Determinant of Prenatal Diagnostic Testing among Women with Increased Risk of Fetal Aneuploidy and Genetic Disorders

Morgan, Tamandra; Tan, Catherine Danielle; Torre, Micaela Della; Jackson-Bey, Tia; DiGiovanni, Laura; Enakpene, Christopher A.

doi:10.1055/a-1692-0309

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…However, amniocentesis carries the risk of fetal loss, worsening alloimmunization due to fetomaternal hemorrhage, and low uptake due to anxiety over the procedure and the risk to the fetus. [19][20][21][22] Subsequently, the fetal antigen status remains unknown for many of these pregnancies and the pregnancy is then monitored with serial antibody titers and MCA-PSV Doppler ultrasound by specialty providers, a process that is time intensive and burdensome both for the pregnant person and the healthcare system. These approaches to monitoring also have significant limitations.…”

Section: Discussionmentioning

confidence: 99%

Cell-free DNA analysis for the determination of fetal red blood cell antigen genotype in alloimmunized pregnancies

Rego,

Balogun,

Emanuel

et al. 2024

Preprint

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ObjectiveTo evaluate the accuracy of NGS-based quantitative cfDNA analysis for fetal antigen genotyping in alloimmunized pregnancies undergoing clinical testing across US practices. Timely identification of the fetal red blood cell antigen genotype for the antigen to which the pregnant person is alloimmunized is vital for determining fetal risk for HDFN and guiding management. Presently in the US, recommended care is to determine fetal antigen genotype with reproductive partner testing and/or amniocentesis. This approach has many limitations, including availability of reproductive partner testing, risk of nonpaternity, and low uptake of invasive testing such as amniocentesis. These barriers to obtaining fetal antigen genotype information lead to pregnancies not at risk for HDFN undergoing burdensome monitoring and, in some cases, unnecessary intervention. PCR-based qualitative cfDNA analysis for fetal antigen genotyping is available in Europe, however, it is offered at later gestational ages, may require a repeat sample, has a higher frequency of inconclusive results for individuals of non-European ancestry, and entails logistical challenges related to shipping and insurance coverage for patients in the US. The availability of a NGS-based quantitative cfDNA analysis for fetal antigen genotyping in the US that is robust for diverse populations and applicable for singleton and twin pregnancies starting at 10 weeks gestation presents an opportunity to assess performance.MethodsPatients with alloimmunized pregnancies undergoing clinical fetal antigen cfDNA analysis were recruited to the study along with the neonates resulting from the pregnancies. The laboratory issued the results prospectively as a part of clinical care. After delivery, neonatal buccal swabs were sent to an outside laboratory, blinded to the fetal cfDNA results, for antigen genotyping, and the results were compared. Concordance was reported for the fetal antigen cfDNA analysis for antigens to which the pregnant person was alloimmunized as well as for all antigens for which the pregnant person was genotype negative.ResultsWe observed complete concordance between the fetal antigen cfDNA analysis result and neonatal genotypes for 503 calls, for 100% sensitivity, specificity, PPV, and NPV across a racial and ethnically diverse cohort.ConclusionThis study demonstrates that cfDNA analysis for determining fetal antigen genotype is more accurate than real-life application of the current recommendations, ie., partner testing and amniocentesis, in a diverse US population. In addition, this noninvasive approach reduces barriers to obtaining timely, accurate information about fetal antigen genotype. These results support the routine implementation of fetal antigen cfDNA analysis to guide care of alloimmunized pregnancies in the US.

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Section: Discussionmentioning

confidence: 99%

Cell-free DNA analysis for the determination of fetal red blood cell antigen genotype in alloimmunized pregnancies

Rego,

Balogun,

Emanuel

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Approximately 3-5% of pregnancies are complicated by congenital anomalies [1]. Early diagnosis improves clinical outcomes [2], yet current screening tools are imperfect.…”

Section: Introductionmentioning

confidence: 99%

Are there foetal extracellular vesicles in maternal blood? Prospects for diagnostic biomarker discovery

et al. 2022

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Prenatal diagnosis of congenital disease improves clinical outcomes; however, as many as 50% of congenital heart disease cases are missed by current ultrasound screening methods. This indicates a need for improved screening technology. Extracellular vesicles (EVs) have attracted enormous interest in recent years for their potential in diagnostics. EVs mediate endocrine signalling in health and disease and are known to regulate aspects of embryonic development. Here, we critically evaluate recent evidence suggesting that EVs released from the foetus are able to cross the placenta and enter the maternal circulation. Furthermore, EVs from the mother appear to be transported in the reverse direction, whilst the placenta itself acts as a source of EVs. Experimental work utilising rodent models employing either transgenically encoded reporters or application of fluorescent tracking dyes provide convincing evidence of foetal-maternal crosstalk. This is supported by clinical data demonstrating expression of placental-origin EVs in maternal blood, as well as limited evidence for the presence of foetal-origin EVs. Together, this work raises the possibility that foetal EVs present in maternal blood could be used for the diagnosis of congenital disease. We discuss the challenges faced by researchers in translating these basic science findings into a clinical non-invasive prenatal test.

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Cell-Free DNA Analysis for the Determination of Fetal Red Blood Cell Antigen Genotype in Individuals With Alloimmunized Pregnancies

Rego,

Ashimi Balogun,

Emanuel

et al. 2024

Obstetrics &Amp; Gynecology

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OBJECTIVE: To evaluate the accuracy of next-generation sequencing–based quantitative cell-free DNA analysis for fetal antigen genotyping in individuals with alloimmunized pregnancies undergoing clinical testing in practices across the United States as early as 10 weeks of gestation, with the objective of identifying individuals with pregnancies at risk for hemolytic disease of the fetus and newborn and guiding management. METHODS: This prospective cohort study included patients with alloimmunized pregnancies undergoing clinical fetal antigen cell-free DNA analysis between 10 0/7 and 37 0/7 weeks of gestation at 120 clinical sites. Both the pregnant person with the alloimmunized pregnancy and the neonates resulting from the pregnancies were included. The laboratory issued the cell-free DNA results prospectively as a part of clinical care. After delivery, neonatal buccal swabs collected between 0 and 270 days of life were sent to an outside independent laboratory for antigen genotyping. The outside laboratory was blinded to the fetal cell-free DNA results, and the results were compared. Concordance was reported for the fetal antigen cell-free DNA analysis for antigens to which the pregnant person was alloimmunized and for all antigens for which the pregnant person was genotype negative. RESULTS: A total of 156 pregnant people who received clinically ordered cell-free DNA fetal antigen testing provided neonatal buccal swabs for genotyping after delivery. Overall, 15.4% of participants were Hispanic, 9.0% were non-Hispanic Black, 65.4% were non-Hispanic White, 4.5% were Asian, 1.3% were more than one race or ethnicity, and 4.5% were unknown. The median gestational age at the time of testing was 16.4 weeks with a median fetal fraction of 11.1%. Concordance between cell-free DNA analysis results and neonatal genotype was determined for 465 antigen calls for the following antigens: K1 (n=143), E (124), C (60), Fya (50), c (47), and D(RhD) (41). These 465 calls included 145 in which the fetus was antigen positive and 320 in which the fetus was antigen negative. We observed complete concordance between prenatal fetal antigen cell-free DNA analysis results and neonatal genotypes for the 465 calls, resulting in 100% sensitivity, specificity, and accuracy. CONCLUSION: In a diverse multicenter cohort, cell-free DNA analysis was highly sensitive and specific for determining fetal antigen genotype as early as 10 weeks of gestation in individuals with alloimmunized pregnancies. Taken together with previously published evidence, this study supports the implementation of cell-free DNA testing to manage individuals with alloimmunized pregnancies in the United States.

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Determinant of Prenatal Diagnostic Testing among Women with Increased Risk of Fetal Aneuploidy and Genetic Disorders

Cited by 3 publications

References 33 publications

Cell-free DNA analysis for the determination of fetal red blood cell antigen genotype in alloimmunized pregnancies

Cell-free DNA analysis for the determination of fetal red blood cell antigen genotype in alloimmunized pregnancies

Are there foetal extracellular vesicles in maternal blood? Prospects for diagnostic biomarker discovery

Cell-Free DNA Analysis for the Determination of Fetal Red Blood Cell Antigen Genotype in Individuals With Alloimmunized Pregnancies

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