Joanne Said

The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies

Marc Rodger and colleagues report the results of their systematic review and meta-analysis of prospective cohort studies that estimated the association of maternal factor V Leiden and prothrombin gene mutation carrier status and placenta-mediated pregnancy complications.

Inherited thrombophilia polymorphisms and pregnancy outcomes in Nulliparous women

OBJECTIVE: To estimate the association between five commonly inherited thrombophilia polymorphisms and adverse pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. METHODS: Healthy nulliparous women (n=2,034) were recruited to this prospective cohort study before 22 weeks of gestation. Genotyping for factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and thrombomodulin polymorphism was performed. Clinicians caring for women were blinded to the results of thrombophilia tests. The primary composite outcome was the development of severe preeclampsia, fetal growth restriction, placental abruption, stillbirth, or neonatal death. RESULTS: Complete molecular results and pregnancy outcome data were available in 1,707 women. These complications were experienced by 136 women (8.0%). Multivariable logistic regression demonstrated two statistically significant findings. Women who carried the prothrombin gene mutation had an odds ratio of 3.58 (95% confidence interval [CI] 1.20–10.61, P=.02) for the development of the composite primary outcome. Homozygous carriers of the MTHFR 1298 polymorphism had an odds ratio of 0.26 (95% CI 0.08–0.86, P=.03). None of the other polymorphisms studied showed a significant association with the development of the primary outcome in this cohort of women. CONCLUSION: Prothrombin gene mutation confers an increased risk for the development of adverse pregnancy outcomes in otherwise asymptomatic, nulliparous women, whereas homozygosity for MTHFR 1298 may protect against these complications. The majority of asymptomatic women who carry an inherited thrombophilia polymorphism have a successful pregnancy outcome. LEVEL OF EVIDENCE: II

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).

The SOMANZ Guidelines for the Management of Hypertensive Disorders of Pregnancy 2014

Accurate blood pressure measurement is important. Attention should be paid to: • Correct posture • Cuff size • DeviceMercury sphygmomanometers remain the gold standard Self-initiated and automated blood pressure monitors may have wide intra-individual error, and their accuracy may be further compromised in preeclamptic women. Aneroid sphygmomanometers may be used but require regular recalibration to ensure accurate measurements. ABPM may help identify women with white coat hypertension.

Cardiovascular Disease Risk in the Offspring of Diabetic Women: The Impact of the Intrauterine Environment

The incidence of gestational diabetes is increasing worldwide, exposing large numbers of infants to hyperglycaemia whilst in utero. This exposure may have a long-term negative impact on the cardiovascular health of the offspring. Novel methods to assess cardiovascular status in the neonatal period are now available—including measuring arterial intima-media thickness and retinal photography. These measures will allow researchers to assess the relative impact of intrauterine exposures, distinguishing these from genetic or postnatal environmental factors. Understanding the long-term impact of the intrauterine environment should allow the development of more effective health policy and interventions to decrease the future burden of cardiovascular disease. Initiating disease prevention aimed at the developing fetus during the antenatal period may optimise community health outcomes.

Altered reference ranges for protein C and protein S during early pregnancy: Implications for the diagnosis of protein C and protein S deficiency during pregnancy

Protein S, protein C and antithrombin are important regulators of coagulation. While deficiencies of these proteins have been linked to adverse pregnancy outcomes, testing for these deficiencies during pregnancy is limited by the use of non-pregnant reference ranges and a limited understanding of the changes that occur during pregnancy. Although several small studies have previously reported on the activity of these proteins during pregnancy, potentially important changes have been overlooked by continuing to compare the activity during pregnancy with non-pregnant reference ranges. In the current study, we investigated the activity of protein S, protein C and antithrombin during the first half of pregnancy in 440 otherwise asymptomatic women who went on to have uncomplicated singleton pregnancies. Consistent with previous studies, we found that antithrombin activity remained unchanged, while protein S activity decreased significantly to a mean level of 46%. We did not observe a progressive decrease in protein S during the second trimester as several studies have suggested previously. In contrast, we observed a potentially biologically significant increase in protein C activity throughout the first 22 weeks of pregnancy. Given the physiological role of protein C, we postulate that this increase may play a role in maintaining early pregnancy through both an anticoagulant and an inflammatory regulation pathway.

Pre-eclampsia and thrombophilia

Pre-eclampsia is a major cause of perinatal and maternal morbidity and mortality worldwide. Although knowledge of the precise aetiology remains uncertain a number of risk factors have been described. Thrombophilias have been associated with pre-eclampsia in a number of studies and it is biologically plausible that they may contribute to the uteroplacental thrombosis that is frequently seen in pre-eclampsia. If this association is confirmed, there is the potential to investigate preventive treatments, including low-molecular-weight heparins, aspirin and folate.

SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014.

This guideline is an evidence based, practical clinical approach to the management of Hypertensive Disorders of Pregnancy. Since the previous SOMANZ guideline published in 2008, there has been significant international progress towards harmonisation of definitions in relation to both the diagnosis and management of preeclampsia and gestational hypertension. This reflects increasing knowledge of the pathophysiology of these conditions, as well as their clinical manifestations. In addition, the guideline includes the management of chronic hypertension in pregnancy, an approach to screening, advice regarding prevention of hypertensive disorders of pregnancy, and discussion of recurrence risks and long term risk to maternal health. The literature reviewed included the previous SOMANZ Hypertensive Disorders of Pregnancy guideline from 2008 and its reference list, plus all other published National and International Guidelines on this subject. Medline, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Registry of Controlled Trials (CCRCT), National Institute for Health and Care Excellence (NICE) Evidence Search, and Database of Abstracts and Reviews of Effects (DARE) were searched for literature published between January 2007 and March, 2014.

Inherited thrombophilias and adverse pregnancy outcomes: a case-control study in an Australian population.

Objective. The primary aim of this study was to examine the association between inherited thrombophilias and adverse pregnancy outcomes in an Australian population. Design. Case–control study. Setting. Two Australian tertiary level maternity hospitals. Population. One hundred and fifteen cases with adverse pregnancy outcomes, comprising severe pre‐eclampsia (n=45), fetal growth restriction (n=44), placental abruption (n=16) or stillbirth (n=10), and 115 controls matched for ethnicity, parity and maternal age. Methods. Genotyping for factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase 677 and 1298 and thrombomodulin polymorphism was performed using Taqman assays in an ABI prism 7700 Sequencer. Pregnancy outcome data were extracted from the medical record at the time of recruitment. Main Outcome Measures. Prevalence of inherited thrombophilias in women with adverse pregnancy outcomes and matched control women. Results. There were no differences in baseline characteristics between cases and control women, apart from duration of gestation and neonatal birthweight. Overall, there was no significant difference in the prevalence of these inherited thrombophilia polymorphisms between cases and control women. Heterozygosity for the factor V Leiden mutation, however, was significantly associated with an increased risk of both stillbirth (odds ratio 9.33, 95% confidence interval 1.36–64.15, p=0.02) and placental abruption (odds ratio 8.62, 95% confidence interval 1.57–47.17, p=0.01). Conclusions. Overall, this study does not support a significant association between inherited thrombophilia polymorphisms and adverse pregnancy outcomes. Our two statistically significant findings should be interpreted with caution given the small number of patients in these subgroups (10 stillbirths and 16 placental abruption cases) and the wide confidence intervals.

The Expression of Placental Proteoglycans in Pre-Eclampsia

Background/Aims: Pre-eclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality. PE is defined clinically as the onset of maternal hypertension and proteinuria following 20 weeks of gestation. It is associated with altered maternal uterine decidual spiral artery remodelling, which may lead to reduced blood flow and increased thrombosis within the uteroplacental vasculature. Proteoglycans (PGs) are macromolecules which have (in combination with glycosaminoglycans) important anticoagulant roles in vascular endothelial environments, including the uteroplacental circulation. The hypothesis under consideration in this study was that differential expression of placental PGs may be associated with PE. Methods: PE and control placental samples were collected with ethics approval and patient consent. RNA and protein were extracted and real-time PCR and Western immunoblotting were performed to determine the expression of the PGs in the samples. Results: Of the nine PGs investigated, none showed increased expression, whereas the mRNA and protein expression of five of them was significantly decreased in the placentae of pre-eclamptic women compared to gestation-matched controls. Conclusion: Therefore, the results of this study support the hypothesis that a placental PG deficiency may contribute to the placental thrombotic lesions characteristic of PE.