Variation in endoglin pathway genes is associated with preeclampsia: a case-control candidate gene association study.

BACKGROUND: Preeclampsia is a hypertensive, multi-system pregnancy disorder whose pathophysiology remains unclear. Elevations in circulating soluble endoglin (sENG) and placental/blood ENG mRNA expression antedate the clinical onset of preeclampsia. This study investigated if endoglin (ENG) pathway genetic variation was also associated with the development of preeclampsia. METHODS: We used a case-control candidate gene association design. Data from 355 white (181 preeclampsia cases/174 controls) and 60 black (30 preeclampsia cases/30 controls) women matched on ancestry, age, and parity were analyzed. Tagging single nucleotide polymorphisms (tSNPs) and potentially functional SNPs in ENG, TGFß1, TGFßR1, ALK1, and TGFßR2 were genotyped with iPLEX® and TaqMan®. Chi-square or Fisher's exact tests were used to conduct allele/genotype/haplotype tests in white/black subgroups separately. Odds ratios were computed with binary logistic regression for tSNPs with significant genotype tests. RESULTS: Of the 49 SNPs evaluated, variation in two ENG tSNPs (rs11792480, rs10121110) and one TGFßR2 tSNP (rs6550005) was associated with preeclampsia in white women (P <0.05, each). In black women, variation in two TGFß1 tSNPs (rs4803455, rs4803457), one TGFßR1 tSNP (rs10739778), and three TGFßR2 tSNPs (rs6550005, rs1346907, rs877572) was associated with preeclampsia (P <0.05, each). Further evaluation of ENG tSNP rs10121110 revealed that white women inheriting the AA genotype were 2.29 times more likely to develop preeclampsia compared to the GG genotype (P = 0.008, [99% CI: 1.02 to 5.13]). For black women, similar evaluation of TGFß1 tSNP rs4803457 revealed women inheriting the CT genotype were 7.44 times more likely to develop preeclampsia than those with the CC genotype (P = 0.005, [99% CI: 1.19 to 46.41]). CONCLUSIONS: ENG pathway genetic variation is associated with preeclampsia. Different ENG pathway genes may be involved in preeclampsia development among white and black women. Additional studies are needed to validate these findings and to determine if genetic variation in ENG pathway genes impacts ENG and sENG levels in preeclampsia.

Bridging global gene expression candidates in first trimester placentas with susceptibility loci from linkage studies of preeclampsia.

Preeclampsia is as a leading cause of maternal and perinatal morbidity and mortality. Prevention, early identification, and individualized treatments may become feasible if reliable early biomarkers can be developed. Towards a systems biology framework, this review synthesizes prior linkage studies and genome scans of preeclampsia with candidates identified in a global gene expression microarray analysis of chorionic villus sampling (CVS) specimens from women who subsequently developed preeclampsia. Nearly 40% of these CVS candidate genes occurred in previously identified susceptibility loci for preeclampsia. Integration of genetic epidemiologic and functional gene expression data could help to elucidate preeclampsia as a complex disease resulting from multiple maternal and fetal/placental factors that each contributes a greater or lesser effect. These loci and related candidate genes are set to substantially improve insights into the first trimester pathogenesis of this pregnancy disorder.

Gene expression of four targets in situ of the first trimester maternal-fetoplacental interface.

EPAS1, FSTL3, IGFBP1, and SEMA3C were localized to determine whether expression is decidual, trophoblastic, or both in the human first trimester maternal-fetoplacental interface. Identified on global genome-wide microarray analysis of chorionic villus sampling tissues in preclinical preeclampsia, these targets were predicted to interact by bioinformatics pathways analysis. In situ hybridization (ISH) with mRNA of each gene was conducted in 10 cases of archived first trimester termination tissues. Randomly selected areas of cells by tissue type yielded the relative proportion of cells expressing mRNA signal in decidual and fetoplacental sites. Data were analyzed using Shapiro-Wilk and Kruskal-Wallis tests (p ≤ .05). The average gestational age was 10.2 weeks. Expression signal for each gene differed by cell type (p < .001). FSTL3 expression was 17 times higher in cells of anchoring columns than areas of decidua without ISH signal. SEMA3C was three times higher in cells of anchoring columns than in decidua. EPAS1 was 1.31 times higher in cells of anchoring columns than in areas of decidua. IGFBP1 was 20 times higher in some decidua versus cells in anchoring columns or villous trophoblast. While all targets were expressed by both maternal and fetoplacental cells, our localizations identified which compartment had relatively higher expression of each gene.

Introducing systems biology for nursing science.

Systems biology expands on general systems theory as the "omics'' era rapidly progresses. Although systems biology has been institutionalized as an interdisciplinary framework in the biosciences, it is not yet apparent in nursing. This article introduces systems biology for nursing science by presenting an overview of the theory. This framework for the study of organisms from molecular to environmental levels includes iterations of computational modeling, experimentation, and theory building. Synthesis of complex biological processes as whole systems rather than isolated parts is emphasized. Pros and cons of systems biology are discussed, and relevance of systems biology to nursing is described. Nursing research involving molecular, physiological, or biobehavioral questions may be guided by and contribute to the developing science of systems biology. Nurse scientists can proactively incorporate systems biology into their investigations as a framework for advancing the interdisciplinary science of human health care. Systems biology has the potential to advance the research and practice goals of the National Institute for Nursing Research in the National Institutes of Health Roadmap initiative.

A comparison of circulating TNF-alpha in obese and lean women with and without preeclampsia.

OBJECTIVES: We hypothesized that TNF-alpha would be higher in obese versus lean women with preeclampsia. METHODS: Total plasma TNF-alpha was measured in a nested case-control study of 123 nulliparous lean and obese control women and women with preeclampsia. RESULTS: Adjusted mean TNF-alpha concentrations were 0.97 +/- 0.11 (pg/mL +/- SEM) in lean controls, 1.01 +/- 0.10 in obese controls, 1.43 +/- 0.11 in lean women with preeclampsia and 1.16 +/- 0.11 in obese women with preeclampsia. Pregnancy outcome was the single predictor of TNF-alpha concentration in the general linear regression model (p = 0.04). CONCLUSION: TNF-alpha concentration was higher in preeclampsia compared with control subjects. Obesity was not associated with higher TNF-alpha concentrations in either preeclampsia or control subjects.

Microarray technology applied to the complex disorder of preeclampsia.

Preeclampsia is a life-threatening perinatal complication with unknown etiology. Microarray technology has characterized global gene expression in complex disorders such as preeclampsia. Nursing research and future practice may incorporate findings from microarray analyses to identify susceptibility to and prevent disease, to diagnose early, and to design and monitor personalized therapies. This overview of microarray technology, with emphasis on how it can inform genomics of preeclampsia, may provide concepts to improve future maternal-neonatal nursing care.

Associating Symptom Phenotype and Genotype in Preeclampsia.

Preeclampsia is a complex genetic disorder with an incompletely understood pathogenesis. Its phenotype may be better elucidated by integrating symptoms. This study aimed to identify symptoms by gestational age and associations with novel preeclampsia candidate genes. Women with a history of preeclampsia recruited from The Preeclampsia Registry completed clinical/demographic, symptom surveys and provided medical records. DNA extracted from saliva was processed with multiplexed assays for eight single-nucleotide polymorphisms (SNPs) selected to tag candidate genes and/or located in symptom susceptibility regions. Groups with versus without symptoms were compared using χ2. Associations between SNPs and symptoms were analyzed as genotype categories and presence/absence of the variant allele. Logistic regression modeling was conducted with exploratory p = .05. In 114 participants, 113 reported at least 1 of the 18 symptoms. Symptoms varied by trimester. Nine symptoms were associated with seven SNPs. Visual disturbances were associated with three SNPs and nausea/vomiting with two SNPs. Modeling adjustment for maternal age and parity resulted in 15 associations between 9 symptoms and 8 SNPs. Medical records demonstrated 100% concordance with self-reported diagnosis and 48% concordance with reported severity. Findings indicated novel symptom-genotype associations in preeclampsia. The small sample was self-selected, but results support future studies including medical records review. When validated, these results may lead to holistic phenotyping of women to characterize subsets of preeclampsia. This approach may optimize health in pregnancy and later life for mothers and offspring through prediction, prevention, and precision nursing care.

Women's and providers' experiences of breech presentation in Jamaica: a qualitative study.

BACKGROUND: Most research on breech relates to medical management of the malpresentation. Little is known about women's or providers' experiences of breech, an obstetrical complication. OBJECTIVES: This study aims to increase the understanding of women's and providers' experiences of breech presentation and to understand the effects of context on these experiences. METHODS: A qualitative descriptive research was conducted in a rural health district of Jamaica. Nine postpartum women who birthed singleton live born breech infants in the past year and five experienced obstetric care providers consented to participate. Content analysis was conducted with data from one-time interviews, observations, and hand searches of maternity ward delivery logs. Member checking was conducted with successive participants and Jamaican health care providers. RESULTS: Findings included realizing the baby was breech, interpreting what breech meant, reacting to breech presentation, and identifying the impact of breech. Rates of breech births were less than 1%. CONCLUSIONS: Symbolic interaction can guide nursing and midwifery education, practice and research of breech presentation. Nurses and midwives can identify and teach women and their significant others about breech and its risks.

Follistatin-like 3 across gestation in preeclampsia and uncomplicated pregnancies among lean and obese women.

The purpose of this study was to examine circulating maternal follistatin-like 3 (FSTL-3) by gestational age and obesity in pregnancy and preeclampsia. FSTL-3 was quantified in maternal plasma collected in each trimester from prepregnancy body mass index-determined groups: 15 lean and 24 obese controls and 20 obese women who developed preeclampsia. Repeated measures mixed models and logistic regression were conducted (P ≤ .05). FSTL-3 was not related to maternal adiposity. FSTL-3 changed across pregnancy in lean controls and obese preeclampsia but not in obese controls. FSTL-3 was higher in preeclampsia in the second trimester compared to lean controls and in the third trimester compared to both control groups. Elevated FSTL-3 at mid-gestation was associated with an increased odds of preeclampsia (odds ratio 3.15; 95% confidence interval 1.19-8.36; P = .02). Elevated FSTL-3 concentrations were attributable to preeclampsia and were associated with increased likelihood of later developing preeclampsia, suggesting further study as a biomarker prior to clinically evident disease.

Genetics and preterm birth.

Although the etiology of preterm birth is incompletely understood, phenotype classifications combined with recent technologies such as genome-wide association studies and next-generation sequencing could lead to discovering genotypes associated with preterm birth. Identifying genetic contributions will allow for genetic screening tests to predict or detect pregnancies with potential for preterm birth. In this article we discuss current knowledge regarding phenotype classifications, genotypes, and their associations with preterm birth.

Variations in discovery-based preeclampsia candidate genes.

Preeclampsia is a common and potentially lethal pregnancy disorder with lifelong increased risk of cardiovascular disease in survivors. Our prior global gene expression microarray analysis led to a novel set of 36 candidates in first trimester placentas of women who subsequently developed preeclampsia. In this report, we present preliminary studies demonstrating biomarkers of genotype and methylation variations in a subset of these candidate genes in maternal leukocyte and fetoplacental DNA of 28 case and 27 control dyads. We tested 84 single nucleotide polymorphisms (SNPs) using MassArray iPLEX and 50 CpG sites using EpiTYPER assays. Promising prediction modeling was identified with 25 SNPs selected using Fisher's exact tests (p ≤ 0.05) and 20 CpG sites selected on fold change. Genotype Distribution Analysis identified SNP variations that differed between nine paired cases versus paired controls. The findings validate the examined candidate genes and support feasibility of methods for further biomarker development. The integrative approach that was implemented begins to translate the 36 candidates toward clinical utility as a screening modality for preeclampsia.

Development of high-fidelity simulated clinical experiences for baccalaureate nursing students.

High-fidelity simulators offer a teaching tool for nurse educators to provide lifelike simulated clinical experiences for baccalaureate nursing students. A group of faculty teaching a variety of clinical courses followed similar steps within frameworks of the American Association of Colleges of Nursing essentials and education theories to create case scenarios. The benefits of simulation experiences for students are discussed and a template for the nurse educator is provided to help develop simulations. This system is illustrated by an example from a high-risk antepartum obstetric scenario.

Is there evidence of separate inflammatory or metabolic forms of preeclampsia?

OBJECTIVES: To examine whether high insulin resistance versus high inflammation identifies subtypes of preeclampsia. METHODS: A cytokine panel, glucose and insulin were measured in 37 preeclampsia plasma samples. Wilcoxon rank sum assessed median concentration of HOMA(IR) by pro-inflammatory:anti-inflammatory ratio. Regression stratifying by BMI and preterm birth was conducted. RESULTS: There was no difference in median HOMA(IR) by the pro-inflammatory:anti-inflammatory ratio (p = 0.16). No subsets scatterplot clusters emerged. A positive correlation between HOMAlog and the ratio was significant (p = 0.04). CONCLUSIONS: No dichotomous subsets of preeclampsia by inflammation versus insulin resistance were detected. Contrary to our hypothesis, insulin resistance was higher as inflammation increased in preeclampsia.

Gene expression in first trimester preeclampsia placenta.

BACKGROUND: The goal of this study was to further validate eight candidate genes identified in a microarray analysis of first trimester placentas in preeclampsia. MATERIAL AND METHOD: Surplus chorionic villus sampling (CVS) specimens of 4 women subsequently diagnosed with preeclampsia (PE) and 8 control women (C) without preeclampsia analyzed previously by microarray and 24 independent additional control samples (AS) were submitted for confirmatory studies by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Downregulation was significant in FSTL3 in PE as compared to C and AS (p = .04). PAEP was downregulated, but the difference was only significant between C and AS (p = .002) rather than between PE and either of the control groups. Expression levels for CFH, EPAS1, IGFBP1, MMP12, and SEMA3C were not statistically different among groups, but trends were consistent with microarray results; there was no anti-correlation. S100A8 was not measurable in all samples, probably because different probes and primers were needed. CONCLUSIONS: This study corroborates reduced FSTL3 expression in the first trimester of preeclampsia. Nonsignificant trends in the other genes may require follow-up in studies powered for medium or medium/large effect sizes. qRT-PCR verification of the prior microarray of CVS may support the placental origins of preeclampsia hypothesis. Replication is needed for the candidate genes as potential biomarkers of susceptibility, early detection, and/or individualized care of maternal-infant preeclampsia.

Participating in research for pregnancy complicated by breech.

Participant-centered clinical research is essential for client-centered evidence-based health care in pregnancy. Breech malpresentation can obstruct labor, contributing to maternal mortality. This qualitative study of women's and providers' experience of breech led to five categories of themes related to participant-centered research: participation in this study, factors impeding women's participation, factors impeding clinical research, development of a participant-centered intervention, and improvement of a pregnancy research infrastructure. The findings contribute to understanding research participation during pregnancy. Gauging research protocols to fit questions of concern, women's and providers' experiences, and practice settings supports participant-centered pregnancy risk reduction research that could decrease maternal mortality.

Clinical implications from an exploratory study of postural management of breech presentation.

The results from an exploratory study of the effectiveness of maternal knee-chest posture for producing cephalic version of breech presentation are shown. Methods are briefly described and clinical implications are presented. Among 25 women, fewer who performed the maternal knee-chest postural intervention experienced fetal cephalic version than women in the control group who did nothing to influence breech presentation. Despite limitations of the underpowered findings, trends in the data may indicate that parity and gestational age were potentially relevant covariates of version. Postural management is not an evidence-based practice. This exploratory study indicates that maternal knee-chest posture may work opposite to the expected direction, but the small sample size precludes generalizations about efficacy of knee-chest postural management. At least one adequately powered trial that controls for parity and gestational age is needed to determine whether knee-chest postural management results in no effect, a small, or small to moderate clinically significant effect.

Maternal posture for cephalic version of breech presentation: a review of the evidence.

BACKGROUND: Maternal posture is commonly recommended to promote cephalic version of breech presentation during pregnancy, but the few studies conducted to examine the efficacy of this obstetric practice are inconclusive. The purpose of this systematic review was to evaluate the research evidence base for postural management of breech presentation. METHODS: This review critically examined the research on maternal posture for breech presentation using guidelines from the third United States Preventive Services Task Force. Database searches were conducted of Ovid Medline, Cumulative Index of Nursing and Allied Health Literature, PubMed, and Cochrane Database of Systematic Reviews, using the keywords "pregnancy," "maternal posture," "maternal position," "postural management," "breech," "presentation." Hand searches were conducted on reference citations from databases, and all research articles, commentaries, and reports of clinical cases were included. RESULTS: Conceptual and methodological issues in the individual studies posed threats to internal validity in each study. Interpretation of the nonsignificant results in the research reports is debatable because the randomized controlled trials were underpowered, and flaws in each study challenged validity of the results. Meta-analysis of previous findings may be inappropriate. CONCLUSIONS: Further research based on explicit theory and improved methods, including sufficient sample size, is needed to determine whether maternal posture promotes cephalic version for pregnant women with breech presentation.