Gestational diabetes mellitus is associated with distinct folate-related metabolites in early and mid-pregnancy: A prospective cohort study.

AIMS: This study aimed to evaluate the association between gestational diabetes mellitus (GDM) and circulating folate metabolites, folic acid (FA) intake, and the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genotype. MATERIALS AND METHODS: A prospective pregnancy cohort study was conducted in Beijing, China, from 2022 to 2023. Circulating folate metabolites, including red blood cell (RBC) 5-methyltetrahydrofolate (5-MTHF), 5, 10-methylene-tetrahydrofolate (5,10-CH2-THF), 5- formyltetrahydrofolate (5-CHO-THF), and unmetabolised folic acid (UMFA), and plasma homocysteine (HCY), 5-MTHF, and methylmalonic acid (MMA), were determined at 6-17 weeks and 20-26 weeks of gestation. FA intake and the MTHFR and MTRR genotype were also examined. GDM was diagnosed between 24 and 28 weeks of pregnancy by a 75-g oral glucose tolerance test (OGTT). The association between the folate status and GDM was ascertained using multivariate generalised linear models, logistic regression models, and restricted cubic spline regression, adjusting for potential confounders. RESULTS: The study included 2032 pregnant women, of whom 392 (19.29%) developed GDM. UMFA above the 75th percentile (≥P75) [adjusted OR (aOR) (95% confidence interval [CI]) = 1.36 (1.01-1.84)], UMFA ≥ P90 [aOR (95% CI) = 1.82 (1.23-2.69)], and HCY ≥ P75 [aOR (95% CI) = 1.40 (1.04-1.88)] in early pregnancy, and RBC 5-MTHF [aOR (95% CI) = 1.48 (1.10-2.00)], RBC 5,10-CH2-THF [aOR (95% CI) = 1.55 (1.15-2.10)], and plasma 5-MTHF [aOR (95% CI) = 1.36 (1.00-1.86)] in mid-pregnancy ≥ P75 are associated with GDM. Higher UMFA levels in early pregnancy show positive associations with the 1-h and 2-h glucose levels during the OGTT, and higher HCY levels are associated with increased fasting glucose levels during the OGTT. In comparison, RBC 5- MTHF and 5,10-CH2-THF, and plasma 5- MTHF in mid-pregnancy are positively associated with the 1-h glucose level (p < 0.05). The MTHFR and MTRR genotype and FA intake are not associated with GDM. CONCLUSIONS: Elevated levels of UMFA and HCY during early pregnancy, along with elevated RBC 5-MTHF and 5,10-CH2-THF and plasma 5-MTHF during mid-pregnancy, are associated with GDM. These findings indicate distinct connections between different folate metabolites and the occurrence of GDM.

Association between light rare earth elements in maternal plasma and the risk of spontaneous preterm birth: a nested case-control study from the Beijing birth cohort study.

BACKGROUND: Parental exposure to rare earth elements (REEs) could increase the risk of premature rupture of membranes, a major cause of spontaneous preterm birth (SPB). In addition, different subtypes of SPB, such as spontaneous preterm labor (SPL) and preterm premature rupture of membranes (PPROM), may have different susceptibility to environmental exposure. Therefore, we investigated the potential associations between REE exposure in different trimesters and SPB and its subtypes. METHODS: A nested case-control study was performed. We included 244 women with SPB as cases and 244 women with full-term delivery as controls. The plasma concentrations of light REEs were measured in the first and third trimesters. Logistic regression was used to analyze the associations between single REE levels and SPB, and Bayesian kernel machine regression (BKMR) was used to analyze the mixed-exposure effect. RESULTS: Exposure to light REEs was associated with SPB and its subtypes only in the third trimester. Specifically, the intermediate- and highest-tertile concentration groups of La and the highest-tertile concentration group of Sm were associated with an increased risk of SPL, with adjusted odds ratios (AORs) of 2.00 (95% CIs: 1.07-3.75), 1.87 (95% CIs: 1.01-3.44), and 1.82 (95% CIs: 1.00-3.30), respectively. The highest-tertile concentration group of Pr was associated with an increased risk of PPROM, with an AOR of 1.69 (95% CIs: 1.00-2.85). Similar results were also found in BKMR models. CONCLUSIONS: La and Sm levels in plasma may be associated with the risk of SPL, and Pr levels in plasma may be associated with the risk of PPROM.

Fetal origins of obesity: a novel pathway of regulating appetite neurons in the hypothalamus of growth-restricted rat offspring.

PURPOSE: Fetal growth restriction causes a series of sequelae, some of which, such as hyperphagia, reduced satiety and postnatal obesity, are believed to be associated with embryonic hypothalamic neurons impairment. The mechanisms underlying the linkage of fetal brain injuries to break the energy homeostasis have not been elucidated completely. Here, we aim to investigate the effect of intrauterine energy restriction on remodeling appetite neurons in the hypothalamus of fetal and postnatal infant rats. METHODS: Low-protein (8%) diet combined with 75% energy restriction was used to establish an animal model. Rats offspring brain tissues, harvested from embryo day 18 and postnatal infant day 1, were sampled for dependent regulator analyses and master neuron assessment. RESULTS: Growth-restricted rats showed the increased expression of Bsx and NPY in the hypothalamus as well as remodeling hypothalamic neurons differentiation compared to controls. Intriguingly, in cells cultured in vitro test, we found that activated effects of Bsx and NPY could be exacerbated by DNMT1 inhibitor. CONCLUSIONS: In embryonic and early postnatal stage of FGR rats, we detected high concentrations of orexigenic neurons in the hypothalamus. DNMT1 activity is correlated with early embryonic neurogenesis by mediating the expression of Bsx and NPY. It may be one of the reasons for the abnormal development of the appetite regulation pathway and higher susceptibility to obesity in FGR offspring.

Neonatal Amino Acids and Acylcarnitines Associated With Maternal Blood Glucose Levels Throughout Pregnancy: Insights From the Beijing Birth Cohort Study.

OBJECTIVE: To determine the association between maternal blood glucose patterns throughout pregnancy and neonatal amino acids and acylcarnitines. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study involving 11,457 singleton pregnant women without preexisting diabetes from the Beijing Birth Cohort Study, along with their neonates born between July 2021 and October 2022 in Beijing, China. Distinct maternal glucose trajectories were identified using a latent class model based on blood glucose levels across the three trimesters, and their association with neonatal circulating metabolites, including 11 amino acids and 33 acylcarnitines, was examined, adjusting for potential confounding factors. RESULTS: Three distinct groups of maternal glucose trajectories were identified: consistent normoglycemia (n = 8,648), mid-to-late gestational hyperglycemia (n = 2,540), and early-onset hyperglycemia (n = 269). Mid-to-late gestational hyperglycemia was associated with decreased levels of amino acids (alanine, arginine, ornithine, and proline) involved in the arginine and proline metabolism and urea cycle pathway, as well as increased levels of C4DC+C5-OH and decreased level of C6DC and C10:1. Early-onset hyperglycemia was associated with elevated levels of free acylcarnitine and C4DC+C5-OH and a decreased level of C10:1, involved in the fatty acid oxidation pathway. However, these associations were primarily observed in male neonates rather than in female neonates. CONCLUSIONS: Our findings revealed a significant link between maternal glucose trajectories throughout pregnancy and neonatal arginine and proline metabolism, urea cycle pathway, and fatty acid oxidation pathway. These results highlight the importance of maintaining optimal blood glucose levels throughout pregnancy to promote healthy neonatal metabolic outcomes.

Butyrate and iso-butyrate: a new perspective on nutrition prevention of gestational diabetes mellitus.

BACKGROUND: Dietary imbalance, such as a lower proportion of complex carbohydrates and a higher protein diet, may contribute to gestational diabetes mellitus (GDM) risks through their metabolisms. However, there is a lack of knowledge regarding the association between butyrate, iso-butyrate, and GDM, which are metabolisms of the two primary nutrients above. This study aimed to clarify the association of butyrate and iso-butyrate with GDM. METHODS: A nested case-control study was conducted based on the Beijing Birth Cohort Study (BBCS) from 2017 to 2018. Totally, 99 singleton women were involved (GDM: n = 49, control: n = 50). All participants provided blood samples twice (in their first and second trimesters). Gas chromatography-mass spectrometry (GC-MS) was used for butyrate and iso-butyrate detection. Unconditional logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis. RESULTS: The results showed that butyrate in the first trimester was negatively correlated with GDM (odds ratio (OR): 0.00, 95% confidential interval (CI): 0.00-0.21, P = 0.008), and iso-butyrate in the second trimester was positively related to GDM (OR: 627.68, 95% CI: 40.51-9724.56, P < 0.001). The ratio (butyrate/iso-butyrate) was negatively associated with GDM, both in the first trimester (OR: 0.00, 95%CI: 0.00-0.05, P < 0.001) and in the second trimester (OR: 0.52, 95% CI: 0.34-0.80, P = 0.003). The area under the curve (AUC) using the ratio in the first trimester combined with clinical risk factors achieved 0.89 (95% CI: 0.83-0.95). Iso-butyrate in the second trimester combined with clinical risk factors achieved an AUC of 0.97 (95% CI: 0.92-1.00). CONCLUSIONS: High iso-butyrate and low butyrate levels may be associated with an increased risk of GDM. As they are produced through dietary nutrient formation by gut microbiota, further studies on the association of dietary intake and butyrate or iso-butyrate concentration in plasma may help find a novel approach to nutritional intervention for GDM.

Maternal cobalt concentration and risk of spontaneous preterm birth: the role of fasting blood glucose and lipid profiles.

Introduction: Spontaneous preterm birth (SPB) is a significant cause of neonatal mortality, yet its etiology remains unclear. Cobalt, an essential trace element, might be a risk factor for SPB. This study aims to investigate the relationship between maternal serum cobalt concentration and SPB, and to clarify the role of blood lipids and fasting blood glucose (FBG) in this relationship. Methods: We conducted a nested case-control study within the Beijing Birth Cohort Study. Serum samples were obtained from 222 pregnant women with SPB and 224 controls during the first (7-13 weeks of pregnancy) and third trimesters (32-42 weeks of pregnancy). Serum cobalt concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS). Fasting blood glucose and lipids levels were detected using a fully automated biochemical immunoassay instrument. Logistic regression models and linear regression models were established to explore the association between serum cobalt concentration and the risk of SPB in pregnant women, and to test the mediating effect of fasting blood glucose (FBG) and lipids. Results: We found that the serum cobalt concentration in mothers with SPB and controls was similar in the first trimester, with values of 0.79 (0.58-1.10) ng/mL and 0.75 (0.51-1.07) ng/mL, respectively. However, in the third trimester, the cobalt concentration increased to 0.88 (0.59-1.14) ng/mL and 0.84 (0.52-1.19) ng/mL, respectively. In the logistic regression model, when considering the third trimester of pregnancy, after adjusting for ethnicity, pre-pregnancy body mass index (BMI), maternal age, education, income, and parity, it was observed that the medium level of cobalt concentration (0.63-1.07 ng/ml) had a negative correlation with the risk of SPB. The odds ratio (OR) was 0.56, with a 95% confidence interval of 0.34-0.90 ng/mL and a p-value of 0.02. This suggests that cobalt in this concentration range played a protective role against SPB. Additionally, it was found that FBG in the third trimester of pregnancy had a partial intermediary role, accounting for 9.12% of the association. However, no relationship between cobalt and SPB risk was found in the first trimester. Conclusion: During the third trimester, intermediate levels of maternal cobalt appear to offer protection against SPB, with FBG playing a partial mediating role. To further clarify the optimal cobalt concentrations during pregnancy for different populations, a multi-center study with a larger sample size is necessary. Additionally, exploring the specific mechanism of FBG's mediating role could provide valuable insights for improving the prevention of SPB.

Molybdenum Concentration and the Risk of Spontaneous Preterm Birth: A Nested Case-Control Study - Beijing Municipality, China, 2018-2020.

What is already known about this topic?: The level of molybdenum (Mo) in a mother's urine has been linked to the growth rate of the fetus and the blood pressure levels in children. What is added by this report?: We evaluated the variations in maternal plasma Mo concentrations throughout pregnancy and their potential association with the risk of spontaneous preterm birth (SPB). What are the implications for public health practice?: Future research must determine the Mo levels in pregnant women across various regions in China. Moreover, particular attention needs to be given to the potential increase in Mo concentration throughout pregnancy and its possible adverse impacts on the health of both the mother and the fetus.

Association of Maternal Plasma Manganese with the Risk of Spontaneous Preterm Birth: A Nested Case-Control Study Based on the Beijing Birth Cohort Study (BBCS) in China.

We performed this study to clarify the dynamic changes in maternal manganese (Mn) concentration during pregnancy and its association with spontaneous preterm birth (SPB). A nested case-control study was conducted based on the Beijing Birth Cohort Study (BBCS) from 2018 to 2020. Singleton pregnancy women aged 18-44 (n = 488) were involved in the study, including 244 cases of SPB and 244 controls. All of the participants provided blood samples twice (in their first and third trimesters). Inductively coupled plasma mass spectrometry (ICP-MS) was used for the laboratory analysis, and unconditional logistic regression was used for the statistical analysis. We found that the maternal Mn levels were significantly higher in the third trimester than those in the first trimester (median: 1.23 vs. 0.81 ng/mL). The SPB risk was increased to 1.65 (95% CI: 1.04-2.62, p = 0.035) in the highest Mn level (third tertile) in the third trimester, especially in normal-weight women (OR: 2.07, 95% CI: 1.18-3.61, p = 0.011) or non-premature rupture of membrane (PROM) women (OR: 3.93, 95% CI: 2.00-7.74, p < 0.001). Moreover, a dose-dependent relationship exists between the SPB risk and maternal Mn concentration in non-PROM women (P trend < 0.001). In conclusion, dynamic monitoring of maternal Mn level during pregnancy would be helpful for SPB prevention, especially in normal-weight and non-PROM women.

Associations of gestational weight gain with birth weight outcomes in early pregnancy weight loss women: Findings from the Beijing Birth Cohort Study.

OBJECTIVE: To explore the relationship between gestational weight gain (GWG) and birth weight outcomes and establish suggested GWG patterns in early pregnancy weight loss women. METHODS: This retrospective study was conducted based on the Beijing Birth Cohort Study from 2014 to 2021 and included 20 688 women. Weight change in early pregnancy was calculated using weight measurements within 16 weeks of gestation. Multivariable logistic regression was used to analyze the relationships of different GWG categories, based on the Chinese standard, and birth weight outcomes. The statistical-based approach was used to determine the optimal GWG ranges and weekly weight gain. RESULTS: Compared to 3313 women who gained appropriate weight in early pregnancy, 2614 women who lost weight in the same period increased the risk of small for gestational age (SGA) (OR = 1.43, 95% CI: 1.14-1.80, P = 0.002). However, the relationship disappeared after adjusting for total GWG. Among the early pregnancy weight loss women, both excessive GWG and inadequate GWG were associated with adverse birth weight outcomes after adjusting for confounders. The suggested GWG range and rate were 11.0 ~ 16.0 kg and 0.46 to 0.67 kg/week from 16 weeks to delivery for women with normal body mass index (BMI) and weight loss in early pregnancy. CONCLUSION: Weight loss in early pregnancy was not the independent risk factor of birth weight outcomes. GWG may offset the expected effects. To achieve optimal outcomes, women with normal BMI and weight loss in early pregnancy need to have a higher weight gain rate in mid-late pregnancy but similar total GWG ranges with the Chinese standard for general women.

Association between serum lipid profile during the first and second trimester of pregnancy as well as their dynamic changes and gestational diabetes mellitus in twin pregnancies: a retrospective cohort study.

BACKGROUND: Abnormal lipid metabolism is associated with gestational diabetes mellitus (GDM) in singleton pregnancies. Data were lacking on twin pregnancies with GDM. We explored the association between serum lipid profiles in the first and second trimesters as well as their dynamic changes and GDM in twin pregnancies. METHODS: This was a retrospective cohort study of 2739 twin pregnancies that underwent a 75-g oral glucose tolerance test (OGTT) and were selected from the Beijing Birth Cohort Study from June 2013 to May 2021. Cholesterol (CHO), triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were measured at mean 9 and 25 weeks of gestation. We described maternal lipid levels in different tertiles that were associated with the risk of GDM stratified for age, pre-BMI, and fertilization type. GDM patients were divided into two groups according to OGTT: elevated fasting plasma glucose only (FPG group) and the rest of the GDM (non-FPG group). We estimated the relative risk of GDM with multivariable logistic regression models. RESULTS: In this study, we found that 599 (21.9%, 599/2739) twin pregnancies developed GDM. They had increased CHO, TG, LDL, and LDL/HDL, decreased HDL levels in the first trimester, and increased TG as well as decreased HDL in the second trimester in univariate analyses, each P < 0.05. In multivariate analysis, when TG > 1.67 mmol/l (upper tertile) in elderly individuals, nonoverweight and ART groups increased the risk of GDM by 2.7-fold, 2.3-fold and 2.2-fold, respectively, compared with TG < 0.96 mmol/l (lower tertile). This effect remained in the abovementioned groups in the second trimester. Moreover, high TGs increased the risk of GDM in the FPG group (OR = 2.076, 95% CI 1.130-3.815) and non-FPG group (OR = 2.526, 95% CI 1.739-3.67) in the first trimester when TG > 1.67 mmol/l, and the rising risk in the non-FPG group as the TG tertile increased remained in the second trimester. HDL predominantly showed a negative association with elevated FPG in the second trimester (p < 0.05). CONCLUSIONS: Twin pregnancies with GDM have higher lipid levels. Increased TGs in the first and second trimesters are strongly associated with GDM, especially in elderly individuals, nonoverweight and ART groups. Lipid profiles varied among different GDM subtypes.