Parental smoking and the risk of congenital heart defects in offspring: An updated meta-analysis of observational studies.

OBJECTIVE: Although previous reviews confirmed maternal active smoking was significantly associated with risk of fetal congenital heart defects (CHDs), association between maternal passive smoking and paternal smoking and risk of CHDs is inconclusive nowadays; furthermore, a complete overview is lacking. A meta-analysis of observational studies was conducted to assess the risk of CHDs associated with maternal active and passive smoking and paternal smoking. METHODS: Seven electronic databases were searched for qualified research up to June 2018. We summarized study characteristics and the summary risk estimates were calculated using either the random-effect model or fixed-effect model. Sensitivity and subgroup analysis were carried out to identify the potential heterogeneity moderators. RESULTS: One hundred and twenty-five studies involving 137,574 CHDs cases in 8,770,837 study participants were included. Overall, maternal active (risk ratio (RR) = 1.25; 95% confidence interval (CI): 1.16-1.34; p < 0.01) and passive (RR = 2.24, 95% CI: 1.81-2.77; p < 0.01) smoking as well as paternal active smoking (RR = 1.74, 95% CI: 1.48-2.06; p < 0.01) were significantly associated with CHDs risk. For specific CHD subtypes, our study showed that maternal active smoking was significantly associated with risk of atrial septal defect (RR = 1.27, 95% CI: 1.02-1.59; p = 0.03) and right ventricular outflow tract obstruction (RR = 1.43, 95% CI: 1.04-1.97; p = 0.03). Relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded consistent results. CONCLUSION: Maternal active smoking, maternal passive smoking as well as paternal smoking all increased the risk of CHDs in offspring. Preventing parental smoking during peri-pregnancy is a priority for CHDs prevention.

Parental alcohol consumption and the risk of congenital heart diseases in offspring: An updated systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to provide updated evidence to assess the association between parental alcohol consumption and the risk of total congenital heart diseases (CHDs) and specific CHD phenotypes in offspring, and explore the possible dose-response pattern. METHODS: PubMed, Embase and Chinese databases were searched with an end-date parameter of July 24, 2019 to identify studies meeting pre-stated inclusion criteria. A random-effects model was used to calculate the overall combined risk estimates. A meta-analysis of the dose-response relationship was performed. Subgroup analysis, sensitivity analysis, and Galbraith plot were conducted to explore potential heterogeneity moderators. RESULTS: A total of 55 studies involving 41,747 CHD cases and 297,587 controls were identified. Overall, both maternal (odds ratio (OR) = 1.16; 95% confidence interval (CI): 1.05-1.27) and paternal (OR = 1.44; 95% CI: 1.19-1.74) alcohol exposures were significantly associated with risk of total CHDs in offspring. Additionally, a nonlinear dose-response relationship between parental alcohol exposure and risk of total CHDs was observed. With an increase in parental alcohol consumption, the risk of total CHDs in offspring also gradually increases. For specific CHD phenotypes, a statistically significant association was found between maternal alcohol consumption and risk of tetralogy of fallot (OR = 1.20; 95% CI: 1.08-1.33). Relevant heterogeneity moderators have been identified by subgroup analysis, and sensitivity analysis yielded consistent results. CONCLUSIONS: Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, our review indicates that parental alcohol exposures are significantly associated with the risk of CHDs in offspring, which highlights the necessity of improving health awareness to prevent alcohol exposure during preconception and conception periods.

Risk of congenital heart defects in offspring exposed to maternal diabetes mellitus: an updated systematic review and meta-analysis.

PURPOSE: A systematic review and meta-analysis was performed to assess the risk of congenital heart defects (CHDs) and its specific phenotypes associated with maternal diabetes mellitus (DM) including pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM). METHODS: PubMed, Embase, Medline, Google Scholar, Cochrane Libraries, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Fulltext Database and China Biology Medicine disc were searched from the inception dates to 15 December 2018, to identify case-control or cohort studies assessing the association between maternal DM and risk of CHDs. The exposure of interest was maternal DM; the outcomes of interest were CHDs and its specific phenotypes. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Subgroup analyses were performed to explore potential heterogeneity moderators. RESULTS: Total 52 studies, which involved 259,917 patients with CHDs among 16,929,835 participants, were included for analysis. Overall, mothers with DM compared with those without DM had a significantly higher risk of CHDs in offspring [odds ratios (OR) = 2.71, 95% confidence intervals (CI) 2.28-3.23]. When data were restricted to different types of DM, a significantly increased risk of CHDs was observed among mothers with PGDM (OR = 3.18, 95% CI 2.77-3.65) and GDM (OR = 1.98, 95% CI 1.66-2.36). Our study suggested the risk of CHDs was significantly higher among mothers with PGDM than those with GDM. Additionally, this study suggested maternal DM was significantly associated with most phenotypes of CHDs; of these, double outlet of the right ventricle (OR = 10.89; 95% CI 8.77-13.53), atrioventricular septal defect (OR = 5.74; 95% CI 3.20-10.27) and truncus arteriosus (OR = 5.06; 95% CI 2.65-9.65) were identified as the first three of the most common phenotypes of CHDs associated with maternal DM. CONCLUSIONS: The maternal DM including PGDM and GDM are significantly associated with risk of CHDs and its most phenotypes. The PGDM seems to be more likely to cause CHDs in offspring than GDM. Further studies are needed to clarify the underlying mechanisms.

Congenital Heart Disease and Risk of Cardiovascular Disease: A Meta-Analysis of Cohort Studies.

Background Despite remarkable success in the surgical and medical management of congenital heart disease ( CHD ), some survivors still experience cardiovascular complications over the long term. The goal of this study was to evaluate the association between CHD and risk of cardiovascular disease ( CVD ) by conducting a meta-analysis of cohort studies. Methods and Results A systematic literature search of several databases was conducted through April 2018 to identify studies reporting the risk of CVD , stroke, heart failure, and coronary artery heart disease in CHD survivors. The quality of individual studies was assessed using the Newcastle-Ottawa scale. The overall risk estimates were pooled using fixed-effects meta-analysis. Subgroup analyses were performed to explore possible sources of heterogeneity. Nine cohort studies comprising 684 200 participants were included. The overall combined relative risks for people with CHD compared with the controls were 3.12 (95% CI, 3.01-3.24) for CVD , 2.46 (95% CI, 2.30-2.63) for stroke, 5.89 (95% CI, 5.58-6.21) for heart failure, and 1.50 (95% CI, 1.40-1.61) for coronary artery heart disease. Significant heterogeneity was detected across studies regarding these risk estimates. Heterogeneity in the risk estimate of CVD was explained by geographic region, type of study design, sample source, age composition, and controlled confounders. Conclusions This meta-analysis of cohort studies of CHD found an association of increased risk of CVD in later life, although we cannot determine whether this association is confounded by a risk factor profile of CVD among CHD survivors or whether CHD is an independent risk factor.

Maternal Viral Infection and Risk of Fetal Congenital Heart Diseases: A Meta-Analysis of Observational Studies.

Background At present, the association between maternal viral infection and risk of congenital heart diseases ( CHD ) in offspring is uncertain; additionally, a complete overview is missing. A meta-analysis of observational studies was performed to address the question of whether women who had a history of viral infection in early pregnancy were at an increased risk of CHD in offspring, compared with mothers without viral infection. Methods and Results Unrestricted searches were conducted, with an end date parameter of July 15, 2018, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases, to identify studies that met prestated inclusion criteria. Seventeen case-control studies involving 67 233 women were included for analysis. Both fixed-effects models (odds ratio [OR], 1.83; 95% CI , 1.58-2.12; P<0.0001) and random-effects models ( OR , 2.28; 95% CI , 1.54-3.36; P<0.0001) suggested that mothers who had a history of viral infection in early pregnancy experienced a significantly increased risk of developing CHD in offspring. For specific viral infections, the risk of developing CHD in offspring was significantly increased among mothers with rubella virus (OR, 3.49, 95% CI, 2.39-5.11 in fixed-effects models; and OR, 3.54; 95% CI, 1.75-7.15 in random-effects models) and cytomegalovirus (OR, 3.95; 95% CI, 1.87-8.36 in fixed-effects models) in early pregnancy; however, other maternal viral infections in early pregnancy were not significantly associated with risk of CHD in offspring. Sensitivity analysis yielded consistent results. No evidence of publication bias was observed. Conclusions Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, the present study suggests that maternal viral infection is significantly associated with risk of CHD in offspring.

Health care and risk of adverse pregnancy outcomes among diabetic women: an updated meta-analysis.

PURPOSE: Diabetic women appear to have adverse pregnancy outcomes. Although there were two meta-analyzes that examined the association between health care and adverse pregnancy outcomes, their results were limited because they only included congenital anomaly and perinatal mortality, and they did not clarify the detailed situations of diabetes and health care. This meta-analysis aims to completely evaluate the effects of health care in improving adverse pregnancy outcomes among diabetic mothers. METHODS: CNKI, EMBASE, Web of Science, and PubMed databases were searched for eligible studies up to December 2017, without any restrictions. Relevant cohort studies characterizing the relationship between health care and adverse pregnancy outcomes were selected for inclusion in the meta-analysis. We also screened the reference list of relevant studies. The fixed-effect models or random-effect models were used to calculate the risk estimates. The potential sources of heterogeneity were explored by stratified and sensitivity analyzes. RESULTS: Twenty-one studies with 6685 cases were included in our analysis. Health care was associated with significantly decreased risk of congenital anomaly (RR 0.237; 95% CI 0.166-0.338), perinatal death (RR 0.457; 95% CI 0.294-0.712), large for gestational age (LGA) (RR 0.794; 95% CI 0.640-0.986), and neonatal hypoglycemia (RR 0.672; 95% CI 0.486-0.929). Publication bias was not found in most results, with the exception of congenital anomaly and small for gestational age (SGA). CONCLUSION: Health care is associated with decreased risk of congenital anomaly, perinatal death, LGA, neonatal hypoglycemia.

Maternal violence experiences and risk of postpartum depression: A meta-analysis of cohort studies.

BACKGROUND: Most of original studies indicated maternal violence experiences is associated with adverse obstetric outcomes, to date, but it is not clear that the association of maternal violence experiences and the risk of postpartum depression (PPD). We aimed to assess the association between maternal violence experiences and risk of developing PPD by performing a meta-analysis of cohort studies. METHODS: PubMed, Google Scholar, Cochrane Libraries and Chinese databases were searched through December 2017 to identify studies that assessed the association between violence and PPD. Meta-analysis was conducted by the RevMan software and Stata software. Potential heterogeneity source was explored by subgroup analysis and potential publication bias was assessed by Begg's funnel plots and Egger's linear regression test. RESULTS: Overall, women experiencing any violence events compared with the reference group were at a higher risk of developing PPD (odds ratio [OR] = 2.04; 95% confidence interval [CI]: 1.72-2.41). Additionally, different types of violence events such as sexual (OR = 1.56; 95%CI: 1.35-1.81), emotional (OR = 1.75; 95%CI: 1.61-1.89), and physical violence (OR = 1.90; 95%CI: 1.36-2.67), as well as domestic (OR = 2.05; 95%CI: 1.50-2.80) or childhood violence (OR = 1.59; 95%CI: 1.34-1.88) also increased the risk of developing PPD. Relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded consistent results. CONCLUSIONS: Maternal violence experiences are significantly associated with risk of developing PPD. These finding highlight the necessary to protect women from any types of violence and formulate preventive strategies to promote the maternal mental health.

Congenital malformations are associated with secondhand smoke among nonsmoking women: A meta-analysis.

BACKGROUND: The association between active maternal smoking and congenital malformations is well established, but little is known about the association between secondhand smoke and congenital malformations. Moreover, studies regarding the association between congenital malformations and secondhand smoke have not yielded consistent results. METHODS: In July 2018, we searched PubMed, EMBASE, and China Biology Medicine databases for observational studies characterizing the relationship between secondhand smoke and congenital malformations of offspring in nonsmoking women. Two reviewers independently decided on whether a study should be included, did data extraction, and assessed study quality. Pooled risks with 95% confidence intervals were calculated using either the fixed-effects models or random-effects models. Further subgroup analyses and sensitivity analyses were performed to explore the potential source of heterogeneity and to examine the robustness of risk estimates. RESULTS: Thirty-three studies with a total of 31 944 cases and 32 335 controls were included. Secondhand smoke exposure was associated with an increased risk of congenital malformations (odds ratio = 1.92; 95% confidence interval 1.61-2.30). Secondhand smoke was correlated with significantly increased risk for digestive system (1.17 [1.05-1.32]), nervous system (1.74 [1.33-2.29]), and cardiovascular system (2.10 [1.32-3.35]) malformations and for oral clefts (1.87 [1.47-2.39]). CONCLUSIONS: Secondhand smoke exposure increases the risk for overall and several organ-system malformations. These findings highlight the necessity of improving community awareness to prevent secondhand smoke exposure during the preconception and conception periods.

Cancer risk among children conceived by fertility treatment.

Prior studies on the association between fertility treatment and childhood cancer risk have generated inconsistent results. We performed a systematic review and meta-analysis of observation studies to summarize the evidence regarding the relation of fertility treatment with childhood cancer risk. A systematic literature search of several databases was conducted through April 2018 to identify relevant studies. The outcomes of interest included overall cancer, haematological malignancies, neural tumours, other solid tumours, and eight specific cancers. The overall risk estimates and corresponding 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Sixteen cohort and thirteen case-control studies were included. Results showed that children conceived by fertility treatment had significantly higher risk for developing overall cancer (relative risk [RR]: 1.16, 95% CI: 1.01, 1.32), haematological malignancies (RR: 1.39, 95% CI: 1.21, 1.60) and other solid tumours (RR: 1.57, 95% CI: 1.14, 2.16). For specific cancers, fertility treatment was associated with a significantly increased risk of leukaemia (RR: 1.31, 95% CI: 1.09, 1.57) and hepatic tumours (RR: 2.26, 95% CI: 1.32, 3.85). Sensitivity analysis validated evidence of the robustness of the findings. The results may demonstrate a possible association between fertility treatment and an increased risk of cancer among the offspring. However, the findings cannot say whether this increased risk is due to the subfertility itself or to the fertility treatment. Further research is needed to address the underlying mechanisms.

Increased maternal Body Mass Index is associated with congenital heart defects: An updated meta-analysis of observational studies.

PURPOSE: To review and summarize the epidemiologic evidence on the association of maternal Body Mass Index (BMI) with risk of congenital heart defects (CHDs) and to assess the possible dose-response patterns. METHODS: Six electronic databases were searched for eligible studies up to April 2018. The summary risk estimates were calculated using either the fixed-effect models or random-effect models. A dose-response meta-analysis was also performed to capture the shape of the observed association. Subgroup and sensitivity analysis were conducted to explore the potential heterogeneity moderators. RESULTS: Twenty-nine studies involving 99,205 CHDs cases among 6,467,422 participants were included in the meta-analysis. Mothers who were overweight (odds ratio [OR] = 1.07; 95% confidence intervals [CI]: 1.00-1.13) and obese (OR = 1.32; 95% CI: 1.21-1.43) had a significantly higher risk of total CHDs in their offspring when compared with those with normal weight. When obesity was further divided into class I (OR = 1.15; 95% CI: 1.11-1.20), class II (OR = 1.26; 95% CI: 1.18-1.34) and class III (OR = 1.42; 95% CI: 1.33-1.51) obesity, a significantly increased risk of total CHDs persisted. Different risks for specific CHD phenotypes were also found in different BMI categories. Furthermore, a nonlinear dose-response relationship between maternal BMI and risk of total CHDs was observed. Subgroup and sensitivity analyses identified the most relevant heterogeneity moderators. CONCLUSION: The increased maternal BMI is associated with the risk of developing CHDs in offspring. Severe obesity can play an independent role in the observed association, but the effect may be mediated by diabetes mellitus. Preventing obesity or excessive weight gain is a priority for CHDs prevention.

[Association of single nucleotide polymorphisms of transcription factors with congenital heart diseases in the Chinese population: a Meta analysis].

OBJECTIVE: To study the association of single nucleotide polymorphisms (SNPs) of transcription factors (NKX2.5, GATA4, TBX5, and FOG2) with congenital heart disease (CHD) in the Chinese population. METHODS: PubMed, Google Scholar, CNKI, Wanfang Data, and Weipu Data were searched for articles on the association of SNPs of target genes with CHD in the Chinese population. If one locus was mentioned in at least two articles, the random or fixed effect model was used to perform a pooled analysis of study results and to calculate the pooled OR and its 95%CI. If a locus was mentioned in only one article, related data were extracted from this article to analyze the association between the SNPs of this locus and CHD. RESULTS: Twenty-three articles were included. The Meta analysis showed that there were significant differences between the CHD and control groups in the genotype and allele frequencies of GATA4 rs1139244 and rs867858 and the genotype frequency of GATA4 rs904018, while there were no significant differences in the SNPs of the other genetic loci between the two groups. The single-article analysis showed that there were significant differences between the two groups in the allele frequencies of NKX2.5 rs118026695/rs703752, GATA4 rs884662/rs12825/rs12458/rs3203358/rs4841588, and TBX5 rs6489956. There were no significant differences in the SNPs of FOG2 locus between the two groups. CONCLUSIONS: The SNPs of some loci in NKX2.5, GATA4, and TBX5 are associated with CHD in the Chinese population, but the association between the SNPs of FOG2 locus and the development of CHD has not been found yet.

Multiple pregnancies achieved with IVF/ICSI and risk of specific congenital malformations: a meta-analysis of cohort studies.

Studies comparing risk of specific congenital malformations (CM) between multiple pregnancies resulting from IVF/intracytoplasmic sperm injection (ICSI) and those conceived naturally report conflicting results; furthermore, there is a lack of a complete overview. This meta-analysis aimed to address which types of CM are increased in IVF/ICSI multiple pregnancies compared with those conceived naturally. All studies testing the association between IVF/ICSI multiple pregnancies and specific CM identified in various databases were considered. The literature search yielded 856 records, of which 21 cohort studies were included for analysis. Overall, multiple pregnancies achieved with IVF/ICSI experienced a significantly higher risk of chromosomal defects (relative risk [RR] = 1.36; 95% confidence interval [CI]: 1.04-1.77), urogenital (RR = 1.18; 95% CI: 1.03-1.36) and circulatory (RR = 1.22; 95% CI: 1.01-1.47) system malformations. However, the remaining specific CM, such as cleft lip and/or palate, eye, ear, face and neck, respiratory, musculoskeletal, nervous and digestive system malformations, were similar in the two groups. No substantial heterogeneity was observed for most outcomes except for digestive (P = 0.094; I2 = 38.3%) and circulatory (P = 0.070; I2 = 35.2%) system malformations. These findings provide additional information on risks of IVF/ICSI for use when counselling patients.

Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis.

PURPOSE: We conducted a systematic review and meta-analysis to estimate the worldwide birth prevalence of total congenital malformations (CMs), major CMs, and specific CMs according to organs and systems classification associated with IVF/ICSI singleton pregnancies. METHODS: Unrestricted searches were conducted, with an end-date parameter of 1 June 2017, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases, to identify cohort studies assessing CMs associated with IVF/ICSI singleton pregnancies. The prevalence estimates were summarized and analyzed by meta-analysis. RESULTS: Thirty-four cohort studies comprising 159,021 IVF/ICSI and 6704,405 spontaneously conceived singleton pregnancies met the inclusion criteria. Among IVF/ICSI singleton pregnancies, pooled estimates of total CMs and major CMs (per 10,000) were 484.3 (95% CI 363.8-641.9) and 475.8 (95% CI 304.9-735.2), respectively; for specific CMs, pooled estimates 13.04 (95% CI 9.90-17.18) for cleft lip and/or palate, 17.01 (95% CI 8.01-36.06) for eye, ear, face, and neck malformations, 16.51(95% CI 11.56-23.57) for nervous system malformations, 36.21 (95% CI 26.20-50.02) for chromosomal defects, 8.31 (95% CI 4.21-16.40) for respiratory system malformations, 38.01 (95% CI 24.06-60.00) for digestive system malformations, 110.25 (95% CI 66.92-181.12) for musculoskeletal system malformations, 108.92 (95% CI 68.73-172.21) for urogenital system malformations, and 77.20 (95% CI 53.25-111.80) for circulatory system malformations. The IVF/ICSI singleton pregnancies compared with those conceived naturally experienced higher prevalence of total CMs, major CMs, and most specific CMs. Significant differences across continents, countries, types of assisted conception, and diagnose time of CMs were observed for total CMs birth prevalence among IVF/ICSI singleton pregnancies. CONCLUSIONS: The IVF/ICSI singleton pregnancies were significantly associated with high birth prevalence of CMs, representing a major global health burden. Significant differences across continents, countries, types of ART, and diagnose time of CMs were found. However, it remains uncertain whether detected differences represent true or methodological differences. In the future, population wide prospective CMs' registries covering the entire world population are needed to determine the exact birth prevalence.

[Impact of in vitro fertilization-embryo transfer on adverse pregnancy outcomes: A prospective cohort study].

OBJECTIVE: To evaluate whether the in vitro fertilization-embryo transfer (IVF-ET) procedures could increases the risks of adverse pregnancy outcomes (APOs) in offspring.
 Methods: A hospital-based prospective cohort design was conducted, which contained a control group of singleton pregnancies with indicators of subfertility who were still conceived naturally after using simple medical treatment (e.g. minimal medical intervention or ovulation induction), and an exposure group consisted of singleton pregnancies who had a history of infertility and IVF-ET treatment. All factors different between two groups in the univariate analysis were included in the multivariable logistic regression to evaluate the independent effect of IVF-ET procedures themselves on APOs.
 Results: After controlling for confounding factors by using multivariate logistic regression analysis, our results showed that pregnancies after IVF-ET experienced a higher risk of preterm birth (OR=1.28, 95% CI 1.05 to 1.56), low birth weight (OR=1.69, 95% CI 1.27 to 2.31), perinatal mortality (OR=5.33, 95% CI 2.44 to 11.81), and congenital malformations (OR=1.83, 95% CI 1.12 to 2.94).
 Conclusion: The IVF-ET operational factors may increase the risk of APOs.

Seasonal Dynamics of Metabolites in Needles of Taxus wallichiana var. mairei.

Seasonal variations of the phytochemicals contents in needles of T. wallichiana var. mairei due to the effects of growth meteorological parameters were investigated in this study. The needles of T. wallichiana var. mairei were collected from different months and the contents of taxoids (paclitaxel, 10-deacetylbaccatin III (10-DAB), baccatin III, cephalomannine, 10-deacetyltaxol (10-DAT)), flavones (ginkgetin, amentoflavone, quercetin) and polysaccharides were quantified by ultra performance liquid chromatography (UPLC) and the resonance light scattering (RIL) method. The content of taxoids gave the highest level of 1.77 ± 0.38 mg·g-1 in January, and the lowest value of 0.61 ± 0.08 mg·g-1 in September. Unlike taxoids, the content of flavonoids was the highest in August. The content of polysaccharides reached peak value of 28.52 ± 0.57 mg·g-1 in September, which was two times higher than the lowest content of 9.39 ± 0.17 mg·g-1 in January. The contents of paclitaxel, 10-DAB, 10-DAT and polysaccharides significantly depended on meteorological parameters. The mean of minimum temperature (R = -0.61) and length of daylight (R = -0.60) were significantly correlated to 10-DAB content, while 10-DAT level showed significant correlation with length of daylight (R = -0.70) and relative humidity (R = 0.70). In addition, temperature had significantly negative effect on the content of paclitaxel and a significantly positive effect on that of polysaccharides. This study enriched the knowledge on the accumulation pattern of metabolites and could help us to determine the collecting time of T. wallichiana var. mairei for medicinal use.