Prevalence of Malnutrition in Children with Congenital Heart Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the global prevalence of malnutrition in children with congenital heart disease (CHD). STUDY DESIGN: A systematic review and meta-analysis were performed. Web of Science, PubMed, Embase, Wanfang Database, China National Knowledge Infrastructure, and China Biology Medicine disc databases were searched for studies published through April 2021. Random-effect model meta-analyses were performed to derive the pooled the prevalence of preoperative underweight, stunting, and wasting in children with CHD. Time-trend analyses of postoperative malnutrition prevalence were undertaken. Subgroup and sensitivity analyses were conducted to explore sources of heterogeneity. Egger test and funnel plots were used to explore public bias. RESULTS: A total of 39 studies were included in this meta-analysis. The pooled estimates of preoperative malnutrition in children with CHD were 27.4% (95% CI, 21.7-34.0) for underweight, 24.4% (95% CI, 19.5-30.0) for stunting, and 24.8% (95% CI, 19.3-31.3) for wasting. Catch-up growth was found in the postoperative period among some children. Different continents were identified as heterogeneity moderators by subgroup analyses. CONCLUSIONS: Children with CHD have a high prevalence of preoperative malnutrition and some show catch-up growth postoperatively. These data can be used as benchmarks in efforts to improve the nutritional status of children with CHD.

Association of MTHFD1 gene polymorphisms and maternal smoking with risk of congenital heart disease: a hospital-based case-control study.

BACKGROUND: MTHFD1 gene may affect the embryonic development by elevated homocysteine levels, DNA synthesis and DNA methylation, but limited number of genetic variants of MTHFD1 gene was focused on the association with congenital heart disease (CHD). This study examined the role of MTHFD1 gene and maternal smoking on infant CHD risk, and investigated their interaction effects in Chinese populations. METHODS: A case-control study of 464 mothers of CHD infants and 504 mothers of health controls was performed. The exposures of interest were maternal tobacco exposure, single nucleotide polymorphisms (SNPs) of maternal MTHFD1 gene. The logistic regression model was used for accessing the strength of association. RESULTS: Mothers exposed to secondhand smoke during 3 months before pregnancy (adjusted odds ratio [aOR] = 1.56; 95% confidence interval [CI]: 1.13-2.15) and in the first trimester of pregnancy (aOR = 2.24; 95%CI: 1.57-3.20) were observed an increased risk of CHD. Our study also found that polymorphisms of maternal MTHFD1 gene at rs1950902 (AA vs. GG: aOR = 1.73, 95% CI: 1.01-2.97), rs2236222 (GG vs. AA: aOR = 2.38, 95% CI: 1.38-4.12), rs1256142 (GA vs.GG: aOR = 1.57, 95% CI: 1.01-2.45) and rs11849530 (GG vs. AA: aOR = 1.68, 95% CI: 1.02-2.77) were significantly associated with higher risk of CHD. However, we did not observe a significant association between maternal MTHFD1 rs2236225 and offspring CHD risk. Furthermore, we found the different degrees of interaction effects between polymorphisms of the MTHFD1 gene including rs1950902, rs2236222, rs1256142, rs11849530 and rs2236225, and maternal tobacco exposure. CONCLUSIONS: Maternal polymorphisms of MTHFD1 gene, maternal tobacco exposure and their interactions are significantly associated with the risk of CHD in offspring in Han Chinese populations. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings. TRIAL REGISTRATION: Registration number: ChiCTR1800016635 .

Association analysis of maternal MTHFR gene polymorphisms and the occurrence of congenital heart disease in offspring.

BACKGROUND: Although many studies showed that the risk of congenital heart disease (CHD) was closely related to genetic factors, the exact pathogenesis is still unknown. Our study aimed to comprehensively assess the association of single nucleotide polymorphisms (SNPs) of maternal MTHFR gene with risk of CHD and its three subtypes in offspring. METHODS: A case-control study involving 569 mothers of CHD cases and 652 health controls was conducted. Thirteen SNPs were detected and analyzed. RESULTS: Our study showed that genetic polymorphisms of maternal MTHFR gene at rs4846052 and rs1801131 were significantly associated with risk of CHD in the homozygote comparisons (TT vs. CC at rs4846052: OR = 7.62 [95%CI 2.95-19.65]; GG vs. TT at rs1801131: OR = 5.18 [95%CI 2.77-9.71]). And six haplotypes of G-C (involving rs4846048 and rs2274976), A-C (involving rs1801133 and rs4846052), G-T (involving rs1801133 and rs4846052), G-T-G (involving rs2066470, rs3737964 and rs535107), A-C-G (involving rs2066470, rs3737964 and rs535107) and G-C-G (involving rs2066470, rs3737964 and rs535107) were identified to be significantly associated with risk of CHD. Additionally, we observed that a two-locus model involving rs2066470 and rs1801131 as well as a three-locus model involving rs227497, rs1801133 and rs1801131 were significantly associated with risk of CHD in the gene-gene interaction analyses. For three subtypes including atrial septal defect, ventricular septal defect and patent ductus arteriosus, similar results were observed. CONCLUSIONS: Our study indicated genetic polymorphisms of maternal MTHFR gene were significantly associated with risk of fetal CHD in the Chinese population. Additionally, there were significantly interactions among different SNPs on risk of CHD. However, how these SNPs affect the development of fetal heart remains unknown, and more studies in different ethnic populations and with a larger sample are required to confirm these findings.

Association of maternal folate use and reduced folate carrier gene polymorphisms with the risk of congenital heart disease in offspring.

Although it is generally recognized that genetic and environmental factors are associated with the risk of congenital heart disease (CHD), the mechanism remains largely uncertain. This study aimed to investigate the association of maternal folate use, the time when folate use was started, and polymorphisms of the reduced folate carrier (RFC1) gene with the risk of CHD in offspring of Chinese descent, which can help provide new insight into the etiology of folate-related birth defects. A case-control study of 683 mothers of CHD patients and 740 mothers of healthy children was performed. The present study showed that mothers who did not use folate were at a significantly increased risk of CHD (OR=2.04; 95% CI: 1.42-2.93). When compared with those who started using folate prior to conception, mothers who started using folate from the first trimester of pregnancy (OR=1.90; 95% CI: 1.43-2.54) or from the second trimester of pregnancy (OR=8.92; 95% CI: 4.20-18.97) had a significantly higher risk of CHD. Maternal RFC1 gene polymorphisms at rs2236484 (AG vs AA: OR=1.79 [95% CI: 1.33-2.39]; GG vs AA: OR=1.64 [95% CI: 1.15-2.35]) and rs2330183 (CT vs CC: OR=1.54 [95% CI: 1.14-2.09]) were also significantly associated with CHD risk. Additionally, the risk of CHD was significantly decreased among mothers who had variant genotypes but used folate when compared with those who had variant genotypes and did not use folate.Conclusion: In those of Chinese descent, maternal folate use and the time when use started are significantly associated with the risk of CHD in offspring. Furthermore, maternal folate supplementation may help to offset some of the risks of CHD in offspring due to maternal RFC1 genetic variants. What is Known: • Folate use could help prevent CHD, but the relationship between the time when folate use is started and CHD has not received sufficient attention. • Studies have assessed the associations of folate metabolism-related genes with CHD, but genes involved in cellular transportation of folate, such as the RFC1 gene, have not garnered enough attention. What is New: • In those of Chinese descents, the time when folate use is started is significantly associated with the risk of CHD in offspring. • Maternal RFC1 polymorphisms were significantly associated with the risk of CHD. • Folate supplementation may help to offset some risks of CHD due to RFC1 genetic variants.

[Association between maternal reduced folate carrier gene polymorphisms and congenital heart disease in offspring: a case-control study].

OBJECTIVE: To study the association between maternal reduced folate carrier (RFC) gene polymorphisms and congenital heart disease (CHD) in offspring. METHODS: A hospital-based case-control study was conducted. The mothers of 683 infants with CHD who attended the Department of Cardiothoracic Surgery, Hunan Children's Hospital, from November 2017 to March 2020 were enrolled as the case group. The mothers of 740 healthy infants without any deformity who attended the hospital during the same period of time were enrolled as the control group. A questionnaire survey was performed to collect the exposure data of subjects. Venous blood samples of 5 mL were collected from the mothers for genetic polymorphism detection. A multivariate logistic regression analysis was used to evaluate the association of RFC gene polymorphisms and their haplotypes with CHD. A generalized multifactor dimensionality reduction method was used to analyze gene-gene interactions. RESULTS: After control for confounding factors, the multivariate logistic regression analysis showed that maternal RFC gene polymorphisms at rs2236484 (AG vs AA:OR=1.91, 95%CI:1.45-2.51; GG vs AA: OR=1.96, 95%CI:1.40-2.75) and rs2330183 (CT vs CC:OR=1.39, 95%CI:1.06-1.83) were significantly associated with the risk of CHD in offspring. The haplotypes of G-G (OR=1.21, 95%CI:1.03-1.41) and T-G (OR=1.25, 95%CI:1.07-1.46) in mothers significantly increased the risk of CHD in offspring. The interaction analysis showed significant gene-gene interactions between different SNPs of the RFC gene in CHD (P < 0.05). CONCLUSIONS: Maternal RFC gene polymorphisms and interactions between different SNPs are significantly associated with the risk of CHD in offspring.

Maternal homocysteine and folate levels and risk of recurrent spontaneous abortion: A meta-analysis of observational studies.

AIM: The aim of the study was to review and summarize the epidemiologic evidence on the associations of homocysteine (HCY) and folate with the risk of recurrent spontaneous abortion (RSA). METHODS: This review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PubMed, Google Scholar, Cochrane Libraries and Chinese databases were searched through May 2019 to identify studies that met prestated inclusion criteria. Either a fixed- or a random-effects model was used to calculate the combined standardized mean difference (SMD) and 95% confidence intervals (CI). RESULTS: Twenty-three studies involving 2052 RSA cases and 1476 healthy controls were included. Overall, women with RSA compared with those without RSA were at a significantly higher level of HCY both in plasma (SMD = 1.34; 95% CI: 0.76-1.93) and in serum (SMD = 1.46; 95% CI: 1.02-1.91), but lower level of folate both in serum (SMD = -1.63; 95% CI: -2.51 to -0.75) and in red blood cells (SMD = -1.30; 95% CI: -1.76 to -0.85). However, a statistically significant association between plasma folate and risk of RSA was not been observed (SMD = -0.82; 95% CI: -1.73 to 0.09). These findings have to be viewed with caution for the significant heterogeneity (I2 : from 88 to 98%). CONCLUSION: High HCY levels in both plasma and serum as well as low folate levels in serum and red blood cells are significantly associated with risk of RSA, which indicates that measures to reduce HCY levels or folate supplementation may help to reduce the risk of RSA. However, prospective studies are needed to confirm our findings.

[Association of maternal diabetes mellitus and UCP2 gene polymorphisms with congenital heart disease in offspring: a case-control study].

OBJECTIVE: To study the association of maternal diabetes mellitus (DM), uncoupling protein 2 (UCP2) gene polymorphisms, and their interaction with the risk of congenital heart disease (CHD) in offspring. METHODS: A hospital-based case-control study was conducted. A total of 464 mothers of children with CHD alone who were diagnosed in Hunan Children's Hospital from March 2018 to August 2019 were enrolled as the case group. A total of 504 mothers of healthy children who were hospitalized during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect the information on exposure. Venous blood samples (5 mL) were collected from the mothers to detect UCP2 gene polymorphisms. A multivariate logistic regression analysis was used to investigate the association of maternal DM, UCP2 gene polymorphisms, and their interaction with CHD in offspring. RESULTS: After control for confounding factors, the multivariate logistic regression analysis showed that mothers with gestational DM (OR=2.96, 95%CI: 1.57-5.59), a history of gestational DM (OR=3.16, 95%CI: 1.59-6.28), and pregestational DM (OR=4.52, 95%CI: 2.41-8.50) significantly increased the risk of CHD in offspring (P<0.05). The polymorphisms of the UCP2 gene at rs659366 (T/C vs C/C: OR=1.49, 95%CI: 1.02-2.16; T/T vs C/C: OR=2.77, 95%CI: 1.67-4.62) and rs660339 (A/A vs G/G: OR=2.19, 95%CI: 1.34-3.58) were significantly associated with risk of CHD in offspring (P<0.05). The interaction analysis showed an interaction between the polymorphisms of the UCP2 gene at rs659366 and rs660339 and maternal DM in the development of CHD (P<0.05). CONCLUSIONS: Maternal DM, UCP2 gene polymorphisms, and their interaction are associated with the development of CHD in offspring.

Conservative management or cesarean hysterectomy for placenta accreta spectrum in middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Cesarean hysterectomy is a dominant and effective approach during delivery in patients with placenta accreta spectrum (PAS). However, as hysterectomy results in a loss of fertility, conservative management is an alternative approach. However, management selection may be affected by a country's overall economic level. Thus the preferred treatment for PAS generates controversy in middle-income countries. OBJECTIVES: We aimed to compare conservative management and cesarean hysterectomy for managing PAS in middle-income countries. SEARCH STRATEGY: China National Knowledge Infrastructure, Wanfang Med Online Databases, Cochrane Library, Ovid MEDLINE, PubMed, Web of Science, EMBASE, clinicaltrials.gov, and Scopus were searched from inception through to October 1, 2022. SELECTION CRITERIA: We included studies that evaluated at least one complication comparing conservative management and hysterectomy. All cases were diagnosed with PAS prenatally and intraoperatively. DATA COLLECTION AND ANALYSIS: The primary outcomes were blood loss, adjacent organ damage, and the incidence of hysterectomy. Descriptive analyses were conducted for studies that did not meet the meta-analysis criteria. A fixed-effects model was used for studies without heterogeneity and a random-effects model was used for studies with statistical heterogeneity. MAIN RESULTS: In all, 11 observational studies were included, with 975 and 625 patients who underwent conservative management and cesarean hysterectomy, respectively. Conservative management was significantly associated with decreased blood loss and lower risks of adjacent organ injury and hysterectomy. Conservative management significantly reduced blood transfusions, hospitalization duration, operative time, intensive care unit admission rates, and infections. There were no significant differences in the risks of coagulopathy, thromboembolism, or reoperation. CONCLUSION: Given short-term complications and future fertility preferences for patients, conservative management appears to effectively manage PAS in middle-income countries. Owing to low levels of evidence, high heterogeneity and insufficient long-term follow-up data, further detailed studies are warranted.

Associated factors of undernutrition in children with congenital heart disease: a cross-sectional study.

Objective: To evaluate the prevalence and associated factors of undernutrition among children with congenital heart disease (CHD) who have not undergone surgeries in China. Methods: This cross-sectional study included 734 CHD children along with their parents. The outcome of interest was undernutrition, including underweight, wasting, and stunting, defined as Z-scores (i.e., weight-for-age, weight-for-height, and height-for-age) ≤-2, according to the World Health Organization (WHO) growth standard. Exposures of interest, containing demographics, obstetric factors, maternal dietary factors, parents' life behaviors and habits, birth-related factors, cardiac-related factors, and preoperative factors, were analyzed using a multivariate logistic regression model to test their associations with undernutrition in CHD children. Results: Overall, 36.1%, 29.7%, and 21.3% of cases were underweight, wasted, and stunted, respectively. Multivariate logistic regression indicated that underweight was associated with demographic factors (including parents' occupational status, family income, and maternal body mass index pre-pregnancy), low birth weight (OR = 4.60, 2.76-7.70), pulmonary hypertension (OR = 4.46, 3.09-6.43), and pneumonia (OR = 1.88, 1.28-2.76). Artificially-fed children were 2.34 (1.36-4.01) times more likely to be underweight. Occupied mothers (OR = 0.62, 0.44-0.88) and fathers (OR = 0.49, 0.26-0.92) served as protective factors, while mothers having gestational complications (OR = 1.56, 1.11-2.18) and exposed to noisy environment (OR = 1.64, 1.11-2.42) during this pregnancy, and pulmonary hypertension (OR = 3.21, 2.30-4.49) increased the chance of wasting in offspring. The odds of being stunted were greater in families with >2 children (OR = 1.88, 1.13-3.14), placental abruption during this pregnancy (OR = 25.15, 2.55-247.89), preterm births (OR = 1.84, 1.02-3.31), low birth weight (OR = 3.78, 2.16-6.62), pulmonary hypertension (OR = 2.35, 1.56-3.53) and pneumonia (OR = 1.93, 1.28-2.90). In subgroup analyses, the associations differed between patients with different feeding patterns (breastfeeding vs. non-breastfeeding), CHD classifications (cyanotic vs. acyanotic), and prematurity (preterm vs. non-preterm). Conclusion: Undernutrition is common in preoperative CHD children. Familial demographics, maternal factors (including having gestational complications and exposure to noisy environment during pregnancy), and patient-related factors (encompassing preterm births, low birth weight, pulmonary hypertension, pneumonia, and feeding pattern) were found to contribute to undernutrition in CHD cases. However, associated factors among the three subgroups of distinct feeding patterns, CHD categorization, and prematurity exhibited varied outcomes, suggesting the necessity for targeted interventions.

Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study.

BACKGROUND: Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring. METHODS: A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted. RESULTS: The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring. CONCLUSIONS: Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

Hypertensive Disorders in Pregnancy Are Associated With Congenital Heart Defects in Offspring: A Systematic Review and Meta-Analysis.

Background: Although research indicates an association between hypertensive disorders of pregnancy (HDP) and congenital heart defects (CHDs) in offspring, consistency is still lacking. Therefore, we aimed to synthesize the updated published epidemiologic evidence to estimate the association of maternal HDP with the risk of total CHDs and its phenotypes in offspring. Methods: A systematic search of Web of Science Database, PubMed, and Embase were searched from inception through April 30, 2021 based on a preprepared protocol, and the reference lists were also manually searched. The combined risk estimates were calculated using either the fixed-effect models or random-effect models. Possible heterogeneity moderators were detected by subgroup, sensitivity analyses, and Galbraith plot. Results: Twenty-four studies involving 477,839 CHDs cases among 40,394,699 participants were included in our meta-analysis. Mothers who had HDP exposure were significantly associated with an increased risk of total CHDs compared with non-exposure. When maternal HDP exposure was further subdivided into pre-eclampsia (OR = 1.79, 95% CI: 1.50-2.13), gestational hypertension (OR = 1.16, 95% CI: 1.02-1.31), and chronic hypertension (OR = 1.68, 95% CI: 1.49-1.89), a significantly increased risk of total CHDs were still presented. Furthermore, a statistically significant increased association was found between maternal HDP exposure and most CHD phenotypes. Besides, relevant heterogeneity moderators have been identified by subgroup and sensitivity analyses. Conclusion: Our study suggested that maternal HDP exposure may be associated with an increase in the risk of CHDs in offspring. These findings highlight the need for greater surveillance of pregnant women with HDP exposure to allow early prevention that may be good for reducing the risk of CHDs in offspring. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [CRD42021268093].

Effect of Maternal Antidepressant Use During the Pre-pregnancy/Early Pregnancy Period on Congenital Heart Disease: A Prospective Cohort Study in Central China.

Background: With the increase in maternal antidepressant prescribing before/during pregnancy, concerns about the safety of antidepressants have come into focus. The purpose of this study was to explore the association between maternal antidepressant use before pregnancy/in early pregnancy and the risk of congenital heart disease (CHD) in children, and to provide a scientific basis for clinical safety of antidepressant use. Methods: The prospective cohort study ultimately included 34,104 singleton pregnancies. Modified Poisson regression model with robust error variances was used to evaluate RRs and 95% confidence intervals (CIs) for the risk of CHD in offspring exposed to maternal antidepressant in the 3 months before pregnancy and early pregnancy. In addition, sensitivity analysis was further performed to explore the robustness of the results. Results: In this study, the maternal antidepressant exposure rate was 2.83% in the 3 months before pregnancy, 2.42% in early pregnancy, and the incidence of CHD was 8.973 per 1,000 live births. We found that maternal antidepressant use in the 3 months before pregnancy and early pregnancy were all associated with an increased risk of CHD, ~2.54 times and 2.87 times, respectively, of non-use of antidepressants after adjusting for potential confounders. This association was also found in CHD specific phenotypic analysis. Of these, offspring whose mothers were exposed to antidepressants in the 3 months before pregnancy had the highest risk of transposition of the great arteries (aOR = 5.50, 95% CI: 1.91-15.88). The offspring of mothers exposed to antidepressants in early pregnancy had the highest risk of developing ventricular septal defect (aOR = 4.80, 95% CI: 2.50-9.24). Sensitivity analysis verified the stability of the results. Conclusions: Maternal antidepressant use in the 3 months before pregnancy and early pregnancy were all associated with an increased risk of CHD in their offspring. In order to reduce the risk of teratogenesis, we recommend that pregnant women prepare for pregnancy after their condition improves or receive the minimum effective dose of medication.

Determinants for Perinatal Mortality in South China: A Prospective Cohort Study.

Objective: To estimate the association of selected maternal and fetal characteristics with the risk of perinatal mortality in South China. Methods: A prospective cohort study was conducted from March 2013 to December 2019. The exposures of interest were maternal sociodemographic characteristics, lifestyle and habits during early pregnancy, and complications of pregnancy. Their effects on the development of perinatal death were analyzed in our study. Results: A total of 44,048 eligible pregnant women were included in the analysis. Of these, 596 fetuses were perinatal deaths (perinatal mortality was 13.5 per 1,000 births). After adjustment, maternal obesity, being employed, history of gestational hypertension, taking antidepressants during early pregnancy, history of gestational diabetes mellitus, gestational diabetes mellitus, infertility drug treatment and assisted reproductive techniques, history of neonatal death, preterm birth, and congenital malformations all significantly increased the risk of perinatal death. Ethnic minority, income > 5,000, multiparous women, and cesarean section associated with reduced risk of perinatal death. Conclusion: Some factors of maternal sociodemographic characteristics, abnormal pregnancy history, lifestyle and habits during early pregnancy, and complications of pregnancy were associated with the risk of perinatal death.

Association Between First-Trimester Maternal Cytomegalovirus Infection and Stillbirth: A Prospective Cohort Study.

Background: Given that the time lag between cytomegalovirus (CMV) screening and diagnosed testing, a better knowledge of the association between pregnant women with CMV screening test positive and stillbirth in an epidemiological perspective was required to assist people being counseled reframe their pregnancy and birth plans based on the magnitude of the risk. Methods: This study recruited 44048 eligible pregnant women from March 13, 2013 to December 31, 2019. Serological tests including CMV-specific IgM and IgG, and IgG avidity index were used to screen for maternal CMV infection and were measured by automated chemiluminescence immunoassay. The association was assessed using the inverse probability of group-weighted multivariate-adjusted log-binomial models. Results: A total of 540 infants ended with a stillbirth (12.3 per 1000 pregnancies), and 2472 pregnancies with maternal CMV infection were screened out (56.1 per 1000 pregnancies) among all eligible pregnancies. In the comparison analysis, 326 infants ended with a stillbirth (86.6 per 1000 pregnancies) in the maternal CMV infection group compared with 214 infants (7.8 per 1000 pregnancies) in the group where mothers were not infected with CMV (RR 12.17; 95% CI 9.43-15.71). After excluding the pregnancies of stillbirth with birth defects, a strong association between the two groups was still observed (RR 9.38; 95% CI 6.92-12.70). Conclusion: Our findings quantified the risk of a woman having a baby with stillbirth if she had a positive serologic CMV screening test in her first trimester, and supported the value of using CMV serologic tests as part of regular testing in pregnant women. Trial registration: Registered in Chinese Clinical Trial Registry Center; registration number, ChiCTR1800016635; registration date, 06/14/2018 (Retrospectively registered); URL of trial registry record, https://www.chictr.org.cn/showproj.aspx?proj=28300.

Pre-Pregnancy Body Mass Index and Risk of Macrosomia and Large for Gestational Age Births with Gestational Diabetes Mellitus as a Mediator: A Prospective Cohort Study in Central China.

This study aimed to examine the risk of macrosomia and large for gestational age (LGA) births in relation to maternal pre-pregnancy body mass index (BMI) status mediated through gestational diabetes mellitus (GDM). This prospective study included 34,104 singleton pregnancies at 8-14 weeks of gestation. The interesting outcomes were macrosomia (≥4000 g) and LGA (≥90th percentile). Mediation analyses were conducted using log-binomial regression adjusted for age, education, parity, fetal sex, and gestational weight gain. The proportion mediated was estimated based on the risk difference scale, and the E-value was utilized to assess potential confounders. Overall, 15.9% of women had GDM, and there were 4.0% macrosomia and 9.9% LGA births. The proportion mediated by GDM on macrosomia was up to 40% among obese women, and the estimate of the total effect was 6.18 (95% CI: 5.26-7.26), of the natural direct effect was 4.10 (95% CI: 3.35-4.99), and of the natural indirect effect was 1.51 (95% CI: 1.31-1.76). Likewise, among overweight women, the proportion mediated by GDM on macrosomia was up to 40%. Furthermore, consistent findings were evident for the outcome of LGA births. Pre-pregnancy overweight/obesity increased the risk of macrosomia and LGA births independently and partly mediated by GDM.

Association between paternal pre-pregnancy body mass index with preterm birth and low birth weight.

Background: With the current global epidemic of obesity, especially among men, there is a need to understand its impact on adverse pregnancy outcomes. This study aimed to assess whether paternal pre-pregnancy body mass index (BMI) was associated with preterm birth and low birth weight in offspring. Methods: Multinomial logistic regression model was used to analyze associations between paternal BMI and preterm birth and low birth weight in different subgroups, the final model was adjusted for confounding factors of mothers and fathers. Further subgroup analysis was conducted to explore the stability of the risk associations. Results: A total of 34,104 participants were included in this study, including 1,442 (4.2%) underweight, 13,930 (40.9%) overweight and 5,008 (14.7%) obese according to paternal BMI. The total incidence of preterm birth was 11.85% (4041/34104), and the incidence of low birth weight was 8.86% (3020/34104). In the total study population, compared with normal weight men, paternal pre-pregnancy overweight or obese was associated with a significantly increased risk of preterm birth [aOR; 95% CI respectively (1.34; 1.25-1.45 vs. 1.26; 1.14-1.40)] and low birth weight [aOR; 95% CI respectively (1.60; 1.46-1.74 vs. 1.40; 1.25-1.58)] in offspring. The results of subgroup analysis showed that the direction of the risk association was consistent, indicating good stability. Conclusion: Paternal pre-pregnancy overweight and obesity were associated with an increased risk of preterm birth and low birth weight in their offspring.

Association of methylenetetrahydrofolate reductase gene polymorphisms and maternal folic acid use with the risk of congenital heart disease.

Background: To systematically evaluate the association of MTHFR genetic polymorphisms, maternal folic acid intake, and the time when folic acid intake was started with the risk of congenital heart disease (CHD) and investigated the role of their interaction on infant CHD risk in Chinese populations. Methods: A case-control study involving 592 CHD cases, 617 health controls, and their mothers was performed. The exposures of interest were single nucleotide polymorphisms (SNPs) of the MTHFR gene, maternal folic acid use, and the time when folic acid use was started. We applied the logistic regression model to explore the strength of association. Results: Our findings showed that mothers lacking folic acid intake had a significantly higher risk of CHD in offspring (aOR = 2.00; 95%CI: 1.34-2.98). Mothers who started to use folic acid from the first trimester of the fetation (aOR = 1.65; 95% CI: 1.22-2.23) or from the second trimester of the fetation (aOR = 7.77; 95% CI: 2.52-23.96), compared with those starting to use folic acid from 3 months previous to the conception, were at a significantly higher risk of CHD in offspring. Genetic variants at rs2066470 (AA vs. GG: aOR = 5.09, 95%CI: 1.99-13.03), rs1801133 (AA vs. GG: aOR = 2.49, 95%CI: 1.58-3.93), and rs1801131 (TG vs. TT: aOR = 1.84, 95%CI: 1.36-2.50; GG vs. TT: aOR = 3.58, 95%CI: 1.68-7.63) were significantly associated with the risk of CHD based on the multivariate analysis. Additionally, statistically significant interactions between maternal folic acid intake and genetic variants of the MTHFR gene at rs1801133 and rs1801131 were observed. Conclusion: An association of maternal folic acid intake and the time when intake was started with the risk of CHD in offspring was found. What's more, maternal folic acid fortification may help counteract partial of the risks of CHD in offspring attributable to MTHFR genetic mutations. Registration number: http://www.chictr.org.cn/edit.aspx?pid=28300&htm=4, identifier: ChiCTR1800016635.

Association of paternal smoking with the risk of neural tube defects in offspring: A systematic review and meta-analysis of observational studies.

PURPOSE: The present study aimed at providing some epidemiological evidences to assess the association of paternal smoking with the risk of neural tube defects (NTDs) and its specific subtypes in offspring, and explore the possible dose-response relationship between paternal smoking and risk of NTDs. METHODS: English and Chinese databases were systematically searched from 1984 to May 2020. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. We also examined the dose-response relationship between parental smoking and risk of NTDs in offspring. Subgroup analyses and sensitivity analyses were conducted to explore possible sources of heterogeneity. RESULTS: A total of 10 case-control studies involving 2,593 cases of NTDs and 45,100 controls were included for analysis. Findings from our study showed that paternal smoking was significantly associated with risk of total NTDs (odds ratio [OR] = 1.68; 95% confidence interval (CI): 1.48-1.92) and two subtypes including anencephaly (OR = 1.41; 95% CI: 1.06-1.86) and encephaloceles (OR = 2.90; 95% CI: 1.00-8.41). Additionally, a linear dose-response relationship between paternal smoking and risk of NTDs was observed, which indicated that the risk of NTDs in offspring was significantly increased by 45% (OR = 1.45, 95% CI: 1.14-1.84) for each increment of half a pack of cigarettes per day. Sensitivity analyses yielded consistent results. No evidence of publication bias was found. CONCLUSIONS: Paternal smoking is significantly associated with the risk of NTDs in offspring. Therefore, it should be recommended that fathers quit smoking before pregnancy to prevent NTDs in offspring.

Male sperm quality and risk of recurrent spontaneous abortion in Chinese couples: A systematic review and meta-analysis.

OBJECTIVE: To assess the association of conventional semen parameters and sperm DNA fragmentation with risk of recurrent spontaneous abortion (RSA). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENTS: Total 1,690 male partners of women with RSA, and 1,337 male partners of fertile control women. INTERVENTIONS: Case-control or cohort studies were determined by searching PubMed, Google Scholar, Cochrane Libraries, China Biology Medicine disc, Chinese Scientific Journals Fulltext Database, China National Knowledge Infrastructure, and Wanfang Database. RSA was defined as two or more previous pregnancy losses. The fertile women refer to the reproductive women who have had at least a normal pregnancy history and no history of abortion. MAIN OUTCOME MEASURES: This study included eight outcome measures: semen volume(ml), semen pH value, sperm density(106/ml), sperm viability (%), sperm progressive motility rate (%), normal sperm morphology rate (%), sperm deformity rate(%), sperm DNA fragmentation index (DFI) (%). The summary measures were reported as standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: Finally, twenty-four studies were included for analysis. Overall, male partners of women with RSA had a significantly lower level of sperm density (SMD = -0.53, 95%CI: - 0.75 to -0.30), sperm viability (SMD = -1.03, 95%CI: - 1.52 to -0.54), sperm progressive motility rate (SMD = -0.76, 95%CI:-1.06 - -0.46), and normal sperm morphology rate (SMD =  -0.56, 95%CI: - 0.99 to -0.12), and had a significantly higher rate of sperm deformity rate (SMD = 1.29, 95%CI: 0.60 - 1.97), and sperm DFI (SMD = 1.60, 95%CI: 1.04 to 2.17), when compared with the reference group. However, there were no statistically significant differences for semen volume (SMD = -0.03, 95%CI: -0.14 - 0.08) and semen pH value (SMD =  -0.23, 95% CI: -0.50 to 0.05) among 2 groups. CONCLUSIONS: The results of this analysis support an association of sperm density, sperm viability, sperm progressive motility rate, normal sperm morphology rate, sperm deformity rate, as well as sperm DFI with RSA. However, given the significant heterogeneity between studies and the lack of more detailed data on the subjects, further large-scale prospective studies are needed.

Associations and interaction effects of maternal smoking and genetic polymorphisms of cytochrome P450 genes with risk of congenital heart disease in offspring: A case-control study.

ABSTRACT: To assess associations and interactions of maternal smoking and cytochrome P450 (CYP450) genetic variants with the developments of congenital heart disease (CHD) and specific subtypes.A case-control study of 654 cases and 666 controls was conducted from November 2017 to March 2020. The exposures of interest were maternal active and passive smoking before/in the early pregnancy and CYP450 genetic polymorphisms. Data were analyzed using the Chi-square test and logistic regression analysis.After adjusting for the potential confounding factors, our study showed maternal active (ORadj = 2.34, 95%CI: 1.19-4.60) or passive (ORadj = 1.76, 95%CI: 1.34-2.31) smoking before pregnancy, passive smoking in the early pregnancy (ORadj = 3.05, 95%CI: 2.26-4.12), as well as polymorphisms of CYP450 at rs1065852 (G/A vs G/G: ORadj = 1.46, 95%CI: 1.07-1.99; A/A vs G/G: ORadj = 1.63, 95%CI: 1.15-2.33) and rs16947 (A/A vs G/G: ORadj = 3.61, 95%CI: 2.09-6.23), were significantly associated with risk of total CHD in offspring. Similar results were also found for some subtypes of CHD. Additionally, significant interactions between maternal smoking and CYP450 genes on the risk of CHD were observed.Maternal smoking and CYP450 genetic variants were associated with increased risk of CHD and specific subtypes in offspring. And the effects of CYP450 genes on CHD may be modified by maternal smoking.