Maternal Serum Biomarkers for Prediction of Adverse Obstetric Outcomes

POLICY NUMBER

A.2.04.152

DESCRIPTION

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.

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 1 in 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. Annually, more than 70,000 women and 500,000 newborns die from preeclampsia worldwide. In the US, this condition is often detected late, only through clinical diagnosis after organ damage has occurred, necessitating premature delivery. Currently, the risk assessment for preeclampsia is based on maternal medical history and clinical risk factors early in pregnancy. In response to the alarming maternal mortality rates in the US, the Foundation for the National Institutes of Health (FNIH) initiated a public-private partnership in 2024. This initiative aims to develop tools for identifying pregnant women at high risk of early-onset preeclampsia. This project is part of the FNIH Biomarkers Consortium and involves collaboration with the National Institutes of Health (NIH) and eight other partners from life sciences companies, academia, and nonprofit and patient advocacy organizations.

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 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 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. 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.

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 PIGF 1-2-3™ (PerkinElmer). 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. 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.

POLICY

The use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of preeclampsia is considered investigational.

The use of maternal serum biomarker tests with or without additional algorithmic analysis for prediction of spontaneous preterm birth is considered investigational.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

11/01/2022: New policy added. Approved by the Medical Policy Advisory Committee.

03/14/2023: Policy reviewed; no changes.

07/01/2023: Code Reference section updated to add new CPT codes 0390U and 0396U.

03/19/2024: Policy description updated regarding hypertensive disorders and tests. Policy statements unchanged.

10/01/2024: Code Reference section updated to add new CPT code 0482U.

12/19/2024: Code Reference section updated to add new CPT code 0524U effective 01/01/2025.

04/09/2025: Policy description updated regarding preeclampsia. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.152

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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