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Review
. 2023 Oct-Dec;24(4):219-231.
doi: 10.18502/jri.v24i4.14149.

Maternal and Fetal Factors Affecting Cell-Free Fetal DNA (cffDNA) Fraction: A Systematic Review

Majid Zaki-Dizaji  1 , Arman Shafiee  2 , Omid Kohandel Gargari  2 , Haniyeh Fathi  2 , Zohreh Heidary  3
Affiliations
Review

Maternal and Fetal Factors Affecting Cell-Free Fetal DNA (cffDNA) Fraction: A Systematic Review

Majid Zaki-Dizaji et al. J Reprod Infertil. 2023 Oct-Dec.

Abstract

Background: Cell-free fetal DNA (cffDNA) is a novel screening method for fetal aneuploidy that facilitated non-invasive prenatal testing (NIPT) through analysis of cffDNA in maternal plasma. However, despite increased sensitivity, it has a number of limitations that may complicate of its results interpretation. Therefore, elucidating factors affecting fetal fraction, as a critical limitation, guides its clinical application.

Methods: In this report, systematic search was carried out through PubMed, Web of Science, and Scopus databases until February 11, 2022 by using keywords consist of "noninvasive prenatal screening", "NIPT", "noninvasive prenatal", "cell free DNA" and "fetal fraction". The articles were screened for eligibility criteria before data extraction.

Results: A total of 39 eligible studies, most published between 2010 and 2020, were included. Based on the results of studies, a negative correlation between maternal age and BMI/body weight with fetal fraction was found. Furthermore, LDL, cholesterol, triglyceride level, metformin, heparin and enoxaparin therapy, hemoglobin-related hemoglobinopathies, and physical activity showed to have negative associations. Interestingly, it seems the ethnicity of patients from South and East Asia has a correlation with fetal fraction compared to Caucasians. Positive correlation was observed between gestational age, free β-hCG, PAPP-A, living in high altitude, and twin pregnancy.

Conclusion: Considering each factor, there was significant inconsistency and controversy regarding their impact on outcomes. Indeed, multiple factors can influence the accuracy of NIPS results, and it is worth noting that the impact of these factors may vary depending on the individual's ethnic background. Therefore, it is important to recognize that NIPS remains a screening test, and comprehensive pre- and post-NIPS counseling should be conducted as part of standard clinical practice.

Keywords: Cell-free DNA; Fetal fraction; Gestational age; Maternal age; Non-invasive prenatal testing.

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Figures

Figure 1.
Figure 1.
PRISMA flow diagram for included studies in the review * The process of selecting and refining articles ultimately led to a final set of 39 included articles
Figure 2.
Figure 2.
Reported factors affecting fetal fraction * Negative correlation between maternal age and BMI/body weight with fetal fraction was detected. Likewise, LDL, cholesterol, triglyceride level, metformin, heparin and enoxaparin therapy, hemoglobin-related hemoglobinopathies, and physical activity showed negative associations. Positive correlation was seen between gestational age, free β-hCG, PAPP-A, living in high altitude, and twin pregnancy. There appears to be a potential race-dependent association with fetal fraction
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