| Coverage Policy Manual | |
| Policy #: | 2022007 |
| Category: | Laboratory |
| Initiated: | February 2022 |
| Last Review: | March 2024 |
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| Maternal Serum Biomarkers for Prediction of Adverse Obstetric Outcomes | |
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| Description: |
Hypertensive disorders in pregnancy affected approximately 1 in 7 delivery hospitalizations between 2017 and 2019 in the US with prevalence being approximately 1 in 5 delivery hospitalizations among Black women and 1 in 3 among women aged 45–55years (Ford, 2022). Preeclampsia is defined as new onset maternal hypertension and proteinuria or new onset hypertension and significant end-organ dysfunction (with or without proteinuria) after the 20th week of gestation (Henderson, 2021).
Maternal complications of preeclampsia include progression to eclampsia, placental abruption, and a life-threatening complication known as the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. In the fetus, preeclampsia can lead to fetal growth restriction and intrauterine fetal death. Preeclampsia can develop in nulliparous women with no known risk factors (SMFM, 2021). Maternal factors associated with an increased risk of preeclampsia include advanced maternal age, presence of a chronic illness such as diabetes mellitus, chronic hypertension, chronic kidney disease, or systemic lupus erythematosus, obesity, multiple gestations, and a prior history of preeclampsia. Preeclampsia can also develop in the postpartum period. In women determined to be at increased risk of developing preeclampsia, the use of daily, low-dose aspirin beginning in the 12th week of gestation is associated with a reduction in risk and is recommended by the U.S. Preventive Services Task Force (USPSTF) and the American College of Obstetricians and Gynecologists (ACOG) (ACOG, 2020; Davidson, 2021).
Despite decades of research, accurate identification of women at risk of preeclampsia, particularly prior to the 20th week of gestation, remains challenging (SMFM, 2021). Standard methods for preeclampsia risk-factor assessment are based on medical and obstetric history and clinical assessment, including routine maternal blood pressure measurement at each prenatal visit (ACOG, 2020). The use of maternal serum biomarker assays as an adjunct to standard preeclampsia risk assessment has been suggested as a mechanism that could improve accurate identification of at-risk individuals. More accurate identification of risk could create an opportunity for additional assessment, surveillance, and interventions that would ultimately reduce the maternal and fetal or newborn morbidity and mortality associated with preeclampsia. Individual maternal serum biomarkers, such as serum placental growth factor (PlGF), soluble Fms-like tyrosine kinase 1 (s-Flt 1), and pregnancy-associated plasma protein A (PAPP-A) have been investigated as predictors of preeclampsia (Poon, 2019). Multivariable preeclampsia risk assessment tools have been developed that incorporate maternal serum biomarkers; several of these tools have been commercially produced (see Regulatory Status) but few have been externally validated (Chaemsaithong, 2020). Clinically useful risk assessment using maternal serum biomarker testing would need to show increased predictive value over standard assessment of preeclampsia risk without serum biomarker testing.
Preterm birth is defined as birth occurring between the 20th and 37th week of pregnancy and can be spontaneous following preterm labor and rupture of membranes or iatrogenic due to clinical interventions for maternal or fetal medical indications. The preterm birth rate was estimated by the Centers for Disease Control (CDC) to be 10.1% (about 360,000 births were preterm among 3,600,000 births) in 2020 in the United States and has consistently been approximately 10% for over a decade (Hamilton, 2021). Preterm birth rates vary according to race and ethnicity independent of social determinants of health, ranging from 8.5% for Asian women to 14.4% for non-Hispanic Black women. Prior preterm birth is the strongest predictor of a subsequent preterm birth, although absolute risk varies according to the gestational age of the prior preterm birth and maternal clinical factors (Mazaki-Tovi, 2007). Characteristics in a current pregnancy that increase the risk of preterm birth include cervical changes (shortened length and/or early dilation), vaginal bleeding or infection, and maternal age under 18 years or over 35 years. Smoking, pre-pregnancy weight, interpregnancy interval, maternal stress, and lack of social support have also been associated with an increased risk of preterm birth. Despite recognition of risk factors, most preterm births occur without clearly identifiable maternal risk factors (Cobo, 2020). Maternal consequences of preterm delivery include intrapartum and postpartum infection. Psychosocial adverse effects including postpartum depression have been reported. Infants born preterm have an increased risk of death up to 5 years of age relative to full-term infants. Preterm birth is also associated with morbidity extending into adulthood (Jackson, 2021).
Cervical length is one measure available to clinicians to assess risk of preterm birth. Shortened cervical length prior to 24 weeks gestation is associated with an increased risk of preterm birth. The ACOG recommends ultrasonographic assessment of cervical length in the second trimester to identify women at an increased risk of preterm birth (Jackson, 2021). In women with a prior history of preterm birth, serial measurement of cervical length using transvaginal ultrasound is recommended, although optimal timing of measurements has not been clinically established. In women without a history of preterm birth or other risk factors, universal ultrasonographic screening of cervical length in women has not been demonstrated to be an effective strategy due to the overall low incidence in this group. In women determined to have a shortened cervix and therefore an increased risk of preterm birth, the use of either vaginal or intramuscular progesterone supplementation has been associated with a reduced risk of preterm birth. There are some limitations in assessment of cervical length in predicting risk of preterm birth. These limitations include uncertainty as to what constitutes “shortened” length, with transvaginal ultrasound measurements ranging from <15 mm to <25 mm implicated in indicating increased risk and uncertainty regarding ideal timing of ultrasonographic assessment (Jackson, 2021).
Given the limitations of cervical length assessment in predicting risk of preterm birth, the use of other biomarkers has been suggested as a mechanism that could improve accurate identification of women at risk of preterm birth, including maternal serum biomarkers (Lucaroni, 2018).
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests. Therefore, maternal serum biomarker tests would be provided by CLIA licensed laboratories.
The B·R·A·H·M·S sFlt-1/ PlGF KRYPTOR Test System (Thermo Fisher Scientific) was cleared for marketing by the FDA as a prognostic test through the De Novo process (DEN220027) in May 2023 (U.S. FDA, 2024). The Test System includes quantitative determination of Placental Growth Factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in human serum and plasma. The clearance letter states that the Test System is to be used along with other laboratory tests and clinical assessments to aid in the risk assessment of pregnant women (singleton pregnancies between gestational age 23+0 to 34+6/7 weeks) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension) for progression to preeclampsia with severe features (as defined by the American College of Obstetricians and Gynecologists (ACOG) guidelines) within 2 weeks of presentation.
Commercially produced, maternal serum biomarker tests for preeclampsia include the Triage PlGF™ (Quidel), Elecsys sFlt-1/PlGF (Roche Diagnostics), and DELFIA Xpress PIGF 1-2-3 (PerkinElmer) (McCarthy, 2019). These commercially produced tests are not currently available in the United States.
The PreTRM test (Sera Prognostics) uses maternal serum biomarkers (insulin-like growth factor binding protein-4 [IBP4] and sex hormone binding globulin [SHBG]) in combination with biometric measures to assess the risk of spontaneous preterm birth (Sera Prognostics, 2021). According to the manufacturer, the PreTRM test is only intended to be used in women aged 18 years or older, who are asymptomatic (that is, with no signs or symptoms of preterm labor, with intact membranes, and with no first trimester progesterone use) with a singleton pregnancy. The PreTRM test is performed via a single blood draw during the 19th week of gestation.
Coding
There are no specific Category 1 CPT codes for these tests. The following CPT code may be billed.
81599 Unlisted multianalyte assay with algorithmic analysis [when specified as a multiple biomarker test for risk of preeclampsia]
The following Proprietary Laboratory Analysis codes may be used to bill for these tests.
0243U Obstetrics (preeclampsia), biochemical assay of placental-growth factor, time-resolved fluorescence immunoassay, maternal serum, predictive algorithm reported as a risk score for preeclampsia
0247U Obstetrics (preterm birth), insulin-like growth factor-binding protein 4 (IBP4), sex hormone-binding globulin (SHBG), quantitative measurement by LC-MS/MS, utilizing maternal serum, combined with clinical data, reported as predictive-risk stratification for spontaneous preterm birth
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Policy/ Coverage: |
Effective June 2022
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of preeclampsia does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of preeclampsia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of spontaneous preterm birth does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of spontaneous preterm birth is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
New policy with literature search using MEDLINE database through December 2021.
Maternal Serum Biomarker Testing for Preeclampsia in Women Without Known Risk Factors
Agrawal et al conducted a systematic review that included 40 observational studies (N=92,687) on the predictive ability of PlGF testing in women without known risk factors (Agrawal, 2019). Studies that analyzed PlGF in conjunction with other biomarkers were excluded. The timing of PlGF testing was <14 weeks in 15 studies, greater than or equal to 14 weeks in 25 studies, and ≥19 weeks in 18 studies. Most studies (37/40) used a definition of preeclampsia that required presence of proteinuria. Individual study sensitivity and specificity ranged from 7% to 93% and 51% to 97%, respectively. When all studies were included in a pooled analysis, sensitivity was 61% (95% confidence interval [CI], 53 to 69%), specificity was 85% (95% CI, 82 to 88%) and heterogeneity was high (I2=99%).
A second systematic review conducted by Agrawal et al assessed the diagnostic accuracy of the sFlt-1/PlGF ratio for prediction of preeclampsia (Agrawal, 2018). The review included 15 studies, all assessing risk after the 19th week of gestation. Among the 15 included studies (N=20,121), 8 were conducted in women (N=19,038) at low-risk of developing preeclampsia based on clinical characteristics. Sensitivity and specificity ranged widely in the individual studies, which reported sensitivities of 23% to 97% and specificities from 64% to 100%. When pooled, sensitivity was 77% (95% CI, 61% to 88%) and specificity was 94% (95% CI, 88% to 97%) with very high heterogeneity (I2=94% and 100%, respectively).
Mazer Zumaeta et al conducted a cohort study (published subsequent to the Agrawal 2019 systematic review) evaluating the diagnostic accuracy of adding measurement of PlGF and PAPP-A using the DELFIA Xpress assay system to standard clinical management (Mazer, Zumaeta, 2020). The study included 60,875 pregnant women undergoing routine, first trimester aneuploidy screening. PlGF and PAPP-A measurement took place at 11 to 13 weeks gestation. The addition of PlGF to maternal clinical characteristics was associated with improvement in the detection rate of preeclampsia at <34 and at <37 weeks (p<.0001 for both time points.) Inclusion of PAPP-A was not associated with improved detection of preeclampsia at <34 weeks (p=.08) but did improve detection rate at <37 weeks (p<.04).
Maternal Serum Biomarker Testing for Preeclampsia in Women With Known Risk Factors
Two systematic reviews conducted by Veisani et al, and Agrawal et al, assessed the diagnostic accuracy of sFlt-1, PlGF, and the sFlt-1/PlGF ratio for prediction of preeclampsia in women with known risk factors (Veisani, 2019; Agrawal, 20198). The Veisani review included 15 studies measuring sFLT-1 or PlGF at gestational weeks 1 to 12 in 1 study and in the 2nd or 3rd trimester in the remaining 14 studies. The review found serum sFlt-1 values above the study cut-off point were associated with an increased risk of preeclampsia based on 3 studies that reported odd ratios ranging from 2.20 to 7.50. The pooled odds ratio for sFlt-1 was 5.20 (95% CI, 1.24 to 9.16) with high heterogeneity (I2=82%). For PlGF, a serum level below the cut-off point was predictive of preeclampsia development based on 4 studies with individual odds ratios ranging from 2.30 to 4.28; pooled odds ratio was 2.53 (95% CI, 1.33 to 3.75) with no heterogeneity (I2=0%).
The systematic review conducted by Agrawal et al, (described above) assessing the diagnostic accuracy of the sFlt-1/PlGF ratio for prediction of preeclampsia included 7 studies conducted in women at high-risk of developing preeclampsia based on clinical characteristics (that is, with known risk factors). Among the included studies, sensitivity ranged from 67% to 100%, and specificity ranged from 68% to 100% (Agrawal, 2018). When pooled, sensitivity was 85% (95% CI, 66% to 94%) and specificity was 87% (95% CI, 76% to 93%). Heterogeneity was high for both measures (I2=75% and 79%, respectively).
McCarthy et al conducted a retrospective analysis of data from industry-sponsored, prospective cohort studies comparing the diagnostic accuracy of 3 commercially produced maternal serum biomarker tests (Triage PlGF, DELFIA XPress PlGF 1-2-3 and Elecsys sFlt-1/PlGF) (McCarthy, 2019). In this analysis, diagnostic accuracy was based on delivery within 14 days of testing due to preeclampsia in women less than 35 weeks gestation. Sensitivities were 81% (95% CI, 61% to 93%), 88% (95% CI, 68% to 97%), and 75% (95% CI, 53% to 90%) for the Triage PlGF, DELFIA, and Elecsys tests, respectively. Corresponding specificities were 80% (95% CI, 74% to 84%), 77% (95% CI, 70% to 83%), and 90% (95% CI, 85% to 94%). The area under the receiver operating characteristic (AUROC) was 0.85 (95% CI, 0.75 to 0.95) for the Triage PlGF test, 0.86 (95% CI, 0.76 to 0.95) for the DELFIA test and 0.88 (95% CI, 0.78 to 0.97) for the Elecsys test.
No RCTs were identified.
Lim et al conducted a systematic review analyzing the clinical utility of sFlt-1 and PlGF individually and in combination as the sFlt-1/PlGF ratio in predicting adverse obstetric outcomes (Lim, 2021). The review only included studies of women (N=9,246) with suspected or confirmed preeclampsia. All of the 33 included studies were observational (prospective cohort, retrospective cohort, or case control), and were heterogeneous in a number of important factors, including the definition of preeclampsia used in the study, the method of evaluating and cut-off values for biomarkers, the definition of adverse obstetric outcomes, and the methods for reporting results. The timing of biomarker testing ranged from 18 to 40 weeks gestation. Evidence on sFlt-1 was too limited to pool. Although both PlGF and the sFlt-1/PlGF ratio were associated with AUROC values that suggested acceptable statistical discrimination for the outcomes analyzed, the clinical utility of the results is limited by significant heterogeneity and/or imprecision for nearly all outcomes.
Maternal Serum Biomarker Testing for Spontaneous Preterm Birth in Women Without Known Risk Factors
Saade et al reported on the development and validation of IBP4 and SHBG testing for prediction of spontaneous preterm birth in the Proteomic Assessment of Preterm Risk (PAPR) study (Saade, 2016). The PAPR study prospectively enrolled 5,501 women with a singleton pregnancy and without risk factors for spontaneous preterm birth from the 17th to 28th week of gestation. Analysis of serum samples collected during the development phase of PAPR identified IBP4 and SHBG as potential predictors of spontaneous preterm delivery based on an analysis of 44 biomarkers. In addition, the optimal timing of serum sampling was determined to be from 19 weeks, 0 days to 21 weeks, 6 days. Following delivery, investigators identified 217 cases of spontaneous preterm birth and 4,292 controls. Using a cut-off of <37 versus ≥37 gestational weeks, the IBP4/SHBG ratio sensitivity was 75% and specificity 74% (95% CI not reported). This corresponded to an AUROC of 0.75 (95% CI, 0.56 to 0.91). Lowering the gestational age cut-off to 35 weeks, sensitivity improved to 100%, specificity 83%, and AUROC 0.93 (95%, CI 0.81 to 1.00). A limitation of the study was the lack of cervical measurement by transvaginal ultrasound in 2/3 of study participants.
Markenson et al assessed the clinical validity of the IBP4/SHBG ratio for prediction of spontaneous preterm birth in The Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP) study (Markenson, 2020). TREETOP prospectively enrolled 5,011 women with a singleton pregnancy who were asymptomatic for preterm birth. TREETOP was planned as a 2-phase study. In the first phase of the study 1,251 (of 5,011) women were randomly selected for inclusion. Of those 1,251 women, 847 who had serum sampling conducted from 19 weeks, 1 day to 20 weeks, 6 days (the optimal timing determined in PAPR) were ultimately included in the results. A cut-off of <32 weeks gestational age was associated with an AUROC of 0.71 (95% CI, 0.55 to 0.87). When stratified according to body mass index (BMI) that was either >37 kg/m2 or ≤22 kg/m2, the AUROC improved to 0.76 (95% CI, 0.59 to 0.93). No data were reported for other potential maternal factors that could impact the predictive ability of the IBP4/SHBG ratio, such as maternal age and cervical length. Sensitivity and specificity were also not reported by Markenson et al. Assessment of these measures is planned for inclusion in the currently unpublished 2nd phase of the TREETOP study.
Both the PAPR and TREETOP studies were funded by Sera Prognostics, the manufacturer of the PreTRM test (SeraPrognostics, 2021).
Maternal Serum Biomarker Testing for Spontaneous Preterm Birth in Women With Known Risk Factors
A systematic review of 72 observational studies (N=89,786) conducted by Conde-Agudelo et al, evaluated 30 biomarkers for prediction of spontaneous preterm birth (Conde-Agudelo, 2011). The review included cohort, cross-sectional, or case-control studies conducted in women with singleton pregnancy and without symptoms indicating impending spontaneous preterm birth. Of the 30 biomarkers assessed in the review, 18 were serum biomarkers that included:
Serum alpha-fetoprotein and estriol were specifically excluded from the review, as they were previously established as having minimal utility in predicting spontaneous preterm birth (Honers, 2009). Seven biomarkers (C-reactive protein, Ferritin, Granulocyte CSF, Interleukin-6, Pregnancy-associated plasma protein, Relaxin, Thrombin-antithrombin III complex) evaluated in multiple studies lacked adequate predictive ability suitable for use in clinical practice. The remaining 11 biomarkers were assessed in single studies and were also poor predictors of spontaneous preterm birth based on low sensitivity.
Practice Guidelines and Position Statements
American College of Obstetricians and Gynecologists and The Society for Maternal-Fetal Medicine
The American College of Obstetricians and Gynecologists (ACOG) issued updated clinical practice guidelines in 2020 on preeclampsia, and 2021 on preterm birth (ACOG, 2020; Jackson, 2021). Maternal serum biomarker screening is described as investigational and is not recommended by ACOG as a factor included in risk assessment for either preeclampsia or spontaneous preterm birth.
The 2021 joint ACOG-Society for Maternal-Fetal Medicine (SMFM) guidance on the use of aspirin for prevention of preeclampsia does not include results of maternal serum biomarker testing among the risk factors to be used to identify women at risk of preeclampsia (ACOG, 2021).
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (USPSTF) issued updated recommendations in 2021 on the use of aspirin for the prevention of preeclampsia (Davidson, 2021). The USPSTF does not include maternal serum biomarker testing among factors used in preeclampsia risk assessment. In addition, the recommendation notes "predictive models that combine risk factors to identify pregnant persons at risk for preeclampsia, such as serum biomarkers, uterine artery Doppler ultrasonography, and clinical history and measures, have been developed. However, there is limited evidence from external validation and implementation studies to demonstrate sufficient accuracy of predictive models for clinical use."
Ongoing and Unpublished Clinical Trials
Currently ongoing and unpublished trials that might influence this review are listed below.
Ongoing
NCT05131282 A Case-control Study to Investigate Serum Markers in Predicting Preeclampsia
Planned Enrollment: 300 Completion Date: Dec 2022
NCT04301518a Prematurity Risk Assessment Combined With Clinical Interventions for Improving Neonatal outcomes
Planned Enrollment: 6,500 Completion Date: Sep 2022
NCT03151330 Serum Assessment of Preterm Birth: Outcomes Compared to Historical Controls
Planned Enrollment: 2,100 Completion Date: Jun 2022
Unpublished
NCT03455387 Evaluation of the SerumMarkers sFLt1 and PlGF for the Prediction of the Complications of the Placental Vascular Pathologies in the 3rd Quarter of the Pregnancy
Planned Enrollment: 250 Completion Date: Mar 2020
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Parry et al conducted a nested case-control study based on data from a prospective cohort study assessing the relationship between a range of maternal serum biomarkers, including sFlt-1, PlGF, and the sFlt-1/PlGF ratio, and risk of preeclampsia (Parry, 2022). The study compared 568 cases of preeclampsia with 911 healthy (term delivery with no adverse pregnancy outcomes) controls. Maternal serum samples were collected at 6 to 13 weeks (first visit) and 16 to 21 weeks (second visit). The study found that women who developed preeclampsia were more likely to have sFlt-1 and PlGF levels below normal at both the first visit and the second visit, and a higher sFlt-1/PlGF ratio at both visits relative to controls. However, AUC analyses did not indicate that these measures had acceptable discrimination at either time point. For sFlt-1, the AUC was 0.56 (95% CI, 0.53 to0.59) at the first visit and 0.54 (95% CI, 0.50 to 0.57) at the second visit. AUCs for PlGF and the sFlt-1/PlGF ratio were 0.56(95% CI, 0.52 to 0.59) and 0.51 (95% CI, 0.48 to 0.54) at the first visit, and 0.62 (95% CI, 0.59 to 0.65) and 0.57 (95% CI, 0.54 to0.60) at the second visit. Results were similar for other maternal serum biomarkers (e.g., PAPP-A), and study authors concluded that use of these biomarkers to predict adverse pregnancy outcomes were not supported by the study results.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In the US, the US Preventive Services Task Force (USPSTF) and the American College of Obstetricians and Gynecologists (ACOG) recommend screening for hypertensive disorders in asymptomatic pregnant persons with blood pressure measurements throughout pregnancy, including in the first trimester. Based on screening, USPSTF and ACOG recommend the use of low-dose aspirin as preventive medication starting at 12 weeks of gestation in persons who are at high risk for preeclampsia and consideration of low-dose aspirin in persons with more than one moderate risk factor. The USPSTF and ACOG criteria for high and moderate risk for preeclampsia are clinical, demographic, and sociodemographic (ACOG, 2020; Davidson, 2021; Henderson, 2023). Currently, maternal serum biomarkers are not included in either USPSTF guidelines or ACOG risk factor assessment when determining appropriate candidates for aspirin prophylaxis.
The USPSTF and ACOG criteria for high and moderate risk for preeclampsia for selection for low-dose aspirin therapy starting in the first trimester are clinical, demographic, and sociodemographic, Clinical management beyond the first trimester involves continued assessment of medical history and clinical risk factors, such as serial blood pressure measurement and screening for proteinuria as part of prenatal care (ACOG, 2020; Davidson, 2021; Henderson, 2023).
The U.S. Preventive Services Task Force (USPSTF) issued updated recommendations in 2023 on screening for hypertensive disorders of pregnancy (Henderson, 2023). The recommendation states: "Several models have been developed with the aim of identifying pregnant individuals who are at risk of developing preeclampsia. Many of these models include variables for medical history, patient characteristics, blood serum biomarkers (e.g., serum placental growth factor), mean arterial pressure (MAP), and ultrasound readings (e.g., Doppler uterine artery pulsatility index). The most extensively researched of these are various iterations of the Fetal Medicine Foundation (FMF) model. Currently, risk assessment and risk prediction tools are being used to inform the use of aspirin for prevention of preeclampsia; however, no randomized controlled trials (RCTs) have incorporated the use of a risk prediction model to evaluate the optimal frequencies or intervals of screening for hypertensive disorders of pregnancy. In the absence of clinical implementation studies, it is not yet clear whether screening informed by risk prediction models would necessarily be superior to risk evaluations based on clinical history taking. Moreover, it remains to be seen whether risk-based screening protocols, regardless of the risk-assessment approach used, could improve outcomes relative to usual care screening."
Clinical validity studies of the kryptor system did not include women in the first trimester (Andersen, 2015; Droge, 2017; van Helden, 2015; Thadhani, 2022).
Four studies have reported performance characteristics of the Kryptor system in second and third trimester (Andersen, 2015; Droge, 2017; van Helden, 2015; Thadhani). Three of the studies21,22,23, reported performance characteristics for both derived and predefined cutoffs (Andersen, 2015; Droge, 2017; van Helden, 2015). The summary below focuses on the predefined cutoffs.
Andersen et al conducted a retrospective, case-controlled study on 39 women with preeclampsia and 76 women with non-hypertensive pregnancies (Andersen, 2015). Study used banked samples from pregnant women from Denmark with a singleton pregnancy. The median age was 39 years, and the median gestational age at blood sampling was 38 to 39 weeks. Preeclampsia was defined as repeated BP above 90 mmHg diastolic and/or 140mm Hg systolic: values of +1 or more for protein in urine. Early-onset prior to34+0 weeks and late-onset 34+0 onwards. Threshold for Positive Index Test: Predefined cutoffs for sFlt–1/PlGF: Early-onset, 33 ('rule-out') 85 ('rule-in') and late-onset, 33 ('rule-out') 110 ('rule-in'). Results include:
Droge et al conducted a retrospective, case-controlled study using banked samples from pregnant patients in Germany (Droge, 2017). Participants were enrolled in 2 clinical studies conducted between 2007 to 2010 and 2013 to 2014 that measured sFlt-1and PlGF in patients with and without preeclampsia and/or fetal growth restriction. Performance characteristics provided for case-control analysis including 33 patients with preeclampsia and 132 age-matched healthy controls. The mean age was 30-31 years, and the study population consisted of 96% White; 2% Black; 2% Asian. Preeclampsia defined according to guidelines of International Society for the Study of Hypertension in Pregnancy. Predefined cutoffs for sFlt–1/PlGF: 33,38, 85. Results include:
Van Helden et al conducted a retrospective, case-controlled study using banked samples from pregnant women with a singleton pregnancy (van Helden, 2015). The study included samples from patients with preeclampsia(n=51) and patients undergoing an 'inconspicuous course of pregnancy' (n=51). The mean age of the participant was 31 years of age with a mean gestational age at blood sampling of 34 weeks. Preeclampsia defined as new onset of hypertension and proteinuria after 20weeks of gestation Early onset, clinical signs started before week 34. Predefined cutoffs for sFlt–1/PlGF: Early-onset, 33 ('rule-out') 85 ('rule-in') Late-onset, 33 ('rule-out') 110 ('rule-in'). Results include the following:
Thadhani et al reported results of the largest study of the Kryptor system (Thadhani, 2022). PRAECIS (Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification; NCT03815110) was a prospective, blinded, multicenter (18 centers) study conducted in the US between 2019 and 2021. The centers included tertiary care and community hospitals in urban and suburban settings. PRAECIS enrolled 1014 pregnant women with singleton pregnancies; 299 in a derivation cohort and 715 in a validation cohort. The participants were between 23+0 and 34+6 weeks gestation with a hypertensive disorder of pregnancy as defined by ACOG. The primary outcome was the development of preeclampsia with severe features within 2 weeks of enrollment which was adjudicated by a committee of maternal fetal medicine experts blinded to the local diagnosis. Preeclampsia with severe features was defined, in short, as (1) severe hypertension; (2) thrombocytopenia; (3) impaired liver function; (4) severe persistent right upper quadrant or epigastric pain; (5) progressive renal insufficiency; (6) pulmonary edema; (7) new-onset cerebral or visual disturbances; and (8) headache unresponsive to medication. See the publication for more specifics on the components of the definition of preeclampsia. Using the development cohort, a sFlt-1: PlGF ratio of ≥40 was chosen as the cutoff that provided the highest sensitivity while maintaining specificity of 70%. The results that follow are for the validation cohort using the cutoffs of 40 for the sFlt-1: PlGF ratio. The validation cohort (n=556) was racially diverse including 6% Asian, 30% Black, 53% White and 16%Hispanic participants. The mean age was 32 years and the mean gestational age at enrollment was 30 weeks. 46% of participants had used aspirin during pregnancy. The incidence of the primary outcome was 33.5%. The overall performance characteristics of the test for predicting preeclampsia with severe features were: 94% sensitivity (95% CI, 89 to 96), 75% specificity (95% CI, 70 to 79), 65% PPV (95% CI, 59 to 71) and 96% NPV (95% CI, 93 to 98). In the subgroup of participants who identified as Black race (n=169), the positive and negative predictive values 66% (95% CI, 51 to 67) and 99% (95% CI, 94to 100), respectively. Subgroup analyses were not reported by aspirin use during pregnancy. Given that aspirin lowers the risk of preeclampsia, the PPV might differ across subgroups of women who did and did not take aspirin during pregnancy. There were 51 adverse maternal outcomes. Adverse maternal outcomes occurred in 16% of the group with a ratio ≥ 40 compared to 3% of the group with a ratio <40 (risk ratio, 5.8; 95% CI, 2.8 to 12.2). There were 288 adverse fetal and neonatal outcomes. Adverse fetal and neonatal outcomes occurred in 80% of the group with a ratio ≥40 compared to 26% in the group with a ratio <40 (risk ratio, 3.1; 95% CI, 2.5 to 3.8). There were 9 fetal deaths, 8 of which were in the group with a ratio ≥40.
Rolnik et al reported results of the ASPRE trial (Rolnik, 2017). ASPRE was a double-blind, placebo-controlled trial including 1776 women with singleton pregnancies (11+0 through 13+6 weeks gestation) who were at high risk for preterm preeclampsia. The participants were randomized to receive aspirin (150 mg per day) or placebo from enrollment until 36 weeks of gestation. The trial was conducted at 13 maternity hospitals in the United Kingdom, Spain, Italy, Belgium, Greece, and Israel. The Fetal Medicine Foundation (FMF) algorithm was used to select women for inclusion. The FMF algorithm includes PlGF as one of its components. PlGF was measured using the DELFIA Xpress system. The primary outcome was delivery with preeclampsia before 37 weeks gestation. The median age was 31 years; 66% of participants were White, 26% were Black. The primary outcome occurred in 1.6% (n=13) of participants in the aspirin group versus 4.3% (n=35) of participants in the placebo group (odds ratio=0.38; 95% CI, 0.20 to 0.74; p<.01). There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events.
5 RCTs have compared health outcomes for patients managed with and without a PlGF or sFlt-1/PlGF ratio test in the second or third trimester (Duhig, 2019; Cerdeira, 2019; Hayes-Ryan, 2021; Peguero, 2021; De Oliveira, 2023). Four of the RCTs were conducted in Europe and one was conducted in South America. All 5 RCTs used tests that are not currently cleared in the US. Three of the RCTs used PlGT or sFlt-1/PlGF ratio results to guide intensity of surveillance (Duhig, 2019; Hayes-Ryan, 2021; De Oliveira, 2023). One RCT used sFlt-1/PlGF ratio results to guide surveillance and hospital admission decisions and 1RCT used PlGT results to guide timing of delivery decisions (Cerdeira, 2019; Peguero, 2021). Results of the trials are discussed below and were mixed. A single trial found that time to preeclampsia diagnosis was shorter and maternal severe adverse outcomes were reduced in the group with care guided by PlGF results compared to usual care. Another trial found that the proportion of women with progression to preeclampsia with severe features was significantly lower in the group guided by PlGF results compared to usual care group. In contrast, the remaining 3 trials did not find that management adding PlGF or sFlt-1/PlGF ratio testing improved outcomes.
Duhig et al reported results of the PARROT multicenter, pragmatic, stepped-wedge, cluster-randomised RCT conducted in 11 maternity units in the UK in 2016 and 2017 (ISRCTN16842031) (Duhig, 2019). The study included 1023 pregnant women (singleton) with suspected pre-eclampsia between 20+0 and 36+6 weeks gestation. During the usual care periods (n=447 women), PlGF measurements were taken but were concealed from clinicians and women. During the intervention periods (n=576 women), the circulating PlGF measurement was revealed, and a clinical management algorithm was used. Samples were processed for PlGF measurements using the Triage test (Quidel). The clinical management algorithm incorporated PlGF measurement into the National Institute for Health and Care Excellence (NICE) guidance for the management of hypertensive pregnancies. Specifically, for PlGF > 100 (normal), the algorithm recommended continuing with usual management; for PlGF between 12 and 100 (low result) the algorithm recommended consideration of increased surveillance; for PlGF <12 (very low result), the algorithm recommended assessing as preeclampsia. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia. Preeclampsia was as defined by the International Society for the Study of Hypertension in Pregnancy 2014 statement and cases were reviewed by a central adjudication panel who were masked to trial allocation. The mean age of participants was 32 years and the mean gestational age at enrollment was 32 to 33 weeks. Racial and ethnic makeup was 66% of participants were White; 13% were Black; 12% were Indian, Pakistani Bangladeshi or Sri Lankan. 41% of participants had been prescribed prophylactic aspirin. The median time to pre-eclampsia diagnosis was 4.1 days with concealed testing compared to 1.9 days with revealed testing (time ratio=0.36, 95% CI, 0.15 to 0.87; p=.03). In the concealed testing group,24 (5%) versus 22 (4%) of the revealed testing group experienced maternal severe adverse outcomes (adjusted odds ratio=0.32,95% CI, 0.11 to 0.96; p=.04). There was not a statistically significant difference in perinatal adverse outcomes (15% vs 14%) or gestational age at delivery (36.6 weeks vs 36.8 weeks).
Cerdeira et al reported results of the INSPIRE (Interventional Study Evaluating the Short-Term Prediction of Preeclampsia/Eclampsia In Pregnant Women With Suspected Preeclampsia) trial (ISRCTN87470468) (Cerdeira, 2019). INSPIRE was an RCT conducted at a single tertiary center in the UK between 2015 and 2017 including 381 pregnant women (singleton) between 24+0 and 37+0 weeks of gestation with a clinical suspicion of preeclampsia. INSPIRE compared standard clinical management alone (n=186) to standard clinical management along with sFlt-1/PlGF ratio result (n=184). Blood samples were collected and processed for all participants but results were revealed only for women randomized to the sFlt-1/PlGF ratio group. In the sFlt-1/PlGF reveal group, a ratio of ≤38 was considered to confer low risk of developing preeclampsia within 7 days and discharge was advised if appropriate given the clinical picture. A ratio >38 was deemed elevated risk and a low threshold for admission and increased surveillance was advised. Final management decisions were at the clinician's discretion. sFlt-1 and PLGF were measured using the Elecsys test (Roche). The primary outcome was preeclampsia-related inpatient admission within 24 hours of the test, within 7days, or by delivery. Preeclampsia related inpatient admission was defined as an admission driven by suspicion of preeclampsia, where preeclampsia was recorded as a differential diagnosis and ongoing blood pressure monitoring, assessment of proteinuria, and preeclampsia blood samples had been requested. Outcome assessors were blinded to sFlt-1/PlGF result and trial group assignment. The median age was 31 years and the median gestational age at enrollment was 34 weeks. 90% of participants were White. Aspirin use during pregnancy was not described. Preeclampsia occurred in 23% (85) of participants. The number of primary outcome admissions was not significantly different between groups (n=48, non-reveal versus n=60, reveal; p=.19).Adverse maternal-fetal outcomes were similar for both groups.
Hayes-Ryan, et al reported results of the PARROT Ireland trial (NCT02881073) (Hayes-Ryan, 2021). PARROT Ireland was a stepped wedge cluster RCT conducted in 7 hospitals in Ireland between 2017 and 2019. The trial enrolled 2313 pregnant women (singleton) between 20+0 and 36+6 weeks gestation with symptoms suggestive of preeclampsia. Participants were randomized to usual care (per national guidelines; n=1057) or usual care plus PlGF testing (n=1234). In the PlGF group, a management algorithm was provided that was based on both the degree of hypertension present and the PlGF result. The algorithm recommended increased surveillance and frequency of review for participants with an abnormal or highly abnormal PlGF result (<100 pg/mL and <12 pg/mL, respectively). Final decisions regarding management remained with the treating clinician. PlGF testing was performed using the Triage test (Quidel). The co-primary outcomes were composite maternal morbidity and composite neonatal morbidity. The maternal morbidity composite included: placental abruption, intensive care admission, central nervous system compromise, cardiorespiratory compromise, hematological compromise, kidney compromise, severe hypertension. The neonatal morbidity composite included: perinatal death, neonatal intensive care unit admission, birthweight ≤5th percentile, Apgar score <7 at 5 minutes, umbilical artery acidosis at birth, admission to neonatal unit, respiratory distress syndrome, intraventricular hemorrhage, retinopathy of prematurity, confirmed infection, necrotizing enterocolitis. All preeclampsia diagnoses were reviewed by a central adjudication panel including a clinical doctor and a research midwife who were blinded to treatment group and PlGF result. The mean age of participants was 32 years and the mean gestational age at enrollment was 32weeks. 90% of participants were European, 3% of participants were African Caribbean or African. The use of aspirin among participants varied across hospitals, from 6% to 48%, and also varied across treatment groups, 28% versus 19% in intervention versus control. There was not a statistically significant difference in the maternal morbidity composite: 38% (457/1202) in the usual care group versus 32% (330/1017) in the PlGF group (adjusted risk ratio=1.01; 95% CI, 0.76 to 1.36; p=.92). Nor was there a statistically significant difference in the neonatal morbidity composite: 43% (527/1202) in the usual care group versus47% (484/1017) in the PlGF group (adjusted risk ratio=1.03; 95% CI, 0.89 to 1.21; p=.67). Post-hoc analysis was performed adjusting the maternal morbidity composite for use of aspirin and was reported to result in similar results.
Peguero et al reported results of an RCT conducted at 7 maternity units in Spain between 2016 and 2019 including 178 pregnant women (singleton) with late preterm preeclampsia from 34+0 to 36+6 weeks gestation (NCT02373839) (Peguero, 2021). The participants were assigned to planned delivery based on PlGF results (n=88) or expectant management under usual care following Spanish guidelines (n=90). A blood sample was collected and analyzed for all participants, but results were revealed only in the PlGF group. PlGF was measured using the Elecsys test. In the PlGF group, planned delivery was recommended if PlGF was below 60 pg/mL. The coprimary outcomes were maternal progression to preeclampsia with severe features as defined by ACOG and neonatal outcome morbidity at hospital discharge determined by the morbidity assessment index for newborns (MAIN) score. The hypothesis for the neonatal coprimary outcome was a noninferiority hypothesis. The mean age of participants was 33 years and the mean gestational age at enrollment was 35 weeks. 51% of participants were White. 21% of participants received low-dose aspirin prophylaxis. The proportion of women with progression to preeclampsia with severe features was significantly lower in the PlGF group (22%) than in the usual care group (42%; adjusted relative risk=0.5; 95% CI, 0.33 to 0.76; p<.01). The proportion of infants with neonatal morbidity was not statistically significantly different between groups (14% versus18% in PlGF versus usual care) and did not contain the noninferiority margin (adjusted relative risk=0.77; 95% CI, 0.39 to 1.53; p=.45).
De Oliveira et al reported results of the PREPARE (Prematurity Reduction by Preeclampsia Care) trial (NCT03073317) (De Oliveira, 2023). PREPARE was a stepped-wedge, cluster RCT conducted in 7 tertiary centers in Brazil from 2017 to 2019. The trial enrolled 1250 pregnant patients (singleton) between 20+0 and 36+6 weeks gestation with suspected or confirmed preeclampsia. The control group (n=566) was managed according to local treatment guidance. The intervention group (n=684) consisted of two risk stratification components. Risk of adverse maternal outcomes related to preeclampsia was estimated using an algorithm called full PIERS which combines maternal symptoms, signs and laboratory tests (von Dadelszen, 2011).
In addition, samples were collected for sFlt-1/PlGF ratio measured using the Elecsys test. If sFlt-1/PlGF ≤38 and full PIERS <10%, patients were considered low risk and clinicians received recommendations to defer delivery, unless clinical conditions deteriorated, with repeat testing. If sFlt-1/PlGF >38 or full PIERS ≥ 10%, patients were considered not low risk, and clinicians received recommendations to increase surveillance. The primary outcome was the proportion of patients with preterm preeclampsia who delivered <37 weeks’ gestation/total deliveries. The median age of participants was 30 years and the median gestational age at enrollment was 33 weeks. The ethnicities were reported as: 47% White, 15% Black, 37% Brown-mixed. 17% of participants received low dose aspirin supplementation. 60% of patients in the intervention group were classified as not low risk based on sFlt-1/PlGF or full PIERS test; most of these were not low risk based on sFlt-1/PlGF alone. The authors acknowledged difficulties with statistical analyses. The denominators vary across outcomes between using the total number of deliveries at the sites and the number of deliveries for preeclampsia. For the primary outcome, 1.1% (375/35,129 total births) in the intervention group versus 1.4% (365/26,847 total births) delivered prior to 37 weeks; however, after adjustment for confounders, the adjusted risk ratio indicated increased risk of the primary outcome in the intervention group (adjusted risk ratio=1.5; 95% CI, 1.0 to 2.0; p=.03). When the denominator was limited to patients with preeclampsia, there was no difference in the proportion of deliveries before 37 weeks (72% vs 66%; adjusted p=.93). The median time from enrollment to delivery was longer in the control group (6.5 versus 9 weeks; adjusted p<.01) (De Oliveira, 2023).
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Results were reported of the ASPRE trial (Rolnik, 2017). ASPRE was a double-blind, placebo-controlled trial including 1776women with singleton pregnancies (11+0 through 13+6 weeks gestation) who were at high risk for preterm preeclampsia. The participants were randomized to receive aspirin (150 mg per day) or placebo from enrollment until 36 weeks of gestation. The trial was conducted at 13 maternity hospitals in the United Kingdom, Spain, Italy, Belgium, Greece, and Israel. The Fetal Medicine Foundation (FMF) algorithm was used to select women for inclusion. The FMF algorithm includes PlGF as one of its components. PlGF was measured using the DELFIA Xpress system. The primary outcome was delivery with preeclampsia before 37 weeks gestation. The median age was 31 years; 66% of participants were White, 26% were Black. The primary outcome occurred in 1.6% (n=13) of participants in the aspirin group versus 4.3% (n=35) of participants in the placebo group(odds ratio=0.38; 95% CI, 0.20 to 0.74; p<.01). There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events.
Results were reported of the largest study of the Kryptor system. PRAECIS (Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification; NCT03815110) was a prospective, blinded, multicenter (18 centers) study conducted in the US between 2019 and 2021. The centers included tertiary care and community hospitals in urban and suburban settings. PRAECIS enrolled 1014 pregnant women with singleton pregnancies; 299 in a derivation cohort and 715 in a validation cohort. The participants were between 23+0 and 34+6 weeks gestation with a hypertensive disorder of pregnancy as defined by ACOG. The primary outcome was the development of preeclampsia with severe features within 2 weeks of enrollment which was adjudicated by a committee of maternal fetal medicine experts blinded to the local diagnosis. Preeclampsia with severe features was defined, in short, as (1) severe hypertension; (2) thrombocytopenia; (3) impaired liver function; (4) severe persistent right upper quadrant or epigastric pain; (5) progressive renal insufficiency; (6) pulmonary edema; (7) new-onset cerebral or visual disturbances; and (8) headache unresponsive to medication. See the publication for more specifics on the components of the definition of preeclampsia. Using the development cohort, a sFlt-1:PlGF ratio of ≥40 was chosen as the cutoff that provided the highest sensitivity while maintaining specificity of 70%. The results that follow are for the validation cohort using the cutoffs of 40for the sFlt-1:PlGF ratio. The validation cohort (n=556) was racially diverse including 6% Asian, 30% Black, 53% White and 16%Hispanic participants. The mean age was 32 years and the mean gestational age at enrollment was 30 weeks. 46% of participants had used aspirin during pregnancy. The incidence of the primary outcome was 33.5%. The overall performance characteristics of the test for predicting preeclampsia with severe features were: 94% sensitivity (95% CI, 89 to 96), 75%specificity (95% CI, 70 to 79), 65% PPV (95% CI, 59 to 71) and 96% NPV (95% CI, 93 to 98). In the subgroup of participants who identified as Black race (n=169), the positive and negative predictive values 66% (95% CI, 51 to 67) and 99% (95% CI, 94to 100), respectively. Subgroup analyses were not reported by aspirin use during pregnancy. Given that aspirin lowers the risk of preeclampsia, the PPV might differ across subgroups of women who did and did not take aspirin during pregnancy. There were51 adverse maternal outcomes. Adverse maternal outcomes occurred in 16% of the group with a ratio ≥ 40 compared to 3% of the group with a ratio <40 (risk ratio, 5.8; 95% CI, 2.8 to 12.2). There were 288 adverse fetal and neonatal outcomes. Adverse fetal and neonatal outcomes occurred in 80% of the group with a ratio ≥40 compared to 26% in the group with a ratio <40 (risk ratio, 3.1; 95% CI, 2.5 to 3.8). There were 9 fetal deaths, 8 of which were in the group with a ratio ≥40. (Thadhani, 2022)
Results were reported of the PARROT multicenter, pragmatic, stepped-wedge, cluster-randomised RCT conducted in 11 maternity units in the UK in 2016 and 2017 (ISRCTN16842031) (Duhig, 2019). The study included 1023 pregnant women (singleton)with suspected pre-eclampsia between 20+0 and 36+6 weeks gestation. During the usual care periods (n=447 women), PlGF measurements were taken but were concealed from clinicians and women. During the intervention periods (n=576 women), the circulating PlGF measurement was revealed and a clinical management algorithm was used. Samples were processed for PlGF measurements using the Triage test (Quidel). The clinical management algorithm incorporated PlGF measurement into the National Institute for Health and Care Excellence (NICE) guidance for the management of hypertensive pregnancies. Specifically, for PlGF > 100 (normal), the algorithm recommended continuing with usual management; for PlGF between 12 and 100 (low result) the algorithm recommended consideration of increased surveillance; for PlGF<12 (very low result), the algorithm recommended assessing as preeclampsia. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia. Preeclampsia was as defined by the International Society for the Study of Hypertension in Pregnancy 2014 statement and cases were reviewed by a central adjudication panel who were masked to trial allocation. The mean age of participants was 32 years and the mean gestational age at enrollment was 32 to 33 weeks. Racial and ethnic makeup was 66% of participants were White; 13% were Black; 12% were Indian, Pakistani Bangladeshi or Sri Lankan. 41% of participants had been prescribed prophylactic aspirin. The median time to pre-eclampsia diagnosis was 4.1 days with concealed testing compared to 1.9 days with revealed testing (time ratio=0.36, 95% CI, 0.15 to 0.87; p=.03). In the concealed testing group,24 (5%) versus 22 (4%) of the revealed testing group experienced maternal severe adverse outcomes (adjusted odds ratio=0.32,95% CI, 0.11 to 0.96; p=.04). There was not a statistically significant difference in perinatal adverse outcomes (15% vs 14%) or gestational age at delivery (36.6 weeks vs 36.8 weeks).
Results were reported of the INSPIRE (Interventional Study Evaluating the Short-Term Prediction of Preeclampsia/ Eclampsia In Pregnant Women With Suspected Preeclampsia) trial (ISRCTN87470468) (Cerdeira, 2019). INSPIRE was an RCT conducted at a single tertiary center in the UK between 2015 and 2017 including 381 pregnant women (singleton) between 24+0 and 37+0weeks of gestation with a clinical suspicion of preeclampsia. INSPIRE compared standard clinical management alone (n=186) to standard clinical management along with sFlt-1/PlGF ratio result (n=184). Blood samples were collected and processed for all participants but results were revealed only for women randomized to the sFlt-1/PlGF ratio group. In the sFlt-1/PlGF reveal group, a ratio of ≤38 was considered to confer low risk of developing preeclampsia within 7 days and discharge was advised if appropriate given the clinical picture. A ratio >38 was deemed elevated risk and a low threshold for admission and increased surveillance was advised. Final management decisions were at the clinician's discretion. sFlt-1 and PLGF were measured using the Elecsys test (Roche). The primary outcome was preeclampsia-related inpatient admission within 24 hours of the test, within 7days, or by delivery. Preeclampsia related inpatient admission was defined as an admission driven by suspicion of preeclampsia, where preeclampsia was recorded as a differential diagnosis and ongoing blood pressure monitoring, assessment of proteinuria, and preeclampsia blood samples had been requested. Outcome assessors were blinded to sFlt-1/PlGF result and trial group assignment. The median age was 31 years and the median gestational age at enrollment was 34 weeks. 90% of participants were White. Aspirin use during pregnancy was not described. Preeclampsia occurred in 23% (85) of participants. The number of primary outcome admissions was not significantly different between groups (n=48, nonreveal versus n=60, reveal; p=.19).Adverse maternal-fetal outcomes were similar for both groups (Cerdeira, 2019).
Results were reported of the PARROT Ireland trial (NCT02881073) (Hayes-Ryan, 2021). PARROT Ireland was a stepped wedge cluster RCT conducted in 7 hospitals in Ireland between 2017 and 2019. The trial enrolled 2313 pregnant women(singleton) between 20+0 and 36+6 weeks gestation with symptoms suggestive of preeclampsia. Participants were randomized to usual care (per national guidelines; n=1057) or usual care plus PlGF testing (n=1234). In the PlGF group, a management algorithm was provided that was based on both the degree of hypertension present and the PlGF result. The algorithm recommended increased surveillance and frequency of review for participants with an abnormal or highly abnormal PlGF result(<100 pg/mL and <12 pg/mL, respectively). Final decisions regarding management remained with the treating clinician. PlGF testing was performed using the Triage test (Quidel). The co-primary outcomes were composite maternal morbidity and composite neonatal morbidity. The maternal morbidity composite included: placental abruption, intensive care admission, central nervous system compromise, cardiorespiratory compromise, hematological compromise, kidney compromise, severe hypertension. The neonatal morbidity composite included: perinatal death, neonatal intensive care unit admission, birthweight≤5th percentile, Apgar score <7 at 5 minutes, umbilical artery acidosis at birth, admission to neonatal unit, respiratory distress syndrome, intraventricular hemorrhage, retinopathy of prematurity, confirmed infection, necrotising enterocolitis. All preeclampsia diagnosis were reviewed by a central adjudication panel including a clinical doctor and a research midwife who were blinded to treatment group and PlGF result. The mean age of participants was 32 years and the mean gestational age at enrollment was 32weeks. 90% of participants were European, 3% of participants were African Caribbean or African. The use of aspirin among participants varied across hospitals, from 6% to 48%, and also varied across treatment groups , 28% versus 19% in intervention versus control. There was not a statistically significant difference in the maternal morbidity composite: 38% (457/1202) in the usual care group versus 32% (330/1017) in the PlGF group (adjusted risk ratio=1.01; 95% CI, 0.76 to 1.36; p=.92). Nor was there a statistically significant difference in the neonatal morbidity composite: 43% (527/1202) in the usual care group versus47% (484/1017) in the PlGF group (adjusted risk ratio=1.03; 95% CI, 0.89 to 1.21; p=.67). Post-hoc analysis was performed adjusting the maternal morbidity composite for use of aspirin and was reported to result in similar results (Hayes-Ryan, 2021).
Results were reported of an RCT conducted at 7 maternity units in Spain between 2016 and 2019 including 178 pregnant women (singleton) with late preterm preeclampsia from 34+0 to 36+6 weeks gestation (NCT02373839) (Peguero, 2021). The participants were assigned to planned delivery based on PlGF results (n=88) or expectant management under usual care following Spanish guidelines (n=90). A blood sample was collected and analyzed for all participants but results were revealed only in the PlGF group. PlGF was measured using the Elecsys test. In the PlGF group, planned delivery was recommended if PlGF was below 60 pg/mL. The coprimary outcomes were maternal progression to preeclampsia with severe features as defined by ACOG and neonatal outcome morbidity at hospital discharge determined by the morbidity assessment index for newborns(MAIN) score. The hypothesis for the neonatal coprimary outcome was a noninferiority hypothesis. The mean age of participants was 33 years and the mean gestational age at enrollment was 35 weeks. 51% of participants were White. 21% of participants received low-dose aspirin prophylaxis. The proportion of women with progression to preeclampsia with severe features was significantly lower in the PlGF group (22%) than in the usual care group (42%; adjusted relative risk=0.5; 95% CI, 0.33 to 0.76;p<.01). The proportion of infants with neonatal morbidity was not statistically significantly different between groups (14% versus18% in PlGF versus usual care) and did not contain the noninferiority margin (adjusted relative risk=0.77; 95% CI, 0.39 to 1.53;p=.45) (Peguero, 2021).
The U.S. Preventive Services Task Force (USPSTF) issued updated recommendations in 2023 on screening for hypertensive disorders of pregnancy (Henderson, 2023). The recommendation states: "Several models have been developed with the aim of identifying pregnant individuals who are at risk of developing preeclampsia. Many of these models include variables for medical history, patient characteristics, blood serum biomarkers (e.g., serum placental growth factor), mean arterial pressure (MAP), and ultrasound readings (e.g., Doppler uterine artery pulsatility index). The most extensively researched of these are various iterations of the Fetal Medicine Foundation (FMF) model. Currently, risk assessment and risk prediction tools are being used to inform the use of aspirin for prevention of preeclampsia; however, no randomized controlled trials (RCTs) have incorporated the use of a risk prediction model to evaluate the optimal frequencies or intervals of screening for hypertensive disorders of pregnancy. In the absence of clinical implementation studies, it is not yet clear whether screening informed by risk prediction models would necessarily be superior to risk evaluations based on clinical history taking. Moreover, it remains to be seen whether risk-based screening protocols, regardless of the risk-assessment approach used, could improve outcomes relative to usual care screening."
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