Prediction and Prevention of Preeclampsia

Introduction

Because preeclampsia increases both morbidity and mortality, primary prevention is a major goal to optimize both short- and long-term health for mother and child. Secondary prevention for women with previous hypertensive disorders of pregnancy is also warranted, due to the association with increased risk of recurrence in the next pregnancy. The previous (fourth) edition of Chesley included a detailed chapter on “Prevention of Preeclampsia and Eclampsia.” In this fifth edition, we chose to focus on today's most common prophylactic measures and their rationale. Readers interested in the broader historical context of preventive measures are referred to this earlier chapter in the fourth edition, and we gratefully acknowledge the authors—Baha M. Sibai, Anne Cathrine Staff, and F. Gary Cunningham—for their work, which inspired the present chapter. As for prevention of eclampsia, the use of magnesium sulfate (in women with severe preeclamptic features) is covered in Chapter 17 , where the authors of this chapter also have contributed with their clinical expertise.

Routine antenatal screening for preeclampsia

First trimester is an optimal time during antenatal care to assess risks for pregnancy complications such as preeclampsia and to make a clinical follow-up plan for the remaining pregnancy. Preconception guidance is preferred in women with high risk of obstetric complications secondary to chronic hypertension, diabetes mellitus, obesity, and renal disease. Most women with new-onset hypertension in pregnancy will not have subjective symptoms except in the case of severe disease onset, when symptoms such as intense headache can herald impending cerebral hemorrhage or eclampsia. This emphasizes the importance of regular antenatal monitoring and screening of all pregnancies for objective signs of preeclampsia including blood pressure measurements for hypertension and urinalysis for proteinuria. This regular follow-up also includes screening for fetal growth restriction, although symphysis-fundus height measurement has limited precision for small for gestational age screening. Patient education on symptoms and signs of preeclampsia as well as home blood pressure monitoring is also important in early detection. Systematic antenatal health care has without doubt dramatically reduced maternal mortality worldwide, including mortality from preeclampsia, by early implementation of antihypertensive therapy and timely delivery, when needed. However, prudent screening during the second half of pregnancy as a part of regular antenatal care for early detection and timely intervention to prevent the most severe outcomes of preeclampsia does not prevent the disease. The only approach that completely nullifies the risk of preeclampsia is to avoid pregnancy, which is not an option for most women wishing for a child, including those at high risk for preeclampsia. Women with early-onset preeclampsia not only have the highest risk for severe morbidity and mortality, but also the highest risk for recurrence, and consequently, may be less likely to undertake a future pregnancy, which makes prevention of early-onset disease especially crucial. That said, preeclampsia–eclampsia at full-term gestation remains a major contributor to maternal and fetal/neonatal morbidity and mortality particularly in low- and middle-income countries. Thus, efforts in optimization of prenatal care and delivery as well as feasible prediction and prevention strategies are also warranted for late-onset preeclampsia.

Early preeclampsia risk stratification for primary prophylaxis

Preeclampsia prevention studies were initiated more than three decades ago. They have targeted reducing the rate of preeclampsia of preeclampsia subtypes such as preeclampsia with preterm delivery, often called early-onset preeclampsia, or of preeclampsia with morbid maternal and fetal outcomes. The definitions vary, with delivery prior to gestational week 34 ⁺⁰ as the threshold for early-onset commonly used, as these pregnancies have the highest rate of severe clinical outcomes. Other studies use the well-established clinical preterm delivery definition of a delivery prior to 37 ⁺⁰ gestational weeks to denote early-onset preeclampsia. The aim of primary prevention of preeclampsia encompasses more than reducing preeclampsia numbers per se. The main goal is to improve clinical outcomes for mother and offspring, both in the short and long term. Most prevention studies have not considered long-term health.

A challenge for any preeclampsia prevention and intervention study is how to identify the complete target population, which is obfuscated by the heterogeneous risk factors, pathophysiology, and outcomes of the syndrome. Clinical risk factors for preeclampsia and gestational hypertension in first and subsequent pregnancies have been the subject of multiple epidemiological studies, as discussed in Chapter 2 (Epidemiology of pregnancy-related hypertension).

The most studied and most used pharmacological prevention of preeclampsia today is low-dose aspirin (acetylsalicylic acid). A clinical assessment screening for risk factors should be offered during the first or early second trimester, as prevention may be most effective when aspirin is started around gestational week 12 (discussed in detail below). Combinations of epidemiologically identified maternal risk factors have been used in early pregnancy triaging to identify women at high risk, as illustrated in Table 18.1 Both American ^, and British clinical obstetric guidelines have recommended that one risk factor classified as a major risk for preeclampsia, or two or more moderate risk factors, should qualify the patient for prevention with low-dose aspirin (81 mg/day in US recommendations and 75–150 mg daily in the UK recommendations) from 12 weeks of pregnancy. Examples of high risk factors for preeclampsia are: preeclampsia during a previous pregnancy, renal disease, autoimmune disease (e.g., systemic lupus erythematosus or antiphospholipid syndrome), type 1 or type 2 diabetes, and chronic hypertension.

The prediction models for preeclampsia restricted to maternal medical and obstetric history have only moderate success in targeting women at risk. The NICE (National Institute for Health and Care Excellence) guidelines using clinical risk factors for identifying high risk (illustrated in Table 18.1 ) have been shown to detect 40% of preeclamptic women with a 10% false positive rate. This limited sensitivity has led to assessment of novel approaches to first trimester screening of preeclampsia that include maternal blood tests of protein biomarkers of placental function (e.g., placental growth factor (PlGF)) ^, as well as uterine artery flow pulsatile index (UtA PI measured by Doppler ultrasound). ^, The latter index can detect early changes in the uteroplacental circulation associated with placental dysfunction (e.g., preeclampsia and fetal growth restriction). As an individual risk indicator for preeclampsia, the UtA PI has a low sensitivity and specificity when used in low-risk populations, but may be useful in complex first and second trimester prediction algorithms for preeclampsia. Combining risk factors improves prediction of preterm preeclampsia risk, as compared to single risk factors or clinical risk factors alone, but is not without false-positive and -negative results. A Bayes theorem-based competing risk model was presented by Poon et al. of the Fetal Medicine Foundation (FMF) in 2009. Its combination of first trimester screening (11–14 weeks) for preeclampsia is more precise than when the traditional clinical guidelines are used. This FMF model includes the well-known clinical risk factors (primiparity, BMI, multiple pregnancy, etc.) and adds information on mean arterial blood pressure (MAP), uteroplacental Doppler flow (UtA PI), as well as maternal blood concentration of PlGF. Inclusion of another circulating placenta related protein (pregnancy-associated plasma protein-A, PAPP-A) has been shown not to improve the performance of such comprehensive risk screening. A woman is considered high-risk when the likelihood is greater than or equal to 1 in 100 based on this first-trimester combined test with maternal risk factors, MAP, UtA PI, and PlGF. This competing risk model has been shown to identify 75% of pregnancies at high risk for preterm preeclampsia (and 45% of any form of preeclampsia) with a false-positive rate of 10% in a mixed European population. Similar results using this risk model were achieved in an Asian population, after adjustments of the model due to lower median values of PlGF at screening. In this Asian population, the competing risk model was superior to both the NICE (2010) and American College of Obstetrics and Gynecology (ACOG) (2018) risk models for preterm preeclampsia. It is reasonable to test the applicability of any prediction model in specific populations, as well as assessing the cost-effectiveness, because many pregnant women need to be screened and to regularly take aspirin, in order to prevent one case of preterm preeclampsia.

At present, despite efficient screening algorithms, many preeclampsia cases remain unpredictable in first trimester, and 25% of high-risk women taking prophylactic aspirin still develop preterm preeclampsia, even with high adherence to the medication (>90%). However, as summarized in a recent review of reviews, the optimal preeclampsia screening method for all populations is not established yet, and regional cost–benefit analyses with health economic evaluations are needed, in line with large global differences in provision of and resources for antenatal and obstetric care. ^{, ,} FIGO (The International Federation of Gynecology and Obstetrics) has endorsed a first trimester complex screening for preeclampsia, but recommends, where resources are limited, a two-stage screening strategy. FIGO recommends first-stage screening by maternal factors and MAP (mean arterial pressure) for all pregnancies, whereas UtA PI and PlGF second-stage screening is recommended for the population deemed at intermediate risk for preterm preeclampsia. Women evaluated as high -risk during these first or second-stage triage system are recommended low-dose aspirin.

Concerns have however been raised regarding the practical utility of this multimodal approach, including health care costs, quality control of measurements (uterine artery PI, biochemical markers), availability of biomarker analysis for clinical use (PlGF is not yet approved by the US Food and Drug Administration), patient anxiety, as well as implications of additional antenatal surveillance and potential for unnecessary interventions including early delivery. As of 2021, ACOG does not recommend the use of biochemical markers and/or uterine artery Doppler for preeclampsia prediction but continues to recommend assessment of clinical risk factors and blood pressure monitoring for early identification of women at risk for early-onset preeclampsia.

Preeclampsia prevention modalities

Like many other interventions, the hope persists that with improved phenotyping of preeclampsia and related placental conditions, future trials will target therapies more effectively in specific groups yielding even better results. Below are listed current recommendations and what not to recommend, based on best available knowledge today.