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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. [ABSTRACT FROM AUTHOR]

Background: Inflammation during pregnancy is hypothesized to influence fetal growth. Eicosanoids, an important class of lipid mediators derived from polyunsaturated fatty acids, can act as both direct influences and biomarkers of inflammation through a variety of biological pathways. However, quantifying these distinct inflammatory pathways has proven difficult. We aimed to characterize a comprehensive panel of plasma eicosanoids longitudinally across gestation in pregnant women and to determine whether levels differed by infant size at delivery.Methods and Findings: Our data come from a case-control study of 90 pregnant women nested within the LIFECODES prospective birth cohort study conducted at Brigham and Women's Hospital in Boston, Massachusetts. This study included 31 women who delivered small for gestational age (SGA) babies (SGA, ≤10th percentile), 28 who delivered large for gestational age (LGA) babies (≥90th percentile), and 31 who delivered appropriate for gestational age (AGA) babies (controls, >10th to <90th percentile). All deliveries occurred between 2010 and 2017. Most participants were in their early 30s (median age: 33 years), of white (60%) or black (20%) race/ethnicity, and of normal pre-pregnancy BMI (median BMI: 23.5 kg/m2). Women provided non-fasting plasma samples during 3 prenatal study visits (at median 11, 25, and 35 weeks gestation) and were analyzed for a panel of eicosanoids. Eicosanoids were grouped by biosynthetic pathway, defined by (1) the fatty acid precursor, including linoleic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA), and (2) the enzyme group, including cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 (CYP). Additionally, the concentrations of the 4 fatty acids (LA, AA, DHA, and EPA) were measured in maternal plasma. Analytes represent lipids from non-esterified plasma. We examined correlations among eicosanoids and trajectories across pregnancy. Differences in longitudinal concentrations between case groups were examined using Bayesian linear mixed effects models, which included participant-specific random intercepts and penalized splines on gestational age. Results showed maternal plasma levels of eicosanoids and fatty acids generally followed U-shaped curve patterns across gestation. Bayesian models showed that associations between eicosanoids and case status varied by biosynthetic pathway. Eicosanoids derived from AA via the CYP and LOX biosynthetic pathways were positively associated with SGA. The adjusted mean concentration of 12-HETE, a LOX pathway product, was 56.2% higher (95% credible interval 6.6%, 119.1%) among SGA cases compared to AGA controls. Eicosanoid associations with LGA were mostly null, but negative associations were observed with eicosanoids derived from AA by LOX enzymes. The fatty acid precursors had estimated mean concentrations 41%-97% higher among SGA cases and 33%-39% lower among LGA cases compared to controls. Primary limitations of the study included the inability to explore the potential periods of susceptibility of eicosanoids on infant size due to limited sample size, along with the use of infant size at delivery instead of longitudinal ultrasound measures to estimate fetal growth.Conclusions: In this nested case-control study, we found that eicosanoids and fatty acids systematically change in maternal plasma over pregnancy. Eicosanoids from specific inflammation-related pathways were higher in mothers of SGA cases and mostly similar in mothers of LGA cases compared to controls. These findings can provide deeper insight into etiologic mechanisms of abnormal fetal growth outcomes. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that protein biomarkers associated with circulating microparticles proteins (CMPs) obtained at the end of the first trimester may detect physiologic changes in maternal-fetal interaction such that the risk of spontaneous preterm delivery ≤35 weeks can be stratified.Objectives: We present here a study extension and validation of the CMP protein multiplex concept using a larger sample set from a multicenter population that allows for model derivation in a training set and characterization in a separate testing set.Materials and Methods: Ethylenediaminetetraacetic acid (EDTA) plasma was obtained from 3 established biobanks (Seattle, Boston, and Pittsburgh). Samples were from patients at a median of 10-12 weeks' gestation, and the CMPs were isolated via size-exclusion chromatography followed by protein identification via targeted protein analysis using liquid chromatography-multiple reaction monitoring-mass (LC-MRM) spectrometry. A total of 87 women delivered at ≤35 weeks, and 174 women who delivered at term were matched by maternal age (±2 years) and gestational age at sample draw (±2 weeks). From our prior work, the CMP protein multiplex comprising F13A, FBLN1, IC1, ITIH2, and LCAT was selected for validation.Results: For delivery at ≤35 weeks, the receiver operating characteristic (ROC) curve for a panel of CMP proteins (F13A, FBLN1, IC1, ITIH2, and LCAT) revealed an associated area under the ROC curve (AUC) of 0.74 (95% CI, 0.63-0.81). A separate panel of markers (IC1, LCAT, TRFE, and ITIH4), which stratified risk among mothers with a parity of 0, showed an AUC of 0.77 (95% CI, 0.61-0.90).Conclusion: We have identified a set of CMP proteins that provide, at 10-12 weeks gestation, a clinically useful AUC in an independent test population. Furthermore, we determined that parity is pertinent to the diagnostic testing performance of the biomarkers for risk stratification. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Polycyclic aromatic hydrocarbons (PAHs) exposure and thyroid hormone levels were assessed up to four times during pregnancy. • Gestational exposure to PAHs was associated with thyroid hormone concentration during pregnancy. • Associations between PAHs and thyroid hormone concentration varied based on study visit and fetal sex. • Certain PAHs exhibited non-linear associations with thyroid hormones and interacted with other PAHs. [ABSTRACT FROM AUTHOR]

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. • Associations between phthalates and gestational weight gain differed by pre-pregnancy BMI. • MCPP and MBP were associated with higher gestational weight gain among participants with obesity. • Some phthalates, including MBP, had non-linear associations with gestational weight gain. [ABSTRACT FROM AUTHOR]

Exposure to some toxic metals, such as lead and cadmium, has been associated with increased oxidative stress. However less is known about other metals and metal mixtures, especially in pregnant women who are a vulnerable population. To study the relationship between exposure to trace metals and oxidative stress, we analyzed a panel of 17 metals and two oxidative stress biomarkers (8-isoprostane and 8-hydroxydeoxyguanosine [8-OHdG]) in urine samples collected at ~26 weeks gestation from pregnant women in Boston (n = 380). We used linear regression models to calculate percent differences and 95% confidence intervals (CI) in oxidative stress markers for an interquartile range (IQR) increase in each urinary metal with adjustment for other metals. In addition, we applied principal components analysis (PCA) and Bayesian kernel machine regression (BKMR), to examine cumulative effects (within correlated groups of exposures as well as overall) and interactions. We estimated 109% (95% CI: 47, 198) higher 8-isoprostane and 71% (95% CI: 45, 102) higher 8-OHdG with an IQR increase in urinary selenium (Se). We also estimated higher 8-isoprostane (47%, 95% CI: 20.5, 79.4) and 8-OHdG (15.3%, 95% CI: 5.09, 26.5) in association with urinary copper (Cu). In our PCA, we observed higher 8-isoprostane levels in association with the "essential" PC (highly loaded by Cu, Se, and Zinc). In BKMR analyses, we also estimated higher levels of both oxidative stress biomarkers with increasing Se and Cu as well as increasing levels of both oxidative stress biomarkers in association with cumulative concentrations of urinary trace metals. We observed higher 8-isoprostane and 8-OHdG levels in association with urinary trace metals and elements, particularly Se and Cu, in linear models and using mixtures approaches. Additionally, increasing cumulative exposure to urinary trace metals was associated with higher levels of both oxidative stress biomarkers. The beneficial effects of these compounds should be carefully questioned. • We examined associations between urinary trace metals and oxidative stress in pregnancy. • Higher oxidative stress was observed with increasing levels of urinary selenium. • Higher oxidative stress was also observed with increasing levels of urinary copper. • Increasing cumulative trace metals was also associated with higher oxidative stress. [ABSTRACT FROM AUTHOR]

• Vitamin D levels in Mongolian third trimester pregnant women are severely depressed. • Levels in pregnant women in Boston are comparatively elevated and less seasonal. • Levels in Boston, but not Mongolia, are associated with targetable risk factors. • Mongolia should consider a combined approach of fortification and supplementation. • This joint approach is warranted in vitamin D deficiency-endemic regions globally. Adequate vitamin D status during pregnancy is important for developing fetal bone strength and density and may play a role in preventing a range of skeletal and non-skeletal diseases in both mothers and children. We previously identified Mongolian women of reproductive age to have the lowest vitamin D levels yet observed in any population globally, which renders this population uniquely important in vitamin D research. In this study, we measured the seasonal distribution of 25-hydroxyvitamin D (25(OH)D) concentration in 390 healthy third trimester pregnant women living in urban and rural Mongolia using DiaSorin LIAISON and compared this distribution to that of 206 third trimester women living in Boston, USA. Also, we analyzed seasonally-independent associations between (25(OH)D) levels and selected predictors in both groups using quantile regression. Mean 25(OH)D levels were significantly higher and less seasonal in Boston (seasonal range: 27.1 ± 7.0–31.5 ± 7.7 ng/ml) than in Mongolia (seasonal range: 11.2 ± 3.9–19.2 ± 6.7 ng/ml). Adjusting for month of blood draw, higher 25(OH)D levels were significantly associated with older age, lower gravidity, lower BMI, and lack of a college or university degree among Boston participants, however, only gravidity was robust to multivariable adjustment. No assessed characteristics were independently predictive in Mongolia, likely due to universally low 25(OH)D levels and a resulting lack of between-person variation. In conclusion, vitamin D status among pregnant Mongolians is severely depressed throughout the year and should be addressed through fortification and supplementation, while in the U.S., deficiency is associated with specific characteristics targetable through supplementation. [ABSTRACT FROM AUTHOR]