Association Between Serum Glycated Hemoglobin Levels at Early Gestation and the Risk of Subsequent Pregnancy Loss in Pregnant Women Without Diabetes Mellitus: Prospective Cohort Study.

BACKGROUND: As a severe morbidity during pregnancy, the etiology of spontaneous pregnancy loss (SPL) remains largely unknown. Serum glycated hemoglobin (HbA1c) level is an established predictor of SPL risk among women with diabetes, but little is known about whether such an association exists among pregnant women without diabetes when glycemic levels are within the normal range. OBJECTIVE: This study aimed to quantify the association between maternal HbA1c levels in early pregnancy and subsequent SPL risk in a cohort of pregnant women without diabetes. METHODS: This prospective cohort study involved 10,773 pregnant women without diabetes enrolled at their first antenatal care visit at a hospital's early pregnancy clinic from March 2016 to December 2018 in Shanghai, China. HbA1c and fasting blood glucose (FBG) levels were examined at enrollment. Participants with diabetes before or pregnancy or those diagnosed with gestational diabetes were excluded. Diagnosis of SPL, defined as fetal death occurring before 28 gestational weeks, was derived from medical records and confirmed via telephone interviews. We used generalized linear models to quantify the associations of continuous and dichotomized maternal HbA1c levels with SPL risk and reported crude and adjusted risk ratios (RRs) and 95% CIs. A restricted cubic spline (RCS) regression model was used to assess the potential nonlinear dose-response relationship. Adjusted covariates included maternal age, education level, preconception BMI, gestational weeks, gravidity, history of adverse pregnancy outcomes, family history of diabetes, folic acid supplementation, and smoking and drinking during the periconception period. RESULTS: In total, 273 (2.5%) SPL cases occurred. Every 0.5% increase in HbA1c levels was linearly associated with a 23% increase in SPL risk (adjusted RR [aRR] 1.23; 95% CI 1.01-1.50). The RCS model revealed that this association was linear (P=.77 for the nonlinearity test). Analyses based on dichotomized HbA1c levels showed a significantly increased risk of SPL when HbA1c levels were ≥5.9% (aRR 1.67; 95% CI 0.67-3.67), and the significance threshold was ≥5.6% (aRR 1.60; 95% CI 1.01-2.54). Sensitivity analyses showed similar results when including the participants with missing SPL records or HbA1c data. Linear associations of HbA1c levels remained significant even in the subgroups without overweight, alcohol consumption, and a family history of diabetes and adverse pregnancy outcomes. Every 1 mmol/L increment in maternal FBG levels was associated with a >2-fold higher risk of SPL (aRR 2.12; 95% CI 1.61-2.80; P<.001). CONCLUSIONS: Higher HbA1c levels in early pregnant women without diabetes are associated with an increased SPL risk in a dose-response manner. Pregnant women with an HbA1c level above 5.6% at early gestation need attention for its potentially increased risk for SPL. Our findings support the need to monitor HbA1c levels to identify individuals at high risk of subsequent SPL in the general population of pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737644; https://clinicaltrials.gov/study/NCT02737644.

Integrative transcriptomics and proteomics analyses to reveal the therapeutic effect and mechanism of Buxue Yimu Pills in medical-induced incomplete abortion rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Medical abortions using mifepristone and misoprostol have been approved in many countries for early pregnancy loss. Despite its high success rate, this medication regimen can result in incomplete abortion, which is responsible for endometrial damage, prolonged uterine bleeding, abdominal pain, etc. Buxue Yimu Pills (BYP) is a famous Chinese medicine prescription that is widely used in the field of gynecology and obstetrics for treating patients with postpartum complications. However, the therapeutic effect and mechanism of BYP remain to be explored. AIM OF THE STUDY: This study aimed to clarify the therapeutic effect and mechanism of action of BYP in postpartum complications using mifepristone and misoprostol-induced incomplete abortion in rats. MATERIALS AND METHODS: Experimental medical-induced incomplete abortion model rats were constructed using mifepristone and misoprostol, and further treated with saline or BYP by intragastric administration. Detailed information regarding the changes in mRNA and protein levels in the uterine tissues of rats regulated by BYP was illustrated by RNA sequencing (RNA-seq) analysis and quantitative proteomics analysis. The differentially expressed genes and proteins were further subjected to Gene Ontology (GO) and pathway enrichment analyses and further verified using quantitative Real-time PCR (qRT-PCR) analysis and western blot assay. RESULTS: BYP administration markedly alleviated the increase in serum prostaglandin F2α (PGF2α) and expression of PGF2α receptor (PGF2αR) in uterine tissues and inhibited the decrease in serum chorionic gonadotrophin (CG). Compared with the model group, 674 genes were upregulated and 344 genes were downregulated by BYP administration; 108 proteins were upregulated and 48 proteins were downregulated by BYP administration. qRT-PCR analysis of the uterine tissues showed that BYP treatment reversed the variation tendency of genes, including Mmp7, Mmp14, Timp2, Col6a4, Jak2, Wnt7a, and Mylk compared with the model group. Western blot analysis showed that BYP administration affected PKCδ, Collagen VI, MMP7, TIMP2, MLCK, and p-MLC protein levels. CONCLUSION: BYP administration facilitated uterine recovery in medical-induced incomplete abortion rats, and this therapeutic effect involved various targets and biological processes, including the TIMP2/MMP7 and MLCK/p-MLC signaling pathways, etc.

Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease : Nested Case-Control and Mendelian Randomization Studies.

BACKGROUND: Periconception folic acid supplementation has been suggested to protect against congenital heart disease (CHD), but the association between maternal red blood cell (RBC) folate, the gold-standard biomarker of folate exposure, and subsequent offspring CHD risk is lacking. OBJECTIVE: To quantify the association between periconception maternal RBC folate and offspring CHD risk. DESIGN: Prospective, nested, case-control study and 1-sample Mendelian randomization. (ClinicalTrials.gov: NCT02737644). SETTING: 29 maternity institutions in 12 districts of Greater Shanghai, China. PARTICIPANTS: All 197 mothers of offspring with CHD and 788 individually matched mothers of unaffected offspring from the SPCC (Shanghai Preconception Cohort). MEASUREMENTS: Maternal RBC folate was measured before or at early pregnancy. Odds ratios [ORs] were estimated using conditional logistic regression after adjustment for covariates. Mendelian randomization was done using the methylenetetrahydrofolate reductase (MTHFR) C677T as the genetic instrument. RESULTS: Case patients had lower median maternal RBC folate concentrations than control participants (714 nmol/L [interquartile range, 482 to 1008 nmol/L] vs. 788 nmol/L [557 to 1094 nmol/L]). Maternal RBC folate concentrations were inversely associated with offspring CHD (adjusted OR per 100 nmol/L, 0.93 [95% CI, 0.89 to 0.99]). The adjusted OR for mothers with periconception RBC folate of 906 nmol/L or more (vs. <906 nmol/L) was 0.61 (CI, 0.40 to 0.93). Mendelian randomization showed that each 100-nmol increase in maternal RBC folate concentrations was significantly associated with reduced offspring CHD risk (OR, 0.75 [CI, 0.61 to 0.92]). LIMITATION: Potential confounding due to unmeasured covariates in the nested case-control study. CONCLUSION: Higher maternal RBC folate is associated with reduced offspring CHD risk. For primary CHD prevention, higher target RBC folate levels than currently recommended for neural tube defect prevention may be needed and warrant further study. PRIMARY FUNDING SOURCE: National Key Research and Development Program of China, National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.

RBC Folate and Serum Folate, Vitamin B-12, and Homocysteine in Chinese Couples Prepregnancy in the Shanghai Preconception Cohort.

BACKGROUND: The protective effects of maternal folate on neural tube defects are well-established. Emerging evidence has shown paternal folate also is related to pregnancy outcome and offspring health. OBJECTIVES: This study aimed to assess the status of red blood cell (RBC) folate and serum folate, vitamin B-12, and homocysteine (Hcy) and their associated factors in a cohort of pregnancy-preparing couples. METHODS: This was a cross-sectional study involving 14,178 participants from the extension of the Shanghai Preconception Cohort conducted in 2018-2021. Circulating biomarker concentrations were measured, and the prevalence of abnormal status was reported. Linear and logistic regression analyses were conducted to examine associations of demographic factors (age, education, and income), lifestyle factors (smoking, drinking, and folic acid supplement use), and BMI with concentrations of the folate-related biomarkers, abnormal status of folate (deficiency and insufficiency) and vitamin B-12 (deficiency and marginal deficiency), and hyperhomocysteinemia. RESULTS: The geometric mean (95% CI) concentrations of RBC folate, serum folate, vitamin B-12, and Hcy were 490 nmol/L (485, 496 nmol/L), 20.1 nmol/L (19.8, 20.3 nmol/L), 353 pmol/L (350, 357 pmol/L), and 7.54 µmol/L (7.48, 7.60 µmol/L) in females, respectively, and 405 nmol/L (401, 409 nmol/L), 13.5 nmol/L (13.4, 13.7 nmol/L), 277 pmol/L (274, 279 pmol/L), and 12.0 µmol/L (11.9, 12.2 µmol/L) in males, respectively. Prevalence of abnormal status was higher in males than females for the 4 folate-related biomarkers: RBC folate deficiency (<340 nmol/L, 32.2% compared with 18.9%), serum folate deficiency (<10.0 nmol/L, 26.5% compared with 7.3%), RBC folate insufficiency (<906 nmol/L, 96.6% compared with 90.1%), serum folate insufficiency (<15.9 nmol/L, 65.5% compared with 31.4%), vitamin B-12 marginal deficiency (148-221 pmol/L, 21.4% compared with 8.8%), and hyperhomocysteinemia (>15.0 µmol/L, 22.1% compared with 2.5%). CONCLUSIONS: Most pregnancy-preparing couples failed to achieve the optimal RBC folate status (>906 nmol/L) as recommended by the WHO. These findings call for attention to the insufficiency status of folate and promising strategies to improve the folate status of the pregnancy-preparing population not exposed to folic acid fortification.

Factors associated with the time to return negative RT-PCR from COVID-19 in paediatric patients: a retrospective cohort study.

OBJECTIVE: This study aimed to describe the epidemiological and clinical features and potential factors related to the time to return negative reverse transcriptase (RT)-PCR in discharged paediatric patients with COVID-19. DESIGN: Retrospective cohort study. SETTING: Unscheduled admissions to 12 tertiary hospitals in China. PARTICIPANTS: Two hundred and thirty-three clinical charts of paediatric patients with confirmed diagnosis of COVID-19 admitted from 1 January 2020 to 17 April 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures: factors associated with the time to return negative RT-PCR from COVID-19 in paediatric patients. SECONDARY OUTCOME MEASURES: epidemiological and clinical features and laboratory results in paediatric patients. RESULTS: The median age of patients in our cohort was 7.50 (IQR: 2.92-12.17) years, and 133 (57.1%) patients were male. 42 (18.0%) patients were evaluated as asymptomatic, while 162 (69.5%) and 25 (10.7%) patients were classified as mild or moderate, respectively. In Cox regression analysis, longer time to negative RT-PCR was associated with the presence of confirmed infection in family members (HR (95% CI): 0.56 (0.41 to 0.79)). Paediatric patients with emesis symptom had a longer time to return negative (HR (95% CI): 0.33 (0.14 to 0.78)). During hospitalisation, the use of traditional Chinese medicine (TCM) and antiviral drugs at the same time is less conducive to return negative than antiviral drugs alone (HR (95% CI): 0.85 (0.64 to 1.13)). CONCLUSIONS: The mode of transmission might be a critical factor determining the disease severity of COVID-19. Patients with emesis symptom, complications or confirmed infection in family members may have longer healing time than others. However, there were no significant favourable effects from TCM when the patients have received antiviral treatment.

[Research advances in chemical constituents and hepatoprotective effect of Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus].

Schisandrae has a long history of medicinal use in China. Domestic and foreign scholars have isolated a variety of chemical constituents from Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus, including lignans, volatile oils, polysaccharides, triterpenoids, organic acids, amino acids and so on. Pharmacological studies have shown that their alcohol extracts, water extracts, lignan monomers and polysaccharides could protect liver injury and reduce enzyme ability by a variety of hepatoprotective effects such as enzyme reducing, liver protecting, and antioxidant effect. In this paper, the researches on the chemical composition, hepatoprotective effect and pharmacokinetics of Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus in the past forty years were systematically collated, in order to provide useful enlightenment for the clinical application and new drug development of Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus in liver protection.

Association of Maternal Folate and Vitamin B12 in Early Pregnancy With Gestational Diabetes Mellitus: A Prospective Cohort Study.

OBJECTIVE: To investigate the association of folate and vitamin B12 in early pregnancy with gestational diabetes mellitus (GDM) risk. RESEARCH DESIGN AND METHODS: The data of this study were from a subcohort within the Shanghai Preconception Cohort Study. We included pregnancies with red blood cell (RBC) folate and vitamin B12 measurements at recruitment (between 9 and 13 gestational weeks) and those with three samples available for glucose measurements under an oral glucose tolerance test. GDM was diagnosed between 24 and 28 weeks' gestation. Odds ratio (OR) and 95% CI of having GDM was used to quantify the association. RESULTS: A total of 1,058 pregnant women were included, and GDM occurred in 180 (17.01%). RBC folate and vitamin B12 were significantly higher in pregnancies with GDM than those without GDM (P values were 0.045 and 0.002, respectively) and positively correlated with 1-h and 2-h serum glucose. Daily folic acid supplementation in early pregnancy increases the risk of GDM; OR (95% CI) was 1.73 (1.19-2.53) (P = 0.004). Compared with RBC folate <400 ng/mL, pregnancies with RBC folate ≥600 ng/mL were associated with ∼1.60-fold higher odds of GDM; the adjusted OR (95% CI) was 1.58 (1.03-2.41) (P = 0.033). A significant trend of risk effect on GDM risk across categories of RBC folate was observed (P trend = 0.021). Vitamin B12 was significantly associated with GDM risk (OR 1.14 per 100 pg/mL; P = 0.002). No significant association of serum folate and percentile ratio of RBC folate/vitamin B12 with GDM was observed. CONCLUSIONS: Higher maternal RBC folate and vitamin B12 levels in early pregnancy are significantly associated with GDM risk, while the balance of folate/vitamin B12 is not significantly associated with GDM.

Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial.

BACKGROUND: Birth defects are the main cause of fetal death, infant mortality and morbidity worldwide. However, the etiology of birth defects remains largely unknown. Maternal folate status during periconception plays an important role in organogenesis and folic acid supplement reduces the risk of neural tube defects, congenital heart diseases, and several other birth defects. This trial seeks to evaluate the effectiveness of folate-oriented tertiary interventions during periconception on the incidence of fetus and birth defects. METHODS: This is a single-blind, two-arm cluster randomized controlled trial in Shanghai, China. Eligible women from 22 clusters are recruited at pre-pregnancy physical examinations clinical settings. Compared to the routine perinatal care group (control arm), folate-oriented tertiary interventions will be provided to the intervention arm. The core interventions consist of assessments of folate status and metabolism, folate intake guidance, and re-evaluation of folate status to ensure red blood cell folate level above 400 ng/ml (906 nmol/L) before pregnancy. Screening and consulting of fetus and birth defects, and treatments of birth defects during pregnancy and afterward will be provided to both arms. The primary outcome is a composite incidence of fetus defects, stillbirth, and neonatal birth defects identified from the confirmation of pregnancy to 28 days after birth. Secondary outcomes include maternal and offspring adverse complications and cost-effectiveness of folate-oriented tertiary interventions. This protocol adheres to the SPIRIT Checklist. DISCUSSION: To achieve the recommended folate status before or during pregnancy is still a challenge worldwide. This community-based cluster-randomized controlled intervention trial will evaluate the effectiveness of a package of interventions aiming at achieving recommended maternal folate status covering pre- and during pregnancy in reducing fetus and birth defects. Our study has the potential to improve the community-based practice of reducing modifiable risk factors of disease and improving primary prevention of the defects in China. The procedures would formulate the policy on folic acid supplementation during periconception against birth defects in primary care settings. TRIAL REGISTRATION: Clinical Trial Registry, NCT03725878 . Prospectively registered on 31 October 2018.

Shanghai Preconception Cohort (SPCC) for the association of periconceptional parental key nutritional factors with health outcomes of children with congenital heart disease: a cohort profile.

PURPOSE: The Shanghai Preconception Cohort (SPCC) was initially established to investigate the associations of parental periconceptional nutritional factors with congenital heart disease (CHD) but has further analysed child growth and development and paediatric diseases. PARTICIPANTS: Preparing-for-pregnancy couples who presented at Shanghai preconception examination clinics and early-pregnancy women before 14 gestational weeks were enrolled to comprise the periconceptional baseline study population. General characteristics, routine clinical data and consumption of diet supplements, such as folic acid and multivitamins, were collected. Blood samples were obtained at preconception and early, middle and late gestations using standard procedures. Multiple nutritional factors, including folate, homocysteine, vitamin A, vitamin D, vitamin E and metals, in the blood samples of participants selected using a case-control design were examined. Genomic DNA was extracted. FINDINGS TO DATE: The baseline population included 8045 preconception couples, 3054 single women and 15 615 early-pregnancy women. Data from 12 402 births were collected, and follow-up of the cohort for other outcomes is ongoing. Currently, 151 cases of CHD were identified after birth. The pilot analysis in a small subgroup showed that approximately 20.0% of preconception women and 44.9% of early-pregnancy women had red blood cell (RBC) folate levels that met the international recommendation for preventing neural tube defects. FUTURE PLANS: Once a sufficient number of CHD cases are achieved, we will investigate the quantitative association of preconception RBC folate levels with CHD using a nested case-control design. The SPCC will be followed up for 18 years to investigate extensive outcomes of growth, development, obesity, and common and rare diseases during childhood and adolescence according to our plan. Blood nutritional factors will be examined in participants selected for specific aims. The SPCC will also allow for prospective cohort studies on extensive research questions. TRIAL REGISTRATION NUMBER: NCT02737644.

Repair of Adult Mammalian Heart After Damages by Oral Intake of Gu Ben Pei Yuan San.

Adult mammalian heart repair after myocardial damage is highly inefficient due to the post-mitotic nature of cardiomyocytes. Interestingly, in traditional Chinese medicine (TCM), there are reported effective treatments of myocardial infarction (MI) and heart failure in adult humans by oral intake of a TCM concoction named Gu Ben Pei Yuan San (GBPYS), which is composed of Panax ginseng, velvet antler, Gekko gecko Linnaeus tail, human placenta, Trogopterus dung, Panax notoginseng, and amber. We fed mice with GBPYS after myocardial damages through everyday self-feeding. We then examined the effect of everyday oral intake of GBPYS on improving cardiac function and myocardial repair in adult mice after apical resection or MI. We found that long-term oral intake of GBPYS significantly improved cardiac function after myocardial damages in adult mice. BrdU, phospho-histone 3, and AuroraB staining indicated increased cell proliferation at the border zone of MI after TCM feeding. GBPYS feeding reduced organ inflammation, induced angiogenesis, and is non-toxic to mice after long-term oral intake. Further, serum derived from TCM-fed MI rats promoted division of both neonatal rat cardiomyocytes and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes in vitro. Oral intake of GBPYS improved heart repair after myocardial damages in adult mice. Our results suggest that there are substances present in GBPYS that help improve adult mammalian heart repair after MI. Also, it could be a good choice of non-invasive alternative therapy for myocardial damages and heart failure after rigorous clinical study in the future.