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.

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.

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.

Psychological health status in postpartum women during COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis pooled the prevalence of psychological symptoms during the COVID-19 pandemic and examined the effects of the pandemic on psychological health in postpartum women. METHODS: A systematic literature search and identification were performed in PubMed, EMBASE, Web of Science, and PsycINFO databases until June 16th, 2021. The fixed or random effect models to estimate the pooled prevalence of postpartum psychological symptoms during the COVID-19 pandemic and the odds ratio (OR) of COVID-19 for psychological symptoms. RESULTS: A total of 29 articles including 20,225 postpartum women during the COVID-19 pandemic and 8312 before the COVID-19 pandemic were identified. During the COVID-19 pandemic, the prevalence of postpartum depressive, anxiety, stress, and post-traumatic stress disorder symptoms were 26.7 % (95 % CI: 22.0-31.9 %), 33.8 % (95 % CI: 21.1-49.4 %), 55.0 % (95%CI: 27.9-79.5 %), and 33.7 % (95%CI: 19.6-51.5 %), respectively. The ORs of COVID-19 pandemic for postpartum depressive and anxiety symptoms were 1.54 (95 % CI: 1.00-2.36) and 2.56 (95%CI: 1.62-4.04). Subgroup analyses revealed that women with >6 weeks after delivery, younger than 35 years old, low income, less education and without breastfeeding experienced a higher risk of depressive or anxiety symptoms after delivery. LIMITATIONS: Only a few of prospective studies were included, and significant but inevitable heterogeneities were found in some analyses. CONCLUSION: A significantly higher proportion of postpartum women were suffered from psychological symptoms during COVID-19 pandemic, particularly in those with >6 weeks after delivery, younger than 35 years old, low income, less education and formula feeding.

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.

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.

Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review.

BACKGROUND: Congenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD. METHODS: Databases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis's five-class evidence grade. RESULTS: A total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as "Moderate". One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed. CONCLUSION: The present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.

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.

The China birth cohort study (CBCS).

The China birth cohort study (CBCS) is a prospective longitudinal, mega-cohort study and the first national-based birth cohort study, aiming to establish a birth cohort covering representative geographical areas of the whole of China to investigate risk factors for birth defects and develop strategies for their reduction. Pregnant women who are of Chinese nationality, are 6-13+6 weeks of gestation, plan to attend the routine antenatal examination and deliver in the study site, and give their informed, written consent are eligible to participate in this study. All participants are followed-up through an in-person interview at 20-23+6 weeks and again at 28-33+6 weeks of gestation, and at delivery, respectively. CBCS has been divided into three phases from 20th November 2017 to 31st December 2021, and the first two phases have now been completed on 29th February 2020, enrolling 120 377 eligible pregnant women during this period. During the same period a total of 40 837 participants had been followed up to the end of pregnancy. Study recruitment will continue until December 2021 to achieve the target of 500 000 participants. Meanwhile, biological samples including peripheral blood, amniocytes, cord blood, placenta, or umbilical cord tissue have been collected from participants according to various conditions. The incidence of birth defects in this group is 2.5% and congenital heart disease is the most common type of birth defect seen so far. A website is in the advanced stages of planning, to allow seamless data transfer and facilitate collaboration with groups around the world.

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.

High concentrations of aluminum in maternal serum and placental tissue are associated with increased risk for fetal neural tube defects.

Aluminum (Al)1 is ubiquitously present in the environment, and human exposure to Al is common. Al has been reported to be involved in various human diseases and adverse pregnancy outcomes, including neural tube defects (NTDs). This study aimed to examine the association between prenatal Al exposure and the risk for NTDs using Al concentrations in maternal serum and placental tissue. The subjects were recruited from six counties/cities in the Shanxi province of northern China from 2003 to 2016. Al concentrations in both types of specimens were assessed using inductively coupled plasma-mass spectrometry. In the maternal serum cohort (200 cases and 400 controls), compared to the lowest tertile concentration of Al, the highest Al tertile was associated with 2.42-fold (95% confidence interval, 1.23-4.87) increased risk after adjustment for confounding factors. In the placental tissue cohort (408 cases and 593 controls), the highest tertile of Al also tended to be associated with an elevated risk for NTDs [adjusted odds ratio, 1.60 (0.94-2.70)]. When analyzed by NTD subtypes, the highest Al tertile was associated with an increased risk for anencephaly in both cohorts after adjustment for confounders [odds ratio, 1.97 (1.15-3.48) in the maternal serum cohort; odds ratio, 4.75 (2.01-12.00) in the placental tissue cohort]. Taken together, using concentrations of Al in maternal serum and placental tissue as exposure markers, we found that prenatal exposure to higher levels of Al is a risk factor for fetal NTDs, especially for the anencephaly subtype.

Single and mixed effects of metallic elements in maternal serum during pregnancy on risk for fetal neural tube defects: A Bayesian kernel regression approach.

Studies of the association between prenatal exposure to metal elements and risk for neural tube defects (NTDs) have produced inconsistent results. Little research has examined the joint effects and interactions of multiple elements. This study examined 273 women with NTD-affected pregnancies and 477 controls. Cadmium, cobalt, chromium, copper, iron, mercury, manganese, molybdenum, lead, and zinc were quantified in maternal serum. Single and mixed effects of these elements on NTD risk were evaluated with Bayesian kernel machine regression, and the effects of individual elements were validated using logistic regression. As a result, NTD risk increased with the concentration of the mixture of the 10 elements. NTD risk rose as the levels of the five toxic elements increased, with effect sizes larger than the overall analyses, but they decreased, albeit non-significantly, as the levels of the five essential elements increased. Lead and manganese showed risk effects on NTDs, with odds ratios (ORs) of 1.94 (1.76-2.13) and 1.25 (1.14-1.38), respectively, with the remaining nine elements remaining at their median. Molybdenum showed a protective effect against NTDs with an OR 0.87 (0.90-0.94). The single-element results were validated using logistic regression. In conclusion, NTD risk increased with concentrations of the five toxic elements, with lead and manganese being the major contributors. Essential elements showed protective effects against NTD risk.

Prenatal exposure to barium and the occurrence of neural tube defects in offspring.

Neural tube defects (NTDs) have a complex etiology. Few studies have assessed alkaline earth metals exposures and occurrence of NTDs. We examined the association between prenatal exposure to magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba) and risk for NTDs in a case-control study, and assessed the teratogenic effects of Ba on mice. Placentas were collected from 408 women with NTD-affected pregnancies and 593 women who delivered healthy infants, and concentrations of these metals were determined as prenatal exposure markers. The single effect of individual exposure and joint effect of coexposure to these metals were evaluated with logistic regression and Bayesian kernel machine regression (BKMR), respectively. Barium chloride (BaCl2) was intragastrically administered to pregnant ICR mice and fetal mice were examined for NTDs. Median concentrations of Mg and Ba were higher in NTD cases than in controls (Pall < 0.001). In logistic regression, higher levels of Ba were associated with 1.6-fold increased risk for NTDs (95% confidence interval: 1.06-2.43). In BKMR, the joint effect of the four-metal mixture on NTD risk increased steadily with the levels of the mixture. A change in Ba concentration from the 25th to 75th percentile displayed a risk effect when the other three metals were fixed at the 25th, 50th or 75th percentile, while such a change in Ca concentration showed a protective effect when the other metals were held at the 25th or 50th percentile. No interactions among metals were found. In the mouse experiment, dams treated with 200 mg/kg BaCl2 showed 16.8% of NTDs in fetal mice, compared to 2.6% in the untreated control group (P < 0.01). Taken together, higher mixture levels of the four alkaline earth metals were associated with increased risk for NTDs, with Ba being the major contributor for the joint effect. Intragastric administration of Ba can induce NTDs in mice.

Neural Tube Defects and ZIC4 Hypomethylation in Relation to Polycyclic Aromatic Hydrocarbon Exposure.

BACKGROUND: Epigenetic dysregulation is one of the postulated underlying mechanisms of neural tube defects (NTDs). Polycyclic aromatic hydrocarbons (PAHs), a group of environmental pollutants that are reported as a risk factor of NTDs, may cause decreased genome-wide DNA methylation. With DNA extracted from neural tissues, this study identified gene(s) whose hypomethylation was related to elevated risk for NTDs and examined whether its hypomethylation is related to PAH exposure. RESULTS: Using data profiled by Infinium HumanMethylation450 BeadChip array from 10 NTD cases and eight controls, ZIC4, CASP8, RAB32, RARA, and TRAF6 were identified to be the top five genes in NTD-related hypomethylated gene families. Among all identified genes, ZIC4 had the largest number of differently methylated CpG sites (n = 13) in the promoter region and 5' UTR. Significantly decreased methylation in the ZIC4 promoter region and 5' UTR was verified in an independent cohort of 80 cases and 32 controls (p < 0.001) utilizing the Sequenom EpiTYPER platform. Hypomethylation of ZIC4 was associated with a higher risk of NTDs [adjusted OR = 1.08; 95% confidence interval (CI): 1.03, 1.13] in a logistic regression model. Mean methylation levels in the promoter region and 5' UTR of ZIC4 tended to be inversely associated with levels of high-molecular-weight PAHs in fetal liver among NTD fetuses (ß [95% CI]: -0.045 [-0.091, 0.001], p = 0.054). Six and three CpG sites in the ZIC4 promoter region and 5' UTR were inversely correlated with antioxidant indicators and protein oxidation markers (ρ: -0.45 to -0.75, p < 0.05) in fetal neural tissues, respectively. In a whole-embryo cultured mouse model, hypomethylation of the Zic4 promoter region and 5' UTR and upregulation of Zic4 were observed, coupled with increased NTD rates after BaP exposure. The antioxidant N-acetyl-L-cysteine normalized the changes observed in the BaP exposure group. CONCLUSION: Hypomethylation of the ZIC4 promoter region and 5' UTR may increase the risk for NTDs; oxidative stress is likely to play a role in the methylation change of Zic4 in response to PAH exposure in NTD formation.

Concentrations of organochlorine pesticides in placental tissue are not associated with risk for fetal orofacial clefts.

Previous epidemiological studies have shown that prenatal exposure to organochlorine pesticides (OCPs) entails a variety of adverse impacts on fetal health, but it is not yet known whether it is associated with risk for orofacial clefts (OFCs). This study of 103 fetuses or newborns with a diagnosis of OFCs (cases) and 103 healthy newborns without malformations (controls) examined whether prenatal exposure to OCPs, as indicated by their concentrations in placental tissue, is a risk factor for OFCs. No differences were found in the median concentrations of OCPs between cases and controls, with exception of o,p'-dichlorodiphenyldichloroethylene, o,p'-dichlorodiphenyldichloroethane, and total o,p'-dichlorodiphenyltrichloroethane (DDTs), whose concentrations were higher in controls than in cases (Ps < 0.05). Although higher concentrations of placental δhexachlorocyclohexane and isodrin were found to be associated with decreased risk for OFCs in logistic regression, no association was observed in the Bayesian kernel machine regression, a novel statistical model in analyzing exposure mixtures. Women who reported periconceptional folic acid supplementation had lower placental concentrations of DDTs than women who did not. In conclusion, no association between levels of OCPs in placental tissue and risk for OFCs was observed in this population. Supplementation with folic acid may help decrease the levels of DDTs in placental tissue, but further studies are needed to confirm this unexpected finding.

Essential trace elements in placental tissue and risk for fetal neural tube defects.

This study examined the associations between concentrations of cobalt (Co), iron (Fe), manganese (Mn), molybdenum (Mo), selenium (Se), and zinc (Zn) in placental tissue and risks for NTDs with a case-control design consisting of 408 fetuses or newborns with neural tube defects (NTDs) and 593 non-malformed fetuses or newborns. The concentrations of Zn and Fe were determined by inductively coupled plasma-emission spectrometer and the other four elements by inductively coupled plasma-mass spectrometer. Element concentrations were presented in ng/g or µg/g dry weight of placental tissue. The associations between the levels of each of the six ETEs and risk for NTDs were evaluated using multivariable logistic regression, and the associations between overall levels of all six ETEs and risk for NTDs were examined using Bayesian kernel machine regression (BKMR). Concentrations above the median concentration of all participants for an individual element were associated with increased risk for NTDs: Mn, 3.17-fold (95% CI 2.35-4.28); Mo, 3.73-fold (95% CI 2.74-5.07); Se, 3.28-fold (95% CI 2.44-4.42); and Zn, 2.85-fold (95% CI 2.13-3.83), and a decreased risk for Co [OR, 0.18 (95% CI 0.14-0.25)]. The risk for NTDs increased with the increase in the concentrations of Mn, Mo, Se, and Zn, but decreased for Co, in the second, third, and fourth quartiles, respectively, compared to their lowest quartile (all Pstrend < 0.01). In BKMR model, the risk for NTDs increased constantly when the overall exposure levels were higher than the median of the six ETEs as a co-exposure mixture, and the associations between Co, Mn, Se, and Zn and NTD risk remained when the remaining five elements were taken into consideration simultaneously. Taken together, when evaluated individually, higher levels of Mn, Se, and Zn in placental tissue are associated with increased risk for NTDs, while higher levels of Co are associated with decreased risk for NTDs; when examined collectively, the risk of NTDs increases continuously when exposure levels are higher than the median of the six ETE mixture.

Concentrations of rare earth elements in maternal serum during pregnancy and risk for fetal neural tube defects.

Rare earth elements (REEs) are ubiquitous in the environment. Animal experiments have shown that many REEs have adverse impacts on the health of fetuses. However, data from humans are scarce. In this study, we examined the associations between concentrations of 10 REEs in maternal serum and the risk for fetal neural tube defects (NTDs). The study included 200 pregnant women with pregnancies affected by NTDs and 400 pregnant women with healthy fetuses/infants. Fifteen REEs in maternal serum were assessed; 10 of them were detectable in over 60% of samples and were included in statistical analyses, including lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), terbium (Tb), dysprosium (Dy), lutetium (Lu), and yttrium (Y). When the elements were considered individually with the use of Logistic regression model, the risk for NTDs increased by 2.78-fold (1.25-6.17) and 4.31-fold (1.93-9.62) for La, and 1.52-fold (0.70-3.31) and 4.73-fold (2.08-10.76) for Ce, in the second and third tertiles, respectively, compared to the lowest concentration tertile. When Bayesian kernel machine regression was used to examine the joint effect of exposure to all 10 REEs, the risk for NTDs increased with overall levels of these REEs and the association between La and NTD risk remained when other nine elements were taken into consideration simultaneously. Taken together, this study shows that the risk for NTDs increases with La concentrations when single REEs are considered and with concentrations of all 10 REEs when these REEs are considered as a co-exposure mixture.