A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre‐eclampsia

Abstract

Pre-eclampsia is a multisystem disorder that typically affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Globally, 76 000 women and 500 000 babies die each year from this disorder. Furthermore, women in low-resource countries are at a higher risk of developing hypertensive disorders of pregnancy and pre-eclampsia compared with those in high-resource countries. This is because socioeconomic, educational, and environmental disadvantages have historically beset vulnerable communities, leading to nutritional disparities, poor-quality diet, obesity, and diabetes (before and during pregnancy), thus increasing the rates of pregnancy complications, in particular pre-eclampsia. Pre-eclampsia has been traditionally defined as the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of pre-eclampsia has been broadened. Now the internationally agreed definition of pre-eclampsia is that proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). These subclassifications are not mutually exclusive. Early-onset pre-eclampsia is associated with a much higher risk of short- and long-term maternal and perinatal morbidity and mortality. High-quality evidence has demonstrated that early-onset and preterm pre-eclampsia can be effectively predicted by a Bayes-based method-derived model that incorporates maternal factors and a series of biological parameters measured at 11–13+6 weeks of gestation. When these high-risk women (with estimated risk ≥1:100) are treated with 150 mg aspirin per night, from 11–14+6 weeks of gestation at a dose of approximately 150 mg to be taken every night until 36+0 weeks of gestation, the rates of early-onset and preterm pre-eclampsia can be reduced by 80% and 60%, respectively. FIGO (the International Federation of Gynecology and Obstetrics) endorsed this first-trimester “screen and prevent” strategy for pre-eclampsia and its pragmatic guidance was published in 2019.1 Current wider-scale antenatal care is based on healthcare models developed in the early 20th century. In 1929 the UK Ministry of Health issued a Memorandum on Antenatal Clinics, recommending that women should first be seen at the 16th week of pregnancy and then at 24 and 28 weeks, fortnightly until 36 weeks, and then weekly until delivery. No explicit rationale was offered for the timing or clinical content of visits, yet these guidelines established the pattern of antenatal care that has been followed throughout the world to the present day. A common assumption has prevailed that antenatal care should be concentrated around the third trimester of pregnancy, where most complications clinically materialize and adverse outcomes can be diagnosed. The current method of monitoring for pre-eclampsia is based on this 90-year-old care pathway that requires that at every clinical visit, women are assessed for hypertension and proteinuria. However, even in the case of early-onset disease, this approach detects hypertension and pre-eclampsia only at a late stage of presentation, which does not necessarily allow optimization of care for both the mother and the fetus, namely stabilization of blood pressure, prophylactic corticosteroid for fetal lung maturation, and transferal to a tertiary referral unit prior to the need for immediate delivery, which is the only definitive treatment for this disorder. In the past decade, major efforts have been made to develop tools for risk stratification and prediction of pre-eclampsia in high-risk women, as well as short-term prediction in women presenting with signs and symptoms of pre-eclampsia and those with confirmed pre-eclampsia. FIGO brought together international experts to discuss and evaluate current knowledge on the topic and develop a document to frame the issues and suggest key actions to address the health burden posed by pre-eclampsia. FIGO’s objective, as outlined in this document, is: (1) to raise awareness of the links between pre-eclampsia and poor maternal and perinatal outcomes as well as of the future health risks to mother and offspring, and demand a clearly defined agenda to tackle this issue globally; and (2) to create a consensus document, which provides guidance on prediction, risk stratification, monitoring, and management of pre-eclampsia in the second and third trimester of pregnancy, and to disseminate and encourage its use. Based on high-quality evidence, the document outlines current global standards for the risk stratification, monitoring, and management of pre-eclampsia in the second and third trimester of pregnancy. It provides the most pragmatic advice for different resource settings—keeping in mind the feasibility, acceptability, and ease of implementation of the advice—to significantly lessen the health and economic burden caused by pre-eclampsia. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as well as for research priorities to bridge the current knowledge and evidence gap. To address pre-eclampsia, FIGO recommends the following: Public health focus: there should be greater international attention focused on pre-eclampsia and to the links between maternal health and noncommunicable diseases on the Sustainable Developmental Goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling and antenatal and postnatal services for women of reproductive age should be prioritized. Greater efforts are required to raise awareness of the benefits of early antenatal visits targeted at women of reproductive age, particularly in low-resource countries. Risk stratification and monitoring in asymptomatic women: appropriate antenatal maternal and fetal surveillance should be put in place for high-risk women for pre-eclampsia. Where resources permit, the following could be included: guidance on recognition of symptoms and when to seek care; home blood pressure monitoring; regular formal clinical assessment (blood pressure measurement, dipstick proteinuria assessment and, where available, testing for hemoglobin, platelet count, serum creatinine, and liver transaminases); fetal ultrasonographic assessment of growth and umbilical artery Doppler; assessment of uterine artery Doppler. Management of women with confirmed pre-eclampsia: women with pre-eclampsia should be assessed in hospital when first diagnosed. Thereafter, some women may be managed as outpatients once it is established that their condition is stable and they can be relied upon to monitor blood pressure at home and seek medical advice when there is rising/raised blood pressure. Appropriate antenatal maternal and fetal surveillance should be put in place. Where resources permit, the following could be included: maternal assessment by components of PIERS models (Pre-eclampsia Integrated Estimate of Risk Scores), maternal laboratory testing, fetal ultrasonographic assessment of growth, umbilical artery Doppler, and fetal cardiotocography. At ≥32 weeks, if there is no access (or access is not yet possible) to fetal cardiotocography and ultrasound, the following should be used to assess fetal risk in hypertensive pregnancy: maternal age, symptoms, and dipstick proteinuria. For nonsevere hypertension management, elevated blood pressure should be treated with antihypertensive therapy with the target to achieve systolic blood pressure and diastolic blood pressure equal to or below 135 and 85 mmHg, respectively. Oral labetalol, nifedipine, and methyldopa should be considered as first-line antihypertensive agents for nonsevere hypertension. Severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg) should be treated urgently with antihypertensive therapy in a monitored setting. Severely elevated diastolic blood pressure should be lowered to a target of 85 mmHg, but gradually over hours to days. Oral nifedipine, oral labetalol, intravenous labetalol, and intravenous hydralazine are considered as first-line antihypertensive agents for severe hypertension. Magnesium sulfate is recommended for the prevention of eclampsia as well as a neuroprotective agent for the prevention of perinatal morbidity in preterm pre-eclampsia requiring delivery at <32 weeks. Delivery plans for women with confirmed pre-eclampsia: delivery for pre-eclampsia at any gestational age is recommended when there is one or more of the following conditions: abnormal neurological features such as severe intractable headache, repeated visual scotomata, eclampsia, or stroke; repeated episodes of severe hypertension despite maintenance treatment with three classes of antihypertensive agents; pulmonary edema or oxygen saturation <90%; progressive thrombocytopenia (particularly <50 × 109/L or need for transfusion); abnormal and rising serum creatinine; abruption with evidence of maternal or fetal compromise; nonreassuring fetal status (including intrauterine fetal death). Mode of delivery is determined by several factors that include gestational age, fetal condition, and other concurrent obstetrics factors such as previous cesarean section. Postpartum care: blood pressure should continue to be monitored after delivery until 6 days after birth, as it is likely to be highest 3–6 days after birth. Antihypertensive therapy that has been administered before birth should be continued after birth for as long as required to maintain blood pressure control. Consideration should be given to administering antihypertensive therapy for any hypertension diagnosed up to 6 days after delivery. Hypertensive pregnancy disorders should be acknowledged as predictors of long-term maternal cardiovascular morbidity. The following measures should be implemented at 6–12 weeks after birth, and periodically thereafter, preferably yearly, following a pregnancy complicated by hypertensive disorders: history and physical examination, blood pressure measurements, and consideration of screening for other cardiovascular risk factors and for diabetes according to additional risk factors. Automated blood pressure devices: Only automated blood pressure devices that have been shown to be accurate in pregnancy and pre-eclampsia should be used. This document is directed at multiple stakeholders with the intention of bringing attention to pre-eclampsia, which is a common and potentially life-threatening complication of pregnancy with grave consequences for both mothers and offspring. This document proposes to create a global framework for action for risk stratification, monitoring, and management of pre-eclampsia. The intended target audience includes: Healthcare providers: all those qualified to care for pregnant women and their newborns but in particular those responsible for managing high-risk women (obstetricians, maternal-fetal medicine specialists, internists, pediatricians, neonatologists, general practitioners/family physicians, midwives, nurses, advance practice clinicians, nutritionists, pharmacists, community health workers, laboratory technicians, etc). Healthcare delivery organizations and providers: governments, federal and state legislators, healthcare management organizations, health insurance organizations, international development agencies, and nongovernmental organizations. Professional organizations: international, regional, and national professional organizations of obstetricians and gynecologists, internists, family practitioners, pediatricians, neonatologists, and worldwide national organizations dedicated to the care of pregnant women with pre-eclampsia. In assessing the quality of evidence and grading of strength of recommendations, this document follows the terminology proposed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group.2 This system uses consistent language and graphical descriptions for the strength and quality of the recommendations and the evidence on which they are based. Strong recommendations are numbered as 1 and conditional (weak) recommendations are numbered 2 (Table 1). For the quality of evidence, cross-filled circles are used: denotes very low-quality evidence; low quality; moderate quality; and high quality evidence (Table 2). High Moderate Low Very low Pre-eclampsia is a multisystem disorder of pregnancy previously defined by the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently the definition of pre-eclampsia has been broadened.3-6 Pre-eclampsia typically affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset.7, 8 Globally, 76 000 women and 500 000 babies die each year from this disorder.9 Furthermore, women in low-resource countries are at a higher risk of developing hypertensive disorders of pregnancy and pre-eclampsia compared with those in high-resource countries. This is because socioeconomic, educational, and environmental disadvantages have historically beset vulnerable communities leading to nutritional disparities, poor-quality diet, obesity, and diabetes (before and during pregnancy), thus increasing the rates of pregnancy complications. FIGO (the International Federation of Gynecology and Obstetrics) has provided pragmatic guidance on addressing the management of hyperglycemia, nutrition, and obesity care during and after pregnancy.10, 11 Pre-eclampsia is traditionally defined as development of hypertension and new proteinuria in a previously normotensive woman. The difficulty in interpreting epidemiological studies of pre-eclampsia is due to the wide variation in the definitions of the disease. There are several definitions for the diagnosis of pre-eclampsia, which have been reported in published literature and proposed by various professional bodies. Consequently, this has resulted in a number of different guidelines produced by professional bodies worldwide for the diagnosis and management of pre-eclampsia.3, 12-14 An internationally agreed definition of pre-eclampsia is, however, that of the International Society for the Study of Hypertension in Pregnancy (ISSHP)6 (Box 1), which is endorsed by FIGO. In women with proteinuric renal disease, an increase in proteinuria during pregnancy is not sufficient per se to diagnose superimposed pre-eclampsia. Refer to Section 7.4 “Antihypertensive therapy” for the definition of severe hypertension. These subclassifications are not mutually exclusive. High-quality evidence has demonstrated that early-onset and preterm pre-eclampsia can be effectively predicted by a Bayes-based method-derived model that incorporates maternal factors and a series of biological parameters measured at 11–13+6 weeks of gestation.15 When these high-risk women (with estimated risk ≥1:100) are treated with 150 mg aspirin per night, from 11–14+6 weeks of gestation until 36+0 weeks of gestation, the rates of early-onset and preterm pre-eclampsia can be reduced by 80% and 60%, respectively.16 FIGO has endorsed this first-trimester “screen and prevent” strategy for pre-eclampsia and its pragmatic guidance was published in 2019.1 In the present guidance, we focus on the risk stratification, monitoring, and management of pre-eclampsia in the second and third trimester of pregnancy. Pre-eclampsia is a heterogeneous, multifactorial syndrome and its etiology is far from understood. Details on the different etiological hypotheses are beyond the scope of this best practice advice. Specific reviews can be found elsewhere.17-19 However, important understanding of the pathophysiology of the disease has been gained by the discovery of the disturbed angiogenic and antiangiogenic balance in women destined to develop pre-eclampsia and associated adverse events. Women with pre-eclampsia exhibit high circulating serum levels of fms-like tyrosine kinase 1 (sFlt-1) and low levels of placental growth factor (PLGF).20 Experimentally, iatrogenic overexpression of sFlt-1 in pregnant rats leads to hypertension, proteinuria, and glomerular endotheliosis—a histological hallmark of pre-eclampsia. In a baboon model for pre-eclampsia (uterine ligation), restoring the angiogenic balance by application of recombinant human PLGF (rhPLGF) ameliorated pre-eclampsia symptoms, such as hypertension and proteinuria.21 Application of short interfering RNAs (siRNAs) leads to reduction of blood pressure and proteinuria via silencing of sFlt-1 expression in experimental models (primates and mice). In humans, extracorporeal removal of excessively elevated sFlt-1 in women with early-onset pre-eclampsia led to a prolongation of the disease.22, 23 These lines of evidence highlight the concept of a disturbed angiogenic balance as being central to the pathophysiology of the disease. This has led to the development of sFlt-1 and PLGF as markers for diagnosis, prognostication, and prediction of the disease, as discussed below. Current wider-scale antenatal care is based on healthcare models developed in the early 20th century. In 1929 the UK Ministry of Health issued a Memorandum on Antenatal Clinics, recommending that women should first be seen at the 16th week of pregnancy and then at 24 and 28 weeks, fortnightly until 36 weeks, and then weekly until delivery.24 No explicit rationale was offered for the timing or clinical content of visits, yet these guidelines established the pattern of antenatal care that has been followed throughout the world to the present day. A common assumption has prevailed that antenatal care should be concentrated around the third trimester of pregnancy, where most complications clinically materialize and adverse outcomes can be diagnosed. The current method of monitoring for pre-eclampsia is based on this 90-year-old care pathway that requires that at every clinical visit, women are assessed for hypertension and proteinuria. However, even in the case of early-onset disease, this approach detects hypertension and pre-eclampsia only at a late stage of presentation, which does not allow optimization of care for both the mother and the fetus, namely stabilization of blood pressure, prophylactic corticosteroid for fetal lung maturation, and transfer to a tertiary referral unit prior to the need for immediate delivery, which is the only definitive treatment for this disorder. In the past decade, major efforts have been made to develop tools for risk stratification and prediction of pre-eclampsia in high-risk women, as well as short-term prediction in women presenting with signs and symptoms of pre-eclampsia. An overview of the existing literature is summarized in the following section. In addition to their use as a first-trimester screening tool, PLGF-based tests have been shown to have high diagnostic accuracy in women with suspected pre-eclampsia. A recent prospective multicenter study demonstrated that low circulating maternal PLGF concentrations had high sensitivity (96%; 95% CI, 89–99) and negative predictive value (98%; 95% CI, 93.0–99.5) in diagnosing pre-eclampsia that required delivery within 14 days in women who presented with suspected pre-eclampsia.25 This UK PELICAN study25 showed that the Triage PLGF test at a cutoff of 100 pg/mL (with ≥100 pg/mL considered a normal result) had a negative predictive value of 98% when used to rule out pre-eclampsia that needed delivery within the next 14 days. Ruling in women with an abnormal result of less than 12 pg/mL (the lower limit of detection) yielded high specificity (>90%) for the same endpoint. These tests were valid in women presenting with suspected pre-eclampsia, which includes women with hypertension, proteinuria, fetal growth restriction, or symptoms suggestive of pre-eclampsia such as headaches or epigastric pain. The test works well between 20 and 34+6 weeks of gestation. The test has some value after 35 weeks (up to 37 weeks) but is not as good.25 The authors went on to implement these thresholds in a pragmatic stepped-wedge trial to see if knowledge of the test influenced behaviors and outcomes. The PARROT trial demonstrated that at an average of 32 weeks of gestation, the availability of PLGF results (using the Triage PLGF test) substantially reduced the time to clinical confirmation of pre-eclampsia (1.9 vs 4.1 days; time ratio 0.36; 95% CI, 0.15–0.87; P = 0.027) and reduced adverse maternal outcomes (4% vs 5%; adjusted odds ratio 0.32, 95% CI, 0.11–0.96; P = 0.043), supporting the adoption of PLGF-based testing into routine clinical practice.26 The high negative predictive value of PLGF-based tests supports their use as a “rule out” tool in women with suspected disease preterm. We suggest their use alongside clinical assessment to help rule out pre-eclampsia in women suspected of developing the disease. While angiogenic markers may be of value in pre-eclampsia given the number of women with both hypertension and dipstick proteinuria at baseline, this remains to be established. In addition, further work is needed to establish the value of repeated PLGF measurements in women presenting with suspected or confirmed pre-eclampsia, particularly after 35 weeks. It is important to mention that currently there are four PLGF-based tests commercially available. Furthermore, that PLGF has different isoforms. The specific rule in/out criteria are dependent on the exact assay (which have different detection characteristics depending on which isoform of PLGF is detected), and whether a ratio of sFlt-1 to PLGF is used. In addition, the prevalence of pre-eclampsia, or the endpoint used, is variable in the different clinical studies using different assays, making direct comparison between studies difficult as the predictive values are highly dependent on prevalence in the given setting. The COMPARE study27 evaluated three of these assays in the same population of women, using the manufacturer's recommended cutoffs: Triage PLGF test (Quidel Corporation, San Diego, CA, USA), the DELFIA-Xpress PLGF 1-2-3-test (PerkinElmer Inc., Waltham, MA, USA), and the Elecsys immunoassay sFlt-1/PLGF ratio (Roche Diagnostics, Mannheim, Germany) (Table 3). Similar performance was demonstrated in the prediction of need for delivery within 14 days in women with suspected pre-eclampsia. Elecsys sFlt-1/PLGF ratio BRAHMS sFlt-1/PLGF plus ratio PELICAN25 PARROT26 PROGNOSIS28 INSPIRE29 The ultimate choice of which assay to use will depend on cost, availability, and clinical utility such as ease of use. All current tests appear to be valuable. The Triage PLGF test and the Elecsys immunoassay sFlt-1/PLGF ratio have been recommended by the National Institute for Health and Care Excellence (NICE) as a rule-out test for pre-eclampsia at less than 35 weeks.31 The National Health Service (NHS) England has funded initiatives to roll out these tests nationally for suspected pre-eclampsia at less than 35 weeks. The role of the sFlt-1/PLGF ratio to predict adverse outcomes related to pre-eclampsia was investigated in a prospective study with 616 women presenting with signs and symptoms of the disease.32 Women were eligible for enrolment when they presented with either elevated blood pressure or proteinuria and/or symptoms such as headache, visual symptoms, right upper quadrant pain, or edema. The primary endpoint was the development of maternal and/or fetal adverse events related to pre-eclampsia within 2 weeks. Maternal adverse events were defined as a combination of hypertension and abnormal liver function tests, disseminated intravascular coagulation, pulmonary edema, or eclampsia. Fetal adverse events included indicated delivery, fetal growth restriction, or fetal or neonatal death. Adverse events occurred in 43.5% of all patients (n = 268) and in 33.5% of women presenting at less than 34 weeks of gestation (n = 59). Women who had an adverse event related to pre-eclampsia had a significantly elevated sFlt-1/PLGF ratio compared with those who did not (47.0, interquartile range [IQR] 15.5–112.2 vs 10.8, IQR 4.1–28.6; P < 0.001). In women who presented at less than 34 weeks of gestation (n = 176), the results were more striking (226.6, IQR 50.4–547.3 vs 4.5, IQR 2.0–13.5; P < 0.001). For women who presented before 34 weeks of gestation, the addition of the sFlt-1/PLGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (area under the receiver operating characteristic curve (AUC) 0.93 for hypertension, proteinuria, and sFlt-1/PLGF ratio versus 0.84 for hypertension and proteinuria alone; P < 0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt-1/PLGF ratio greater than 85 compared with 15.8% of women with an sFlt-1/PLGF ratio less than 85 (hazard ratio, 15.2; 95% CI, 8.0–28.7).32 In the PROGNOSIS study,28 a prospective observational study conducted in 14 countries, the ability of the sFlt-1/PLGF ratio to predict the absence of pre-eclampsia within 1 week and to predict the presence of pre-eclampsia within 4 weeks in women with signs and symptoms of pre-eclampsia was investigated. This study included 1050 pregnant women aged 18 years or older at 24–36+6 weeks of gestation with clinical symptoms of the disease such as new onset of hypertension or aggravation of pre-existing hypertension; new onset of proteinuria or aggravation of existing proteinuria; the presence of typical symptoms of the disease such as headache, right upper quadrant abdominal pain, edema, or weight gain; as well as an abnormal uterine artery Doppler. The prevalence of pre-eclampsia in the full dataset was 17.8%. In the development cohort of 500 women, the single cutoff of 38 was found to be predictive for the primary endpoint, which was then evaluated in the validation cohort of another 550 women. In women with suspected pre-eclampsia according to the PROGNOSIS criteria, the negative predictive value of an sFlt-1/PLGF ratio ≤38 for ruling out the occurrence of pre-eclampsia within 1 week was 99.3% (95% CI, 97.9–99.9). The positive predictive value of an sFlt-1/PLGF ratio >38 for ruling in the occurrence of pre-eclampsia within 4 weeks was 36.7% (95% CI, 28.4–45.7). The positive predictive value for the occurrence of a combined endpoint of pre-eclampsia/eclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) or maternal and/or fetal adverse outcomes within 4 weeks was 65.5% (95% CI, 56.3–74.0).28 In an exploratory post hoc analysis of the PROGNOSIS dataset it was demonstrated that an sFlt-1/PLGF ratio of ≤38 can rule out pre-eclampsia within 4 weeks with a negative predictive value of 94.3% (95% CI, 91.7–96.3).33 Evidence from this analysis shows the importance of repeated measurements in women with signs and symptoms of the disease. Women with suspected pre-eclampsia who developed the disorder had a significantly larger median increase in the sFlt-1/PLGF ratio at 2 weeks (delta [Δ] 31.22) and 3 weeks (Δ48.97) after the first blood draw, compared with those who did not (Δ1.45 and Δ2.39, respectively; P < 0.001). These results were validated in the PROGNOSIS Asia study.34 This multicenter study enrolled 764 women with suspected pre-eclampsia in 25 centers in Asia. Suspected pre-eclampsia was defined as in the PROGNOSIS study; however, only severe persistent epigastric pain and new onset of visual disturbances were considered as potential symptoms related to pre-eclampsia. In this study an sFlt-1/PLGF ratio cutoff of ≤38 was shown to have a negative predictive value of 98.6% (95% CI, 97.2–99.4) for ruling out pre-eclampsia within 1 week and a ratio >38 demonstrated a positive predictive value of 30.3% (95% CI, 23.0–38.5) for ruling in pre-eclampsia within 4 weeks. The positive predictive value for the occurrence of a combined endpoint of pre-eclampsia/eclampsia/HELLP syndrome or maternal and/or fetal adverse outcomes within 4 weeks was 65.0% (95% CI, 56.6–72.8).34 A prospective cohort study of nulliparous women investigated the added value of the sFlt-1/PLGF ratio in a high-risk and low-risk population.35 High-risk of pre-eclampsia was defined as either: (1) maternal characteristics, using the UK NICE guideline; or (2) elevated 20 weeks uterine artery Doppler, defined as a mean pulsatility index in the highest decile. Blood sampling was performed at approximately 20, 28, and 36 weeks. The primary outcomes were pre-eclampsia and delivery <28 weeks or pre-eclampsia and delivery <37 weeks (for 20 weeks sample); pre-eclampsia and delivery <37 weeks (28 weeks sample); and pre-eclampsia with severe features (36 weeks sample). A total of 4099 women were recruited, the incidence of pre-eclampsia was 6.5% (265/4099) in total, 0.1% before 28 weeks, 0.65% before 36 weeks, and 2.8% developed severe pre-eclampsia after 36 weeks. The screening performance at 20, 28, and 36 weeks was 0.70 (95% CI, 0.43–0.97), 0.80 (95% CI, 0.70–0.89), and 0.81 (95% CI, 0.77–0.86), respectively. Women with an sFlt-1/PLGF ratio >38 (n = 19) at 28 weeks had an incidence of pre-eclampsia of 32% leading to preterm delivery. The positive predictive value was similar in low- and high-risk women (33% vs 31%, P = 0.91). At 36 weeks, women with an sFlt-1/PLGF ratio >38 (n = 566) had an incidence of severe pre-eclampsia of 10%. Among women with no prior risk factors, an sFlt-1/PLGF ratio ≤38 had a high negative predictive value for subsequent development of severe disease (>99%). Sovio et al.35 tested the cutoffs of 85 (<34 weeks) and 110 (>34 weeks) in their cohort. Four out of seven women with an sFlt-1/PLGF ratio >85 at 28 weeks delivered preterm with a diagnosis of pre-eclampsia (positive predictive value 57%). At 36 weeks, 70 women had an sFlt-1/PLGF ratio >110 and 21 developed severe disease (po