Normal early pregnancy: a transient state of epigenetic change favoring hypomethylation
ABSTRACT: The objective of this study was to analyze genome-wide differential methylation patterns in maternal leukocyte DNA in early pregnant and non-pregnant states. This is an age- and body mass index-matched case-control study comparing the methylation patterns of 27,578 cytosine-guanine (CpG) sites in 14,495 genes in maternal leukocyte DNA in early pregnancy (n=14), in the same women postpartum (n=14), and in nulligravid women (n=14) on a BeadChip platform. Transient widespread hypomethylation was found in early pregnancy as compared with the non-pregnant states. Methylation of nine genes was significantly different in early pregnancy compared to both postpartum and nulligravid states (< 10% False Discovery Rate). Early pregnancy may be characterized by widespread hypomethylation compared to non-pregnant states; there is no apparent permanent methylation imprint after a normal-term gestation. Nine potential candidate genes were identified as differentially methylated in early pregnancy and may play a role in the maternal adaptation to pregnancy. Overall design: This is an age- and body mass index-matched case-control study comparing the methylation patterns of 27,578 cytosine-guanine (CpG) sites in 14,495 genes in maternal leukocyte DNA in early pregnancy (n=14), in the same women postpartum (n=14), and in nulligravid women (n=14) on a BeadChip platform.
Project description:The objective of this study was to analyze genome-wide differential methylation patterns in maternal leukocyte DNA in early pregnant and non-pregnant states. This is an age- and body mass index-matched case-control study comparing the methylation patterns of 27,578 cytosine-guanine (CpG) sites in 14,495 genes in maternal leukocyte DNA in early pregnancy (n=14), in the same women postpartum (n=14), and in nulligravid women (n=14) on a BeadChip platform. Transient widespread hypomethylation was found in early pregnancy as compared with the non-pregnant states. Methylation of nine genes was significantly different in early pregnancy compared to both postpartum and nulligravid states (< 10% False Discovery Rate). Early pregnancy may be characterized by widespread hypomethylation compared to non-pregnant states; there is no apparent permanent methylation imprint after a normal-term gestation. Nine potential candidate genes were identified as differentially methylated in early pregnancy and may play a role in the maternal adaptation to pregnancy. This is an age- and body mass index-matched case-control study comparing the methylation patterns of 27,578 cytosine-guanine (CpG) sites in 14,495 genes in maternal leukocyte DNA in early pregnancy (n=14), in the same women postpartum (n=14), and in nulligravid women (n=14) on a BeadChip platform.
Project description:CONTEXT:Psychiatric disorders and substance use during pregnancy are associated with adverse outcomes for mothers and their offspring. Information about the epidemiology of these conditions in this population is lacking. OBJECTIVE:To examine sociodemographic correlates, rates of DSM-IV Axis I psychiatric disorders, substance use, and treatment seeking among past-year pregnant and postpartum women in the United States. DESIGN:National survey. SETTING:Face-to-face interviews conducted in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions. PARTICIPANTS:A total of 43 093 respondents were interviewed, of whom 14 549 were women 18 to 50 years old with known past-year pregnancy status. MAIN OUTCOME MEASURES:Prevalence of 12-month DSM-IV Axis I psychiatric disorders, substance use, and treatment seeking. RESULTS:Past-year pregnant and postpartum women had significantly lower rates of alcohol use disorders and any substance use, except illicit drug use, than nonpregnant women. In addition, currently pregnant women had a lower risk of having any mood disorder than nonpregnant women. The only exception was the significantly higher prevalence of major depressive disorder in postpartum than in nonpregnant women. Age, marital status, health status, stressful life events, and history of traumatic experiences were all significantly associated with higher risk of psychiatric disorders in pregnant and postpartum women. Lifetime and past-year treatment-seeking rates for any psychiatric disorder were significantly lower among past-year pregnant than nonpregnant women with psychiatric disorders. Most women with a current psychiatric disorder did not receive any mental health care in the 12 months prior to the survey regardless of pregnancy status. CONCLUSIONS:Pregnancy per se is not associated with increased risk of the most prevalent mental disorders, although the risk of major depressive disorder may be increased during the postpartum period. Groups of pregnant women with particularly high prevalence of psychiatric disorders were identified. Low rates of maternal mental health care underscore the need to improve recognition and delivery of treatment for mental disorders occurring during pregnancy and the postpartum period.
Project description:Pre-pregnancy overweight/obesity and excessive gestational weight gain (GWG) independently predict negative maternal and child health outcomes. To date, however, interventions that target GWG have not produced lasting improvements in maternal weight or health at 12-months postpartum. Given that interventions solely aimed at addressing GWG may not equip women with the skills needed for postpartum weight management, interventions that address health behaviors over the perinatal period might maximize maternal health in the first postpartum year. Thus, the current study leveraged a sequential multiple assignment randomized trial (SMART) design to evaluate sequences of prenatal (i.e., during pregnancy) and postpartum lifestyle interventions that optimize maternal weight, cardiometabolic health, and psychosocial outcomes at 12-months postpartum. Pregnant women (N?=?300; ?16?weeks pregnant) with overweight/obesity (BMI???25?kg/m2) are being recruited. Women are randomized to intervention or treatment as usual on two occasions: (1) early in pregnancy, and (2) prior to delivery, resulting in four intervention sequences. Intervention during pregnancy is designed to moderate GWG and introduce skills for management of weight as a chronic condition, while intervention in the postpartum period addresses weight loss. The primary outcome is weight at 12-months postpartum and secondary outcomes include variables of cardiometabolic health and psychosocial well-being. Analyses will evaluate the combination of prenatal and postpartum lifestyle interventions that optimizes maternal weight and secondary outcomes at 12-months postpartum. Optimizing the sequence of behavioral interventions to address specific needs during pregnancy and the first postpartum year can maximize intervention potency and mitigate longer-term cardiometabolic health risks for women.
Project description:INTRODUCTION:HIV incidence is high during pregnancy and breastfeeding with HIV acquisition risk more than doubling during pregnancy and the postpartum period compared to when women are not pregnant. The World Health Organization recommends offering pre-exposure prophylaxis (PrEP) to pregnant and postpartum women at substantial risk of HIV infection. However, maternal PrEP national guidelines differ and most countries with high maternal HIV incidence are not offering PrEP. We conducted a systematic review of recent research on PrEP safety in pregnancy to inform national policy and rollout. METHODS:We used a standard Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) approach to conduct a systematic review by searching for completed, ongoing, or planned PrEP in pregnancy projects or studies from clinicaltrials.gov, PubMed and NIH RePORTER from 2014 to March 2019. We performed a systematic review of studies that assess tenofovir disoproxil fumarate (TDF)-based oral PrEP safety in pregnant and breastfeeding HIV-uninfected women. RESULTS AND DISCUSSION:We identified 14 completed (n = 5) and ongoing/planned (n = 9) studies that evaluate maternal and/or infant outcomes following PrEP exposure during pregnancy or breastfeeding. None of the completed studies found differences in pregnancy or perinatal outcomes associated with PrEP exposure. Nine ongoing studies, to be completed by 2022, will provide data on >6200 additional PrEP-exposed pregnancies and assess perinatal, infant growth and bone health outcomes, expanding by sixfold the data on PrEP safety in pregnancy. Research gaps include limited data on (1) accurately measured PrEP exposure within maternal and infant populations including drug levels needed for maternal protection; (2) uncommon perinatal outcomes (e.g. congenital anomalies); (3) infant outcomes such as bone growth beyond one year following PrEP exposure; (4) outcomes in HIV-uninfected women who use PrEP during pregnancy and/or lactation. CONCLUSIONS:Expanding delivery of PrEP is an essential strategy to reduce HIV incidence in pregnancy and breastfeeding women. Early safety studies of PrEP among pregnant women without HIV infection are reassuring and ongoing/planned studies will contribute extensive new data to bolster the safety profile of PrEP use in pregnancy. However, addressing research gaps is essential to expanding PrEP delivery for women in the context of pregnancy.
Project description:Pregnant and postpartum women may be at increased risk of violent death including homicide and suicide relative to nonpregnant women, but US national data have not been reported since the implementation of enhanced mortality surveillance.The objective of the study was to estimate homicide and suicide ratios among women who are pregnant or postpartum and to compare their risk of violent death with nonpregnant/nonpostpartum women.Death certificates (n = 465,097) from US states with enhanced pregnancy mortality surveillance from 2005 through 2010 were used to compare mortality among 4 groups of women aged 10-54 years: pregnant, early postpartum (pregnant within 42 days of death), late postpartum (pregnant within 43 days to 1 year of death), and nonpregnant/nonpostpartum. We estimated pregnancy-associated mortality ratios and compared with nonpregnant/nonpostpartum mortality ratios to identify differences in risk after adjusting for potential levels of pregnancy misclassification as reported in the literature.Pregnancy-associated homicide victims were most frequently young, black, and undereducated, whereas pregnancy-associated suicide occurred most frequently among older white women. After adjustments, pregnancy-associated homicide risk ranged from 2.2 to 6.2 per 100,000 live births, depending on the degree of misclassification estimated, compared with 2.5-2.6 per 100,000 nonpregnant/nonpostpartum women aged 10-54 years. Pregnancy-associated suicide risk ranged from 1.6-4.5 per 100,000 live births after adjustments compared with 5.3-5.5 per 100,000 women aged 10-54 years among nonpregnant/nonpostpartum women. Assuming the most conservative published estimate of misclassification, the risk of homicide among pregnant/postpartum women was 1.84 times that of nonpregnant/nonpostpartum women (95% confidence interval, 1.71-1.98), whereas risk of suicide was decreased (relative risk, 0.62, 95% confidence interval, 0.57-0.68).Pregnancy and postpartum appear to be times of increased risk for homicide and decreased risk for suicide among women in the United States.
Project description:To compare genome-wide methylation profiles in maternal leukocyte DNA between normotensive and preeclamptic pregnant women at delivery.Age, body mass index matched case-control comparison of methylation at 27,578 cytosine-- guanine sites in 14,495 genes in maternal leukocyte DNA in women with preeclampsia (PE; n?=?14) and normotensive controls (n?=?14).PE was associated with widespread differential methylation favoring hypermethylation. Pathway analysis identified the best matched process as a neuropeptide signaling pathway (p?<?10(-5)); best matched disease as eclampsia (p?<?9.97?×?10(-20)). Significantly differentially methylated genes (GRIN2b. GABRA1. PCDHB7, and BEX1) are associated with seizures.Altered maternal leukocyte DNA methylation is associated with PE at delivery, and differential methylation of certain neuronal genes may explain the risk for eclampsia.
Project description:<h4>Background</h4>Pregnancy induces physiological adaptations that may involve, or contribute to, alterations in the genomic landscape. Pregnancy also increases the nutritional demand for choline, an essential nutrient that can modulate epigenomic and transcriptomic readouts secondary to its role as a methyl donor. Nevertheless, the interplay between human pregnancy, choline and the human genome is largely unexplored.<h4>Methodology/principal findings</h4>As part of a controlled feeding study, we assessed the influence of pregnancy and choline intake on maternal genomic markers. Healthy third trimester pregnant (n?=?26, wk 26-29 gestation) and nonpregnant (n?=?21) women were randomized to choline intakes of 480 mg/day, approximating the Adequate Intake level, or 930 mg/day for 12-weeks. Blood leukocytes were acquired at study week 0 and study week 12 for microarray, DNA damage and global DNA/histone methylation measurements. A main effect of pregnancy that was independent of choline intake was detected on several of the maternal leukocyte genomic markers. Compared to nonpregnant women, third trimester pregnant women exhibited higher (P<0.05) transcript abundance of defense response genes associated with the innate immune system including pattern recognition molecules, neutrophil granule proteins and oxidases, complement proteins, cytokines and chemokines. Pregnant women also exhibited higher (P<0.001) levels of DNA damage in blood leukocytes, a genomic marker of oxidative stress. No effect of choline intake was detected on the maternal leukocyte genomic markers with the exception of histone 3 lysine 4 di-methylation which was lower among pregnant women in the 930 versus 480 mg/d choline intake group.<h4>Conclusions</h4>Pregnancy induces transcriptional activation of the peripheral innate immune system and increases oxidative DNA damage among healthy third trimester pregnant women.
Project description:In the United States, eradication and reduction of vaccine-preventable diseases through immunization has directly increased life expectancy by reducing mortality. Although immunization is a public priority, vaccine coverage among adult Americans is inadequate. The Institute of Medicine, the Community Preventive Services Task Force, and other public health entities have called for the development of innovative programs to incorporate adult vaccination into routine clinical practice. Obstetrician-gynecologists are well suited to serve as vaccinators of women in general and more specifically pregnant women. Pregnant women are at risk for vaccine-preventable disease-related morbidity and mortality and adverse pregnancy outcomes, including congenital anomalies, spontaneous abortion, preterm birth, and low birth weight. In addition to providing direct maternal benefit, vaccination during pregnancy likely provides direct fetal and neonatal benefit through passive immunity (transplacental transfer of maternal vaccine-induced antibodies). This article reviews: 1) types of vaccines; 2) vaccines specifically recommended during pregnancy and postpartum; 3) vaccines recommended during pregnancy and postpartum based on risk factors and special circumstances; 4) vaccines currently under research and development for licensure for maternal-fetal immunization; and 5) barriers to maternal immunization and available patient and health care provider resources.
Project description:Pregnancy triggers a physiological change in weight status. Postpartum weight retention in the childbearing years can substantially alter a woman's weight gain trajectory, with several potential contributing factors identified. Most research has relied on women's recall of pre-pregnancy weight during pregnancy or later, and not considered risk factors in combination. Using measured pre-pregnancy weight, this study aimed to examine the associations of maternal postpartum weight retention with parity, pre-pregnancy BMI, excessive gestational weight gain (GWG), maternal serum vitamin D concentration and dietary Glycaemic Index in early and late pregnancy, and breastfeeding duration, including analysis of the combined impact of potentially modifiable risk factors.Prospective cohort study of 12?583 non-pregnant women aged 20-34 years in Southampton (UK) who were assessed prior to pregnancy, with those who subsequently became pregnant followed up in early and late gestation, and after delivery (n=2559 in the final sample). Linear regression models examined potential predictors of weight retention in adjusted individual and multivariate analyses, and as a risk factor score.Compared with pre-pregnancy weight, 73% of women retained some weight at 6 months postpartum (mean (s.d.): 3.5 (6.2) kg). In the adjusted multivariate model, women who were primiparous, had a lower pre-pregnancy BMI, excessive GWG, a lower early pregnancy vitamin D concentration and breastfed for <6 months had greater weight retention 6 months postpartum (P<0.05 for all variables). For each additional modifiable risk factor (excessive GWG, low vitamin D concentration in early pregnancy and short breastfeeding duration; scale 0-3), women retained an additional 2.49?kg (95% CI: 2.16, 2.82; P<0.001).Having a greater number of modifiable risk factors was associated with greater weight retention 6 months postpartum. Initiatives supporting women to target these risk factors in the years prior to, during and after pregnancy could impact on their weight gain trajectory and later risk of adverse weight-related outcomes.
Project description:OBJECTIVES: Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. METHODS: HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using (14) C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. RESULTS: Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12 h (AUC12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43-86% and 10-14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73-90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature. CONCLUSIONS: Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.