital heart diseases in offspring: An exploratory study

Experimental evidence has indicated a correlation between in-utero exposure to neonicotinoid pesticides (NEOs) and adverse birth outcomes in mammals. However, the distribution of NEO exposure during human pregnancy, as well as its association with congenital heart diseases (CHDs), the most common birth defects, are unclear. Our purpose was to explore the distribution of and contributing factors to NEO exposure in pregnant women during early-mid pregnancy and to assess the associations between NEOs and CHDs. This nested case-control study was conducted within an ongoing prospective birth cohort study and enrolled 141 CHD singletons and their 282 individually matched controls. Six “parent” NEOs and three NEO metabolites were measured in maternal serum collected at an average gestational age of 16 weeks, using liquid chromatography-tandem mass spectrometry. Logistic regression was used to quantify the NEOs-CHDs associations and explore potential contributing factors to serum NEO levels in controls. N-desmethyl acetamiprid (N-dm-ACE) and imidacloprid (IMI) were the most frequently detected NEOs, found in 100% and 20% of maternal sera, respectively. We did not find a statistically significant association between total NEOs and overall CHDs. However, there was a trend towards a higher risk of septal defects with greater serum NEOs (ORs ranged from 1.80 to 2.36), especially nitro-containing NEOs represented by IMI. Pregnant women with lower education had elevated serum total NEOs compared to women with higher education (OR = 48.39, 95% CI: 23.48–99.72). Pregnant women were primarily exposed to N-dm-ACE and IMI during early-mid pregnancy. Gestational exposure to NEOs may be associated with an increased risk of septal defects, but the evidence is limited at present. Education is a potential contributing factor to NEO exposure in pregnant women. Larger and more precise studies with longitudinal biospecimen collection, are recommended to validate our exploratory findings.

The siren song of cicadas: Early-life pesticide exposure and later-life male mortality

This paper studies the long-term effects of in-utero and early-life exposure to pesticide use on adulthood and old-age longevity. We use the cyclical emergence of cicadas in the eastern half of the United States as a shock that raises the pesticide use among tree crop growing farmlands. We implement a difference-in-difference framework and employ Social Security Administration death records over the years 1975–2005 linked to the complete count 1940 census. We find that males born in top-quartile tree-crop counties and exposed to a cicada event during fetal development and early-life live roughly 2.2 months shorted lives; those with direct farm exposure face a reduction of nearly a year. We provide empirical evidence to examine mortality selection before adulthood, endogenous fertility, and differential data linkage rates. Additional analyses suggests that reductions in education and income during adulthood are potential mechanisms of impact. Our findings add to our understanding of the relevance of early-life insults for old-age health and mortality.

Implementation of eat, sleep, console for Neonatal Opioid Withdrawal Syndrome (NOWS): A quality improvement project

BackgroundThe opioid abuse crisis has caused a 6-fold increased incidence of neonatal opioid withdrawal syndrome (NOWS) from 2000 to 2017. The Finnegan Neonatal Abstinence Scoring System (FNASS) has been used to score withdrawal symptoms since 1975. New research using the Eat, Sleep, Console (ESC) assessment and model of care has improved the care of infants with in-utero exposure to opioids. MethodsThe QI project at 2 hospitals compared 12 months of retrospective data to a prospective 12-month trial of ESC implementation. One hospital also compared ESC and FNASS simultaneously. Nurses and providers received training and education. ResultsIn the baseline period, 142 infants were scored for withdrawal, with an ALOS of 7.6 days, an average NICU LOS of 118.7 h (4.9 days), and 32 required pharmacologic treatment with an average length of treatment of 369.8 h (15.4 days). In the study period, 142 were assessed for withdrawal, with a decreased ALOS of 6.5 days (p = 0.2287), a decreased NICU LOS of 89.6 h (p = 0.2295), and 10 required pharmacologic treatment (p = 0.00024) with an increased average length of treatment of 387.3 h (p = 0.8609). Out of 71 infants assessed simultaneously with FNASS and ESC, 37 had FNASS scores that met the threshold for pharmacologic treatment, and only 6 infants received pharmacologic treatment. ConclusionImplementation of ESC improves the care of infants and reduces hospital stays and the need for pharmacologic intervention in the management of NOWS. It optimizes the infant's functioning through nonpharmacologic care provided by parent(s) reserving pharmacologic treatment only for those infants unable to eat, sleep, or console.

Neonatal immune cells have heightened responses following in-utero exposure to chorioamnionitis or COVID-19.

Chorioamnionitis alters neonatal immune responses. Gestational COVID-19 infection is associated with adverse pregnancy outcomes, but its impact on neonatal immunity is unclear. We hypothesized that gestational COVID-19 exposure would result in exaggerated neonatal immune responses, similar to chorioamnionitis-exposed neonates. Term umbilical cord blood mononuclear cells (CBMCs) were isolated from neonates exposed to chorioamnionitis, gestational COVID-19 or unexposed controls. CBMCs were cultured and stimulated with heat-killed Escherichia coli, Streptococcus agalactiae or Staphylococcus epidermidis. A multiplexed protein assay was used to measure cytokine levels in cell culture supernatants and flow cytometry was used to evaluate cellular-level cytokine expression. Both chorioamnionitis-exposed and COVID-19 exposed CBMCs demonstrated upregulation of IL-1β and IL-6 compared to unexposed CBMCs, while only COVID-19 exposure resulted in IL-8 upregulation. There were no differences between chorioamnionitis-exposed and COVID-19 exposed CBMCs when these groups were directly compared. Flow cytometry demonstrated immune cell subset specific differences in cytokine expression between the exposure groups. The fetal/neonatal response to maternal inflammation differed based on immune cell subset and etiology of inflammation, but the global neonatal cytokine responses were similar between exposure groups. This suggests that targeting perinatal inflammation rather than the specific etiology may be a possible therapeutic approach. Neonatal immune cells have similar pathogen-associated global cytokine responses, but different cell-level immune responses, following in-utero exposure to chorioamnionitis or COVID-19. This is the first study to directly compare immune responses between neonates exposed to chorioamnionitis and COVID-19. This suggests that the fetal/neonatal cellular response to perinatal inflammation differs based on the etiology and severity of maternal inflammation, but still results in a similar overall inflammatory profile regardless of the cause of perinatal inflammation.

Diuretic use in pregnancy: data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC)

Abstract Background Data on diuretic use during pregnancy are limited and show varying results. Therefore, it remains unsure whether they can be safely used. Purpose Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. Methods The Registry of Pregnancy and Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital abnormalities and fetal growth, after adjustment for potential confounders. Results Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (n=332, 86%). Women who used diuretics during pregnancy, compared to those without, were older (30.9 vs 29.4 years; p<0.001), had a higher BMI (25.3 vs 23.9 kg/m2; p<0.001), were more likely to live in a low-middle income country (63.1% vs 38.1%; p<0.001), and more likely to have chronic hypertension (9.9% vs 6.4%; p=0.007), atrial fibrillation/flutter (7.1% vs 1.5%; p<0.001), signs of heart failure (27.2% vs 9.2%; p<0.001) and/or an estimated LVEF below 40% (19.9% vs 3.3%; <0.001). Diuretic use during the first trimester was not independently associated with fetal or neonatal congenital abnormalities (OR 1.30; 95% CI 0.66-2.55). After adjustment for confounders, diuretic use during pregnancy was not independently associated with small for gestational age (OR 1.36; 95% CI 0.97-1.91). Conclusions Based on our data, diuretics can be used safely during pregnancy and discontinuation of diuretics prior or during pregnancy in women with appropriate indication seems not to be necessary. However, for treatment of systemic hypertension, alternative antihypertensive agents with more safety data regarding perinatal outcomes, such as labetalol or nifedipine, are preferred.

The role of parental composition in improved birth outcomes during the COVID-19 pandemic in Finland

Abstract Background In some high-income contexts, the COVID-19 pandemic was associated with improved birth outcomes, which was hypothesised to be caused by a positive effect of the pandemic on maternal health. Conversely, an improvement in birth outcomes may have been driven by pandemic-induced compositional changes in parental characteristics, which are associated with health outcomes at birth. Research on this consequence of the COVID-19 pandemic is critical for understanding pandemic-induced changes in population health (inequalities) and planning of public service provision. Methods We analysed population-wide data on birth outcomes and parental sociodemographic characteristics from Finland collected between January 2015 and December 2021 (n = 336,000). The total effect of pandemic-induced compositional changes on birth weight and preterm birth rate was estimated by segmented regression models using three conception cohorts: a) conceived prior to May 2019, b) conceived between June 2019 and February 2020 (to account for in-utero exposure to the pandemic), and c) conceived during the pandemic between March 2020 and February 2021 (to prevent selection bias). Preliminary Results Adjusting for secular trends and seasonality, and accounting for in-utero exposure to the pandemic, the estimated effect of parental compositional change on average birth weight was 36.5 grams [95%CI: 24.8; 48.3]. Correspondingly, this compositional change was associated with a 16.2% [95%CI: 8.8%; 23%] lower risk of preterm birth for babies conceived during the pandemic. Conclusions Pandemic-induced changes in parental composition drove the modest increase in birth weight and substantial reduction in preterm births for babies conceived during the pandemic. Should the postponed pregnancies among population groups at risk for worse birth outcomes eventually realise post-COVID-19, health care and educational systems may need to prepare for cohort-specific variations in service demand. Key messages • Improvement in birth weight and preterm birth rate among babies conceived during the COVID-19 pandemic were driven by pandemic-induced changes in parental composition. • Further research using natural experimental designs on this compositional change and health outcomes can inform future public service provision.

Neonatal AVPR1a Methylation and In-Utero Exposure to Maternal Smoking.

(1) Introduction: Epigenetic changes have been proposed as a biologic link between in-utero exposure to maternal smoking and health outcomes. Therefore, we examined if in-utero exposure to maternal smoking was associated with infant DNA methylation (DNAm) of cytosine-phosphate-guanine dinucleotides (CpG sites) in the arginine vasopressin receptor 1A AVPR1a gene. The AVPR1a gene encodes a receptor that interacts with the arginine vasopressin hormone and may influence physiological stress regulation, blood pressure, and child development. (2) Methods: Fifty-two infants were included in this cohort study. Multivariable linear models were used to examine the effect of in-utero exposure to maternal smoking on the mean DNAm of CpG sites located at AVPR1a. (3) Results: After adjusting the model for substance use, infants with in-utero exposure to maternal smoking had a reduction in DNAm at AVPR1a CpG sites by -0.02 (95% CI -0.03, -0.01) at one month of age. In conclusion, in-utero exposure to tobacco smoke can lead to differential patterns of DNAm of AVPR1a among infants. Conclusions: Future studies are needed to identify how gene expression in response to early environmental exposures contributes to health outcomes.

Types of diabetes during pregnancy and risk of depression and anxiety in offspring from childhood to young adulthood.

To assess maternal pre-existing type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM) during pregnancy and risk of depression and anxiety from childhood to young adulthood in offspring. This birth cohort included singletons born during 1995-2015, followed using electronic medical records through 2020. Cox regression was used to estimate hazard ratio (HR) of depression or anxiety diagnosis during follow-up associated with in-utero exposure to maternal diabetes. Among 439 590 offspring, 29 891 (6.8%) had depression and 51 918 (11.8%) had anxiety. T1D, followed by T2D and GDM requiring antidiabetes medication were associated with risk of depression and anxiety in offspring. Compared with no diabetes during pregnancy, the adjusted HRs (95% confidence interval) of depression in offspring associated with T1D, T2D or GDM requiring medications were 1.44 (1.09-1.91), 1.30 (1.15-1.47) and 1.18 (1.11-1.26) respectively; conversely, HRs were 0.97 (0.82-1.15) for T2D and 0.99 (0.94-1.04) for GDM without medications. The associations with anxiety followed similar patterns. The significant associations were observed for offspring ages 5-12 and >12-18 years and attenuated for 18-25 years. These data suggest that the severity of diabetes (T1D vs. T2D requiring medications vs. GDM requiring medications) during pregnancy may increase the vulnerability of offspring for depression or anxiety.

Use of CFTR modulators in special populations, part 1: Pregnancy and lactation.

Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for duplications and relevance. Relative to pregnancy or breastfeeding, a total of 18 publications were included for review. Majority of case reports and surveys concluded maternal and infant health were preserved throughout gestation. Likewise, breastfeeding infant case reports show possible changes in liver function and lens opacities, though risk may be increased with both in-utero and breastfeeding exposure. Ivacaftor (IVA) and lumacaftor (LUM) concentrations in fetal cord blood and maternal blood were found to be equivalent. Yet, low concentrations of IVA and LUM were detectable in breastmilk and infant plasma. Current safety data surrounding CFTR modulator use in the setting of pregnancy and lactation is relatively reassuring; however, long-term safety remains unclear, necessitating ongoing observation, and reporting by care teams. As such, treatment decisions should be individualized and coproduced.

6.36 Associations Between In-Utero Superstorm Sandy Exposure and Suboptimal Basal Ganglia Brain Development: Moderating Roles of Clinical Behavioral Phenotypes

6.36 Associations Between In-Utero Superstorm Sandy Exposure and Suboptimal Basal Ganglia Brain Development: Moderating Roles of Clinical Behavioral Phenotypes

Increased HbA1c During Pregnancy is Associated with In-utero Exposure to PM2.5 at Levels below Current Air Quality Guidelines

Increased HbA1c During Pregnancy is Associated with In-utero Exposure to PM2.5 at Levels below Current Air Quality Guidelines