Christine East

Genome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene

Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58×10−7, OR = 1.57; rs12711941, p = 4.26×10−7, OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11×10−7). These SNPs reside in an intergenic region less than 15 kb downstream from the 3′ terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r2 = 0.92), but not (r2<0.80) with any other genotyped SNP ±250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.48×10−7, OR = 1.59) in strong LD with the two significant GWAS SNPs (r2>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).

Update on intrapartum fetal pulse oximetry

This article examines the current status of fetal pulse oximetry (FPO) as a means of intrapartum assessment of fetal wellbeing.

Factors Affecting Maternal Perception of Fetal Movement

Maternal perception of fetal movement is an important screening method for fetal well-being, as decreased fetal movement is associated with a range of pregnancy pathologies and poor pregnancy outcomes. An understanding of factors that may affect perception could help clinicians to determine the importance of maternal reports of decreased fetal movement. This review considers factors that may affect maternal perception of fetal movement and the sensitivity of maternal perception of fetal movements in comparison with ultrasound and other objective methods of movement detection. There is conflicting evidence on whether parity, gestational age, overweight and obesity, and placental location affect perception. This may be related to the small sample sizes of available studies and lack of consistent definitions of factors that may affect the ability of mothers to perceive movement. There is some evidence that psychological factors and duration of fetal movement may affect perception, and that strong movements and those including trunk movement are more likely to be perceived. The proportion of fetal breathing movements that mothers perceive has not been investigated. Research is also lacking as to whether there needs to be contact of fetal part(s) with maternal structures for movement to be perceived, and whether fetal position, amniotic fluid volume, maternal position, sedatives, or other drugs affect movement perception. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to define variables that may affect a mothers ability to perceive fetal movements, describe different methods of fetal movement counting, and summarize how fetal movements may be related to fetal well-being.

Fate Of Abstracts Published In The Proceedings Of The First Annual Perinatal Society Of Australia And New Zealand Congress In 1997

Objectives:  To examine the fate of research presented at the first annual Perinatal Society of Australia and New Zealand (PSANZ) Congress in 1997, by determining: the rate of publication in peer‐reviewed biomedical journals; publication rate by discipline; journals in which work was published; concordance for aims, conclusions, authors and number of study subjects; and time from presentation to publication.

Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q

Background Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. Methodology/Principal Findings The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord-Trøndelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women). Conclusion/Significance TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia pathogenesis, and propose the rs16972194 variant as a candidate for further functional evaluation.

Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease

Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics, SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P = 0.0027), a synonymous LRP1B SNP (rs35821928, P = 0.0001), an UTR-3 RND3 SNP (rs115015150, P = 0.0024) and a missense GCA SNP (rs17783344, P = 0.0020). We replicated the LCT SNP association (P = 0.02) and observed a borderline association for the GCA SNP (P = 0.07) in an independent Australian case-control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover, these four SNP associations could not be replicated in two additional case-control populations from Norway and Finland. These four SNPs, however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of pre-eclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVD-related risk factors.

Fetal Oxygen Saturation Monitoring in Labour: An Analysis of 118 Cases

Summary: Fetal oxygen saturation (FSpO2) was recorded during labour to determine the relationship between FSpO2 and indicators of fetal well‐being, including umbilical blood gases, xanthine (X), hypoxanthine (Hx) and Apgar scores. This is one of me largest reported series of fetal pulse oximetry, with 118 fetuses monitored for over 329 hours. Mean FSpO, for all cases was 46.9% (SD=9.1%). There was no correlation between FSpO, during the last 10 minutes of monitoring and arterial pH, Hx or X. A mean FSpO2, ≤ 30% was associated with a 5 minute Apgar score of ≤ 7 in the majority of cases. One fetus had a mean FSpO2, <30% during the final 10 minutes of monitoring and an umbilical arterial pH<7.20, while there were 10 fetuses with an umbilical arterial pH<7.20, and mean FSpO2, ≥ 30%. As these numbers are small, a larger series is necessary to further characterize the small number of fetuses who are significantly hypoxic.

Mindfulness and perinatal mental health: A systematic review.

BACKGROUND Perinatal stress is associated with adverse maternal and infant outcomes. Mindfulness training may offer a safe and acceptable strategy to support perinatal mental health. AIM To critically appraise and synthesise the best available evidence regarding the effectiveness of mindfulness training during pregnancy to support perinatal mental health. METHODS The search for relevant studies was conducted in six electronic databases and in the grey literature. Eligible studies were assessed for methodological quality according to standardised critical appraisal instruments. Data were extracted and recorded on a pre-designed form and then entered into Review Manager. FINDINGS Nine studies were included in the data synthesis. It was not appropriate to combine the study results because of the variation in methodologies and the interventions tested. Statistically significant improvements were found in small studies of women undertaking mindfulness awareness training in one study for stress (mean difference (MD) -5.28, 95% confidence intervals (CI) -10.4 to -0.42, n=22), two for depression (for example MD -5.48, 95% CI -8.96 to -2.0, n=46) and four for anxiety (for example, MD -6.50, 95% CI -10.95 to -2.05, n=32). However the findings of this review are limited by significant methodological issues within the current research studies. CONCLUSION There is insufficient evidence from high quality research on which to base recommendations about the effectiveness of mindfulness to promote perinatal mental health. The limited positive findings support the design and conduct of adequately powered, longitudinal randomised controlled trials, with active controls.

Risk stratification in early pregnancy for women at increased risk of gestational diabetes

AIM To evaluate the addition of fasting glucose and lipids to a simple, validated risk prediction tool for gestational diabetes (GDM) applied in early pregnancy. METHODS Women at risk of developing GDM on a validated risk prediction tool were recruited in early pregnancy into a large randomised controlled trial. Outcome measures included fasting biochemical markers (glucose, lipids) at 12-15 weeks gestation and GDM diagnosis (28 weeks gestation). Multivariable logistic regression was used to identify additional predictive biochemical variables for GDM, with corresponding receiver operator characteristic (ROC) curves generated. Unadjusted and adjusted models were derived for both the Australasian Diabetes in Pregnancy (ADIPS) and the International Association for Diabetes in Pregnancy Study Group (IADPSG) GDM diagnostic criteria. RESULTS 51 (23%) Women were diagnosed with GDM based on ADIPS criteria, with 60 (30%) diagnosed based on IADPSG criteria. In all four regression models, fasting glucose was the strongest predictor for GDM development with an odds ratio range of 4.7-6.3 (ADIPS) and 8.8-10 (IADPSG). ROC curves revealed an area under the curve of 0.79 (95% CI: 0.72-0.86) for ADIPS criteria and 0.83 (95% CI: 0.77-0.90) for IADPSG criteria for adjusted models. CONCLUSIONS In a two-step approach, when applied with a validated risk prediction tool, fasting glucose in early pregnancy was predictive of GDM and incrementally improved risk identification, presenting potential for an early pregnancy, GDM risk screening strategy for streamlining of pregnancy care and opportunity for preventive intervention.

Passive detection of accelerometer-recorded fetal movements using a time-frequency signal processing approach

This paper describes a multi-sensor fetal movement (FetMov) detection system based on a time-frequency (TF) signal processing approach. Fetal motor activity is clinically useful as a core aspect of fetal screening for well-being to reduce the current high incidence of fetal deaths in the world. FetMov are present in early gestation but become more complex and sustained as the fetus progresses through gestation. A decrease in FetMov is an important element to consider for the detection of fetal compromise. Current methods of FetMov detection include maternal perception, which is known to be inaccurate, and ultrasound imaging which is intrusive and costly. An alternative passive method for the detection of FetMov uses solid-state accelerometers, which are safe and inexpensive. This paper describes a digital signal processing (DSP) based experimental approach to the detection of FetMov from recorded accelerometer signals. The paper provides an overview of the significant measurement and signal processing challenges, followed by an approach that uses quadratic time-frequency distributions (TFDs) to appropriately deal with the non-stationary nature of the signals. The paper then describes a proof-of-concept with a solution consisting of a detection method that includes (1) a new experimental set-up, (2) an improved data acquisition procedure, and (3) a TF approach for the detection of FetMov including TF matching pursuit (TFMP) decomposition and TF matched filter (TFMF) based on high-resolution quadratic TFDs. Detailed suggestions for further refinement are provided with preliminary results to establish feasibility, and considerations for application to clinical practice are reviewed.