Chromium levels in placental tissue and neural tube defects: Association and mechanistic study.

Human exposure to chromium (Cr) is common but little is known about its adverse effects on pregnancy outcomes. This study aimed to explore the association between Cr exposure and the risk of neural tube defects (NTDs) and the underlying mechanisms of Cr-induced NTDs. 593 controls and 408 NTD cases with placentas were included in this study. Chromium trichloride (Cr(III)) and potassium dichromate (Cr(VI)) were intragastrically administered to pregnant mice and the number of NTDs was recorded. The odds ratio for total NTDs in the highest exposure group in placenta was 4.18 (95% confidence interval (CI), 1.97-8.84). The incidence of fetal NTDs in mice administered with Cr(III) showed a dose-response relationship. Cr(VI) didn't show teratogenicity of NTDs whereas increased the stillbirth rate. Prenatal exposure to Cr(III) increased levels of oxidative stress and apoptosis in fetal mice. RNA-sequencing results indicated significant enrichment of the MAPK pathway. RT-qPCR and Western blot analysis revealed that Cr(III) induced increased expression of p-JNK, p-P38, and Casp3. Toxicological effects can be partly antagonized by antioxidant supplementation. High chromium exposure was associated with increased human NTD risks. Excessive Cr(III) exposure can induce NTDs in fetal mice by increasing apoptosis through upgrading oxidative stress and then activating JNK/P38 MAPK signaling pathway.

Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring.

BACKGROUND: As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. METHODS: In this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. RESULTS: Only 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01-10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. CONCLUSIONS: Intentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

Prenatal exposure to poly/perfluoroalkyl substances and risk for congenital heart disease in offspring.

Congenital heart disease (CHD) is the most prevalent congenital malformation worldwide, and the association between per- and polyfluoroalkyl substances (PFASs) exposure and CHD in population has only received limited study. Therefore, we conducted a multicenter case-control study to explore the associations between prenatal exposure to individual PFASs, and also a PFAS mixture, and CHD risk, including 185 CHDs and 247 controls in China from 2016 to 2021. Thirteen PFASs in maternal plasma were quantified using liquid chromatography-tandem mass spectrometry. Logistic regression and two multipollutant models (Bayesian kernel machine regression [BKMR] and quantile g-computation [qgcomp]) were used to assess the potential associations between any individual PFAS, and also a PFAS mixture, and CHD risk. After adjusting for potential confounders, logistic regression indicated significant associations between elevated levels of perfluorononanoic acid (odds ratio [OR]= 1.30, 95% confidence intervals [CI]: 1.07-1.58), perfluorodecanoic acid (OR=2.07, 95%CI: 1.32-3.26), and perfluoroundecanoic acid (OR=2.86, 95%CI:1.45-5.65) and CHD risk. The BKMR model and qgcomp approach identified that a significant positive association between the PFAS mixture and risk for CHD. These findings provide essential evidence that there is indeed a health crisis associated with PFASs and that it is linked to CHD.

Prevalence and Trends of Birth Defects - Five Counties, Shanxi Province, China, 2003-2022.

What is already known about this topic?: The Shanxi Province, located in northern China, holds the highest prevalence of birth defects (BDs) across the country. Following the implementation of a nationwide folic acid supplementation program in 2009, a significant reduction of 53.89% in the prevalence of neural tube defects (NTDs) was observed in Shanxi from 2012 to 2017. However, despite this decrease, the prevalence rate for congenital heart defects (CHDs) in 2017 was over four times that of the 2012 rate. Since 2014, CHDs have emerged as the most predominant BD in Shanxi. What is added by this report?: The present study has identified a marked reduction in the prevalence of both total BDs and NTDs in five counties within Shanxi over the past two decades. As of 2017-2022, NTDs continue to be the most prevalent BDs recorded in this region. Contrarily, there has been a noteworthy increase in the prevalence of CHDs, ranking them among the top five most common BDs in the region between 2017 and 2022, though their rate remains below the national average. Additionally, the proportion of external anomalies remains high. Nevertheless, due to constrained access to primary healthcare services and diagnostic facilities, the early detection rate for internal anomalies, particularly CHDs, may be underestimated in the region. What are the implications for public health practice?: The results of this study underscore the necessity for augmented efforts in promoting folic acid supplementation as a preventive measure for NTDs. Moreover, improvements in the distribution of medical resources within this region are recommended, particularly the introduction and enforcement of local training programs aimed at enhancing CHD screening and diagnostic processes in these respective counties.

Associations among bisphenol A, its analogs, and chlorinated derivatives in placenta and risk for neural tube defects: A case-control study.

Bisphenol A (BPA) and its analogs such as bisphenol Z (BPZ) are widely used in the production of consumer products, but few studies have investigated the associations among BPA, its analogs, and chlorinated derivatives (collectively, BPs) and risk for NTDs. This study investigated the associations between concentrations of BPs in the placenta and risk for NTDs. This was a case-control study including 122 NTDs and 164 controls. BPs in the placenta were determined using liquid chromatography-tandem mass spectrometry. The associations between BPs and NTD risk were evaluated using conventional logistic regression and weighted quantile sum regression (WQS) models. In the logistic regression, exposure to higher levels of BPA and BPZ was associated with increased NTD risk (odds ratio [OR] = 3.17, 95 % confidence interval [CI], 1.22-8.22; OR = 3.11, 95 % CI, 1.20-8.09, respectively). Meanwhile, a significant dose-response relationship was found between BPA and BPZ concentrations and NTD risk. In the WQS model, a quartile increase in WQS index resulted in 4.34 (95 % CI: 1.69, 11.20) higher odds for NTDs, and BPA and BPZ accounted for most of the weight index in the joint effects of BPs. In conclusion, high levels of BPs in the placenta are associated with increased risk for NTDs, of which BPA and BPZ are important risk factors.

Indoor air pollution from coal combustion and tobacco smoke during the periconceptional period and risk for neural tube defects in offspring in five rural counties of Shanxi Province, China, 2010-2016.

Indoor air pollution may increase the risk for neural tube defects (NTDs) in Chinese rural populations. However, this association remains a subject of debate. We conducted a population-based case-control study of 222 NTD and 517 control mothers recruited between 2010 and 2016 in five rural areas in northern China. An indoor air pollution exposure evaluation index (IAPEEI) was used to evaluate mothers' exposure to tobacco-sourced and coal-sourced indoor air pollution. Essential characteristics were collected using structured questionnaires within 10 days of delivery. We found that exposure to indoor air pollution (IAPEEI ≥ 1) can lead to 3.41 times the risk of conceiving NTD fetuses compared with the no-exposure group (IAPEEI = 0) (adjusted odds ratio and 95 % confidence interval: 3.41 [2.34-5.02]). The risk increased with increasing IAPEEI score, indicating a clear dose-response trend (P < 0.001). Using a coal stove for heating (especially in the bedroom) and passive smoking are significantly associated with an increased likelihood of NTD occurrence. Exposure to indoor air pollution is a daily reality for rural women in China, and its impact on reproductive health deserves extensive attention.

The PM2.5 concentration reduction improves survival rate of lung cancer in Beijing.

INTRODUCTION: Long-term exposure to ambient fine particulate matter (PM2.5) has been linked to increases in the incidence of lung cancer. However, more evidence is needed to conclude its effects on lung cancer survival. OBJECTIVES: The study aimed to explore the relationship between long-term PM2.5 exposure and lung cancer survival and evaluated the benefits of clean air actions in Beijing. METHODS: A whole-population cohort study was conducted on lung cancer patients diagnosed between 2001 and 2017. An atmospheric chemical transport model was used to estimate exposure under a counterfactual scenario without the policy and then quantified the effect of the policy. Cox regression models were used with the seasonality-adjusted PM2.5 as the main effect. RESULTS: A 10 µg/m3 increase in PM2.5 was estimated to be with a 6.5 % (95 % CI: 4.8 %, 8.2 %) increase in the mortality rates. The association was heterogeneous and modified by individual-level characteristics. The clean air actions were estimated to have prevented 3548 (95 % CI: 3280, 3825) premature deaths and to have prolonged survival time by 4.29 months (95 % CI: 0.01, 25.11). CONCLUSION: Our findings suggest that PM2.5 exposure lowers the survival rate for lung cancer. The clean air actions implemented in Beijing can protect lung cancer patients by increasing their survival time. SYNOPSIS: Long-term exposure to PM2.5 can lower lung patients' survival rates whereas the clean air actions in Beijing have prolonged these patients' survival time by reducing PM2.5 level.

Prenatal exposure to silver is associated with an elevated risk for neural tube defects: a case-control study.

Exposure to copper, silver, and titanium has been reported to be associated with a variety of adverse effects on humans, but it is little focused on the fetus. We investigated the associations between prenatal exposure to the three metals (copper, silver, and titanium) and risk for fetal neural tube defects (NTDs). Placental samples from 408 women with pregnancies affected by NTDs and 593 women with normal pregnancies were collected from 2003 to 2016 in Pingding, Xiyang, Shouyang, Taigu, and Zezhou counties of China. Multilevel mixed-effects logistic regression and Bayesian kernel machine regression (BKMR) were used to evaluate the single and joint effects of the metals on NTDs. Silver was associated with an increased risk for NTDs in a dose-response fashion in single-metal logistic regression, with adjusted odds ratios (95% confidence intervals) of 1.78 (1.04-3.06) and 1.92 (1.11-3.32) in the second and third tertiles, respectively, compared to the lowest tertile. BKMR revealed toxic effects of silver on NTDs and the association appeared to be linear. No interaction of silver with any of the other two metals was observed. Besides, silver concentration was positively correlated with maternal certain dietary intakes. Placental high silver concentrations are associated with an elevated risk for NTDs. Maternal diet may be a source of silver exposure.

Association between cooking fuel and folate insufficiency among pregnant women in Northern China.

This study explored whether using a coal or biomass stove for cooking was associated with a greater risk of red blood cell (RBC) folate insufficiency among pregnant women compared to using clean energy. A researcher-designed questionnaire was used to collect information on exposure-related factors and confounding factors. RBC folate concentrations were examined by microbiological assay. Binary logistic regression analysis was used to identify factors related to RBC folate insufficiency. The use of coal or firewood for cooking was associated with an increased risk of RBC folate insufficiency (<906 nmol/L) compared to gas. In subgroup analyses, associations between the use of polluting cooking fuels and folate insufficiency were positive for both urban and rural residents and statistically significant for rural women. Efforts to promote the use of clean energy and proper ventilation, especially in rural areas, are recommended to improve the health of pregnant women and their offspring.

Non-Isolated Neural Tube Defects with Comorbid Malformations Are Responsive to Population-Level Folic Acid Supplementation in Northern China.

OBJECTIVE: Comorbid congenital malformation of multiple organs may indicate a shared genetic/teratogenic causality. Folic acid supplementation reduces the population-level prevalence of isolated neural tube defects (NTDs), but whether complex cases involving independent malformations are also responsive is unknown. We aimed to describe the epidemiology of NTDs with comorbid malformations in a Chinese population and assess the impact of folic acid supplementation. STUDY DESIGN: Data from five counties in Northern China were obtained between 2002 and 2021 through a population-based birth defects surveillance system. All live births, stillbirths, and terminations because of NTDs at any gestational age were recorded. NTDs were classified as spina bifida, anencephaly, or encephalocele. Isolated NTDs included spina bifida cases with presumed secondary malformations (hydrocephalus, hip dislocation, talipes). Non-isolated NTDs were those with independent concomitant malformations. RESULTS: A total of 296,306 births and 2031 cases of NTDs were recorded from 2002-2021. A total of 4.8% of NTDs (97/2031) had comorbid defects, which primarily affected the abdominal wall (25/97), musculoskeletal system (24/97), central nervous system (22/97), and face (15/97). The relative risk of cleft lip and/or palate, limb reduction defects, hip dislocation, gastroschisis, omphalocele, hydrocephalus, and urogenital system defects was significantly greater in infants with NTDs than in the general population. Population-level folic acid supplementation significantly reduced the prevalence of both isolated and non-isolated NTDs. CONCLUSION: Epidemiologically, non-isolated NTDs follow similar trends as isolated cases and are responsive to primary prevention by folic acid supplementation. Various clinically-important congenital malformations are over-represented in individuals with NTDs, suggesting a common etiology.

Natural copper isotopic abnormity in maternal serum at early pregnancy associated to risk of spontaneous preterm birth.

Spontaneous preterm birth (SPB) has drawn public attention due to its increasing incidence and adverse effects on fetal growth. Effect of copper (Cu) imbalance in maternal bodies on the risk of SPB remains a subject of debate, and the related mechanisms are still unraveled. Here we applied natural stable copper isotopes to explore the underlying association and mechanism of copper imbalance with SPB using a nested case-control study. We collected maternal sera at the early pregnancy stage and then measured their copper isotopic ratio (65Cu/63Cu, expressed as δ65Cu) as well as physiological and biochemical indexes from women with and without delivering SPB. We found that SPB cases had no significant difference in serum copper level from their controls, but their serum copper was significantly isotopically heavier than the controls (δ65Cu value = 0.15 ± 0.34 ‰ versus -0.15 ± 0.17 ‰, P = 0.0149). Compared with the controls with lower δ65Cu values, the crude odds ratio (OR) associated with SPB risk increased to 4.00 (95 % confidence interval (CI): 1.37-11.70) and the adjusted OR reached up to 11.35 (95 % CI: 1.35-95.60). Furthermore, via the copper isotopic fractionation, we revealed that dietary intake and blood ceruloplasmin may play more important roles than blood lipids and mother-to-child transmission in the copper imbalance associated with SPB. Further studies will be needed to understand the mechanisms of isotope fractionation related to reproductive health.

Elevated concentrations of chromium in maternal serum, umbilical cord serum, and cord tissue are associated with an increased risk for orofacial clefts.

Chromium (Cr) exposure during gestation causes malformations in animal experiments. In this multicenter case-control study, we initially involved 130 orofacial clefts (OFCs) and 260 controls to assess the association between Cr concentration and risk for OFCs. Then, umbilical cord serum (49 vs. 119) and cord tissue (84 vs. 142) were used to validate the association between Cr and OFCs. We found that maternal serum Cr concentrations in OFC cases were significantly higher than those in controls. Compared with the lowest tertile of maternal serum Cr concentration, the highest tertile of Cr increased the risk for OFCs [OR = 2.14 (1.14-4.05)]. In the validation cohort of umbilical cord serum and tissue, higher concentrations of Cr were associated with increased risks for OFCs in a dose-dependent manner (all Ps for trends <0.05). Cr concentrations in maternal serum and cord serum showed a positive correlation. The Cr concentration in cord serum was inversely correlated with egg and milk consumption frequencies, and the Cr concentration in cord tissue was positively associated with indoor coal burning. In conclusion, prenatal Cr exposure is a risk factor for OFCs, and indoor coal burning during pregnancy may be one of the sources of Cr exposure.

Periconceptional Folic Acid Supplementation and Newborn Birth Weights.

Background: The relationship between maternal folic acid supplementation and the birth weights of offspring remains inconclusive. Aim: To examine the associations between maternal supplementation with folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA) and newborn birth weights, as well as the risk of small for gestational week age (SGA) and large for gestational week age (LGA) newborns. Methods: Data on 31,107 births from 2015 to 2018 were extracted from the population-based prenatal health care system in a district of Beijing. Generalized linear and logistic regression models were used to evaluate the association between maternal periconceptional folic acid supplementation and birth weights or with risk of small for gestational week age (SGA) and large for gestational week age (LGA). Results: Compared with newborns whose mothers did not use any folic acid supplements, the newborns with maternal periconceptional folic acid supplementation had similar median birth weight but had a lower risk of SGA [adjusted odds ratio (aOR) = 0.81 (95% CI: 0.68-0.97)], however newborns born to mothers who took multiple micronutrients with folic acid (MMFA) with high compliance had a 25.59 g (95% CI: 6.49-44.69) higher median birth weight. Periconceptional women took folic acid only (FAO) (aOR = 0.83; 95%CI: 0.67-1.01) or MMFA (aOR = 0.74; 95%CI: 0.60-0.91) with high compliance decreased the risk of SGA, but has no impact on the risk of LGA. Conclusion: Periconceptional FAO supplementation has no impact on the median birth weight of offspring and the risk of LGA. Compared with FAO, MMFA supplementation may increase the average birth weight, and a high compliance of supplementation with FAO or MMFA may reduce the risk of SGA, with MMFA having ad stronger effect than FAO.

Maternal exposure to heavy metals and risk for severe congenital heart defects in offspring.

BACKGROUND: Congenital heart defects (CHDs) are the most common congenital malformations with a complex etiology, and environmental factors play an important role. Large epidemiology studies on prenatal exposure to selected heavy metals and their association with risk for CHDs are scarce and joint effects are not well understood. OBJECTIVES: To examine the association between prenatal exposure to selected heavy metals and risk for CHDs. METHODS: Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the maternal plasma concentrations of arsenic, cadmium, mercury, lead, and manganese were in 303 CHD cases and 303 healthy controls that were recruited in eight hospitals in China. Generalized linear mixed model (GLMM) and Bayesian kernel machine regression (BKMR) were fitted to evaluate the individual and joint effects of metal concentrations on CHDs. RESULTS: In GLMM, two metals were each significantly associated with an increased risk for CHDs [adjusted odds ratio (95% confidence interval): mercury, 2.88 (1.22-6.77); lead, 2.74 (1.00-7.57)]. In BKMR, CHD risk increased with mixture levels of the five metals when their concentrations were at the 40th percentile or higher, compared to when all metals were below their 35th percentile, and mercury was the major metal that contributed to the mixture effect. The interaction between mercury and lead was observed in BKMR. CONCLUSIONS: Using metal concentrations in maternal plasma obtained during the second or third trimester as exposure markers, we found that the risk of CHDs increased with the levels of the mixtures of As, Cd, Hg, Pb, and Mn, with Hg being the most important contributor to the mixture effect.

Alkali and alkaline earth elements in maternal serum and occurrence of orofacial clefts in offspring.

Alkali elements (AEs) and alkaline earth elements (AEEs) play critical roles in numerous physiological and pathological processes. However, the effects of maternal exposure to AEs and AEEs on the risk for fetal orofacial clefts (OFCs) remain unclear. We explored the associations between levels of eight AEs and AEEs in maternal serum during pregnancy and occurrence of fetal OFCs. Concentrations of four AEs and four AEEs in maternal serum of 130 OFC cases and 260 non-malformed controls were assessed. Multilevel mixed-effects logistic regression and bayesian kernel machine regression (BKMR) were performed to evaluate the single and combined effects, respectively, of exposure to AEs and AEEs on OFC risk. When individual elements were analyzed separately as categorical variables, the odds of OFCs increased by 2.08-fold (1.10-3.93) and 2.35-fold (1.24-4.45) for sodium and by 1.98-fold (1.04-3.77) and 1.92-fold (1.21-3.61) for strontium but decreased by 0.54-fold (0.29-0.98) and 0.42-fold (0.22-0.78) for potassium in the second and third tertiles, respectively, with the lowest tertile concentration being used as the referent. When all eight elements were considered as a mixture, potassium and calcium showed protective effects, whereas sodium and strontium increased odds of OFCs in the BKMR model. No joint effect on OFC risk was observed when the eight elements were considered as a mixture. Taken together, higher levels of sodium and strontium in maternal serum were associated with an increased odds of fetal OFCs, whereas higher levels of potassium in maternal serum were associated with a decreased odds of OFCs.

Selenium protects against the likelihood of fetal neural tube defects partly via the arginine metabolic pathway.

BACKGROUND AND AIMS: Neural tube defects (NTDs) are severe congenital malformations and have a complex etiology. This study aimed to explore the association between selected essential trace elements (ETEs) and metabolic pathway markers in the serum of women and the likelihood of NTDs. METHODS: The study included 99 mothers of offspring with and 114 mothers of offspring without NTDs. Five ETEs (iron, zinc, selenium [Se], cobalt, and molybdenum) and 106 metabolic pathway markers in maternal serum were quantified. The associations between ETEs and metabolic pathway markers and the chance of NTDs were examined. Mediating effects of the metabolic pathway markers on the association between Se and the likelihood of NTDs were evaluated. RESULTS: Compared to a Se concentration below the median, a concentration above the median was associated with a decreased chance of NTDs with an odds ratio of 0.29 (95% confidence interval: 0.11-0.66). The concentrations of 32 metabolic pathway markers differed between mothers of offspring with and without NTDs; five of these (asymmetric dimethylarginine, ornithine, glutamate, proline, and phenylalanine) were associated with increased chances of NTDs, with adjusted odds ratios of 3.01 (1.31-7.31), 2.79 (1.18-6.86), 2.38 (1.03-5.75), 2.41 (1.05-5.75), and 2.27 (1.09-5.40), respectively, for the higher interquartile of concentration compared to the lower one. Three arginine pathway metabolic markers (i.e., dimethylarginine, ornithine, and proline) mediated the association between Se and the occurrence of NTDs. CONCLUSION: This study suggests an association between Se and a reduced chance of NTDs. The arginine pathway may play a role in mediating this association.

Placental concentrations of alkali metals and their associations with neural tube defects in offspring.

INTRODUCTION: The role of alkali metals in the development of neural tube defects (NTDs) is little known. We examined the associations between placental concentrations of lithium (Li), sodium (Na), potassium (K), rubidium (Rb), and cesium (Cs), and the occurrence of NTDs in fetuses. METHODS: 408 women who had NTD-affected pregnancies and 593 women who delivered healthy infants were included. Logistic regression, weight quantile sum regression (WQSR), and Bayesian kernel machine regression (BKMR) were applied to assess whether these metals are associated with the occurrence of NTDs. RESULTS: Cs showed an inverse association with the odds of NTDs [adjusted odds ratio (aOR): 0.58, 95% confidence interval (CI): 0.36-0.91] in single-metal logistic model. Estimates did not change much in the multiple-metal logistic model. In WQSR, the WQS index was inversely associated with the odds of NTDs (aOR: 0.62, 95%CI: 0.51-0.75), in which Cs (weighted 0.45) had the highest weight. In BKMR, the odds of NTDs decreased with the levels of the five-metal mixtures. Cs was associated with decreased odds of NTDs when the remaining four metals were fixed at their 25th and 50th percentiles, while Na was associated with increased odds of NTDs when setting other metals at the 25th, 50th, or 75th percentile. DISCUSSION: A high concentration of Cs and Na in placental tissue was respectively associated with decreased and increased odds of NTDs. In addition, the occurrence of NTDs decreased with the levels of the five-metal mixtures.

Maternal Periconceptional Folic Acid Supplementation and Risk for Fetal Congenital Heart Defects.

OBJECTIVE: To determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid on the prevention of fetal congenital heart defects (CHDs). STUDY DESIGN: Data were drawn from a Prenatal Health Care System and a Birth Defects Surveillance System in a district of Beijing, China. A total of 63 969 singleton births, live or stillborn, 308 CHDs among them, during 2013 to 2018 were included. Associations between different patterns of supplementation and risk for total CHDs or main types of CHDs were evaluated with risk ratios (RRs). RESULTS: For folic acid or multiple micronutrients containing folic acid users compared with nonusers, the adjusted RRs (ARRs) for total CHDs, critical CHD, and ventricular septal defect (VSD) were 0.60 (95% CI, 0.44-0.83), 0.41 (95% CI, 0.26-0.67), and 0.47 (95% CI, 0.30-0.74), respectively. When we compared multiple micronutrients containing folic acid users with folic acid users, the ARRs were 0.84 (95% CI, 0.66-1.09), 0.64 (95% CI, 0.41-1.00), and 0.94 (95% CI, 0.63-1.41) for total CHDs, critical CHD, and VSD, respectively. We also found that, compared with supplementation initiated after conception, supplementation initiated before conception was associated with a lower risk for CHDs: the ARRs were 0.68 (95% CI, 0.48-0.95) for total CHDs and 0.26 (95% CI, 0.10-0.71) for critical CHD, but 1.08 (95% CI, 0.63-1.83) for VSD. CONCLUSIONS: Maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid seems to decrease the risk for CHDs, especially critical CHD, in offspring. Supplementation confers a greater protective effect when it is initiated before conception. We did not find any difference between folic acid and multiple micronutrients containing folic acid in terms of preventing CHDs.

Associations of maternal exposure to 41 metals/metalloids during early pregnancy with the risk of spontaneous preterm birth: Does oxidative stress or DNA methylation play a crucial role?

BACKGROUND: Few studies have explored the effects of multiple types of metals/metalloids on spontaneous preterm birth (SPB). A nested case-control study was conducted in Shanxi Province to investigate the associations between maternal exposure to 41 metals/metalloids during early pregnancy and the risk of SPB, and to clarify the underlying mechanisms of oxidative stress and DNA methylation. METHODS: A total of 74 controls with full-term delivery and 74 cases with SPB were included in the nested case-control study. The metals/metalloids in serum and the DNA adducts in peripheral blood cell DNA were determined using ICP-MS and UPLC-QqQ-MS/MS, respectively. Unconditional logistic regression models were employed to estimate the associations of the risk of SPB with the metal concentrations, as well as with the levels of oxidative stress/DNA methylation. In addition, linear regression models were used to investigate the associations between the metal/metalloid concentrations and the levels of oxidative stress/DNA methylation. RESULTS: After adjusting for potential confounders, the concentrations of Mn, Fe, Cu, Nd, Hg, and Pb in maternal serum during early pregnancy were positively associated with the risk of SPB. Compared with the lowest levels (Quartile 1) of Mn, Fe, Cu, Nd, Hg, and Pb, the odds ratios of SPB increased to 5.21 (95% CI: 1.63, 16.68), 3.47 (95% CI: 1.07, 11.21), 16.23 (95% CI: 3.86, 68.18), 10.54 (95% CI: 2.79, 39.86), 5.88 (95% CI: 1.72, 20.11), and 4.09 (95% CI: 1.31, 12.77) in the highest levels (Quartile 4), respectively. A significant increase in 8-OHdG was associated with the increased exposure to Fe, Pr, Eu, Er, and Lu. The levels of 5-MdC, 5-HmdC, and N6-MdA-the indicators of DNA methylation-were associated with exposure to multiple metals/metalloids. However, no significant associations were observed between the levels of oxidative stress or DNA methylation and the risk of SPB. CONCLUSIONS: Exposure to multiple types of metals/metalloids during early pregnancy is positively associated with the risk of SPB. Oxidative stress and DNA methylation are significantly associated with exposure to multiple metals/metalloids. Systemic oxidative stress and DNA methylation have not been proven to be the mediating mechanisms of metals increasing the risk of SPB.

Prenatal uranium exposure and risk for fetal neural tube defects: A case-control study in women living in a rural area of northern China.

The adverse effects of uranium exposure on human health are well-known; less is known, however, regarding its association with congenital malformations. We conducted a case-control study to examine the association between prenatal exposure to uranium and risk for fetal neural tube defects (NTDs) using the concentration of uranium in placental tissue as an exposure marker in 408 NTD cases and 593 healthy controls. Uranium concentration was quantified with an inductively coupled plasma mass spectrometer. The odds ratios of NTDs for uranium exposure levels, categorized into quartiles, were estimated using logistic regression. The median concentration of uranium in the NTD group (0.409 ng/g) was significantly higher than that in the control group (0.218 ng/g). The risk for NTDs increased 2.52-fold (95% CI, 1.85-3.45) for concentrations of uranium above the median value for all participants. After adjusting for confounders, the risk for NTDs increased 1.36-fold (95% CI, 1.25-6.17), 1.77-fold (95% CI, 1.09-2.85), and 3.60-fold (95% CI, 2.30-5.64) for the second, third, and fourth quartiles of uranium concentrations compared to the lowest quartile, respectively. Prenatal exposure to uranium is a risk factor for NTDs in this population. Prospective studies are needed to further validate this finding.