Medical Policy

This document addresses serum biomarker testing to identify individuals at increased risk of preeclampsia during pregnancy. Serum biomarkers that may be used to predict preeclampsia include placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A), levels of which tend to drop during pregnancy in asymptomatic individuals who later develop preeclampsia. Moreover, the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1), which tends to increase in preeclampsia and PlGF may be calculated to test for the presence or absence of preeclampsia. In addition, there are other potential serum protein biomarkers, such as retinol-binding protein 4 (RBP4) and endoglin (ENG), the concentrations of which can be assessed and results combined into a risk-score to identify individuals at high risk of preeclampsia.

Note: This document does not apply to routine tests performed during pregnancy such as urine protein analysis, blood pressure, renal function labs, liver function labs, and complete blood count (CBC).

Please see the following related document for additional information:

• ADMIN.00002 Preventive Health Guidelines

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Investigational and Not Medically Necessary:

Serum biomarker tests to diagnose, screen for, or assess risk of preeclampsia are considered investigational and not medically necessary.

This document describes clinical studies and expert recommendations, and explains whether serum biomarker tests for risk of preeclampsia are clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Preeclampsia is a potential complication of pregnancy that usually includes high blood pressure leading to possible kidney or other organ damage, as well as threaten the life of the unborn baby. Blood tests have been proposed to help identify proteins in the blood to identify individuals at risk of preeclampsia, help identify the early development of preeclampsia, or help diagnose it in individuals with symptoms preeclampsia. Such tests are called serum or blood biomarker tests, and they use blood samples to measure protiens such as placental growth factor (PlGF), pregnancy-associated plasma protein-A (PAPP-A), soluble fms-like tyrosine kinase-1 (sFlt-1), and others. Although some studies suggest that these blood tests may help predict or identify preeclampsia the available evidence is unclear about the benefits serum biomarker testing at this time.

What the Studies Show

Researchers have studied several serum biomarkers that may be linked to preeclampsia. Some studies found that lower levels of PlGF or PAPP-A, or higher soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratios, were associated with a greater chance of developing preeclampsia. In some studies, combining biomarkers with other information, such as blood pressure, ultrasound findings, and pregnancy risk factors, improved prediction compared with using risk factors alone. However, results varied across studies, and the accuracy of these tests ranged from moderate to high depending on the population studied and the testing method used.

A key limitation is that studies have not shown that adding these biomarker tests to standard pregnancy care improves health outcomes such as kidney failure, problems with the placenta, low platelet counts and bleeding, liver problems, preterm delivery, small-for-gestational-age infants, and maternal death. No studies have directly compared screening based on traditional risk factors alone with screening that also included biomarkers. Professional organizations note that the tests do not reliably predict who will develop preeclampsia and that better studies are needed to know if biomarker testing improves health. Potential concerns include false-positive results, which may identify people as high risk when they would not develop preeclampsia, and false-negative results, which may miss people who later develop the condition.

Is this clinically appropriate?

Serum biomarker tests used to diagnose, screen for, or assess the risk of preeclampsia are not clinically appropriate because they have not been proven to improve health. Standard monitoring, including blood pressure measurements and evaluation for signs of preeclampsia, remains the established approach.

Studies show that some biomarkers are associated with preeclampsia and may help estimate risk. However, studies have not consistently shown that these tests improve prediction beyond established risk factors and routine clinical evaluation. In addition, no randomized controlled trials have shown that using these tests in routine care leads to better outcomes for pregnant people or babies. Professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), state that these tests remain investigational because their predictive accuracy and clinical usefulness have not been adequately demonstrated. Better studies are needed to know if biomarker testing improves health.

(Return to Description/Scope)

Summary

Preeclampsia is a potential complication of pregnancy characterized by high blood pressure leading to possible kidney or other organ damage. If untreated, preeclampsia can lead to serious or fatal complications, including maternal death and fetal loss. The current standard of care for identification of preeclampsia is via routine blood pressure monitoring and physical exam, as well as evaluation for proteinuria, liver enzymes, and liver function tests. Use of serum biomarkers has been proposed as an adjunct to these methods.

Observational studies evaluating serum biomarker testing have found moderate sensitivity and specificity of placental growth factor (PIGF) for predicting preeclampsia. Studies have not consistently found that biomarkers improved the accuracy of testing beyond maternal risk factors. Serum biomarker tests have not been directly compared in randomized controlled trials (RCTs) with screening using maternal risk factors only. One RCT, the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial, evaluated the effect of aspirin compared to placebo in high-risk individuals, identified via a model incorporating maternal risk factors, biomarkers and other factors. Aspirin significantly reduced the relative risk of preterm preeclampsia by 62%, though the absolute risk reduction was modest (2.68%) and no significant difference was observed for term preeclampsia. Professional guidelines are similar: the U.S. Preventive Services Task Force (USPSTF) recommends routine blood pressure screening without mentioning biomarkers and the American College of Obstetricians and Gynecologists (ACOG) maintains biomarkers remain investigational due to limited predictive accuracy and insufficient clinical utility and  the International Federation of Gynecology and Obstetrics (FIGO)recommends that all women should receive preterm screening with maternal risk factors and blood pressure in the first trimester. They point out that biomarkers need further evidence to define their role in early prediction of PE.

Discussion

Prediction of Preeclampsia

Asymptomatic pregnancies

A number of observational studies evaluating the predictive accuracy of PlGF screening have been published and these have been evaluated in a meta-analysis. The study, by Agrawal and colleagues (2019), reviewed 40 observational studies published through May 23, 2018 that included participants with singleton pregnancies who had no signs or symptoms of preeclampsia at the time of PlGF testing. The studies had a total sample size of 92,687 women, and 3189 (3.4%) of these developed preeclampsia. In individual studies, the sensitivity of PlGF testing for predicting preeclampsia varied from 7% to 93%, and the specificities varied from 51% to 97%. When data were pooled, the overall sensitivity was 0.61 (95% confidence interval [CI], 0.53 to 0.69) and the overall specificity was 0.85 (95% CI, 0.82 to 0.88).

Data from several large prospective screening studies were published after the meta-analysis. Tan and colleagues (2018) reported on 61,174 singleton pregnancies, 1770 (2.9%) of which had developed preeclampsia. At an examination between 11 weeks 0 days to 13 weeks 6 days gestation, medical history was assessed. Uterine artery pulsatility index (UtA-PI) and mean arterial pressure (MAP) were measured and serum concentration of PlGF and pregnancy-associated plasma protein-A (PAPP-A) was assessed. The investigators calculated models predicting preeclampsia with various combinations of predictors. At a screen-positive rate of 10% for preeclampsia, the detection rate using maternal factors alone was 44.8% (95% CI, 40.5% to 49.2%) for preeclampsia < 37 weeks. The addition of PlGF to maternal factors increased the detection rate to 60.6% (95% CI, 56.3% to 64.9%), and the addition of PAPP-A to maternal factors increased it slightly to 48.5% (95% CI, 44.1% to 52.9%). The combination of MAP and UtA-PI and maternal factors increased the detection rate to 68.4% (95% CI, 64.1% to 72.3%). When PlGF, MAP and UtA-PI were considered, along with maternal factors, the detection rate was 74.8% (95% CI, 70.8% to 78.5%). The addition of PAPP-A rather than PlGF, to the model containing maternal factors, MAP and UtA-PI, did not improve the detection rate.

In 2020, Mazer Zumaeta and colleagues reported on 60,875 women with singleton pregnancies, 1736 (2.9%) of whom developed preeclampsia. Participants underwent a range of screening tests during their first routine first-trimester hospital visit, including serum concentrations of the biomarkers PlGF and PAPP-A (using a DELFIA^® Xpress system, Revvity Inc., Waltham, MA). In an analytic model with a fixed screen-positive rate of 10%, the addition of serum PAPP-A did not improve the prediction of preeclampsia beyond that provided by maternal factors, MAP and the UtA-PI. The addition of PlGF did significantly improve the screening model compared with maternal factors alone and maternal factors and PAPP-A. Moreover, the performance of screening with PlGF, maternal factors, MAP and UtA-PI was superior to screening with PAPP-A, maternal factors, MAP and UtA-PI.

Tzanaki (2025) conducted a systematic review and meta-analysis evaluating PAPP-A as a first-trimester biomarker for predicting preeclampsia. The analysis included 22 prospective studies involving 33,651 pregnancies, of which 2001 developed preeclampsia. Women who subsequently developed preeclampsia had significantly lower first-trimester PAPP-A levels than controls. The association was strongest for early-onset preeclampsia (EOPE), where pooled analysis of 249 EOPE cases and 23,834 controls demonstrated a significantly lower level of PAPP-A in the EOPE cases, suggesting that low first-trimester PAPP-A levels are associated with increased risk of subsequent preeclampsia. Limitations of this study include heterogeneity among studies reflecting differences in study populations, laboratory assays, biomarker cutoff values, and reporting of preeclampsia subtypes. Some studies did not distinguish between early- and late-onset disease, potentially contributing to inconsistent results, and two studies reported findings that differed from the overall trend. Additionally, evidence from prior reviews suggests that PAPP-A alone has relatively limited predictive accuracy and performs best when incorporated into multimarker algorithms that include maternal characteristics, uterine artery Doppler findings, MAP, and other biomarkers such as PlGF.

Li (2026) reported on a retrospective case-control study that found lower first-trimester PAPP-A, higher free β-hCG, and higher neutrophil-to-lymphocyte ratio (NLR) were independently associated with subsequent development of preeclampsia and with adverse perinatal outcomes among women who developed preeclampsia. A combined model incorporating these three biomarkers performed better than any marker alone, achieving an area under the receiver operating characteristic curve (AUC) of 0.793 for predicting preeclampsia and 0.804 for predicting a composite adverse perinatal outcome, although discrimination remained only moderate. Because the study was retrospective, single-center, included only 350 women, and lacked external validation or comparison with established screening algorithms, the findings suggest potential biological relevance rather than proven clinical utility. Larger prospective studies are needed before these biomarkers can be considered reliable standalone screening tools for preeclampsia risk assessment.

Demuth (2026) conducted a prospective cohort study evaluating the soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio as a predictor of preeclampsia in asymptomatic women who had not given birth to a live baby previously. The study suggests that the sFlt-1:PlGF ratio has excellent predictive performance for early and preterm preeclampsia, particularly when measured at 20-24 weeks for early-onset disease (AUC 0.99) and at 30-34 weeks for preterm disease (AUC 0.96). However, the evidence is based on only eight preterm preeclampsia cases, making the results vulnerable to statistical instability. While the findings support the biologic and clinical potential of the sFlt-1:PlGF ratio as a risk-stratification tool in asymptomatic pregnancies, larger studies with more outcome events and validation in diverse populations are needed before routine screening use can be recommended.

No studies were identified that evaluated the mProbe (mProbe, Inc., Palo Alto, CA) preeclampsia test, which assesses levels of retinol-binding protein 4 (RBP4), endoglin (ENG) and Kinase Insert Domain Receptor (KDR). However, studies have evaluated the association between levels of individual proteins assessed in the test and preeclampsia. A 2019 prospective study by Leaños-Miranda of 1002 pregnant women presenting with preeclampsia, found that soluble endoglin (sEng) levels increased progressively with disease severity and were strongly associated with both maternal and neonatal complications. Women with the highest sEng concentrations had substantially increased risks of adverse outcomes, including renal failure, placental abruption, thrombocytopenia, elevated liver enzymes, preterm delivery, small-for-gestational-age infants, and maternal death. These findings suggest that sEng may be a useful prognostic biomarker for assessing severity and identifying women with preeclampsia who are at greatest risk for adverse outcomes, although further prospective studies are needed before routine clinical implementation . A 2022 systematic review and meta-analysis by Hamdan and colleagues found that levels of RBP4 were significantly higher in pregnant women with preeclampsia (n=569) compared with healthy controls (n=1411). The standardized mean difference (SMD) was 0.55 (95% CI, 0.06 to 1.05; p=0.028), indicating a moderate positive association between elevated RBP4 and preeclampsia.

Symptomatic pregnancies

In 2016, Zeisler and colleagues published findings from a prospective, multicenter, observational study evaluating whether the sFlt-1:PlGF ratio could predict the short-term absence or presence of preeclampsia in women with singleton pregnancies and suspected preeclampsia between 24 and 36 weeks of gestation. The study enrolled 1,273 women, of whom 1,050 met eligibility criteria and were included in the analysis (500 in the development cohort and 550 in the validation cohort). Researchers derived and validated an sFlt-1:PlGF ratio cutoff of 38. The primary finding was that an sFlt-1:PlGF ratio ≤38 was highly effective at ruling out preeclampsia within 1 week. In the validation cohort, the negative predictive value (NPV) was 99.3% (95% CI, 97.9-99.9), with 80.0% sensitivity and 78.3% specificity. Conversely, an sFlt-1:PlGF ratio >38 predicted development of preeclampsia within 4 weeks with a positive predictive value (PPV) of 36.7% (95% CI, 28.4-45.7), 66.2% sensitivity, and 83.1% specificity. The biomarker ratio also demonstrated good overall discriminatory ability. In the validation cohort, the AUC was 86.1% (95% CI, 79.8-92.4) for ruling out preeclampsia within 1 week and 82.3% (95% CI, 77.3-87.3) for ruling in preeclampsia within 4 weeks. Additionally, an sFlt-1:PlGF ratio ≤38 predicted the absence of fetal adverse outcomes within 1 week with an NPV of 99.3%, while a ratio >38 predicted fetal adverse outcomes within 4 weeks with a PPV of 47.5% in the validation cohort. Limitations include that the cutoff value was validated only using the Roche Elecsys sFlt-1 and PlGF assays, so the optimal threshold may differ with other testing platforms and the study was observational rather than randomized, meaning it did not evaluate whether incorporating the test into clinical decision-making improves outcomes or reduces hospitalizations. Also, the study included only singleton pregnancies in the primary analysis, limiting generalizability to multifetal gestations.

A 2020 prospective, multicenter observational study by Barton and colleagues enrolled 753 pregnant women with signs or symptoms of preeclampsia < 35 weeks’ gestation. PlGF levels were retrospectively analyzed from plasma samples, with a normal level of PlGF defined as > 100 pg/mL. A total of 542 (72%) of women delivered at < 37 weeks’ gestation and 358 (47%) delivered at < 34 weeks’ gestation. Compared with women with a normal PlGF level, women with PlGF ≤ 100 pg/ml had a significantly shorter time to delivery in multivariate models adjusting for gestational age and final diagnosis of preeclampsia (hazard ratio [HR], 7.17, 95% CI, 5.08 to 10.13).

A 2022 study by Thadhani and colleagues evaluated the BRAHMS PlGF and sFlt-1 KRYPTOR test (Thermo Fisher Scientific, Henningsdorf, Germany). The prospective study included 1014 hospitalized women over 18 years old with singleton pregnancies between 23 weeks, 0 days and 34 weeks, 6 days’ gestation who had a hypertensive disorder of pregnancy. The primary aim of the study was to validate the test, which measures the sFlt-1:PlGF ratio for predicting the development of preeclampsia with special features within 2 weeks of testing. Special features included severe hypertension, thrombocytopenia, impaired liver function, severe persistent right upper quadrant or epigastric pain, progressive renal insufficiency, pulmonary edema, new-onset cerebral or visual disturbances or medication-resistant headache. Initially, the test was evaluated in a derivation cohort. A total of 220 of 299 enrolled participants were included in the cohort; the remainder were excluded because they met criteria for special features at enrollment. From this derivation cohort, the investigators selected an sFlt-1:PlGF ratio of ≥ 40 for determining a positive test. For the validation cohort, 715 women were enrolled, of which 159 (22%) met criteria for special features at admission and were excluded, leaving 556 participants. The incidence of preeclampsia with special features within 2 weeks was 33.5%. Using the BRAHMS test with a cutoff of ≥ 40 for predicting preeclampsia with special features yielded a sensitivity of 94% (95% CI, 89 to 96%), a specificity of 75% (70 to 79%), a PPV of 65% (95% CI, 59 to 71%) and an NPV of 96% (95% CI, 93 to 98). The investigators also compared the performance of the sFlt-1:PlGF ratio to standard markers, including blood pressure, liver function tests, platelet counts and serum creatinine. They found an AUC for the sFlt-1:PlGF ratio of 0.92. The AUC for the individual standard markers were as follows: systolic blood pressure, 0.67; diastolic blood pressure, 0.70; platelet count, 0.57; and creatinine, 0.65. The authors did not state whether the above markers were systematically accessed. The article did not discuss whether use of the BRAHMS test would change clinical management or improve health outcomes.

Several meta-analyses of studies evaluating the performance of biomarkers and prediction of adverse outcomes in preeclampsia have been published. A meta-analysis of studies evaluating the sFLt-1:PlGF ratio in singleton pregnancies both with and without suspected preeclampsia was published in 2018 by Agrawal and colleagues. The investigators included 15 observational studies with a total of 534 cases of preeclampsia and 19,587 controls. The pooled sensitivity of the sFLt-1:PlGF ratio for predicting preeclampsia was 80% (95% CI, 68 to 88%) and the pooled specificity was 92% (95% CI, 87 to 96%). Separate analyses were not conducted for studies that included women with suspected preeclampsia compared to those that included women without suspected preeclampsia. In 2021, Lim and colleagues reviewed studies on the biomarkers soluble fms-like tyrosine kinase-1 (sFLt-1), PlGF and the sFLt-1:PlGF ratio. A total of 33 studies were included in their analysis, all of which were observational and included women with suspected and/or confirmed preeclampsia or hypertensive disorders of pregnancy. A meta-analysis of 7 studies on PlGF found a pooled sensitivity of 76% (95% CI, 54% to 89%) and a pooled specificity of 71% (95% CI, 55% to 83%) for predicting preterm birth. A meta-analysis of 5 studies on the sFLt-1:PlGF ratio found a pooled sensitivity of 74% (95% CI, 59% to 85%) and a pooled specificity of 80% (95% CI, 67% to 89%) for predicting preterm birth. An analysis of the diagnostic accuracy of the sFLt-1:PlGF ratio for predicting adverse maternal outcomes included 5 studies and found a pooled sensitivity of 67% (95% CI, 46% to 82%) and a pooled specificity of 77% (95% CI, 66% to 86%).

Clinical Utility of Serum Biomarker Tests

No RCTs were identified that compared participant management or clinical outcomes in pregnant individuals screened for preeclampsia with maternal risk factors only as opposed to individuals screened with maternal risk factors plus biomarkers such as PlGF or PAPP-A.

The ASPRE trial was a double-blind RCT comparing treatment with 150 mg per day of aspirin compared to placebo from 11-14 until 36 weeks’ gestation in individuals at increased risk (at least 1 in 100) of delivery with preterm (< 37 weeks’ gestation) preeclampsia (Rolnik, 2017). Risk of preterm preeclampsia was assessed using an algorithm that included maternal risk factors, MAP, the UtA-PI and the maternal serum biomarkers PAPP-A and PlGF. PlGF concentrations were measured using the PlGF 1-2-3tm kits (Revvity Inc). After initial exclusions, 25,797 individuals pregnant with singletons were screened for eligibility and 2707 (10.5%) individuals were eligible for participation. Of these, 1595 (59%) agreed to participate; 785 were assigned to the aspirin group and 806 were assigned to the placebo group. In the aspirin group, there were 13 (1.66%) observed cases of preterm preeclampsia and 53 (6.75%) cases of term preeclampsia. In the placebo group, there were 35 (4.34%) cases of preterm preeclampsia and 59 (7%) cases of term preeclampsia. The rate of preterm preeclampsia was 62% lower in the aspirin-treated group than the placebo group, but there was no significant difference in term preeclampsia between the groups. In the trial, only about 10% of individuals screened were found to be at increased risk of preterm preeclampsia. Moreover, the 62% risk reduction for preterm preeclampsia in the ASPRE trial was a relative risk; the absolute risk reduction was 2.68%. Furthermore, the study lacked a comparison between the maternal risk factors alone and maternal risk factors plus biomarkers.

Professional Organizations

The USPSTF recommendation on preeclampsia screening (2023) is: “The USPSTF recommends screening for hypertensive disorders in pregnant persons with blood pressure measurements throughout pregnancy. (B recommendation).” The recommendation does not mention screening with biomarker tests.

In 2020, ACOG stated, “biomarkers and ultrasonography cannot accurately predict preeclampsia and should remain investigational.” The ACOG document stated:

…Extensive work has identified some angiogenic factors (soluble fms-like tyrosine kinase-[sFlt-1], placental growth factor [PlGF], and soluble endoglin) in the second trimester as likely tools for the prediction of early-onset preeclampsia. However, no single test reliably predicts preeclampsia and further prospective investigation is required to demonstrate clinical utility. In the first trimester of pregnancy, it has been reported that a combination of low maternal serum concentrations of PlGF, high uterine artery pulsatility index, and other maternal parameters, identified 93.1% of patients who would develop preeclampsia requiring delivery before 34 weeks of gestation. However, the results of this study are based on mathematical modeling derived from a nested case-control study applied to a large cohort of almost 7,800 patients in which PlGF was measured only in the case-control group. The calculated positive predictive value was only 21.2%, indicating that approximately 79% of the women in the screen-positive group would not develop hypertensive disorders during pregnancy. Of note, a similar algorithm underperformed in a subsequent randomized trial performed by the same research group. Thus, biomarkers and ultrasonography cannot accurately predict preeclampsia and should remain investigational.

FIGO (Poon, 2019) initially supported biomarkers-based screening in its May 2019 article, The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Preeclampsia (PE): A Pragmatic Guide for First Trimester Screening and Prevention by stating that “All pregnant women should be screened for preterm PE during early pregnancy by the first-trimester combined test with maternal risk factors and biomarkers as a one-step procedure.” An erratum was published in September 2019, followed by an additional correction in October 2019:

Universal Screening: All pregnant women should be screened for preterm PE during early pregnancy in the first trimester with maternal risk factors and blood pressure. Biomarkers offer a potential for early diagnosis and effective treatment; however, the global community recognizes that further evidence for their applicability in all populations and ethnic groups is required at this stage. While several studies have evaluated the role of biomarkers or a combination of physical and chemical measurements, further studies are needed to define their additional role in improving early prediction of preterm PE. FIGO encourages all countries and its member associations to adopt and promote strategies to ensure quality research and eventual consensus.

Preeclampsia affects approximately 5 to 10% of pregnancies in the United States (Centers for Disease Control [CDC], 2024). Diagnostic criteria for preeclampsia are new-onset hypertension and proteinuria or, in the absence of proteinuria, new-onset hypertension in combination with any of the following: thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema or unexplained new-onset headache unresponsive to medication (American College of Obstetricians and Gynecologists [ACOG], 2020).

Standard practice regarding preeclampsia prevention is to screen for traditional risk factors for preeclampsia at the first prenatal visit. At subsequent prenatal visits, preeclampsia screening generally consists of measuring blood pressure. Measurement of blood pressure before 20 weeks can establish baseline values with which to compare values later in pregnancy. The U.S. Preventive Services Task Force (USPSTF,2021) recommended that individuals with at least one high-risk factor receive low-dose aspirin to prevent preeclampsia. Factors suggesting high-risk include a history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal disease or an autoimmune disease (for example, systemic lupus erythematosus, antiphospholipid syndrome). Similarly, in 2018, ACOG and the Society for Maternal-Fetal Medicine (SMFM) recommended the following:

• Low-dose aspirin (81 mg/day) prophylaxis is recommended in women at high risk of preeclampsia and should be initiated between 12 weeks and 28 weeks of gestation (optimally before 16 weeks) and continued daily until delivery.
• Low-dose aspirin prophylaxis should be considered for women with more than one of several moderate risk factors for preeclampsia.

Individuals with preeclampsia are monitored for worsening of the condition. Preeclampsia can be a progressive disorder and impact multiple systems. ACOG (2020) identified the following maternal conditions that, if present, would indicate expedited delivery after stabilization:

• Uncontrolled severe-range blood pressures (persistent systolic blood pressure 160 mm Hg or more or diastolic blood pressure 110 mm Hg or more not responsive to antihypertensive medication)
• Persistent headaches, refractory to treatment
• Epigastric pain or right upper quadrant pain unresponsive to repeat analgesics
• Visual disturbances, motor deficit or altered sensorium
• Stroke
• Myocardial infarction
• HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets)
• New or worsening renal dysfunction (serum creatinine greater than 1.1 mg/dL or twice baseline)
• Pulmonary edema
• Eclampsia
• Suspected acute placental abruption or vaginal bleeding in the absence of placenta previa

Screening for biomarkers in serum is proposed as a supplement to the assessment of risk factor screening. Levels of placental growth factor (PlGF) tend to drop during pregnancy in women who later develop pre-eclampsia, and this drop may precede the development of signs or symptoms of preeclampsia (Argawal, 2019). Moreover, the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) tends to be elevated in symptomatic pregnant individuals before the onset of overt preeclampsia (Zeisler, 2016). In addition, lower levels of pregnancy-associated plasma protein-A (PAPP-A), which has been used for several decades in screening for fetal aneuploidies, has been associated with increased risk of adverse pregnancy outcomes such as preeclampsia (Kalousová, 2014).

Revvity Inc. offers two PlGF Preeclampsia Screening tests. The DELFIA Xpress PlGF 1-2-3^TM kit quantifies the level of free PlGF in maternal serum. The kit is intended for use in the first trimester of pregnancy but can be used after 20 weeks’ gestation as a standalone PlGF test. Revvity Inc. also offers the DELFIA Xpress sFlt-1/PlGF Ratio kit, which is intended to be used in the second and third trimesters for individuals with signs or symptoms of preeclampsia. The second and third trimester test determines serum soluble fms-like tyrosine kinase-1 (sFlt-1) and PlGF levels, and expresses them as a ratio (sFlt-1 to PlGF ratio). An increased ratio can be used as an aid to identify preeclampsia.

The Preeclampsia Screen | T1℠ test (Eurofins NTD Genetics, Melville, NY) assesses the risk of early onset preeclampsia. Early onset preeclampsia is defined as preeclampsia that results in delivery before 34 weeks’ gestation. The test, which is performed between 10 weeks, 0 days and 13 weeks, 6 days gestation, calculates a risk score based on personal history, ultrasound markers, blood pressure, and 3 serum biomarkers, PlGF as well as PAPP-A and alpha fetoprotein (AFP).

The Elecsys^® sFlt-1/PlGF (Preeclampsia) (Roche Diagnostics, Indianapolis, IN) measures the sFlt-1:PlGF ratio. It is intended to be used with first trimester screening to aid in the diagnosis of preeclampsia and identify women who may benefit from prophylactic treatment with aspirin. The U.S. Food and Drug Administration (FDA) granted clearance for this test on February 7, 2025 (K241453).

Thermo Fisher’s BRAHMS sFlt-1/PlGF KRYPTOR Test measures the sFlt-1:PlGF ratio. The test is designed for use with women with singleton pregnancies between 23 weeks, 0 days and 34 weeks, 6 days gestation who are hospitalized for hypertensive disorders of pregnancy to identify cases likely to progress to preeclampsia with severe features. In 2023, the test received De Novo classification by the FDA as a Class II device. The FDA determined that the Class II device satisfied the requirement for Special Controls such as determining that test results were accurate. The FDA document stated, “FDA believes that class II (special) controls provide reasonable assurance of the safety and effectiveness of the device type.”

mProbe’s preeclampsia test is another test designed to be used in the first trimester of pregnancy to identify women at increased risk of preeclampsia who might benefit from prophylactic aspirin therapy. The test examines three proteins (retinol-binding protein 4 [RBP4], endoglin [ENG] and Kinase Insert Domain Receptor [KDR]), and uses a proprietary algorithm to develop a preeclampsia risk score.

The QTriage^® PlGF Test (QuidelOrtho^TM, San Diego, CA) is used in conjunction with other clinical information to aid in the diagnosis of preeclampsia.

Female: Refers to sex assignment at birth, The gender descriptions used in this document, for example, ‘female’, ‘woman’, and ‘women’, refer to the reproductive capacity of the individual, regardless of gender identity or expression.

Preeclampsia: High blood pressure disorder related to pregnancy.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Agrawal S, Cerdeira AS, Redman C, Vatish M. Meta-analysis and systematic review to assess the role of soluble FMS-like tyrosine kinase-1 and placenta growth factor ratio in prediction of preeclampsia: the SaPPPhirE Study. Hypertension. 2018; 71(2):306-316.
2. Agrawal S, Shinar S, Cerdeira AS, et al. Predictive performance of PlGF (placental growth factor) for screening preeclampsia in asymptomatic women: a systematic review and meta-analysis. Hypertension. 2019; 74(5):1124-1135.
3. Barton JR, Woelkers DA, Newman RB, et al. Placental growth factor predicts time to delivery in women with signs or symptoms of early preterm preeclampsia: a prospective multicenter study. Am J Obstet Gynecol. 2020; 222(3):259.e1-e259.e11.
4. Hamdan HZ, Ali T, Adam I. Association between retinol-binding protein 4 levels and preeclampsia: a systematic review and meta-analysis. Nutrients. 2022; 14(24):5201.
5. Kalousová M, Muravská A, Zima T. Pregnancy-associated plasma protein A (PAPP-A) and preeclampsia. Adv Clin Chem. 2014; 63:169-209.
6. Leaños-Miranda A, Navarro-Romero CS, Sillas-Pardo LJ, et al. Soluble endoglin as a marker for preeclampsia, its severity, and the occurrence of adverse outcomes. Hypertension. 2019; 74(4):991-997.
7. Li X, Ying J, Xu B, et al. First-trimester β-hCG, PAPP-A, and NLR in relation to preeclampsia and perinatal outcomes: a case-control study. Sci Prog. 2026; 109(1):368504261430053.
8. Lim S, Li W, Kemper J, Nguyen A, et al. Biomarkers and the prediction of adverse outcomes in preeclampsia: a systematic review and meta-analysis. Obstet Gynecol. 2021; 137(1):72-81.
9. Mazer Zumaeta A, Wright A, et al. Screening for pre-eclampsia at 11-13 weeks' gestation: use of pregnancy-associated plasma protein-A, placental growth factor or both. Ultrasound Obstet Gynecol. 2020; 56(3):400-407.
10. Rolnik DL, Wright D, Poon LCY, et al. ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol. 2017; 50(4):492-495.
11. Tan MY, Syngelaki A, Poon LC, et al. Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation. Ultrasound Obstet Gynecol. 2018; 52(2):186-195.
12. Thadhani T, Lemoine E, Rana S, et al. Circulating angiogenic factor levels in hypertensive disorders of pregnancy. NEJM Evidence. 2022; 1(12):1-13.
13. Tzanaki I, Makrigiannakis A, Lymperopoulou C, et al. Pregnancy-associated plasma protein A (PAPP-A) as a first trimester serum biomarker for preeclampsia screening: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2025; 38(1):2448502.
14. Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016; 374(1):13-22.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin, Number 222. Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2020; 135(6):e237-e260.
2. American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal Fetal Medicine (SMFM). Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol. 2018; 132(1):e44-e52.
3. Centers for Disease Control and Prevention. Preeclampsia, Genomics and Public Health. 2022. Available at: https://blogs.cdc.gov/genomics/2022/10/25/preeclampsia/#:~:text=Preeclampsia%20is%20estimated%20to%20occur,and%20500%2C000%20fetal%20deaths%20worldwide. Accessed on July 30, 2026.
4. Demuth B, Cavalcanti D, Guerby P, et al. SFlt-1/PlGF ratio for the prediction of preeclampsia in asymptomatic women. J Obstet Gynaecol Can. 2026 Apr 27; [Epub ahead of print]. Available at: https://pubmed.ncbi.nlm.nih.gov/42055253/. Accessed on July 30, 2026.
5. Poon LC, Shennan A, Hyett JA, et al. Erratum to "The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention" [Int J Gynecol Obstet 145 Suppl. 1 (2019) 1-33]. Int J Gynaecol Obstet. 2019; 146(3):390-391.
6. Society for Maternal and Fetal Medicine (SMFM) Patient Safety and Quality Committee. Combs CA, Montgomery DM. Society for Maternal-Fetal Medicine Special Statement: checklists for preeclampsia risk-factor screening to guide recommendations for prophylactic low-dose aspirin. Am J Obstet Gynecol. 2020; 223(3):B7-B11.
7. U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force final recommendation statement. September 28, 2021. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication#fullrecommendationstart. Accessed on July 30, 2026.
8. U.S. Preventive Services Task Force. Hypertensive Disorders of Pregnancy: September 19, 2023. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertensive-disorders-pregnancy-screening. Accessed on July 30, 2026.

1. National Institute of Child Health and Human Development (NICHD). Preeclampsia and Eclampsia. Last Reviewed January 31, 2017. Available at: https://www.nichd.nih.gov/health/topics/preeclampsia. Accessed on July 30, 2026.

Endoglin
Placental Growth Factor
Pregnancy-associated plasma protein-A
Retinol-binding protein 4

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