Maternal Serum Biomarkers for Prediction of Adverse Obstetric Outcomes Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 07|01|2025 POLICY LAST REVIEWED: 03|19|2025 OVERVIEW Improved accuracy of the identification of pregnant people at risk of preeclampsia and spontaneous preterm birth has the potential to reduce maternal and perinatal morbidity and mortality. Assessment of historical risk and clinical factors represents the traditional approach to diagnosis and planning interventions. Maternal serum biomarker testing is proposed as an adjunct to standard screening to identify pregnant people at risk of preeclampsia and spontaneous preterm birth. The following test(s) are addressed in this policy: • PlGF Preeclampsia Screen (PerkinElmer Genetics, Inc) CPT code 0243U • PreTRM® (Sera Prognostics, Inc®) CPT code 0247U • PreClaraTM Ratio (sFlt 1/PlGF) (Thermo Fisher Scientific) CPT code 0524U (Test Name Revision Effective 1/1/2026) MEDICAL CRITERIA Not applicable PRIOR AUTHORIZATION Not applicable. Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.
In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member. POLICY STATEMENT Medicare Advantage Plans and Commercial Products The use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of preeclampsia is considered not covered for Medicare Advantage Plans and not medically necessary for Commercial Products as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
The use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of spontaneous preterm birth is considered not covered for Medicare Advantage Plans and not medically necessary for Commercial Products as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
Medical Coverage Policy | Maternal Serum Biomarkers for Prediction of Adverse Obstetric Outcomes

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

Commercial Products Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information.

COVERAGE Benefits may vary between groups/contracts. Please refer to the Evidence of Coverage or Subscriber Agreement for applicable not medically necessary/not covered laboratory benefits/coverage.

BACKGROUND Preeclampsia Hypertensive disorders in pregnancy affected approximately 1 in 7 delivery hospitalizations between 2017 and 2019 in the US with a prevalence of approximately 1 in 5 delivery hospitalizations among Black women and 1in 3 among women aged 45 to 55 years. 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.

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. 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).

Despite decades of research, accurate identification of women at risk of preeclampsia, particularly prior to the 20th week of gestation, remains challenging. 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. 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. Multivariable preeclampsia risk assessment tools have been developed that incorporate maternal serum biomarkers; several of these tools have been commercially produced but few have been externally validated. 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.

Spontaneous Preterm Birth 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

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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. 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. 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 over35 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. 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.

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. 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.

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.

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. 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 PlGF 1-2-3™ (PerkinElmer). These commercially produced tests are not currently available in the United States.

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The PreTRM™ test (Sera Prognostics) uses maternal serum biomarkers (insulin-like growth factor bindingprotein-4 [IBP4] and sex hormone binding globulin [SHBG]) in combination with biometric measures to assess the risk of spontaneous preterm birth. 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.

For individuals who are pregnant without known risk factors for preeclampsia who receive maternal serum biomarker testing with or without additional algorithmic analysis, the evidence includes systematic reviews of observational clinical validity studies and a randomized controlled trial (RCT) that selected eligible participants based on an algorithm that included biomarker testing results. Relevant outcomes are test validity, maternal and perinatal morbidity and mortality, symptoms, functional outcomes, quality of life, hospitalizations, and resource utilization. The clinical validity studies primarily included populations from Europe and tests that are not cleared for use in the US. Placental growth factor (PlGF) cutoffs for identifying high risk pregnant people were not prespecified and varied significantly. The RCT used a test not cleared for use in the US to identify people for enrollment. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are pregnant with known risk factors for preeclampsia who receive maternal serum biomarker testing with or without additional algorithmic analysis, the evidence includes systematic reviews of observational clinical validity studies and RCTs. Relevant outcomes are test validity, maternal and perinatal morbidity and mortality, symptoms, functional outcomes, quality of life, hospitalizations, and resource utilization. Studies evaluating the predictive ability of maternal serum biomarker testing have found measurement of sFlt-1, PlGF, and the sFlt-1/PlGF ratio can identify women at risk of developing preeclampsia. One sFlt-1/PlGF ratio test system (KRYPTOR) has been cleared in the US. One prospective observational study (PRAECIS) has been conducted in a second and third trimester, US population reporting clinical validity of the KRYPTOR test system. PRAECIS included a racially diverse population reflective of US diversity. While PRAECIS proposed a cutoff for the sFlt-1:PlGF ratio of 40, other publications have proposed various cutoffs. The clinical decision that would be informed by the test is unclear. While 5 RCTs have been conducted using various biomarker tests, the KRYPTOR test system has not been used in any RCTs. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are pregnant without known risk factors for spontaneous preterm birth who receive maternal serum biomarker testing with or without additional algorithmic analysis, the evidence includes an RCT and cohort studies. Relevant outcomes are test validity, maternal and perinatal morbidity and mortality, symptoms, functional outcomes, quality of life, hospitalizations, and resource utilization. Measurement of the insulin-like growth factor binding protein-4 (IBP4) and sex hormone binding globulin (SHBG) ratio demonstrated acceptable discrimination in identifying asymptomatic women who may be at risk of preterm birth, based on evidence from 2 industry-sponsored cohort studies. However, a randomized trial did not find a difference in risk of preterm birth with use of the commercially produced PreTRM test, which includes theIBP4/SHBG ratio as part of an algorithmic analysis, versus no use. There were also no differences in neonatal outcomes in infants of women who underwent PreTRM testing versus no testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are pregnant with known risk factors for spontaneous preterm birth who receive maternal serum biomarker testing with or without additional algorithmic analysis, the evidence includes a systematic review of observational studies. Relevant outcomes are test validity, maternal and perinatal morbidity and mortality, symptoms, functional outcomes, quality of life, hospitalizations, and resource utilization. The systematic review did not identify any individual biomarker that adequately identified women at risk of spontaneous preterm birth based on high sensitivity and specificity. No studies assessing maternal

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

serum biomarkers as part of an algorithmic analysis were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CODING Medicare Advantage Plans and Commercial Products The following CPT code(s) are considered not covered for Medicare Advantage Plans and not medically necessary for Commercial Products:

PlGF Preeclampsia Screen 0243U Obstetrics (preeclampsia), biochemical assay of placental-growth factor, time-resolved fluorescence immunoassay, maternal serum, predictive algorithm reported as a risk score for preeclampsia

PreTRM® 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

PreClaraTM Ratio (sFlt 1/PlGF)
0524U Obstetrics (preeclampsia), sFlt- 1/PlGF ratio, immunoassay, utilizing serum or plasma, reported as a value (Test Name Revision Effective 1/1/2026)

RELATED POLICIES Biomarker Testing Mandate Proprietary Laboratory Analyses (PLA) and Multianalyte Assays with Algorithmic Analyses (MAAA)

PUBLISHED Provider Update, May 2025

REFERENCES

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22. Dröge LA, Höller A, Ehrlich L, et al. Diagnosis of preeclampsia and fetal growth restriction with the sFlt-1/PlGF ratio: Diagnostic accuracy of the automated immunoassay Kryptor®. Pregnancy Hypertens. Apr 2017; 8: 31-36. PMID 28501276
23. van Helden J, Weiskirchen R. Analytical evaluation of the novel soluble fms-like tyrosine kinase 1 and placental growth factor assays for the diagnosis of preeclampsia. Clin Biochem. Nov 2015; 48(16- 17):1113-9. PMID 26129879
24. Thadhani R, Lemoine E, Rana S, et al. Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy. NEJM Evid 2022; 1 (12).
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26. Thermo Scientific. Product Specifications: BRAHMS sFlt-1 KRYPTOR.https://www.brahms.de/images/00_downloads/prenatal-screening/product-sheet-sflt1- kryptor-en.pdf.Accessed January 8, 2024.
27. Agrawal S, Cerdeira AS, Redman C, et al. 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. Feb 2018; 71(2): 306-316. PMID 29229743
28. Lim S, Li W, Kemper J, et al. Biomarkers and the Prediction of Adverse Outcomes in Preeclampsia: A Systematic Review and Meta-analysis. Obstet Gynecol. Jan 01 2021; 137(1): 72-81. PMID 33278298
29. Moore Simas TA, Crawford SL, Bathgate S, et al. Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women. J Matern Fetal Neonatal Med. Jul 2014; 27(10): 1038-48. PMID24066977
30. Chaiworapongsa T, Romero R, Savasan ZA, et al. Maternal plasma concentrations of angiogenic/anti- angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia. J Matern Fetal Neonatal Med. Oct 2011; 24(10): 1187-207. PMID 21827221
31. Duhig KE, Myers J, Seed PT, et al. Placental growth factor testing to assess women with suspected pre- eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. May 042019; 393(10183): 1807-1818. PMID 30948284

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 7 (401) 274-4848 WWW.BCBSRI.COM

32. Cerdeira AS, O'Sullivan J, Ohuma EO, et al. Randomized Interventional Study on Prediction of Preeclampsia/Eclampsia in Women With Suspected Preeclampsia: INSPIRE. Hypertension. Oct 2019;74(4): 983-990. PMID 31401877
33. Hayes-Ryan D, Khashan AS, Hemming K, et al. Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland). BMJ. Aug 13 2021; 374: n1857. PMID 34389547
34. Peguero A, Herraiz I, Perales A, et al. Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial. Am J Obstet Gynecol. Sep 2021; 225(3): 308.e1-308.e14. PMID 33823150
35. De Oliveira L, Roberts JM, Jeyabalan A, et al. PREPARE: A Stepped-Wedge Cluster-Randomized Trial to Evaluate Whether Risk Stratification Can Reduce Preterm Deliveries Among Patients With Suspected or Confirmed Preterm Preeclampsia. Hypertension. Oct 2023; 80(10): 2017-2028. PMID 37431663
36. von Dadelszen P, Payne B, Li J, et al. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. Jan 15 2011; 377(9761): 219-27. PMID21185591
37. Saade GR, Boggess KA, Sullivan SA, et al. Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. Am J Obstet Gynecol. May 2016; 214(5): 633.e1- 633.e24.PMID 26874297
38. Markenson GR, Saade GR, Laurent LC, et al. Performance of a proteomic preterm delivery predictor ina large independent prospective cohort. Am J Obstet Gynecol MFM. Aug 2020; 2(3): 100140. PMID33345877
39. Branch DW, VanBuren JM, Porter TF, et al. Prediction and Prevention of Preterm Birth: A Prospective, Randomized Intervention Trial. Am J Perinatol. Jul 2023; 40(10): 1071-1080. PMID 34399434
40. Conde-Agudelo A, Papageorghiou AT, Kennedy SH, et al. Novel biomarkers for the prediction of the spontaneous preterm birth phenotype: a systematic review and meta-analysis. BJOG. Aug 2011; 118(9):1042-54. PMID 21401853
41. Honest H, Forbes CA, Durée KH, et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess. Sep2009; 13(43): 1-627. PMID 19796569
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43. Magee LA, Brown MA, Hall DR, et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis management recommendations for international practice. Pregnancy Hypertens. Mar 2022; 27: 148-169. PMID 35066406

44. National Institute For Health and Care Excellence (NICE). Diagnostics consultation document PLGF- based testing to help diagnose suspected preterm preeclampsia (update of DG23). https://www.nice.org.uk/guidance/indevelopment/gid-dg10040/documents. Accessed January 2, 2024.

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