Cohort profile: the Environmental Reproductive and Glucose Outcomes (ERGO) Study (Boston, Massachusetts, USA) - a prospective pregnancy cohort study of the impacts of environmental exposures on parental cardiometabolic health.

PURPOSE: Pregnancy and the postpartum period are increasingly recognised as sensitive windows for cardiometabolic disease risk. Growing evidence suggests environmental exposures, including endocrine-disrupting chemicals (EDCs), are associated with an increased risk of pregnancy complications that are associated with long-term cardiometabolic risk. However, the impact of perinatal EDC exposure on subsequent cardiometabolic risk post-pregnancy is less understood. The Environmental Reproductive and Glucose Outcomes (ERGO) Study was established to investigate the associations of environmental exposures during the perinatal period with post-pregnancy parental cardiometabolic health. PARTICIPANTS: Pregnant individuals aged ≥18 years without pre-existing diabetes were recruited at <15 weeks of gestation from Boston, Massachusetts area hospitals. Participants completed ≤4 prenatal study visits (median: 12, 19, 26, 36 weeks of gestation) and 1 postpartum visit (median: 9 weeks), during which we collected biospecimens, health histories, demographic and behavioural data, and vitals and anthropometric measurements. Participants completed a postpartum fasting 2-hour 75 g oral glucose tolerance test. Clinical data were abstracted from electronic medical records. Ongoing (as of 2024) extended post-pregnancy follow-up visits occur annually following similar data collection protocols. FINDINGS TO DATE: We enrolled 653 unique pregnancies and retained 633 through delivery. Participants had a mean age of 33 years, 10% (n=61) developed gestational diabetes and 8% (n=50) developed pre-eclampsia. Participant pregnancy and postpartum urinary phthalate metabolite concentrations and postpartum glycaemic biomarkers were quantified. To date, studies within ERGO found higher exposure to phthalates and phthalate mixtures, and separately, higher exposure to radioactive ambient particulate matter, were associated with adverse gestational glycaemic outcomes. Additionally, certain personal care products used in pregnancy, notably hair oils, were associated with higher urinary phthalate metabolite concentrations, earlier gestational age at delivery and lower birth weight. FUTURE PLANS: Future work will leverage the longitudinal data collected on pregnancy and cardiometabolic outcomes, environmental exposures, questionnaires, banked biospecimens and paediatric data within the ERGO Study.

Associations of urinary polycyclic aromatic hydrocarbon (PAH) metabolites and their mixture with thyroid hormone concentration during pregnancy in the LIFECODES cohort: A repeated measures study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine disruptors resulting from incomplete combustion. Pregnancy represents a particularly vulnerable period to such exposures, given the significant influence of hormone physiology on fetal growth and pregnancy outcomes. Maternal thyroid hormones play crucial roles in fetal development and pregnancy outcomes. However, limited studies have examined gestational PAH exposure and maternal thyroid hormones during pregnancy. METHODS: Our study included 439 women enrolled in the LIFECODES birth cohort in Boston, aiming to explore the relationship between urinary PAH metabolites and thyroid hormones throughout pregnancy. Urine samples for PAH metabolite analysis and plasma samples for thyroid hormone were measured up to four visits throughout gestation. Single pollutant analyses employed linear mixed effect models to investigate individual associations between each PAH metabolite and thyroid hormone concentration. Sensitivity analyses were conducted to assess potential susceptibility windows and fetal-sex-specific effects of PAH exposure. Mixture analyses utilized quantile g-computation to evaluate the collective impact of eight PAH metabolites on thyroid hormone concentrations. Additionally, Bayesian kernel machine regression (BKMR) was employed to explore potential non-linear associations and interactions between PAH metabolites. Subject-specific random intercepts were incorporated to address intra-individual correlation of serial measurements over time in both single pollutant and mixture analyses. RESULTS: Our findings revealed positive trends in associations between PAH metabolites and thyroid hormones, both individually and collectively as a mixture. Sensitivity analyses indicated that these associations were influenced by the study visit and fetal sex. Mixture analyses suggested non-linear relationships and interactions between different PAH exposures. CONCLUSIONS: This comprehensive investigation underscores the critical importance of understanding the impact of PAH exposures on thyroid hormone physiology during pregnancy. The findings highlight the intricate interplay between environmental pollutants and human pregnancy physiology, emphasizing the need for targeted interventions and public health policies to mitigate adverse outcomes associated with prenatal PAH exposure.

Prenatal Per- and Polyfluoroalkyl Substances (PFAS) and Maternal Oxidative Stress: Evidence from the LIFECODES Study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals linked to adverse pregnancy outcomes. Although their underlying biological mechanisms are not fully understood, evidence suggests PFAS may disrupt endocrine functions and contribute to oxidative stress (OS) and inflammation. OBJECTIVE: We examined associations between early pregnancy PFAS exposure and OS biomarkers, exploring potential effect modifications by fetal sex and maternal race. METHODS: We used data from 469 LIFECODES participants with measured plasma PFAS (median 10 weeks gestation) and repeated measures (median 10, 18, 26, and 35 weeks gestation) of urinary OS biomarkers [8-iso-prostaglandin-F2α (8-isoprostane) and 8-hydroxydeoxyguanosine (8-OHdG)]. Protein damage biomarkers (chlorotyrosine, dityrosine, and nitrotyrosine) were additionally measured in plasma from a subset (N=167) during the third visit. Associations between each PFAS and OS biomarkers were examined using linear mixed-effects models and multivariable linear regressions, adjusting for potential confounders, including maternal age, race, education level, pre-pregnancy BMI, insurance status, and parity. Effect modifications were evaluated by including an interaction term between each PFAS and fetal sex or maternal race in the models. RESULTS: We observed significant positive associations between PFOS and 8-isoprostane, with a 9.68% increase in 8-isoprostane levels (95% CI: 0.10%, 20.18%) per interquartile range increase in PFOS. In contrast, PFUA was negatively associated [9.32% (95% CI: -17.68%, -0.11%)], while there were suggestive positive associations for MPAH and PFOA with 8-isoprostane. The associations of several PFAS with 8-OHdG varied by fetal sex, showing generally positive trends in women who delivered females, but negative or null in those who delivered males. No significant effect modification by maternal race was observed. CONCLUSIONS: This study provides evidence linking PFAS exposure to OS during pregnancy, with potential sex-specific effects of certain PFAS on 8-OHdG. Further research should explore additional OS/inflammatory biomarkers and assess the modifying effects of dietary and behavioral patterns across diverse populations.

TNF-α inhibitor use during pregnancy and the risk of preeclampsia: population-based cohort study.

BACKGROUND: Although the clinical importance of preeclampsia is widely recognized, few treatment options are available for prevention. TNF-α inhibitors have been hypothesized to potentially prevent the disease. We aimed to examine whether exposure to TNF-α inhibitors during pregnancy reduces the risk of preeclampsia. METHODS: We conducted a population-based pregnancy cohort study using nationwide samples of publicly (Medicaid data, 2000-2018) and commercially (MarketScan Research Database, 2003-2020) insured pregnant women linked to their liveborn infants. Exposure was ascertained based on a filled prescription or administration code for TNF-α inhibitors during the first and second trimester of pregnancy. The outcomes included early-onset preeclampsia, late-onset preeclampsia, and small-for-gestational age. For baseline confounding adjustment, we leveraged propensity score overlap weights to estimate risk ratios (RR). RESULTS: Among 4 315 658 pregnancies in the Medicaid and the MarketScan cohort, 2736 (0.063%) were exposed to TNF-α inhibitors during the first trimester and 1712 (0.040%) during the second trimester. After adjustment, the risk of early-onset preeclampsia was not decreased among mothers exposed during the first trimester compared with unexposed women with treatment indications [RRpooled: 1.25, 95% confidence interval (CI) 0.93-1.67]. Similarly, the risk of late-onset preeclampsia was not decreased among mothers exposed during the second trimester compared with unexposed women (RRpooled: 0.99, 95% CI 0.81-1.22). CONCLUSION: Contrary to the hypothesis, exposure to TNF-α inhibitors during pregnancy did not appear to be associated with a reduced risk of early-onset or late-onset preeclampsia. These findings do not support consideration of the use of TNF-α inhibitors for the prevention of preeclampsia.

Supplementation with antioxidant micronutrients in pregnant women with obesity: a randomized controlled trial.

BACKGROUND/OBJECTIVE: Obesity increases maternal morbidity and adversely affects child health. Maternal inflammation may play a role in adverse outcomes. The objective of this study was to determine whether providing a higher dose of antioxidant micronutrients to pregnant women with obesity would raise concentrations of key antioxidant vitamins and impact inflammation and oxidative stress during pregnancy. SUBJECTS/METHODS: This was a double-blind, randomized controlled trial. We recruited pregnant women with a body mass index (BMI) ≥ 30 kg/m2 at their initial prenatal visit ( < 13 weeks gestation) and collected blood and urine samples at baseline, 24-28 weeks, and 32-36 weeks to measure micronutrient concentrations (vitamin C, E, B6 and folate), markers of inflammation (C-reactive protein, interleukin-6, 8, and 1ß) and oxidative stress (8-epi-PGF2α and malondialdehyde). We collected maternal and infant health data from enrollment to delivery as secondary outcomes. We enrolled 128 participants (64 in each arm), and 98 (49 in each arm) completed follow-up through delivery. INTERVENTION: Both groups received a standard prenatal vitamin containing the recommended daily allowance of micronutrients in pregnancy. In addition, the intervention group received a supplement with 90 mg vitamin C, 30 αTU vitamin E, 18 mg vitamin B6, and 800 µg folic acid, and the control group received a placebo. RESULTS: The intervention group had higher vit B6 (log transformed (ln), ß 24-28 weeks: 0.76 nmol/L (95% CI: 0.40, 1.12); ß 32-36 weeks: 0.52 nmol/L (95% CI: 0.17, 0.88)) than the control group. Vitamins C, E, erythrocyte RBC folate concentrations did not differ by randomization group. The intervention did not impact biomarkers of inflammation or oxidative stress. There were no differences in maternal or neonatal clinical outcomes by randomization group. CONCLUSIONS: Higher concentrations of antioxidant vitamins during pregnancy increased specific micronutrients and did not impact maternal inflammation and oxidative stress, which may be related to dosing or type of supplementation provided. CLINICAL TRIAL REGISTRATION: Clinical Trial Identification Number: NCT02802566; URL of the Registration Site: www. CLINICALTRIALS: gov .

Predictors of upstream inflammation and oxidative stress pathways during early pregnancy.

BACKGROUND: Inflammation and oxidative stress are critical to pregnancy, but most human study has focused on downstream, non-causal indicators. Oxylipins are lipid mediators of inflammation and oxidative stress that act through many biological pathways. Our aim was to characterize predictors of circulating oxylipin concentrations based on maternal characteristics. METHODS: Our study was conducted among 901 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured a targeted panel of oxylipins in early pregnancy plasma and urine samples from several biosynthetic pathways, defined by the polyunsaturated fatty acid (PUFA) precursor and enzyme group. We evaluated levels across predictors, including characteristics of participants' pregnancy, socioeconomic determinants, and obstetric and medical history. RESULTS: Current pregnancy and sociodemographic characteristics were the most important predictors of circulating oxylipins concentrations. Plasma oxylipins were lower and urinary oxylipins higher for participants with a later gestational age at sampling (13-23 weeks), higher prepregnancy BMI (obesity class I, II, or III), Black or Hispanic race and ethnicity, and lower socioeconomic status (younger age, lower education, and uninsured). For example, compared to those with normal or underweight prepregnancy BMI, participants with class III prepregnancy obesity had 45-46% lower plasma epoxy-eicosatrienoic acids, the anti-inflammatory oxylipins produced from arachidonic acid (AA) by cytochrome P450, and had 81% higher urinary 15-series F2-isoprostanes, an indicator of oxidative stress produced from non-enzymatic AA oxidation. Similarly, in urine, Black participants had 92% higher prostaglandin E2 metabolite, a pro-inflammatory oxylipin, and 41% higher 5-series F2-isoprostane, an oxidative stress indicator. CONCLUSIONS: In this large pregnancy study, we found that circulating levels of oxylipins were different for participants of lower socioeconomic status or of a systematically marginalized racial and ethnic groups. Given associations differed along biosynthetic pathways, results provide insight into etiologic links between maternal predictors and inflammation and oxidative stress.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Cord blood DNA methylation signatures associated with preeclampsia are enriched for cardiovascular pathways: insights from the VDAART trial.

BACKGROUND: Preeclampsia has been associated with maternal epigenetic changes, in particular DNA methylation changes in the placenta. It has been suggested that preeclampsia could also cause DNA methylation changes in the neonate. We examined DNA methylation in relation to gene expression in the cord blood of offspring born to mothers with preeclampsia. METHODS: This study included 128 mother-child pairs who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), where assessment of preeclampsia served as secondary outcome. We performed an epigenome-wide association study of preeclampsia and cord blood DNA methylation (Illumina 450 K chip). We then examined gene expression of the same subjects for validation and replicated the gene signatures in independent DNA methylation datasets. Lastly, we applied functional enrichment and network analyses to identify biological pathways that could potentially be involved in preeclampsia. FINDINGS: In the cord blood samples (n = 128), 263 CpGs were differentially methylated (FDR <0.10) in preeclampsia (n = 16), of which 217 were annotated. Top pathways in the functional enrichment analysis included apelin signaling pathway and other endothelial and cardiovascular pathways. Of the 217 genes, 13 showed differential expression (p's < 0.001) in preeclampsia and 11 had been previously related to preeclampsia (p's < 0.0001). These genes were linked to apelin, cGMP and Notch signaling pathways, all having a role in angiogenic process and cardiovascular function. INTERPRETATION: Preeclampsia is related to differential cord blood DNA methylation signatures of cardiovascular pathways, including the apelin signaling pathway. The association of these cord blood DNA methylation signatures with offspring's long-term morbidities due to preeclampsia should be further investigated. FUNDING: VDAART is funded by National Heart, Lung, and Blood Institute grants of R01HL091528 and UH3OD023268. HMK is supported by Jane and Aatos Erkko Foundation, Paulo Foundation, and the Pediatric Research Foundation. HM is supported by K01 award from NHLBI (1K01HL146977-01A1). PK is supported by K99HL159234 from NIH/NHLBI.

A randomized controlled trial comparing the efficacy of nifedipine and enalapril in the postpartum period.

BACKGROUND: Postpartum hypertension is a common medical complication of pregnancy and is associated with increased healthcare use, including unplanned interactions with the medical system and readmission, which can add significant stress to both a newly postpartum patient and the medical care delivery system. We currently do not know what the best antihypertensive treatment for postpartum hypertension is and tend to use antihypertensives commonly used during pregnancy. However, the mechanism of action of angiotensin-converting enzyme inhibitors may be well suited for the pathophysiology of hypertension in the postpartum period and may help to provide better control of hypertension and, in turn, decrease healthcare use. OBJECTIVE: This study aimed to determine if enalapril is superior to nifedipine in preventing prolonged hospitalizations, unplanned medical visits, and/or readmission among women with postpartum hypertension. STUDY DESIGN: We performed an open-label, randomized controlled trial (ClinicalTrials.gov registered: NCT04236258) in which patients ≥18 years with chronic hypertension, gestational hypertension, or preeclampsia were recruited to receive either 10 mg enalapril daily or 30 mg extended-release nifedipine daily as an initial antihypertensive agent in the period from delivery to 6 weeks postpartum. Recruitment occurred at a tertiary academic hospital from January 2020 to February 2021. Exclusion criteria included being on an antihypertensive when pregnancy started or requiring ≥2 daily antihypertensives during pregnancy. The antihypertensive regimen was managed by the participants' obstetrical provider after the initial randomization. The primary outcome was a composite of prolonged hospitalization, unplanned clinic visits, triage visits, and/or readmission. A total of 40 patients in each arm were needed to detect a decrease in the primary outcome rate from 70% to 40% (α=0.05; power 0.80). Analyses were performed based on the intention-to-treat principal, and each arm was oversampled because of the risk for participant dropout. RESULTS: A total of 47 patients were randomized to each arm. Aside from the mode of delivery and twin gestation, the maternal demographics were similar between the 2 groups. The primary outcome occurred in 31 of 47 patients (66%) randomized to the nifedipine group and in 30 of 47 (64%) randomized to the enalapril group (P=.83). There was no significant difference in the primary outcome after controlling for mode of delivery and twin gestation. More patients in the enalapril arm had a second antihypertensive added during their primary hospitalization (16 vs 6) and more patients in the nifedipine arm were still on their antihypertensive at 2 weeks postpartum (42 vs 36). There were no adverse events in either group. CONCLUSION: Enalapril was not superior to nifedipine when used as an initial antihypertensive in the immediate postpartum period in terms of decreasing healthcare use.

Validation of parental recall questionnaire to classify preterm delivery subtypes: Spontaneous preterm labour, preterm premature rupture of membranes and clinician-initiated preterm delivery.

BACKGROUND: Preterm delivery (PTD) includes three main presenting subtypes: spontaneous preterm labour (sPTL), preterm premature rupture of membranes (pPROM) and clinician-initiated preterm delivery (ciPTD). PTD subtype data are rarely available from birth registries and are onerous to derive from medical records. OBJECTIVES: To develop and test the validity of a questionnaire to classify PTD subtype based on birthing parent recall of labour and delivery events. METHODS: The questionnaire was sent in 2022 to 581 patients with PTD history documented in the LIFECODES study, a hospital-based birth cohort in Boston, Massachusetts. Eighty-two respondents reported 94 PTDs that could be linked to medical records. Data on PTD subtype were extracted from medical records as the reference standard. RESULTS: Medical records indicated 47 spontaneous (24 sPTL, 23 pPROM) and 47 ciPTD deliveries occurring a median eight years earlier. The sensitivity and specificity of the recall questionnaire were 88% (95% confidence interval: 68, 97%) and 89% (79, 95%) for sPTL; 96% (78, 100%) and 94% (86, 98%) for pPROM; and 83% (69, 92%) and 100% (92, 100%) for ciPTD, respectively. Greater time since pregnancy did not degrade the sensitivity or specificity of the parental recall questionnaire. CONCLUSIONS: Although derived from a modest sample, the moderate-to-high sensitivity and specificity of the parental recall questionnaire to classify sPTL, pPROM and ciPTD demonstrates its potential for large studies of PTD and for correction of misclassification bias. Future studies are required to test the questionnaire in a variety of populations.

Longitudinal Associations between Ambient Air Pollution and Angiogenic Biomarkers among Pregnant Women in the LIFECODES Study, 2006-2008.

BACKGROUND: Exposures to ambient air pollution during pregnancy have been linked to adverse pregnancy outcomes such as preeclampsia and fetal growth restriction. Although evidence has shown that women with preeclampsia have higher ratio of soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF ratio), the potential impact of air pollution on markers of placental growth and function has not been well studied. OBJECTIVES: We aimed to examine longitudinal associations between ambient air pollution exposure and angiogenic factors among pregnant women in LIFECODES, a prospective birth cohort and biorepository in Massachusetts in the United States. METHODS: PlGF and sFlt-1 were measured among pregnant women using plasma samples collected around 10, 18, 26, and 35 wk' gestation. Women's exposures to ozone (O3), fine particulate matter with aerodynamic diameter ≤2.5µm (PM2.5), and nitrogen dioxide (NO2) within 1, 2, 4, and 8 wk prior to each plasma sample collection were estimated based on geocoded residential addresses, and mixed effect linear regression models were fitted to assess their associations with sFlt-1/PlGF ratio, sFlt-1 (ng/mL), and PlGF (pg/mL). Percent changes in outcomes associated with each interquartile range increase in exposures were reported, along with their 95% confidence intervals. RESULTS: A total of 1,066 pregnant women were included. In the multipollutant models, significant associations were observed for increased sFlt-1/PlGF ratio (PM2.5 3-8 wk' gestation, NO2: 35-39 wk' gestation), elevated sFlt-1 (O3: 26-34 wk' gestation, PM2.5: 3-8 wk' gestation), decreased sFlt-1 (NO2: 4-8 wk' gestation), and decreased PlGF (NO2: 34-39 wk' gestation) after adjusting for sociodemographic status, smoking, drinking, body mass index, parity, history of chronic hypertension, and conception time. DISCUSSION: Exposures to PM2.5 during early pregnancy and exposures to O3 and NO2 during late pregnancy were associated with increased sFlt-1/PlGF ratio, elevated sFlt-1 and with decreased PlGF, which may be a potential mechanism underlying ambient air pollution's impacts on adverse pregnancy and birth outcomes. https://doi.org/10.1289/EHP11909.

Validation of a non-invasive prenatal test for fetal RhD, C, c, E, K and Fya antigens.

We developed and validated a next generation sequencing-(NGS) based NIPT assay using quantitative counting template (QCT) technology to detect RhD, C, c, E, K (Kell), and Fya (Duffy) fetal antigen genotypes from maternal blood samples in the ethnically diverse U.S. population. Quantitative counting template (QCT) technology is utilized to enable quantification and detection of paternally derived fetal antigen alleles in cell-free DNA with high sensitivity and specificity. In an analytical validation, fetal antigen status was determined for 1061 preclinical samples with a sensitivity of 100% (95% CI 99-100%) and specificity of 100% (95% CI 99-100%). Independent analysis of two duplicate plasma samples was conducted for 1683 clinical samples, demonstrating precision of 99.9%. Importantly, in clinical practice the no-results rate was 0% for 711 RhD-negative non-alloimmunized pregnant people and 0.1% for 769 alloimmunized pregnancies. In a clinical validation, NIPT results were 100% concordant with corresponding neonatal antigen genotype/serology for 23 RhD-negative pregnant individuals and 93 antigen evaluations in 30 alloimmunized pregnancies. Overall, this NGS-based fetal antigen NIPT assay had high performance that was comparable to invasive diagnostic assays in a validation study of a diverse U.S. population as early as 10 weeks of gestation, without the need for a sample from the biological partner. These results suggest that NGS-based fetal antigen NIPT may identify more fetuses at risk for hemolytic disease than current clinical practice, which relies on paternal genotyping and invasive diagnostics and therefore is limited by adherence rates and incorrect results due to non-paternity. Clinical adoption of NIPT for the detection of fetal antigens for both alloimmunized and RhD-negative non-alloimmunized pregnant individuals may streamline care and reduce unnecessary treatment, monitoring, and patient anxiety.

A century of Illinois hover flies (Diptera: Syrphidae): museum and citizen science data reveal recent range expansions, contractions, and species of potential conservation significance.

Hover flies of the family Syrphidae are a highly diverse group of insects that exhibit varied life histories and provide numerous ecosystem services. Despite their importance, they are highly understudied, and many biological and distributional patterns remain unknown in regions like the midwestern United States. Data from specimens exist in regional insect collections but is largely undigitized and thus inaccessible to much of the scientific community. Here, we report our efforts to identify, recurate, and digitize thousands of specimens from the Illinois Natural History Survey Insect Collection. We then combine these data with existing datasets to compile a comprehensive checklist of Illinois hover fly fauna, assess for temporal range expansion/contraction trends, and identify species of potential conservation significance. All total, the over 20,000 specimens/records we examined revealed 209 species within 71 genera and all 4 subfamilies of Syrphidae to have ever occurred in Illinois. Based on previously published data, 68 of these species are new Illinois state records and 36 expand the previously known range significantly. Numerous species found in Illinois historically have only recently been reported further north, while others of historically southern distribution appear to be extending their range northward, possibly due to anthropogenic factors like climate change. Furthermore, 73 species have not been reported in Illinois since at least 1995, and 27 are deemed to be of potential conservation significance with few to no recent records in the Midwest or elsewhere. Our findings illustrate the importance of routine expansion, curation, and digitization of natural history collections.

Prenatal per- and polyfluoroalkyl substances (PFAS) exposure in relation to preterm birth subtypes and size-for-gestational age in the LIFECODES cohort 2006-2008.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals widely used in consumer and industrial products. Numerous studies have linked prenatal PFAS exposures to increased risks of adverse pregnancy outcomes such as preterm birth (PTB) and small-for-gestational age (SGA).However, limited evidence is available for the effects of PFAS on PTB subtypes and large-for-gestational age (LGA). OBJECTIVE: To examine the associations of PFAS with PTB [overall, placental (pPTB), spontaneous (sPTB)], BW Z-score, and size-for-gestational age (SGA, LGA). METHODS: Our nested case-control study included 128 preterm cases and 373 term controls from the LIFECODES cohort between 2006 and 2008 (n = 501). Plasma concentrations of nine PFAS were measured in early pregnancy samples. Logistic regression was used to assess individual PFAS-birth outcome associations, while Bayesian Kernel Machine Regression (BKMR) was used to evaluate the joint effects of all PFAS. Effect modification by fetal sex was examined, and stratified analyses were conducted to obtain fetal sex-specific estimates. RESULTS: Compared to term births, the odds of pPTB were higher from an interquartile range increase in perfluorodecanoic acid (PFDA) (OR = 1.60, 95% CI: 1.00-2.56), perfluorononanoic acid (PFNA) (OR = 1.67, 95% CI: 1.06-2.61), and perfluoroundecanoic acid (PFUA) (OR = 1.77, 95% CI: 1.00-3.12), with stronger associations observed in women who delivered males. BKMR analysis identified PFNA as the most important PFAS responsible for pPTB (conditional PIP = 0.78), with increasing ORs at higher percentiles of PFAS mixture. For LGA, positive associations were observed with PFDA and perfluorooctanoic acid in females only, and with PFUA in males only. BKMR analysis showed increasing, but null effects of PFAS mixture on LGA. CONCLUSIONS: The effect of prenatal exposure to single and multiple PFAS on PTB and LGA depended on fetal sex. Future studies should strongly consider examining PTB subtypes and sex-specific effects of PFAS on pregnancy outcomes.

Association of Early Pregnancy Perfluoroalkyl and Polyfluoroalkyl Substance Exposure With Birth Outcomes.

Importance: Prenatal perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been linked to adverse birth outcomes. Previous research showed that higher folate concentrations are associated with lower blood PFAS concentrations in adolescents and adults. Further studies are needed to explore whether prenatal folate status mitigates PFAS-related adverse birth outcomes. Objective: To examine whether prenatal folate status modifies the negative associations between pregnancy PFAS concentrations, birth weight, and gestational age previously observed in a US cohort. Design, Setting, and Participants: In a prospective design, a prebirth cohort of mothers or pregnant women was recruited between April 1999 and November 2002, in Project Viva, a study conducted in eastern Massachusetts. Statistical analyses were performed from May 24 and October 25, 2022. Exposure: Plasma concentrations of 6 PFAS compounds were measured in early pregnancy (median gestational week, 9.6). Folate status was assessed through a food frequency questionnaire and measured in plasma samples collected in early pregnancy. Main Outcomes and Measures: Birth weight and gestational age, abstracted from delivery records; birth weight z score, standardized by gestational age and infant sex; low birth weight, defined as birth weight less than 2500 g; and preterm birth, defined as birth at less than 37 completed gestational weeks. Results: The cohort included a total of 1400 mother-singleton pairs. The mean (SD) age of the mothers was 32.21 (4.89) years. Most of the mothers were White (73.2%) and had a college degree or higher (69.1%). Early pregnancy plasma perfluorooctanoic acid concentration was associated with lower birth weight and birth weight z score only among mothers whose dietary folate intake (birth weight: ß, -89.13 g; 95% CI, -166.84 to -11.42 g; birth weight z score: -0.13; 95% CI, -0.26 to -0.003) or plasma folate concentration (birth weight: -87.03 g; 95% CI, -180.11 to 6.05 g; birth weight z score: -0.14; 95% CI, -0.30 to 0.02) were below the 25th percentile (dietary: 660 µg/d, plasma: 14 ng/mL). No associations were found among mothers in the higher folate level groups, although the tests for heterogeneity did not reject the null. Associations between plasma perfluorooctane sulfonic acid and perfluorononanoate (PFNA) concentrations and lower birth weight, and between PFNA and earlier gestational age were noted only among mothers whose prenatal dietary folate intake or plasma folate concentration was in the lowest quartile range. No associations were found among mothers in higher folate status quartile groups. Conclusions and Relevance: In this large, US prebirth cohort, early pregnancy exposure to select PFAS compounds was associated with adverse birth outcomes only among mothers below the 25th percentile of prenatal dietary or plasma folate levels.

Maternal exposure to phthalates and total gestational weight gain in the LIFECODES birth cohort.

Excessive gestational weight gain contributes to adverse maternal and neonatal outcomes. Environmental exposures such as phthalates may lead to metabolic dysregulation, and studies suggest possible associations between maternal phthalate exposure and altered gestational weight gain. We assessed the association between nine maternal phthalate metabolites and measures of total gestational weight gain (pre-pregnancy to median 35.1 weeks of gestation) in a case-control study nested within LIFECODES (N = 379), a prospective birth cohort from Boston, Massachusetts (2006-2008). Our primary outcome was total gestational weight gain z score, a measure independent of gestational age that can provide a less biased estimate of this association. Our secondary outcomes were total gestational weight gain, rate of gestational weight gain, and adequacy ratio. The results were stratified by pre-pregnancy body mass index category. We found that concentrations of mono-(3-carboxypropyl) phthalate (MCPP) and mono-n-butyl phthalate (MBP) were positively associated with total gestational weight gain z scores among participants with obesity: adjusted mean difference (95% Confidence Interval [CI]) = 0.242 (0.030 - 0.455) and 0.105 (-0.002 - 0.212) corresponding to an excess weight gain of 1.81 kg and 0.77 kg at 35 weeks of gestation per interquartile range-increase in MCPP and MBP, respectively. Also, among participants with obesity, MBP demonstrated a potential non-linear relationship with gestational weight gain in cubic spline models. These findings suggest that phthalates may be related to higher gestational weight gain, specifically, among individuals with pre-pregnancy obesity. Future research should investigate whether pregnant people with obesity represent a subpopulation with sensitivity to phthalate exposures.

Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum.

Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality.

Fetal growth trajectories of babies born large-for-gestational age in the LIFECODES Fetal Growth Study.

BACKGROUND: Babies born large-for-gestational age have an increased risk of adverse health outcomes, including birth injuries, childhood obesity, and cardiometabolic disorders. However, little work has been done to characterize patterns of fetal growth among large-for-gestational age births, which may further elucidate high- and low-risk subgroups. OBJECTIVE: This study aimed to identify subgroups of large-for-gestational age births based on trajectories of fetal growth derived from prenatal ultrasound measurements and explore differences in sociodemographic, pregnancy, and birth outcome characteristics across subgroups. STUDY DESIGN: This study identified and described trajectories of fetal growth among large-for-gestational age births (n=235) in the LIFECODES Fetal Growth Study. Ultrasound measurements of fetal growth in middle to late pregnancy were abstracted from health records. Group-based multi-trajectory modeling was applied to measurements of head circumference, abdominal circumference, and femur length z-scores to identify multivariate trajectories of fetal growth. Moreover, sociodemographic variables, pregnancy characteristics, and birth outcomes based on trajectory membership were summarized. RESULTS: This study identified 4 multivariate trajectories of fetal growth among large-for-gestational age births: catch-up growth (n=28), proportional abdominal circumference-to-femur length growth (n=67), disproportional abdominal circumference-to-femur length growth (n=96), and consistently large (n=44). Fetuses in the "catch-up growth" group exhibited small relative sizes in midpregnancy (ie, below average head circumference, abdominal circumference, and femur length z-scores) and large relative sizes in late pregnancy. Growth among these births was driven by increases in relative abdominal circumference and head circumference sizes. Participants who delivered births assigned to this group were less likely to have normal glucose control (40% vs 65%-75%) and more likely to have pregestational diabetes mellitus (36% vs 10%-17%) than other large-for-gestational age subgroups. In addition, the babies in this trajectory group were more likely to have macrosomia (86% vs 67%-73%) and to be admitted to the neonatal intensive care unit (32% vs 14%-21%) than other large-for-gestational age subgroups. In contrast, babies in the "consistently large" group had the largest relative size for all growth parameters throughout gestation and experienced a lower risk of adverse birth outcomes than other large-for-gestational age subgroups. CONCLUSION: This study characterized several trajectories of fetal growth among large-for-gestational age births, which were related to different pregnancy characteristics and the distribution of adverse birth outcomes. Although the number of individuals within some trajectories was small, a subgroup that exhibited a catch-up growth phenotype during gestation was identified, which may be uniquely associated with exposure to pregestational diabetes mellitus and a higher risk of admission to the neonatal intensive care unit. These results have highlighted that the risk of adverse outcomes may not be evenly distributed across all large-for-gestational age births.