Objective  To develop a practical evidence based list of clinical risk factors that can be assessed by a clinician at ≤16 weeks’ gestation to estimate a woman’s risk of pre-eclampsia. Design  Systematic review and meta-analysis of cohort studies. Data sources  PubMed and Embase databases, 2000-15. Eligibility criteria for selecting studies  Cohort studies with ≥1000 participants that evaluated the risk of pre-eclampsia in relation to a common and generally accepted clinical risk factor assessed at ≤16 weeks’ gestation. Data extraction  Two independent reviewers extracted data from included studies. A pooled event rate and pooled relative risk for pre-eclampsia were calculated for each of 14 risk factors. Results  There were 25 356 688 pregnancies among 92 studies. The pooled relative risk for each risk factor significantly exceeded 1.0, except for prior intrauterine growth restriction. Women with antiphospholipid antibody syndrome had the highest pooled rate of pre-eclampsia (17.3%, 95% confidence interval 6.8% to 31.4%). Those with prior pre-eclampsia had the greatest pooled relative risk (8.4, 7.1 to 9.9). Chronic hypertension ranked second, both in terms of its pooled rate (16.0%, 12.6% to 19.7%) and pooled relative risk (5.1, 4.0 to 6.5) of pre-eclampsia. Pregestational diabetes (pooled rate 11.0%, 8.4% to 13.8%; pooled relative risk 3.7, 3.1 to 4.3), prepregnancy body mass index (BMI) >30 (7.1%, 6.1% to 8.2%; 2.8, 2.6 to 3.1), and use of assisted reproductive technology (6.2%, 4.7% to 7.9%; 1.8, 1.6 to 2.1) were other prominent risk factors. Conclusions  There are several practical clinical risk factors that, either alone or in combination, might identify women in early pregnancy who are at “high risk” of pre-eclampsia. These data can inform the generation of a clinical prediction model for pre-eclampsia and the use of aspirin prophylaxis in pregnancy.

https://www.bmj.com/content/bmj/353/bmj.i1753.full.pdf

Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies

The placenta sits at the interface between the maternal and fetal vascular beds where it mediates nutrient and waste exchange to enable in utero existence. Placental cells (trophoblasts) accomplish this via invading and remodeling the uterine vasculature. Amazingly, despite being of fetal origin, trophoblasts do not trigger a significant maternal immune response. Additionally, they maintain a highly reliable hemostasis in this extremely vascular interface. Decades of research into how the placenta differentiates itself from embryonic tissues to accomplish these and other feats have revealed a previously unappreciated level of complexity with respect to the placenta's cellular composition. Additionally, novel insights with respect to roles played by the placenta in guiding fetal development and metabolism have sparked a renewed interest in understanding the interrelationship between fetal and placental well-being. Here, we present an overview of emerging research in placental biology that highlights these themes and the importance of the placenta to fetal and adult health.

Placenta: The Forgotten Organ

Preeclampsia, a hypertensive disorder of pregnancy is estimated to complicate 2%-8% of pregnancies and remains a principal cause of maternal and fetal morbidity and mortality. Preeclampsia may present at any gestation but is more commonly encountered in the third trimester. Multiple risk factors have been documented, including: family history, nulliparity, egg donation, diabetes, and obesity. Significant progress has been made in developing tests to predict risk of preeclampsia in pregnancy, but these remain confined to clinical trial settings and center around measuring angiogenic profiles, including placental growth factor or newer tests involving metabolomics. Less progress has been made in developing new treatments and therapeutic targets, and aspirin remains one of the few agents shown to consistently reduce the risk of developing preeclampsia. This review serves to discuss recent advances in risk factor identification, prediction techniques, and management of preeclampsia in antenatal, intrapartum, and postnatal patients.

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Risk factors and effective management of preeclampsia

The National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy has defined four categories of hypertension in pregnancy: chronic hypertension, gestational hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension. A maternal blood pressure measurement of 140/90 mm Hg or greater on two occasions before 20 weeks of gestation indicates chronic hypertension. Pharmacologic treatment is needed to prevent maternal end-organ damage from severely elevated blood pressure (150 to 180/100 to 110 mm Hg); treatment of mild to moderate chronic hypertension does not improve neonatal outcomes or prevent superimposed preeclampsia. Gestational hypertension is a provisional diagnosis for women with new-onset, nonproteinuric hypertension after 20 weeks of gestation; many of these women are eventually diagnosed with preeclampsia or chronic hypertension. Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. Adverse pregnancy outcomes related to severe preeclampsia are caused primarily by the need for preterm delivery. HELLP (i.e., hemolysis, elevated liver enzymes, and low platelet count) syndrome is a form of severe preeclampsia with high rates of neonatal and maternal morbidity. Magnesium sulfate is the drug of choice to prevent and treat eclampsia. The use of magnesium sulfate for seizure prophylaxis in women with mild preeclampsia is controversial because of the low incidence of seizures in this population.

Hypertensive Disorders of Pregnancy

The focus on disease mechanisms underlying the hypertension and proteinuria defining preeclampsia has increased knowledge of the pathophysiology yet we lack both therapy and predictors. We propose this is in part due to the fact that diagnostic findings identify a "preeclampsia syndrome" but do not necessarily indicate the most important pathophysiology nor if organs are involved as cause or consequence. The increased risk for later life cardiovascular disease in women who develop preeclampsia suggests the stress test of pregnancy exposes pre-existing subclinical vascular disease. The dogma that inadequate trophoblast invasion and ischemia/reperfusion injury to the placenta is "the" cause of preeclampsia is more relevant to early onset preeclampsia (<34 weeks). There is much less evidence for defective placentation in late onset preeclampsia where maternal constitutive factors or susceptibility to vascular damage is more relevant. The contribution of differing disease phenotypes to the syndrome may explain the inability of biomarker studies to identify all preeclampsia. Identification of phenotypes will require large amounts of prospective clinical data and biospecimens, collected in a harmonized manner with analysis in an unbiased discovery approach.

Preeclampsia: Syndrome or Disease?

More than half of all cases of preeclampsia occur in healthy first-time pregnant women. Our aim was to develop a method to predict those at risk by combining clinical factors and measurements of biomarkers in women recruited to the Screening for Pregnancy Endpoints (SCOPE) study of low-risk nulliparous women. Forty-seven biomarkers identified on the basis of (1) association with preeclampsia, (2) a biological role in placentation, or (3) a role in cellular mechanisms involved in the pathogenesis of preeclampsia were measured in plasma sampled at 14 to 16 weeks' gestation from 5623 women. The cohort was randomly divided into training (n=3747) and validation (n=1876) cohorts. Preeclampsia developed in 278 (4.9%) women, of whom 28 (0.5%) developed early-onset preeclampsia. The final model for the prediction of preeclampsia included placental growth factor, mean arterial pressure, and body mass index at 14 to 16 weeks' gestation, the consumption of ≥3 pieces of fruit per day, and mean uterine artery resistance index. The area under the receiver operator curve (95% confidence interval) for this model in training and validation cohorts was 0.73 (0.70-0.77) and 0.68 (0.63-0.74), respectively. A predictive model of early-onset preeclampsia included angiogenin/placental growth factor as a ratio, mean arterial pressure, any pregnancy loss <10 weeks, and mean uterine artery resistance index (area under the receiver operator curve [95% confidence interval] in training and validation cohorts, 0.89 [0.78-1.0] and 0.78 [0.58-0.99], respectively). Neither model included pregnancy-associated plasma protein A, previously reported to predict preeclampsia in populations of mixed parity and risk. In nulliparous women, combining multiple biomarkers and clinical data provided modest prediction of preeclampsia.

Early Pregnancy Prediction of Preeclampsia in Nulliparous Women, Combining Clinical Risk and Biomarkers The Screening for Pregnancy Endpoints (SCOPE) International Cohort Study

Michael Raymundo

Papers

Early Pregnancy Prediction of Preeclampsia in Nulliparous Women, Combining Clinical Risk and Biomarkers The Screening for Pregnancy Endpoints (SCOPE) International Cohort Study