Family history of pre-eclampsia and cardiovascular disease as risk factors for pre-eclampsia: the GenPE case-control study.

Objective: To determine whether family history of pre-eclampsia and cardiovascular disease is consistently associated with the occurrence of pre-eclampsia sub-phenotypes and fetal growth restriction (FGR).Material and Methods: We conducted a case-control study in which cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight Colombian cities between 2000 and 2012. Odds of pre-eclampsia among women with a positive family history of pre-eclampsia or cardiovascular disease were compared to women without affected relatives (logistic regression modeling and multinomial logistic regression model [Ajusted]).Results: A total of 3510 pre-eclampsia cases and 4512 controls with data on family history of pre-eclampsia were included in analyses. A subsample of 3086 cases and 3888 controls also provided information on family history of cardiovascular disease. Women whose mothers had pre-eclampsia had 3.38 (95% CI 2.89, 3.96) higher odds than those who did not, and having an affected sister increased pre-eclampsia odds by 2.43 (95% CI 2.02, 2.93). The effect of having both mother and sister affected with pre-eclampsia was stronger than the two independent risk factors (OR 4.17 [95% CI 2.60, 6.69]). Women with parental history of cardiovascular disease also had an increased risk of pre-eclampsia (OR 1.58 [95% CI 1.24, 2.01]).Conclusions: Family history of pre-eclampsia increased the risk of PE. The impact of family history of cardiovascular disease on pre-eclampsia was more conservative, but serves to support the hypothesis that pre-eclampsia may reflect the premature exposure of underlying cardiovascular dysfunction, precipitated by the stress test of pregnancy.

Preeclampsia and Cardiovascular Disease in a Large UK Pregnancy Cohort of Linked Electronic Health Records: A CALIBER Study.

BACKGROUND: The associations between pregnancy hypertensive disorders and common cardiovascular disorders have not been investigated at scale in a contemporaneous population. We aimed to investigate the association between preeclampsia, hypertensive disorders of pregnancy, and subsequent diagnosis of 12 different cardiovascular disorders. METHODS: We used linked electronic health records from 1997 to 2016 to recreate a UK population-based cohort of 1.3 million women, mean age at delivery 28 years, with nearly 1.9 million completed pregnancies. We used multivariable Cox models to determine the associations between hypertensive disorders of pregnancy, and preeclampsia alone (term and preterm), with 12 cardiovascular disorders in addition to chronic hypertension. We estimated the cumulative incidence of a composite end point of any cardiovascular disorder according to preeclampsia exposure. RESULTS: During the 20-year study period, 18 624 incident cardiovascular disorders were observed, 65% of which had occurred in women under 40 years. Compared to women without hypertension in pregnancy, women who had 1 or more pregnancies affected by preeclampsia had a hazard ratio of 1.9 (95% confidence interval 1.53-2.35) for any stroke, 1.67 (1.54-1.81) for cardiac atherosclerotic events, 1.82 (1.34-2.46) for peripheral events, 2.13 (1.64-2.76) for heart failure, 1.73 (1.38-2.16) for atrial fibrillation, 2.12 (1.49-2.99) for cardiovascular deaths, and 4.47 (4.32-4.62) for chronic hypertension. Differences in cumulative incidence curves, according to preeclampsia status, were apparent within 1 year of the first index pregnancy. Similar patterns of association were observed for hypertensive disorders of pregnancy, while preterm preeclampsia conferred slightly further elevated risks. CONCLUSIONS: Hypertensive disorders of pregnancy, including preeclampsia, have a similar pattern of increased risk across all 12 cardiovascular disorders and chronic hypertension, and the impact was evident soon after pregnancy. Hypertensive disorders of pregnancy should be considered as a natural screening tool for cardiovascular events, enabling cardiovascular risk prevention through national initiatives.

Lipid profile, plasma apolipoproteins, and pre-eclampsia risk in the GenPE case-control study.

BACKGROUND AND AIMS: Pre-eclampsia constitutes a leading cause of maternal and perinatal morbidity and mortality. Pre-eclampsia susceptibility is believed to be associated with altered lipid profiles and abnormal lipid metabolism via lipid peroxidation that leads to endothelial dysfunction. The goal of this study was to evaluate the association of maternal blood lipid and apolipoprotein levels with pre-eclampsia in a large-scale study. METHODS: Using data from a large case-control study (1366 cases of pre-eclampsia and 1741 normotensive controls), the association between the distributions of eight lipid fractions and pre-eclampsia risk was evaluated using adjusted logistic regression models. Pre-eclampsia was defined as blood pressure ≥140/90 mmHg and proteinuria ≥300 mg/24 h (>1 + dipstick). Sub-group analyses were conducted for early (<34 weeks) and late (≥37 weeks) pre-eclampsia, estimating the effect of 1 standard deviation increase in log-transformed lipid fraction levels in adjusted multinomial regression models. RESULTS: After adjustment for potential confounders, concentrations of triglycerides, apolipoprotein E (ApoE) and the relationship between apolipoprotein B and A1 (ApoB/ApoA1) showed the strongest associations with pre-eclampsia, particularly for those cases with an early onset. CONCLUSIONS: Higher levels of triglycerides, ApoE and the ApoB/ApoA1 ratio are associated with an increased risk of pre-eclampsia. Further studies that allow for a causal inference are needed to confirm or refute the aetiological role of blood lipids in pre-eclampsia.

Enrichment of Clinically Relevant Organisms in Spontaneous Preterm-Delivered Placentas and Reagent Contamination across All Clinical Groups in a Large Pregnancy Cohort in the United Kingdom.

In this study, differences in the placental microbiota from term and preterm deliveries in a large pregnancy cohort in the United Kingdom were studied by using 16S-targeted amplicon sequencing. The impacts of contamination from DNA extraction, PCR reagents, and the delivery itself were also examined. A total of 400 placental samples from 256 singleton pregnancies were analyzed, and differences between spontaneous preterm-, nonspontaneous preterm-, and term-delivered placentas were investigated. DNA from recently delivered placentas was extracted, and screening for bacterial DNA was carried out by using targeted sequencing of the 16S rRNA gene on the Illumina MiSeq platform. Sequenced reads were analyzed for the presence of contaminating operational taxonomic units (OTUs) identified via sequencing of negative extraction and PCR-blank samples. Differential abundances and between-sample (beta) diversity metrics were then compared. A large proportion of the reads sequenced from the extracted placental samples mapped to OTUs that were also found for negative extractions. Striking differences in the compositions of samples were also observed, according to whether the placenta was delivered abdominally or vaginally, providing strong circumstantial evidence for delivery contamination as an important contributor to observed microbial profiles. When OTU- and genus-level abundances were compared between the groups of interest, a number of organisms were enriched in the spontaneous preterm-delivery cohort, including organisms that have been associated previously with adverse pregnancy outcomes, specifically Mycoplasma spp. and Ureaplasma spp. However, analyses of the overall community structure did not reveal convincing evidence for the existence of a reproducible "preterm placental microbiome."IMPORTANCE Preterm birth is associated with both psychological and physical disabilities and is the leading cause of infant morbidity and mortality worldwide. Infection is known to be an important cause of spontaneous preterm birth, and recent research has implicated variation in the "placental microbiome" in the risk of preterm birth. Consistent with data from previous studies, the abundances of certain clinically relevant species differed between spontaneous preterm- and nonspontaneous preterm- or term-delivered placentas. These results support the view that a proportion of spontaneous preterm births have an intrauterine-infection component. However, an additional observation from this study was that a substantial proportion of sequenced reads were contaminating reads rather than DNA from endogenous, clinically relevant species. This observation warrants caution in the interpretation of sequencing outputs from low-biomass samples such as the placenta.

Genetic Analyses in Small-for-Gestational-Age Newborns.

Context: Small for gestational age (SGA) can be the result of fetal growth restriction, which is associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the current study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more copy number variations (CNVs) and disturbed methylation and sequence variants may be present in genes associated with fetal growth. Design: A prospective cohort study of subjects with a low birth weight for gestational age. Setting: The study was conducted at an academic pediatric research institute. Patients: A total of 21 SGA newborns with a mean birth weight below the first centile and a control cohort of 24 appropriate-for-gestational-age newborns were studied. Interventions: Array comparative genomic hybridization, genome-wide methylation studies, and exome sequencing were performed. Main Outcome Measures: The numbers of CNVs, methylation disturbances, and sequence variants. Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern, and one sequence variant explaining SGA. Additional methylation disturbances and sequence variants were present in 20 patients. In 19 patients, multiple abnormalities were found. Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We concluded that CNVs, methylation disturbances, and sequence variants all contribute to prenatal growth failure. These genetic workups can be an effective diagnostic approach in SGA newborns.

A new biological and clinical resource for research into pregnancy complications: The Baby Bio Bank.

About 20% of pregnancies are affected by some form of complication. Research has shown that anomalies in implantation, development, and growth of the fetus; ineffective nutrient exchange between mother and fetus due to placental dysfunction; and maternal problems such as hypertension or infection during pregnancy can all lead to adverse pregnancy outcomes. However, the molecular aetiology of such events remains poorly understood. Fetal growth restriction (FGR), recurrent miscarriage (RM), preterm birth (PTB), and pre-eclampsia (PE) are the most common pregnancy complications encountered in the UK and these outcomes can result in an array of morbidities in both mother and baby, and in the most severe cases in mortality. We need to know more about normal pregnancy and where the important triggers are for failure. This prompted us to collect a large set of biological samples with matching clinical data from over 2500 normal and abnormal pregnancies, for use in research into these conditions. This paper outlines the nature of these sample sets and their availability to academia and industry, with the intention that their widespread use in research will make significant contributions to the improvement of maternal and fetal health worldwide (http://www.ucl.ac.uk/tapb/sample-and-data-collections-at-ucl/biobanks-ucl/baby-biobank).

The role and interaction of imprinted genes in human fetal growth.

Identifying the genetic input for fetal growth will help to understand common, serious complications of pregnancy such as fetal growth restriction. Genomic imprinting is an epigenetic process that silences one parental allele, resulting in monoallelic expression. Imprinted genes are important in mammalian fetal growth and development. Evidence has emerged showing that genes that are paternally expressed promote fetal growth, whereas maternally expressed genes suppress growth. We have assessed whether the expression levels of key imprinted genes correlate with fetal growth parameters during pregnancy, either early in gestation, using chorionic villus samples (CVS), or in term placenta. We have found that the expression of paternally expressing insulin-like growth factor 2 (IGF2), its receptor IGF2R, and the IGF2/IGF1R ratio in CVS tissues significantly correlate with crown-rump length and birthweight, whereas term placenta expression shows no correlation. For the maternally expressing pleckstrin homology-like domain family A, member 2 (PHLDA2), there is no correlation early in pregnancy in CVS but a highly significant negative relationship in term placenta. Analysis of the control of imprinted expression of PHLDA2 gave rise to a maternally and compounded grand-maternally controlled genetic effect with a birthweight increase of 93/155 g, respectively, when one copy of the PHLDA2 promoter variant is inherited. Expression of the growth factor receptor-bound protein 10 (GRB10) in term placenta is significantly negatively correlated with head circumference. Analysis of the paternally expressing delta-like 1 homologue (DLK1) shows that the paternal transmission of type 1 diabetes protective G allele of rs941576 single nucleotide polymorphism (SNP) results in significantly reduced birth weight (-132 g). In conclusion, we have found that the expression of key imprinted genes show a strong correlation with fetal growth and that for both genetic and genomics data analyses, it is important not to overlook parent-of-origin effects.

Paternally expressed, imprinted insulin-like growth factor-2 in chorionic villi correlates significantly with birth weight.

CONTEXT: Fetal growth involves highly complex molecular pathways. IGF2 is a key paternally expressed growth hormone that is critical for in utero growth in mice. Its role in human fetal growth has remained ambiguous, as it has only been studied in term tissues. Conversely the maternally expressed growth suppressor, PHLDA2, has a significant negative correlation between its term placental expression and birth weight. OBJECTIVE: The aim of this study is to address the role in early gestation of expression of IGF1, IGF2, their receptors IGF1R and IGF2R, and PHLDA2 on term birth weight. DESIGN: Real-time quantitative PCR was used to investigate mRNA expression of IGF1, IGF2, IGF1R, IGF2R and PHLDA2 in chorionic villus samples (CVS) (n = 260) collected at 11-13 weeks' gestation. Expression was correlated with term birth weight using statistical package R including correction for several confounding factors. RESULTS: Transcript levels of IGF2 and IGF2R revealed a significant positive correlation with birth weight (0.009 and 0.04, respectively). No effect was observed for IGF1, IGF1R or PHLDA2 and birth weight. Critically, small for gestational age (SGA) neonates had significantly lower IGF2 levels than appropriate for gestational age neonates (p = 3.6 × 10(-7)). INTERPRETATION: Our findings show that IGF2 mRNA levels at 12 weeks gestation could provide a useful predictor of future fetal growth to term, potentially predicting SGA babies. SGA babies are known to be at a higher risk for type 2 diabetes. This research reveals an imprinted, parentally driven rheostat for in utero growth.