Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.

BACKGROUND: Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae. OBJECTIVE: The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated. STUDY DESIGN: The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25-50th percentile; quartile 3, 50-70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18-34 years), and infant sex. RESULTS: Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6-13.8), quartile 3 (score, 13.9-15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04-2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02-1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27-2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05-1.19; P=3.0×1004) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48-10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11-2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex. CONCLUSION: In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae.

Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies.

INTRODUCTION: Accumulating epidemiological evidence points to strong genetic susceptibility to placental abruption (PA). However, characterization of genes associated with PA remains incomplete. We conducted a genome-wide association study (GWAS) of PA and a meta-analysis of GWAS. METHODS: Participants of the Placental Abruption Genetic Epidemiology (PAGE) study, a population based case-control study of PA conducted in Lima, Peru, were genotyped using the Illumina HumanCore-24 BeadChip platform. Genotypes were imputed using the 1000 genomes reference panel, and >4.9 million SNPs that passed quality control were analyzed. We performed a GWAS in PAGE participants (507 PA cases and 1090 controls) and a GWAS meta-analysis in 2512 participants (959 PA cases and 1553 controls) that included PAGE and the previously reported Peruvian Abruptio Placentae Epidemiology (PAPE) study. We fitted population stratification-adjusted logistic regression models and fixed-effects meta-analyses using inverse-variance weighting. RESULTS: Independent loci (linkage-disequilibrium<0.80) suggestively associated with PA (P-value<5e-5) included rs4148646 and rs2074311 in ABCC8, rs7249210, rs7250184, rs7249100 and rs10401828 in ZNF28, rs11133659 in CTNND2, and rs2074314 and rs35271178 near KCNJ11 in the PAGE GWAS. Similarly, independent loci suggestively associated with PA in the GWAS meta-analysis included rs76258369 near IRX1, and rs7094759 and rs12264492 in ADAM12. Functional analyses of these genes showed trophoblast-like cell interaction, as well as networks involved in endocrine system disorders, cardiovascular diseases, and cellular function. CONCLUSIONS: We identified several genetic loci and related functions that may play a role in PA risk. Understanding genetic factors underlying pathophysiological mechanisms of PA may facilitate prevention and early diagnostic efforts.

Childhood abuse and early menarche among Peruvian women.

PURPOSE: Childhood abuse has been associated with age of menarche in some studies, but not all, and few have assessed the independent associations of sexual and physical abuse with early menarche. We examined the association between childhood abuse and early menarche among pregnant women in Lima, Peru. METHODS: Multinomial logistic regression procedures were used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for early menarche (≤11 years) in relation to any physical or sexual childhood abuse, physical abuse only, sexual abuse only, and both physical and sexual abuse in a cohort of 1,499 pregnant (first trimester) women. RESULTS: Approximately 69% of participants reported experiencing physical or sexual abuse in childhood. The frequencies of physical abuse only, sexual abuse only, and both physical and sexual abuse were 37.4%, 7.7%, and 24.5%, respectively. Compared with women who reported no childhood abuse, those who reported any childhood abuse had a 1.38-fold increased odds of early menarche (95% CI, 1.01-1.87). Compared with no abuse, the odds of early menarche was 1.60-fold among women with childhood sexual abuse only (OR, 1.60; 95% CI, .93-2.74) and 1.56-fold for those with both physical and sexual abuse (OR, 1.56; 95% CI, 1.07-2.25) during childhood. Isolated physical abuse was weakly associated with early menarche (OR, 1.23; 95% CI, .87-1.74). There was no clear evidence of association of childhood abuse with late menarche (≥15 years). CONCLUSIONS: Childhood abuse, particularly joint physical and sexual abuse, is associated with early menarche. Our findings add to an expanding body of studies documenting the enduring adverse health consequences of childhood abuse.

Association of childhood physical and sexual abuse with intimate partner violence, poor general health and depressive symptoms among pregnant women.

OBJECTIVE: We examined associations of childhood physical and sexual abuse with risk of intimate partner violence (IPV). We also evaluated the extent to which childhood abuse was associated with self-reported general health status and symptoms of antepartum depression in a cohort of pregnant Peruvian women. METHODS: In-person interviews were conducted to collect information regarding history of childhood abuse and IPV from 1,521 women during early pregnancy. Antepartum depressive symptomatology was evaluated using the Patient Health Questionnaire-9. Multivariable logistic regression procedures were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Any childhood abuse was associated with 2.2-fold increased odds of lifetime IPV (95%CI: 1.72-2.83). Compared with women who reported no childhood abuse, those who reported both, childhood physical and sexual abuse had a 7.14-fold lifetime risk of physical and sexual IPV (95%CI: 4.15-12.26). The odds of experiencing physical and sexual abuse by an intimate partner in the past year was 3.33-fold higher among women with a history of childhood physical and sexual abuse as compared to women who were not abused as children (95%CI 1.60-6.89). Childhood abuse was associated with higher odds of self-reported poor health status during early pregnancy (aOR = 1.32, 95%CI: 1.04-1.68) and with symptoms of antepartum depression (aOR = 2.07, 95%CI: 1.58-2.71). CONCLUSION: These data indicate that childhood sexual and physical abuse is associated with IPV, poor general health and depressive symptoms in early pregnancy. The high prevalence of childhood trauma and its enduring effects of on women's health warrant concerted global health efforts in preventing violence.

Comparative performance of Patient Health Questionnaire-9 and Edinburgh Postnatal Depression Scale for screening antepartum depression.

OBJECTIVE: We sought to evaluate the psychometric properties of two widely used screening scales: the Patient Health Questionnaire (PHQ-9) and Edinburgh Postnatal Depression Scale (EPDS) among pregnant Peruvian women. METHODS: This cross-sectional study included 1517 women receiving prenatal care from February 2012 to March 2013. A structured interview was used to collect data using PHQ-9 and EPDS. We examined reliability, construct and concurrent validity between two scales using internal consistency indices, factor structures, correlations, and Cohen׳s kappa. RESULTS: Both scales had good internal consistency (Cronbach׳s alpha>0.8). Correlation between PHQ-9 and EPDS scores was fair (rho=0.52). Based on exploratory factor analysis (EFA), both scales yielded a two-factor structure. EFA including all items from PHQ-9 and EPDS yielded four factors, namely, "somatization", "depression and suicidal ideation", "anxiety and depression", and "anhedonia". The agreement between the two scales was generally fair at different cutoff scores with the highest Cohen׳s kappa being 0.46. CONCLUSIONS: Both the PHQ-9 and EPDS are reliable and valid scales for antepartum depression assessment. The PHQ-9 captures somatic symptoms, while EPDS detects depressive symptoms comorbid with anxiety during early pregnancy. Our findings suggest simultaneous administration of both scales may improve identification of antepartum depressive disorders in clinical settings.

Generation C: prevalence of and risk factors for chlamydia trachomatis among adolescents and young women in Lima, Peru.

OBJECTIVE: Adolescent and young adult women in urban, socioeconomically disadvantaged areas are at high risk of contracting sexually transmitted infections (STIs). We assessed associations of Chlamydia trachomatis (CT) infection with both traditional STI risk factors, and partner and partnership-related factors among low-income women in Lima, Peru, by age group. METHODS: In a cross-sectional analysis of CT infection among 1290 postpartum women, cervical swabs were collected for CT polymerase chain reaction (PCR) within 48 h after delivery, and a structured interview was completed. Multivariate logistic regression was used to evaluate risk factors for CT, with separate models stratified by age: adolescents (12-19 years), young women (20-24 years), and older women (>or=25 years). RESULTS: CT was detected in 9.6% of adolescents, 9.0% of young women, and 5.4% of older women (p = 0.03). Among adolescents, history of drug use (odds ratio [OR] = 5.62, 95% confidence interval [CI] 1.03-30.6) and short duration of current partnership (OR = 2.6, 95% CI 1.14-5.93) were the strongest predictors of CT infection. Among young women, younger age at coitarche (OR = 0.74 for each year older, 95% CI 0.60-0.91) and low income (OR = 2.40, 95% CI 1.04-5.55) were associated with CT, while self-report of ever using condoms was protective (OR = 0.22, 95% CI 0.08-0.61). Among older women, only younger age at coitarche was related to CT (OR = 0.85, 95% CI 0.75-0.97). CONCLUSIONS: Risk factors for CT among women in Lima, Peru, differed for adolescents, young women, and older women, which may reflect differences in biology and/or immunology of CT as well as variability in the occurrence of specific risk behaviors by age group.

Partner- and partnership-related risk factors for preterm birth among low-income women in Lima, Peru.

A woman's partner and the characteristics of their partnership can play an important role in the health of her pregnancy. Yet, with the notable exception of intimate partner violence, there has been little previous research addressing the associations between partner- or partnership-related factors and birth outcomes. This analysis tested the hypothesis that risk factors related specifically to partner or partnership characteristics increased the risk for preterm birth. Between 2003 and 2005, a total of 580 preterm cases (20-36 weeks gestational age at delivery) and 633 term controls (> or =37 weeks) were selected from women delivering at an obstetric hospital in Lima, Peru. Each woman completed a confidential, structured interview and provided biological specimens within 48 h after delivery. Multivariable logistic regression was used to assess associations between partner and partnership characteristics and preterm birth. After adjustment for behavioral, demographic, and obstetric risk factors, ever having had a partner with a history of drug use (aOR = 1.91, 95% CI 1.22-2.99), ever having had anal sex (aOR = 1.40, 95% CI 1.07-1.84), having a current partner with a history of visiting prostitutes (aOR = 1.69, 95% CI 1.22-2.33), and perceiving one's current partner as a "womanizer" (aOR = 1.34, 95% CI 1.02-1.77) were significantly associated with an elevated risk of preterm birth when tested in separate models. These four factors were then used to create a composite partnership risk score, which showed an increasing dose-response relationship with preterm birth risk (per additional partner risk factor: aOR = 1.31, 95% CI 1.16-1.49). These results highlight the importance of considering a broader set of risk factors for preterm birth, specifically those related to a woman's partner and partnership characteristics. Further research could clarify the specific mechanisms through which these partner and partnership characteristics may increase the risk of preterm birth.