Sensigene Fetal RHD Genotyping

Lab Management Guidelines v2.0.2019 SensiGene Fetal RHD Genotyping

MOL.TS.275.A v2.0.2019 Procedures addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.

Procedure addressed by this guideline Procedure code SensiGene RhD Assay 81403

What is RhD

Definition

Women who are Rhesus D negative (RhD-) exposed to fetal RhD+ erythrocytes can develop anti-Rh antibodies (Rh-isoimmunization), which have the potential to permeate the placenta and cause hemolytic disease. If proper screening and treatment procedures are not carried out, Rh-isoimmunization has the potential to result in fetal/neonatal morbidity and mortality. Early identification of pregnancies with high risk for isoimmunization can better prepare both mothers and physicians for proper course of treatment, which may include fetal transfusion (during early pregnancy) or scheduled labor induction (for later pregnancies). The prevalence of RhD- blood type varies by race, where 15% of Caucasians, 5%-8% of African Americans, and 1%- 2% of Asians and Native Americans are RhD-.1  Amniocentesis is the chief modality employed to assess fetal blood type; however, invasive procedures such as amniocentesis and chorionic villus sampling (CVS) have the potential to increase risk of fetal-maternal hemorrhage, which can lead to severe complications. An estimated 50% of previously sensitized women are considered low-risk for fetal RhD incompatibility; therefore, an alternative, noninvasive assay may reduce the number of unnecessary invasive procedures, as well as parental stress in cases involving sensitized women.2 In cases where RhD hemolytic antibodies are not produced, identification of the fetus as RhD- is necessary to manage the use of anti-D prophylaxis immune globulin, and it may reduce need for intensive prenatal monitoring to predict and treat fetal anemia.3

Test information  SensiGene® RHD Assay is a non-invasive, prenatal blood-test developed to evaluate circulating cell-free fetal DNA (ccffDNA) derived from the placenta. This ccffDNA in maternal plasma is used to detect the incompatibility between the mother’s blood-type and the fetus’ blood-type. It can determine the presence of the

fetal RhD genotype in RhD- mothers, as early as 10 weeks’ gestation. This assay may reduce the utilization of invasive procedures that may increase maternal sensitization.4  SensiGene® Fetal RHD Genotyping assay, produced by Sequenom, isolates exons 4, 5, and 7 of the RhD gene (locus chromosome 1), psi-pseudogene in exon 4, and 3 targets on the Y chromosome (SRY, TTTY, DBY), all of which are known to be the directly related to the genetic basis for RhD- phenotypes.  Reasons to determine fetal RhD status utilizing ccffDNA in maternal blood may include o avoiding the cost of paternity test/paternal genotyping o identifying fetal RhD status in the absence of maternal anti-Rh antigens o determining fetal RhD- status for parents opposed to immunization/vaccination o reducing the need for CVS or amniocentesis in RhD-sensitized patients  This assay analyzes ccffDNA, which comprises approximately 3% to 6% of cell-free DNA in maternal plasma. Identification of specific exons of the RhD gene, not generally present in RhD- patients, has been found to predict an RhD+ fetus.4

Guidelines and evidence

The American College of Obstetricians and Gynecologists

In 2017 the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin stating, “However, at current costs, noninvasive assessment of fetal Rh D status is not recommended for routine use at present”.5

The Society for Maternal Medicine

In 2015 The Society for Maternal-Fetal Medicine (SMFM) issued a Clinical Guideline regarding the diagnosis and management of the fetus at risk for anemia. The guideline makes no specific recommendations about the use of cell-free DNA in maternal plasma to determine fetal RhD status. However, Figure 2 of their Clinical Guideline, “Algorithm for clinical management of the red cell alloimmunized pregnancy,” allows for “Free fetal e DNA testing for Rh(D) status or amniocentesis for fetal Rh(D) genotyping.”6 n e

Peer Reviewed Literature G i s  The available evidence suggests that the clinical validity of the fetal RHD n genotyping using the SensiGene® assay is relatively high since the test e demonstrates good accuracy in correctly predicting fetal RHD status.1,2,7-10 However, S

there is a risk of false positive results with use of the test.

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 There is limited evidence regarding the clinical utility of the SensiGene RHD Assay to change clinician treatment decisions and ultimately improve patient-health outcomes compared with conventional modes of testing. Additional research is required to determine the performance of RhD genotyping with maternal plasma in improving patient health outcomes compared with amniocentesis and CVS.

Criteria  This test is considered investigational and/or experimental.

o Investigational and experimental (I&E) molecular and genomic (MolGen) tests refer to assays involving chromosomes, DNA, RNA, or gene products that have insufficient data to determine the net health impact, which typically means there is insufficient data to support that a test accurately assesses the outcome of interest (analytical and clinical validity), significantly improves health outcomes (clinical utility), and/or performs better than an existing standard of care medical management option. Such tests are also not generally accepted as standard of care in the evaluation or management of a particular condition. o In the case of MolGen testing, FDA clearance is not a reliable standard given the number of laboratory developed tests that currently fall outside of FDA oversight and FDA clearance often does not assess clinical utility.

References

1. Moise KJ, Boring NH, O'Shaughnessy R, Simpson LL, Wolfe HM, Baxter JK, McLennan G. Circulating cell‐ free fetal DNA for the detection of RHD status and sex using reflex fetal identifiers. Prenatal Diagnosis. 2013; 1: 95-101. 2. Bombard AT, Akolekar R, Farkas DH, VanAgtmael AL, Aquino F, Oeth P, Nicolaides KH. Fetal RHD genotype detection from circulating cell‐ free fetal DNA in maternal plasma in non‐ sensitized RhD negative women. Prenatal Diagnosis. 2011; 8: 802- 808. 3. American Congress of Obstetrics and Gynecology (ACOG). ACOG Practice

Bulletin No. 75: Management of alloimmunization during pregnancy. Clinical e Management Guidelines for Obstetrician-Gynecologists. 2006; 2: 457-464. n ® 4. Sequenom (2017). SensiGene Fetal RHD Genotyping Blood Test. Retrieved from e

https://www.sequenom.com/tests/reproductive-health/sensigene-rhd G i

5. American College of Obstetricians and Gynecologists (ACOG). ACOG Practice s Bulletin No. 181: Prevention of Rh Alloimmunization. Obstetrics and Gynecology. n 2017;130(2):e57-e70. e

6. Mari G, Norton ME, Stone J, Berghella V, Sciscione AC, Tate D, Schenone MH. S

Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: the fetus at risk

for anemia – diagnosis and management. American Journal of Obstetrics and

Gynecology. 2015;212(6):697-710.

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7. Tynan JA, Angkachatchai V, Ehrich M, Paladino T, van den Boom D, Oeth P. Multiplexed analysis of circulating cell-free fetal nucleic acids for noninvasive prenatal diagnostic RHD testing. American Journal of Obstetrics and Gynecology. 2011; 3: 251.e1-e6. 8. Chitty LS, Finning K, Wade A, Soothill P, Martin B, Oxenford K, Massey E. Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: Population based cohort study. BMJ. 2014; 349: g5243 9. Moise KJ, Gandhi M, Boring NH, O'Shaughnessy R, Simpson, LL, Wolfe HM, Skupski DW. Circulating cell-free DNA to determine the fetal RhD status in all three trimesters of pregnancy. Obstetrics & Gynecology. 2016; 6: 1340-1346. 10. Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy of cell‐ free fetal DNA‐‐ based non invasive prenatal testing in singleton pregnancies: A systematic review and bivariate meta‐ analysis. BJOG: An International Journal of Obstetrics & Gynaecology. 2017; 1: 32-46. e n e G i s n e S

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