Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. We conducted an untargeted metabolome-wide association study to identify the metabolic perturbations and molecular mechanisms underlying the association between cotinine, a widely used biomarker of tobacco exposure, and adverse birth outcomes. We collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014–2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed by an untargeted HRM workflow using generalized linear models, followed by pathway enrichment analysis and chemical annotation, with a meet-in-the-middle approach. The median maternal urinary cotinine concentrations were 5.93 μg/g creatinine and 3.69 μg/g creatinine in early and late pregnancy, respectively. In total, 16,481 and 13,043 metabolic features were identified in serum samples at each visit from positive and negative electrospray ionization modes, respectively. Twelve metabolic pathways were found to be associated with both cotinine concentrations and adverse birth outcomes during early and late pregnancy, including tryptophan, histidine, urea cycle, arginine, and proline metabolism. We confirmed 47 metabolites associated with cotinine levels, preterm birth, and shorter gestational age, including glutamate, serine, choline, and taurine, which are closely involved in endogenous inflammation, vascular reactivity, and lipid peroxidation processes. The metabolic perturbations associated with cotinine levels were related to inflammation, oxidative stress, placental vascularization, and insulin action, which could contribute to shorter gestations. The findings will support the further understanding of potential internal responses in association with tobacco smoke exposures, especially among African American women who are disproportionately exposed to high tobacco smoke and experience higher rates of adverse birth outcomes.

While the effects of ambient pollutants on adverse perinatal outcomes have been studied, most studies have focused on preterm birth, stillbirth, and low birthweight. Few studies have examined the effects of ambient pollutants on prelabor rupture of membranes (PROM). This study was designed to explore the acute effects of ambient pollutants on both term PROM (TPROM) and preterm PROM (PPROM). We enrolled pregnant women receiving antenatal care between October 2013 and December 2019 at the International Peace Maternity and Child Health Hospital (IPMCHH). The effects of ambient pollutants (including PM₂.₅, PM₁₀, SO₂, CO, NO₂, and 8-h O₃) on TPROM and PPROM were estimated using generalized additive models (GAMs). Exposure-response relationship curves were also evaluated using GAMs after adjustment for confounding factors. Potential lagged effects were examined using various lag models. The data of 100,200 pregnant women who delivered at IPMCHH were analyzed. The fitted spline curves for PPROM were similar to the temporal trends of PM₂.₅, PM₁₀, SO₂, CO and NO₂ but not O₃, while those for TPROM were different from the temporal trends of all six air pollutants. An increased risk of PPROM was associated with increased concentrations of PM₂.₅, PM₁₀, SO₂ and CO on lag days 2 and 3, while no association was found between PPROM and daily concentration of O₃. After adjustment for confounding factors, there was a shift in the exposure-response curves, indicating associations between PPROM and PM₂.₅, PM₁₀, SO₂, and CO on lag days 2–3. Interaction effects of PM₂.₅, PM₁₀, SO₂, and CO were also found to increase the risk of PPROM. In conclusion, acute exposures to six critical air pollutants were not associated with an increased risk of TPROM; however, PM₂.₅, PM₁₀, SO₂, and CO were found to interact, increasing the risk for PPROM on lag days 2 and 3.

Recent studies suggests that air pollution, from among others road traffic, can influence growth and development of the human foetus during pregnancy. The effects of air pollution from heavy industry on birth outcomes have been investigated scarcely.Our aim was to investigate the associations of air pollution from heavy industry on birth outcomes.A cross-sectional study was conducted among 4488 singleton live births (2012–2017) in the vicinity of a large industrial area in the Netherlands. Information from the birth registration was linked with a dispersion model to characterize annual individual-level exposure of pregnant mothers to air pollutants from industry in the area. Associations between particulate matter (PM₁₀), nitrogen oxides (NOX), sulphur dioxide (SO₂), and volatile organic compounds (VOC) with low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) were investigated by logistic regression analysis and with gestational age, birth weight, birth length, and head circumference by linear regression analysis.Exposures to NOX, SO₂, and VOC (per interquartile range of 1.16, 0.42, and 0.97 μg/m³ respectively) during pregnancy were associated with LBW (OR 1.20, 95%CI 1.06–1.35, OR 1.20, 95%CI 1.00–1.43, and OR 1.21, 95%CI 1.08–1.35 respectively). NOX and VOC were also associated with PTB (OR 1.14, 95%CI 1.01–1.29 and OR 1.17, 95%CI 1.04–1.31 respectively). Associations between exposure to air pollution and birth weight, birth length, and head circumference were statistically significant. Higher exposure to PM₁₀, NOX, SO₂ and VOC (per interquartile range of 0.41, 1.16, 0.42, and 0.97 μg/m³ respectively) was associated with reduced birth weight of 21 g to 30 g.The 90th percentile industry-related PM₁₀ exposure corresponded with an average birth weight decrease of 74 g.

Manganese (Mn) is an essential trace element, but an excess or accumulation can be toxic. Until now, few studies have examined the effects of maternal Mn level on the risk of spontaneous preterm birth (SPB). The aims of this study were to examine the association between maternal Mn level and the risk of SPB at the early stage of pregnancy, and investigate whether this association was modified by single nucleotide polymorphisms (SNPs) in genes of superoxide dismutase (SOD) and catalase (CAT). We conducted a nested case-control study in three maternal and child health care hospitals in Shanxi province, China, from December 2009 to December 2013. From an overall cohort of 4229 women, 528 were included in our study, including 147 cases of SPB and 381 controls. Maternal blood samples were collected during 4–22 gestational weeks. The maternal serum concentrations of Mn was measured using inductively coupled plasma–mass spectrometry. We found the maternal Mn concentration in the case group (median: 1.55 ng/mL) was significantly higher than that in the control group (median: 1.27 ng/mL). Compared to the lowest level, the SPB risk was significantly increased to 1.44 (95%CI: 0.60–3.43), 2.42 (95%CI: 1.06–5.55) and 2.46 (95%CI: 1.08–5.62) respectively for the second, third and fourth quartiles in first trimester, but not significant in second trimester or overall. When exposure to a high Mn level, women who with AA (6.36, 95%CI: 1.57–25.71) and AG (3.04, 95%CI: 1.59–5.80) of rs2758352, with CC (2.34, 95%CI: 1.31–4.18) of rs699473, and with GG (2.26, 95%CI: 1.22–4.16) of rs769214 were more likely to develop a SPB, but not among women with other genotypes. In conclusion, high maternal serum Mn level is associated with the increased SPB risk in first trimester, and the association is modified by maternal SNPs of SOD2, SOD3 and CAT.

Thallium (Tl) is a well-recognized hazardous toxic heavy metal that has been reported to have embryotoxicity and fetotoxicity. However, little is known about its association with preterm birth (PTB) in humans. We aimed to evaluate the predictors of Tl exposure and assessed its relation with PTB. The study population included 7173 mother-infant pairs from a birth cohort in Wuhan, China. Predictors of Tl concentrations were explored using linear regression analyses, and associations of Tl exposure with risk of PTB or gestational age at birth were estimated using logistic regression or generalized linear models. The geometric mean and median values of urinary Tl concentrations were 0.28 μg/L (0.55 μg/g creatinine) and 0.29 μg/L (0.53 μg/g creatinine). We found that maternal urinary Tl concentrations varied by gestational weight gain, educational attainment, multivitamin and iron supplementations. Women with Tl concentrations higher than 0.80 μg/g creatinine were at higher risk of giving birth prematurely versus those with Tl concentrations lower than 0.36 μg/g creatinine [adjusted odds ratio (95% confidence interval (CI)): 1.55 (1.05, 2.27)], and the association was more pronounced in PTB with premature rupture of membranes (PROM) rather than in PTB without PROM. About 3-fold increase in creatinine-corrected Tl concentrations were associated with 0.99-day decrease in gestational length (95% CI: −1.36, −0.63). This is the first report on the associations between maternal Tl exposure and the risk of PTB.

Triclosan (TCS) is a suspected endocrine disrupting chemical which is widely used in consumer products as an antibacterial agent. But findings in human studies focusing on the fetal developmental effects of prenatal TCS exposure were rare and inconsistent. This study aimed to determine maternal urinary TCS and investigate its association with birth outcomes. Pregnant women (n = 1006) were randomly selected from the prospective Healthy Baby Cohort (HBC) enrolled in 2014. TCS levels were determined in maternal urine samples collected at delivery and recorded birth outcomes were obtained from the medical records. Multiple linear regressions were applied to evaluate associations of maternal urinary TCS levels with birth outcomes including birth weight, birth length, and gestational age. Logistic regressions were used to evaluate associations with preterm birth, late term birth, and low birth weight. The geometric mean concentrations for TCS and specific gravity (SG) adjusted TCS in maternal urines were 0.73, 0.78 ng/mL, respectively. In the crude model, one ln-unit increase of urinary SG-adjusted TCS concentration was associated with a 0.30-day [95% confidence interval (CI): 0.00, 0.60] increase in gestational age; however, the associations were not statistically significant after adjustment for covariates. No significant associations of SG-adjusted TCS concentrations with birth weight and birth length were observed. Maternal SG-adjusted TCS concentrations were not related to preterm birth, late term birth, and low birth weight (all p > 0.10). Our findings reported a relatively low level of TCS among Chinese pregnant women. With such exposure level, we did not find strong evidence for associations between maternal TCS exposure and birth outcomes. Longitudinal studies concerning about different potential effects of TCS on perinatal health are necessary.

Lead (Pb) is a well-known developmental toxicant. The aim of the present study was to analyze the association between maternal serum Pb level and risk of preterm birth in a population-based birth cohort study. The present study analyzed a sub-study of the China-Anhui Birth Cohort that recruited 3125 eligible mother-and-singleton-offspring pairs. Maternal serum Pb level was measured by graphite furnace atomic absorption spectrometry. All subjects were classified into three groups by tertile division according to serum Pb level: Low-Pb (L-Pb, <1.18 μg/dl), Medium-Pb (M-Pb, 1.18–1.70 μg/dl), and High-Pb (H-Pb, ≥1.71 μg/dl). The rate of preterm birth was 2.8% among subjects with L-Pb, 6.1% among subjects with M-Pb, and 8.1% among subjects with H-Pb, respectively. After controlling confounding factors, the adjusted OR for preterm birth was 2.33 (95%CI: 1.49, 3.65) among subjects with M-Pb and 3.09 (95%CI: 2.01, 4.76) among subjects with H-Pb. Of interest, maternal Pb exposure in early gestational stage than in middle gestational stage was more susceptible to preterm birth. Moreover, maternal serum Pb level was only associated with increased risk of late preterm birth. The present study provides evidence that maternal serum Pb level during pregnancy is positively associated with risk of preterm birth in a Chinese population.

Low birth weight (<2500 g) (LBW), premature birth (<37 weeks of gestation) (PB), and late foetal death (<24 h of life) (LFD) are causes of perinatal morbi-mortality, with short- and long-term social and economic health impacts. This study sought to identify gestational windows of susceptibility during pregnancy and to analyse and quantify the impact of different air pollutants, noise and temperature on the adverse birth outcomes.Time-series study to assess the impact of mean daily PM2.5, NO2 and O3 (μg/m3), mean daily diurnal (Leqd) and nocturnal (Leqn) noise levels (dB(A)), maximum and minimum daily temperatures (°C) on the number of births with LBW, PB or LFD in Madrid across the period 2001–2009. We controlled for linear trend, seasonality and autoregression. Poisson regression models were fitted for quantification of the results. The final models were expressed as relative risk (RR) and population attributable risk (PAR).Leqd was observed to have the following impacts in LBW: at onset of gestation, in the second trimester and in the week of birth itself. NO2 had an impact in the second trimester. In the case of PB, the following: Leqd in the second trimester, Leqn in the week before birth and PM2.5 in the second trimester. In the case of LFD, impacts were observed for both PM2.5 in the third trimester, and minimum temperature. O3 proved significant in the first trimester for LBW and PB, and in the second trimester for LFD.Pollutants concentrations, noise and temperature influenced the weekly average of new-borns with LBW, PB and LFD in Madrid. Special note should be taken of the effect of diurnal noise on LBW across the entire pregnancy. The exposure of pregnant population to the environmental factors analysed should therefore be controlled with a view to reducing perinatal morbi-mortality.

Preconception and prenatal exposure to phthalates has been associated with an increased risk of preterm birth. However, it is unclear whether there are periods of heightened susceptibility during pregnancy. This prospective cohort study included 386 women undergoing fertility treatment who gave birth to a singleton infant during 2005 through 2018. Eleven phthalate metabolites were measured in spot urine samples collected at each trimester. In approximately 50% of participants, two metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), a phthalate substitute, were also measured. The molar sum of four di(2-ethylhexyl) phthalate metabolites (∑DEHP) was calculated. We evaluated the associations of mean maternal biomarker concentrations with risk of preterm birth using modified log-binomial models and utilized multiple informant models to compare trimester-specific associations. We examined the relative biomarker concentration across gestation comparing women with preterm birth to women with term delivery using quadratic mixed model. The risk ratio for preterm birth associated with a one-unit increase in the natural log-transformed urinary concentrations of ∑DEHP (mean during pregnancy) was 1.21 (95% confidence interval (CI): 0.84, 1.72). In multiple informant models, these associations were strongest in the third trimester (RR = 1.51; 95% CI: 1.17, 1.95). Estimated mean ∑DEHP concentrations were higher among women with preterm than term delivery, especially late in gestation. Associations with preterm birth were also observed for each of the four individual DEHP metabolites. Detection of cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), a metabolite of DINCH, appeared to be positively related to preterm birth. In this prospective cohort of subfertile couples, maternal ∑DEHP metabolite concentrations during pregnancy were associated with an increased risk of preterm birth, particularly during late gestation.

The ongoing transition to renewable fuel sources has led to increased use of wood and other biomass fuels. The physiochemical characteristics of biomass combustion derived aerosols depends on appliances, fuel and operation procedures, and particles generated during incomplete combustion are linked to toxicity. Frequent indoor wood burning is related to severe health problems such as negative effects on airways and inflammation, as well as chronic hypoxia and pathological changes in placentas, adverse pregnancy outcome, preterm delivery and increased risk of preeclampsia. The presence of combustion-derived black carbon particles at both the maternal and fetal side of placentas suggests that particles can reach the fetus. Air pollution particles have also been shown to inhibit trophoblast migration and invasion, which are vital functions for the development of the placenta during the first trimester. In this study we exposed a placental first trimester trophoblast cell line to wood smoke particles emitted under Nominal Burn rate (NB) or High Burn rate (HB). The particles were visible inside exposed cells and localized to the mitochondria, causing ultrastructural changes in mitochondria and endoplasmic reticulum. Exposed cells showed decreased secretion of the pregnancy marker human chorionic gonadotropin, increased secretion of IL-6, disrupted membrane integrity, disrupted proliferation and contained specific polycyclic aromatic hydrocarbons (PAHs) from the particles. Taken together, these results suggest that wood smoke particles can enter trophoblasts and have detrimental effects early in pregnancy by disrupting critical trophoblast functions needed for normal placenta development and function. This could contribute to the underlying mechanisms leading to pregnancy complications such as miscarriage, premature birth, preeclampsia and/or fetal growth restriction. This study support the general recommendation that more efficient combustion technologies and burning practices should be adopted to reduce some of the toxicity generated during wood burning.