TY - JOUR
T1 - Cell-free DNA fetal fraction in twin gestations in single-nucleotide polymorphism-based noninvasive prenatal screening
AU - Hedriana, Herman
AU - Martin, Kimberly
AU - Saltzman, Daniel
AU - Billings, Paul
AU - Demko, Zachary
AU - Benn, Peter
N1 - Funding Information:
This work was funded by Natera, Inc.
Funding Information:
This work was funded by Natera, Inc. Zachary Demko and Paul Billings are employees of Natera, Inc and hold stock in the company. Kimberly Martin and Peter Benn are consultants to Natera and hold stock options. Herman Hedriana is a former employee of Natera and does not own stock or hold stock options. Daniel Salzman serves on the advisory board of Natera; he is not an employee and does not receive any financial compensation from Natera. FF data were collected for SNP-based NIPS performed between 1 October 2017 and 30 April 2018. Plasma samples were analyzed at a Clinical Laboratory Improvement Act (CLIA)-certified and College of American Pathologists (CAP)-accredited laboratory (Natera, Inc; San Carlos, CA) using a previously published SNP-based NIPS methodology. Presence or absence of twins was based on information provided by the referring physician. In rare instances, the SNP analysis indicated an undocumented DZ twin pregnancy, and these cases were included only if confirmed by the referring physician. Testing was not offered when there was a known fetal death prior to the time of NIPS. Zygosity assessment was performed by identifying the number of genetically distinct individuals represented in the maternal plasma sample; two distinct sources indicated MZ twins (one pair of genetically identical twins and the mother) while three distinct sources indicated DZ twins (two genetically distinct twins and the mother). FF was estimated using over 13 000 SNP loci on targeted chromosomes for singleton and twin fetuses based on the minor allele frequencies: specifically, a combined FF for MZ twins because they are genetically identical, and two distinct FF estimates for DZ twins. For the purpose of this descriptive study, FF were collated for MZ, DZ, and singleton pregnancies, in addition to the inclusion of maternal age, gestational age, and maternal weight at the time of NIPS blood draw. Excluded were all data with absent FF for causes of inadequate sample, incomplete referral information or uninterpretable for reasons unrelated to FF, and FF less than 1% (the limit required for reliable measurement and to exclude other atypical situations such as samples from nonpregnant women and gross gestational age errors). Although the testing was available from nine completed weeks gestational age, for the purposes of this study, we limited the analyses of FF to the time when most screening is conducted, 10 to 20 completed weeks gestational age. Specific clinical information including interpretation of the results was not abstracted. Summed and individual FFs for MZ, DZ, and singleton (S) pregnancies were compared. Where appropriate, data evaluation included descriptive statistics, two-sided t-test, and one-way analysis of variance (ANOVA) at the 5% significance level. No Bonferroni correction for multiple tests was applied to minimize type II (false negative) associations. The study was based on retrospective analysis of deidentified data and therefore fell under an IRB exemption protocol, as determined by Ethical & Independent Review Services, Corte Madera, CA (E&I) protocol #: 17113-02.
Publisher Copyright:
© 2019 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Objectives: The performance of noninvasive prenatal screening (NIPS) for fetal aneuploidy in twin pregnancies is dependent on the amount of placentally derived cell-free DNA, the “fetal fraction (FF),” present in maternal plasma. We report FF values in monozygotic (MZ) and dizygotic (DZ) pregnancies. Methods: We reviewed FF in pregnancies at 10 to 20 completed weeks gestational age based on single-nucleotide polymorphism (SNP)-based NIPS where zygosity was routinely established in twin pregnancies. The cohort included 121 446 (96.3%) singleton, 1454 (1.2%) MZ, and 3161 (2.5%) DZ pregnancies. For DZ twins, individual FFs were measured. Results: Combined FF for DZ and MZ fetuses were 35% and 26% greater than singletons, respectively. The individual FF contributions from each fetus in DZ twins were, on average, 32% less than singletons. FF in DZ twin pairs were moderately correlated (Pearson correlation coefficient.66). When a threshold of 2.8% FF was applied to define uninterpretable results, 1.7% (2102/121 446) of singletons, 0.8% (11/1454) of MZ pairs, and 5.6% (178/3161) of DZ pairs were uninterpretable. Conclusion: For optimal aneuploidy NIPS in twin pregnancies, zygosity should be established and in DZ twins FF for both fetuses should be determined to identify those cases where results can be reliably interpreted.
AB - Objectives: The performance of noninvasive prenatal screening (NIPS) for fetal aneuploidy in twin pregnancies is dependent on the amount of placentally derived cell-free DNA, the “fetal fraction (FF),” present in maternal plasma. We report FF values in monozygotic (MZ) and dizygotic (DZ) pregnancies. Methods: We reviewed FF in pregnancies at 10 to 20 completed weeks gestational age based on single-nucleotide polymorphism (SNP)-based NIPS where zygosity was routinely established in twin pregnancies. The cohort included 121 446 (96.3%) singleton, 1454 (1.2%) MZ, and 3161 (2.5%) DZ pregnancies. For DZ twins, individual FFs were measured. Results: Combined FF for DZ and MZ fetuses were 35% and 26% greater than singletons, respectively. The individual FF contributions from each fetus in DZ twins were, on average, 32% less than singletons. FF in DZ twin pairs were moderately correlated (Pearson correlation coefficient.66). When a threshold of 2.8% FF was applied to define uninterpretable results, 1.7% (2102/121 446) of singletons, 0.8% (11/1454) of MZ pairs, and 5.6% (178/3161) of DZ pairs were uninterpretable. Conclusion: For optimal aneuploidy NIPS in twin pregnancies, zygosity should be established and in DZ twins FF for both fetuses should be determined to identify those cases where results can be reliably interpreted.
UR - http://www.scopus.com/inward/record.url?scp=85075424503&partnerID=8YFLogxK
U2 - 10.1002/pd.5609
DO - 10.1002/pd.5609
M3 - Article
C2 - 31711265
AN - SCOPUS:85075424503
SN - 0197-3851
VL - 40
SP - 179
EP - 184
JO - Prenatal Diagnosis
JF - Prenatal Diagnosis
IS - 2
ER -