Associations of Serum Perfluoroalkyl Substances and Placental Human Chorionic Gonadotropin in Early Pregnancy, Measured in the UPSIDE Study in Rochester, New York.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely detected in pregnant women and associated with adverse outcomes related to impaired placental function. Human chorionic gonadotropin (hCG) is a dimeric glycoprotein hormone that can indicate placental toxicity. OBJECTIVES: Our aim was to quantify the association of serum PFAS with placental hCG, measured as an intact molecule (hCG), as free alpha-(hCGα) and beta-subunits (hCGß), and as a hyperglycosylated form (h-hCG), and evaluate effect measure modification by social determinants and by fetal sex. METHODS: Data were collected from 326 pregnant women enrolled from 2015 to 2019 in the UPSIDE study in Rochester, New York. hCG forms were normalized for gestational age at the time of blood draw in the first trimester [multiple of the median (MoM)]. Seven PFAS were measured in second-trimester maternal serum. Multivariate imputation by chained equations and inverse probability weighting were used to evaluate robustness of linear associations. PFAS mixture effects were estimated by Bayesian kernel machine regression. RESULTS: Perfluorohexane sulfonic acid (PFHxS) [hCGß: 0.29 log MoM units per log PFHxS; 95% confidence interval (CI): 0.08, 0.51] and perfluorodecanoic acid (PFDA) (hCG: -0.09; 95% CI: -0.16, -0.02) were associated with hCG in the single chemical and mixture analyses. The PFAS mixture was negatively associated with hCGα and positively with hCGß. Subgroup analyses revealed that PFAS associations with hCG differed by maternal race/ethnicity and education. Perfluoropentanoic acid (PFPeA) was associated with hCGß only in Black participants (-0.23; 95% CI: -0.37, -0.09) and in participants with high school education or less (-0.14; 95% CI: -0.26, -0.02); conversely, perfluorononanoic acid (PFNA) was negatively associated with hCGα only in White participants (-0.15; 95% CI: -0.27, -0.03) and with hCGß only in participants with a college education or greater (-0.19; 95% CI: -0.36, -0.01). These findings were robust to testing for selection bias, confounding bias, and left truncation bias where PFAS detection frequency was <100%. Two associations were negative in male (and null in female) pregnancies: Perfluoroundecanoic acid (PFUnDA) with hCGα, and PFNA with h-hCG. CONCLUSIONS: Evidence was strongest for the association between PFHxS and PFDA with hCG in all participants and for PFPeA and PFNA within subgroups defined by social determinants and fetal sex. PFAS mixture associations with hCGα and hCGß differed, suggesting subunit-specific types of toxicity and/or regulation. Future studies will evaluate the biological, clinical and public health significance of these findings. https://doi.org/10.1289/EHP12950.

Molecular pathways in placental-fetal development and disruption.

The first trimester of pregnancy ranks high in priority when minimizing harmful exposures, given the wide-ranging types of organogenesis occurring between 4- and 12-weeks' gestation. One way to quantify potential harm to the fetus in the first trimester is to measure a corollary effect on the placenta. Placental biomarkers are widely present in maternal circulation, cord blood, and placental tissue biopsied at birth or at the time of pregnancy termination. Here we evaluate ten diverse pathways involving molecules expressed in the first trimester human placenta based on their relevance to normal fetal development and to the hypothesis of placental-fetal endocrine disruption (perturbation in development that results in abnormal endocrine function in the offspring), namely: human chorionic gonadotropin (hCG), thyroid hormone regulation, peroxisome proliferator activated receptor protein gamma (PPARγ), leptin, transforming growth factor beta, epiregulin, growth differentiation factor 15, small nucleolar RNAs, serotonin, and vitamin D. Some of these are well-established as biomarkers of placental-fetal endocrine disruption, while others are not well studied and were selected based on discovery analyses of the placental transcriptome. A literature search on these biomarkers summarizes evidence of placenta-specific production and regulation of each biomarker, and their role in fetal reproductive tract, brain, and other specific domains of fetal development. In this review, we extend the theory of fetal programming to placental-fetal programming.

A study on the association of placental and maternal urinary phthalate metabolites.

BACKGROUND: Phthalate exposure in pregnancy is typically estimated using maternal urinary phthalate metabolite levels. Our aim was to evaluate the association of urinary and placental tissue phthalates, and to explore the role of maternal and pregnancy characteristics that may bias estimates. METHODS: Fifty pregnancies were selected from the CANDLE Study, recruited from 2006 to 2011 in Tennessee. Linear models were used to estimate associations of urinary phthalates (2nd, 3rd trimesters) and placental tissue phthalates (birth). Potential confounders and modifiers were evaluated in categories: temporality (time between urine and placenta sample), fetal sex, demographics, social advantage, reproductive history, medication use, nutrition and adiposity. Molar and quantile normalized phthalates were calculated to facilitate comparison of placental and urinary levels. RESULTS: Metabolites detectable in >80% of both urine and placental samples were MEP, MnBP, MBzP, MECPP, MEOHP, MEHHP, and MEHP. MEP was most abundant in urine (geometric mean [GM] 7.00 ×102 nmol/l) and in placental tissue (GM 2.56 ×104 nmol/l). MEHP was the least abundant in urine (GM 5.32 ×101 nmol/l) and second most abundant in placental tissue (2.04 ×104 nmol/l). In aggregate, MEHP differed the most between urine and placenta (2.21 log units), and MEHHP differed the least (0.07 log units). MECPP was positively associated between urine and placenta (regression coefficient: 0.31 95% CI 0.09, 0.53). Other urine-placenta metabolite associations were modified by measures of social advantage, reproductive history, medication use, and adiposity. CONCLUSION: Phthalates were ubiquitous in 50 full-term placental samples, as has already been shown in maternal urine. MEP and MEHP were the most abundant. Measurement and comparison of urinary and placental phthalates can advance knowledge on phthalate toxicity in pregnancy and provide insight into the validity and accuracy of relying on maternal urinary concentrations to estimate placental exposures. IMPACT STATEMENT: This is the first report of correlations/associations of urinary and placental tissue phthalates in human pregnancy. Epidemiologists have relied exclusively on maternal urinary phthalate metabolite concentrations to assess exposures in pregnant women and risk to their fetuses. Even though it has not yet been confirmed empirically, it is widely assumed that urinary concentrations are strongly and positively correlated with placental and fetal levels. Our data suggest that may not be the case, and these associations may vary by phthalate metabolite and associations may be modified by measures of social advantage, reproductive history, medication use, and adiposity.

Application of 4-way decomposition to the analysis of placental-fetal biomarkers as intermediary variables between maternal body mass index and birthweight.

Human chorionic gonadotropin (hCG) is a placental hormone measured in pregnancy to predict individual level risk of fetal aneuploidy and other complications; yet may be useful in understanding placental origins of child development more generally. hCG was associated with maternal body mass index (BMI) and with birthweight. The primary aim here was to evaluate hCG as a mediator of maternal BMI effects on birthweight by causal mediation analysis. Subjects were 356 women from 3 U.S. sites (2010-2013). The 4-way decomposition method using med4way (STATA) was applied to screen for 5 types of effects of first trimester maternal BMI on birthweight: the total effect, the direct effect, mediation by hCG, additive interaction of BMI and hCG, and mediation in the presence of an additive interaction. Effect modification by fetal sex was evaluated, and a sensitivity analysis was performed to evaluate the assumption of unmeasured confounding. Additional placental-fetal biomarkers [pregnancy associated plasma protein A (PAPPA), second trimester hCG, inhibin-A, estriol, alpha fetoprotein] were analyzed for comparison. For first trimester hCG, there was a 0.20 standard deviation increase in birthweight at the 75th vs. 25th percentile of maternal BMI (95% CI 0.04, 0.36). Once stratified, the direct effect association was null in women carrying females. In women carrying males, hCG did not mediate the relationship. In women carrying females, there was a mediated effect of maternal BMI on birthweight by hCG in the reverse direction (-0.06, 95% CI: -0.12, 0.01), and a mediated interaction in the positive direction (0.06, 95% CI 0.00, 0.13). In women carrying males, the maternal BMI effect on birthweight was reverse mediated by PAPPA (-0.09, 95% CI: -0.17, 0.00). Sex-specific mediation was mostly present in the first trimester. Second trimester AFP was a positive mediator of maternal BMI effects in male infants only (0.06, 95% CI: -0.01, 0.13). Effect estimates were robust to potential bias due to unmeasured confounders. These findings motivate research to consider first trimester placental biomarkers and sex-specific mechanisms when quantifying the effects of maternal adiposity on fetal growth.

Second-Trimester Placental and Thyroid Hormones Are Associated With Cognitive Development From Ages 1 to 3 Years.

Adequate maternal thyroid hormone (TH) is necessary for fetal brain development. The role of placental human chorionic gonadotropin (hCG) in ensuring the production of TH is less well understood. The objective of the study was to evaluate 1) associations of placental hCG and its subunits, and maternal TH in the second trimester, and 2) the single and joint effects of TH and placental hormones on cognitive development and communication at ages 1 and 3 years. Fifty individuals (5%) were selected from the CANDLE (Conditions Affecting Neurocognitive Development and Early Learning) pregnancy cohort in Memphis, Tennessee, with recruitment from 2006 to 2011, to equally represent male and female fetuses. Participants were 68% Black and 32% White. Hormones measured were maternal thyroid (thyrotropin [TSH] and free thyroxine [FT4]) and placental hormones (hCG, its hyperglycosylated form [hCG-h], and free α- [hCGα] and ß-subunits [hCGß]) in maternal serum (17-28 weeks). The primary outcome measurement was the Bayley Scales of Infant and Toddler Development. All forms of hCG were negatively associated with FT4 and not associated with TSH. hCGα was associated with cognitive development at age 1 year and jointly interacted with TSH to predict cognitive development at age 3 years. This pilot study added insight into the thyrotropic actions of hCG in the second trimester, and into the significance of this mechanism for brain development. More research is warranted to elucidate differences between hCGα, hCGß, and hCG-h in relation to TH regulation and child brain function.

A toolkit for the application of placental-fetal molecular biomarkers in epidemiologic studies of the fetal origins of chronic disease.

PURPOSE OF REVIEW: In this review, we provide essential background knowledge and an analytical framework for the application of placental-fetal molecular biomarkers in fetal origins chronic disease epidemiology. The widely available and highly quantitative placental hormone human chorionic gonadotropin (hCG) is used as an example. hCG is currently used for diagnosing fetal genetic disorders; yet it can and should be expanded to understanding the fetal origins of chronic diseases. We provide justification and methods to do this. RECENT FINDINGS: Ten papers published in the last 5 years were identified with supportive findings relevant to the application of biomarkers of hCG in epidemiologic studies on the developmental origins of health and disease (DOHaD). SUMMARY: There is increasing and consistent evidence that placental-fetal biomarkers may be highly informative in observational studies, as exemplified by hCG, with the correct approaches for measurement and data analysis.

First trimester mechanisms of gestational sac placental and foetal teratogenicity: a framework for birth cohort studies.

BACKGROUND: The function of the gestational sac (GS) and the placenta in the closely related processes of embryogenesis and teratogenicity in the first trimester has been minimally described. The prevailing assumption is that direct teratogenic effects are mediated by the critical extraembryonic organ, the placenta, which either blocks or transfers exposures to the foetus. Placental transfer is a dominant mechanism, but there are other paradigms by which the placenta can mediate teratogenic effects. Knowledge of these paradigms and first trimester human developmental biology can be useful to the epidemiologist in the conduct of biomarker-based studies of both maternal and child health. OBJECTIVE AND RATIONALE: Our aim is to provide a causal framework for modelling the teratogenic effects of first trimester exposures on child health outcomes mediated by the GS and placenta using biomarker data collected in the first trimester. We initially present first trimester human developmental biology for the sake of informing and strengthening epidemiologic approaches. We then propose analytic approaches of modelling placental mechanisms by way of causal diagrams using classical non-embryolethal teratogens (diethylstilboestrol [DES], folic acid deficiency and cytomegalovirus [CMV]) as illustrative examples. We extend this framework to two chronic exposures of particular current interest, phthalates and maternal adiposity. SEARCH METHODS: Information on teratogens was identified by a non-systematic, narrative review. For each teratogen, we included papers that answered the five following questions: (i) why were these exposures declared teratogens? (ii) is there a consensus on biologic mechanism? (iii) is there reported evidence of a placental mechanism? (iv) can we construct a theoretical model of a placental mechanism? and (v) can this knowledge inform future work on measurement and modelling of placental-foetal teratogenesis? We prioritized literature specific to human development, the organogenesis window in the first trimester and non-embryolethal mechanisms. OUTCOMES: As a result of our review of the literature on five exposures considered harmful in the first trimester, we developed four analytic strategies to address first trimester placental mechanisms in birth cohort studies: placental transfer and direct effects on the foetus (DES and maternal adiposity), indirect effects through targeted placental molecular pathways (DES and phthalates), pre-placental effects through disruptions in embryonic and extraembryonic tissue layer differentiation (folic acid deficiency), and multi-step mechanisms that involve maternal, placental and foetal immune function and inflammation (DES and CMV). WIDER IMPLICATIONS: The significance of this review is to offer a causal approach to classify the large number of potentially harmful exposures in pregnancy when the exposure occurs in the first trimester. Our review will facilitate future research by advancing knowledge of the first trimester mechanisms necessary for researchers to effectively associate environmental exposures with child health outcomes.

Shape Detection using Semi-parametric Shape-Restricted Mixed Effects Regression Spline with Applications.

Linear models are widely used in the field of epidemiology to model the relationship between placental-fetal hormone and fetal/infant outcome. When researchers suspect curvilinear relationship exists, some nonparametric techniques, including regression splines, smoothing splines and penalized regression splines, can be used to model the relationship (Korevaar et al. 2016; Wu and Zhang 2006). By applying these nonparametric techniques, researchers can relax the linearity assumption and capture scientifically meaningful or appropriate shapes. In this paper, we focus on the regression spline technique and develop a method to help researchers select the most suitable shape to describe their data among increasing, decreasing, convex and concave shapes. Specifically, we develop a mixed effects regression spline to model hormonal data described in this paper. The proposed methodology is general enough to be applied to other similar problems. We illustrate the method using a state-wide prenatal screening program data set.

Association between prediagnostic leukocyte telomere length and breast cancer risk: the Singapore Chinese Health Study.

BACKGROUND: Telomeres and telomerase play key roles in the chromosomal maintenance and stability. Recent epidemiological studies have shown that longer telomeres are associated with increased risk of several cancer types. However, epidemiological data for telomere length and risk of breast cancer are sparse. METHODS: We prospectively studied the association between telomere length and risk of breast cancer in 14,305 middle-aged or older Chinese women of the Singapore Chinese Health Study including 442 incident breast cancer cases after 12.3 years of follow-up. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiple quantitative polymerase chain reaction method. The Cox proportional hazard regression method was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for breast cancer associated with longer telomeres after adjustment for potential confounders. RESULTS: Longer telomeres were significantly associated with higher risk of breast cancer in a dose-dependent manner (Ptrend = 0.006); the highest quartile of telomere length was associated with a statistically significant 47% higher risk of breast cancer compared with the lowest quartile of telomere length after the adjustment for age and other known risk factors for breast cancer (HRQ4 vs Q1 = 1.47, 95% CI = 1.11, 1.94). CONCLUSIONS: The findings of the present study support the hypothesis that longer telomeres may be a risk factor for breast cancer. Telomere length in peripheral blood leukocytes may be developed as a biomarker for breast cancer risk prediction.

Reliability and Validity of Survey Instruments to Measure Work-Related Fatigue in the Emergency Medical Services Setting: A Systematic Review.

BACKGROUND: This study sought to systematically search the literature to identify reliable and valid survey instruments for fatigue measurement in the Emergency Medical Services (EMS) occupational setting. METHODS: A systematic review study design was used and searched six databases, including one website. The research question guiding the search was developed a priori and registered with the PROSPERO database of systematic reviews: "Are there reliable and valid instruments for measuring fatigue among EMS personnel?" (2016:CRD42016040097). The primary outcome of interest was criterion-related validity. Important outcomes of interest included reliability (e.g., internal consistency), and indicators of sensitivity and specificity. Members of the research team independently screened records from the databases. Full-text articles were evaluated by adapting the Bolster and Rourke system for categorizing findings of systematic reviews, and the rated data abstracted from the body of literature as favorable, unfavorable, mixed/inconclusive, or no impact. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was used to evaluate the quality of evidence. RESULTS: The search strategy yielded 1,257 unique records. Thirty-four unique experimental and non-experimental studies were determined relevant following full-text review. Nineteen studies reported on the reliability and/or validity of ten different fatigue survey instruments. Eighteen different studies evaluated the reliability and/or validity of four different sleepiness survey instruments. None of the retained studies reported sensitivity or specificity. Evidence quality was rated as very low across all outcomes. CONCLUSIONS: In this systematic review, limited evidence of the reliability and validity of 14 different survey instruments to assess the fatigue and/or sleepiness status of EMS personnel and related shift worker groups was identified.

Effect of Task Load Interventions on Fatigue in Emergency Medical Services Personnel and Other Shift Workers: A Systematic Review.

BACKGROUND: Modifying the task load of Emergency Medical Services (EMS) personnel may mitigate fatigue, sleep quality and fatigue related risks. A review of the literature addressing task load interventions may benefit EMS administrators as they craft policies related to mitigating fatigue. We conducted a systematic review of the peer-reviewed literature to address the following question: "In EMS personnel, do task load interventions mitigate fatigue, mitigate fatigue-related risks, and/or improve sleep?" (PROSPERO 2016:CRD42016040114). METHODS: We performed a systematic review of the literature that described use of randomized controlled trials, quasi-experimental studies, and observational study designs. We retained and reviewed research that involved EMS personnel or similar shift worker groups 18 years of age and older. Studies of 'healthy volunteers' and non-shift worker populations were excluded. Studies were included where the methodology of the study implied a theoretical framework of task load (or workload) affecting fatigue, and then fatigue related outcomes. Outcomes of interest included personnel safety, patient safety, personnel performance, acute fatigue, and cost to system. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology to summarize findings and assess quality of evidence from very low to high quality. RESULTS: The search strategy yielded 3,394 unique records resulting in 58 records included as potentially eligible. An additional 69 studies were reviewed in full following searches of bibliographies. We detected wide variation in the description and measurement of task load in the retained and excluded research. Among 127 potentially relevant studies reviewed in full, five were judged eligible. None of the retained studies reported findings germane to personnel safety, patient safety, or cost to system. We judged most studies to have serious or very serious risk of bias. CONCLUSIONS: The effect of task load interventions on fatigue, fatigue-related risks, and/or sleep quality was not estimable and the overall quality of evidence was judged low or very low. There was considerable heterogeneity in how task load was defined and measured.

Shorter Versus Longer Shift Durations to Mitigate Fatigue and Fatigue-Related Risks in Emergency Medical Services Personnel and Related Shift Workers: A Systematic Review.

BACKGROUND: This study comprehensively reviewed the literature on the impact of shorter versus longer shifts on critical and important outcomes for Emergency Medical Services (EMS) personnel and related shift worker groups. METHODS: Six databases (e.g., PubMed/MEDLINE) were searched, including one website. This search was guided by a research question developed by an expert panel a priori and registered with the PROSPERO database of systematic reviews (2016:CRD42016040099). The critical outcomes of interest were patient safety and personnel safety. The important outcomes of interest were personnel performance, acute fatigue, sleep and sleep quality, retention/turnover, long-term health, burnout/stress, and cost to system. Screeners worked independently and full-text articles were assessed for relevance. Data abstracted from the retained literature were categorized as favorable, unfavorable, mixed/inconclusive, or no impact toward the shorter shift duration. This research characterized the evidence as very low, low, moderate, or high quality according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: The searched yielded n = 21,674 records. Of the 480 full-text articles reviewed, 100 reported comparisons of outcomes of interest by shift duration. We identified 24 different shift duration comparisons, most commonly 8 hours versus 12 hours. No one study reported findings for all 9 outcomes. Two studies reported findings linked to both critical outcomes of patient and personnel safety, 34 reported findings for one of two critical outcomes, and 64 did not report findings for critical outcomes. Fifteen studies were grouped to compare shifts <24 hours versus shifts ≥24 hours. None of the findings for the critical outcomes of patient and personnel safety were categorized as unfavorable toward shorter duration shifts (<24 hours). Nine studies were favorable toward shifts <24 hours for at least one of the 7 important outcomes, while findings from one study were categorized as unfavorable. Evidence quality was low or very low. CONCLUSIONS: The quality of existing evidence on the impact of shift duration on fatigue and fatigue-related risks is low or very low. Despite these limitations, this systematic review suggests that for outcomes considered critical or important to EMS personnel, shifts <24 hours in duration are more favorable than shifts ≥24 hours.

Endothelial nitric oxide synthase gene single nucleotide polymorphisms and the risk of hypertension: A meta-analysis involving 63,258 subjects.

The endothelial nitric oxide synthase (eNOS) gene plays an important role in regulating vascular tone and blood pressure. Recently, the eNOS G894T and T-786C single nucleotide polymorphisms (SNPs) were intensively studied with regard to their associations with hypertension. However, the results of these studies were inconsistent. Therefore, we conducted the so far largest meta-analysis to better assess the correlations between eNOS SNPs and hypertension. Eligible articles were searched in PubMed, Medline, Embase, Scopus, and CNKI up to April 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between eNOS SNPs and the risk of hypertension. A total of 95 case-control studies involving 29,308 hypertension cases and 33,950 healthy controls were analyzed. The overall meta-analysis results showed that eNOS G894T and T-786C SNPs were both significantly associated with the risk of hypertension, the T allele of G894T SNP (G versus T, P < 0.00001, OR = 0.82, 95% CI 0.76-0.89) and C allele of T-786C SNP (T versus C, P = 0.004, OR = 0.92, 95% CI 0.87-0.97) conferred an increased susceptibility to hypertension. Further subgroup analyses yielded similar positive results for G894T SNP in essential hypertension, gestational hypertension, and Asian ethnicity, and that for T-786C SNP in essential hypertension and Asian population. Overall, our findings suggest that eNOS G894T and T-786C SNPs were both significantly correlated with hypertension. Additionally, the T allele of G894T SNP and C allele of T-786C SNP may serve as potential biological markers for hypertension susceptibility in Asians.

Associations of IL-10 genetic polymorphisms with the risk of urologic cancer: a meta-analysis based on 18,415 subjects.

BACKGROUND: Interleukin-10 (IL-10) is a powerful modulator of anti-tumor immune responses. The IL-10 promoter region polymorphisms are known to regulate IL-10 production, and thus are thought to be implicated in tumorigenesis. Recently, the roles of these polymorphisms in urologic cancer have been extensively studied, with conflicting results. Therefore, we conducted the present meta-analysis to better elucidate the correlations between IL-10 polymorphisms and urologic cancer risk. METHODS: Eligible articles were searched in PubMed, Medline, Embase, Scopus and CNKI up to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between IL-10 polymorphisms and the risk of urologic cancer. RESULTS: A total of 22 case-control studies including 8572 patients and 9843 controls were analyzed. The overall meta-analysis results showed that IL-10 -592C>A polymorphism was significantly associated with urologic cancer in CA versus AA (P = 0.04, OR 0.87, 95% CI 0.76-0.99) and AA versus CC+CA (P = 0.03, OR 1.15, 95% CI 1.02-1.31). Subgroup analyses by cancer types suggested there were significant associations between all the three investigated IL-10 polymorphisms and bladder cancer. However, subgroup analyses by ethnicity only detected a weak association between IL-10 -819C>T and Asian population. CONCLUSIONS: Our findings suggests that IL-10 -592C>A polymorphism may implicate with urologic cancer risk. Besides, promoter region polymorphisms of IL-10 may serve as potential biological markers, especially for bladder cancer. Furthermore, IL-10 -819C>T polymorphism may contribute to urologic cancer susceptibility in Asians while all the three studied variants of IL-10 did not relate to Caucasian urologic cancer predisposition.

Efficacy and Safety of Transcatheter Aortic Valve Implantation for Bicuspid Aortic Valves: A Systematic Review and Meta-Analysis.

PURPOSE: To elucidate the performance of transcatheter aortic valve implantation (TAVI) in bicuspid aortic valve (BAV) patients through a systematic review and meta-analysis. METHODS: A systematic literature review was performed by searching eligible articles in PubMed, Medline, EMBASE, Google Scholar and CNKI. Meta-analysis of included case-control/cohort studies was further conducted. Relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were used to compare clinical outcomes of BAV patients and non-BAV patients. RESULTS: A total of 17 articles including eight case reports, four case series and five case-control/cohort studies with 166 BAV patients were analyzed. Device success rate achieved for TAVI in this cohort of BAV patients was 95.2%. The 30-day mortality rate was 8.4%, and the medium-term (range from 6 months to 2 years) mortality rate reported was 17.9%. Overall, the performance of TAVI in BAV patients was comparable to that in non-BAV patients, as reported by the included case-control/cohort studies (30-day mortality rate: RR = 1.05, 95%CI 0.57-1.95, p = 0.87; Device success rate: RR = 1.00, 95%CI 0.95-1.05, p = 0.94; Incidence of moderate to severe paravalvular regurgitation: RR = 1.25, 95%CI 0.85-1.84, p = 0.25). CONCLUSION: The present study suggested that TAVI may be a feasible and safe treatment modality for BAV patients.

Associations of NKX2-5 Genetic Polymorphisms with the Risk of Congenital Heart Disease: A Meta-analysis.

The NKX2-5 gene is a vital regulator of cardiac formation and development. Recently, the roles of NKX2-5 63A>G polymorphism and 606G>C polymorphism in congenital heart disease (CHD) have been extensively studied, with conflicting results. The aim of the present study was to better elucidate the associations between NKX2-5 genetic polymorphisms and CHD risk through a meta-analysis. Eligible articles were searched in PubMed, MEDLINE, EMBASE, Google Scholar and CNKI up to December 2015. Odds ratios (ORs) and 95 % confidence intervals were used to detect any potential associations between NKX2-5 genetic polymorphisms and CHD risk. Heterogeneity between studies was assessed with Q test and I (2) statistic. Subgroup analysis and sensitivity analysis were performed to test the reliability and stability of the results, and funnel plots were applied to estimate publication bias. A total of 13 case-control studies including 2245 CHD patients and 1953 healthy controls were analyzed. The overall meta-analysis results showed that NKX2-5 63A>G polymorphism and 606G>C polymorphism were not significantly associated with CHD risk. Subgroup analysis was further performed for NKX2-5 63A>G polymorphism based on types of CHD and ethnicity of study population, and similar negative results were found in all subgroups. Our findings suggested that NKX2-5 63A>G polymorphism and 606G>C polymorphism may not be implicated in the pathogenesis of CHD.