Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels.

Background: Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA).

Methods: We studied a prospective cohort of nulliparous women (3968 mother-child pairs).

A multi-ancestry genome-wide association study identifies novel candidate loci in the RARB gene associated with hypertensive disorders of pregnancy.

Genetic factors related to pregnancy-related traits are understudied, especially in ancestrally diverse cohorts. To assess maternal contributions to hypertensive disorders of pregnancy (HDP), we performed a multi-ancestry genome-wide association study (GWAS) of HDP in data from the North Carolina-based Personalized Environment and Genes Study (PEGS) cohort with validation in the UK Biobank (UKBB). The GWAS revealed two maternal loci associated with HDP at the genome-wide significance level.

Association between maternal hemoglobin concentration and educational attainment in mid-childhood in a high-resource obstetric setting: a prospective cohort study.

Background: Although maternal hemoglobin levels during pregnancy are commonly associated with perinatal outcomes, their link to childhood neurodevelopment remains uncertain.

Objective: This study aimed to examine the associations between maternal hemoglobin in early and late pregnancy and the educational attainment of offspring mid-childhood in a high-resource obstetric setting.

Study Design: Pregnancy data from a prospective birth cohort (Pregnancy Outcome Prediction Study, Cambridge, United Kingdom, 2008-2012, N=3285) were linked to mid-childhood educational outcomes (Department for Education, United Kingdom).

Placental Streptococcus agalactiae DNA is associated with neonatal unit admission and foetal pro-inflammatory cytokines in term infants.

Streptococcus agalactiae (Group B Streptococcus; GBS) is a common cause of sepsis in neonates. Previous work detected GBS DNA in the placenta in ~5% of women before the onset of labour, but the clinical significance of this finding is unknown. Here we re-analysed this dataset as a case control study of neonatal unit (NNU) admission.

Prediction of spontaneous preterm birth using supervised machine learning on metabolomic data: A case-cohort study.

Objectives: To identify and internally validate metabolites predictive of spontaneous preterm birth (sPTB) using multiple machine learning methods and sequential maternal serum samples, and to predict spontaneous early term birth (sETB) using these metabolites.

Design: Case-cohort design within a prospective cohort study.

Setting: Cambridge, UK.

Association between adverse pregnancy outcome and placental biomarkers in the first trimester: A prospective cohort study.

Objective: To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human chorionic gonadotrophin [beta-hCG], placenta growth factor [PlGF] and soluble fms-like tyrosine kinase receptor-1 [sFlt-1]) and a range of adverse pregnancy outcomes (APOs).

Design: Prospective cohort study of nulliparous singleton pregnancy.

Setting: Cambridge, UK.

Objective measures of smoking and caffeine intake and the risk of adverse pregnancy outcomes.

Background: In pregnancy, women are encouraged to cease smoking and limit caffeine intake. We employed objective definitions of smoking and caffeine exposure to assess their association with adverse outcomes.

Methods: We conducted a case cohort study within the Pregnancy Outcome Prediction study to analyse maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively.

Association between antenatal diagnosis of late fetal growth restriction and educational outcomes in mid-childhood: A UK prospective cohort study with long-term data linkage study.

Background: Fetal growth restriction (FGR) is associated with a suboptimal intrauterine environment, which may adversely impact fetal neurodevelopment. However, analysing neurodevelopmental outcomes by observed birthweight fails to differentiate between true FGR and constitutionally small infants and cannot account for iatrogenic intervention. This study aimed to determine the relationship between antenatal FGR and mid-childhood (age 5 to 7 years) educational outcomes.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction.

Background: Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR.

Metabolomic Identification of a Novel, Externally Validated Predictive Test for Gestational Diabetes Mellitus.

Context: Undiagnosed gestational diabetes mellitus (GDM) is a major preventable cause of stillbirth. In the United Kingdom, women are selected for diagnostic testing for GDM based on risk factors, including body mass index (BMI) > 30 kg/m2.

Objective: To improve the prediction of GDM using metabolomics.

A Maternal Serum Metabolite Ratio Predicts Large for Gestational Age Infants at Term: A Prospective Cohort Study.

Context: Excessive birth weight is associated with maternal and neonatal complications. However, ultrasonically estimated large for gestational age (LGA; >90th percentile) predicts these complications poorly.

Objective: To determine whether a maternal serum metabolite ratio developed for fetal growth restriction (FGR) is predictive of birth weight across the whole range, including LGA at birth.

Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction.

Background: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain.

Do Mass Spectrometry-Derived Metabolomics Improve the Prediction of Pregnancy-Related Disorders? Findings from a UK Birth Cohort with Independent Validation.

Many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or have an offspring born small/large for gestational age (SGA/LGA) do not meet the criteria for high-risk pregnancies based upon certain maternal risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders.

The RNA landscape of the human placenta in health and disease.

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR).

Slowing of fetal growth and elevated maternal serum sFLT1:PlGF are associated with early term spontaneous labor.

Background: The physiological control of human parturition at term is unknown.

Objective: This study aimed to test the hypothesis that slowing of fetal growth or elevated maternal serum levels of markers of placental hypoxia in late gestation will be associated with earlier term labor.

Study Design: We observed 2208 women having first births and performed serial blinded ultrasonography and immunoassay of soluble fms-like tyrosine kinase-1 and placenta growth factor.

The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice.

The conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and ∼50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development.

Fetal umbilical artery Doppler as a tool for universal third trimester screening: A systematic review and meta-analysis of diagnostic test accuracy.

The objective of this study was to investigate the accuracy of universal third trimester umbilical artery (UA) Doppler to predict adverse pregnancy outcome at term. We searched Medline, EMBASE, the Cochrane library and ClinicalTrials.gov from inception to October 2020 and we also analyzed previously unpublished data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction (POP) study.