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Low fetal fraction and adverse pregnancy outcomes— systematic review of the literature and metanalysis

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Abstract

Purpose

While cell-free DNA (cfDNA) screening has emerged as a screening modality for common aneuploidies, further research and several publications over the past decade suggested some correlation between the low concentrations of cfDNA and a number of pregnancy-related complications. The primary goal of this systematic review and meta-analysis was to assess the potential value of low-ff levels in the prediction of subsequent PE/PIH, GDM, SGA/FGR, and PTB. The meta-analysis results aim at summarizing the currently available literature data and determining the clinical relevance of this biochemical marker and the potential necessity for additional investigation of its utility in complications other than the detection of common aneuploidies.

Methods

This systematic review and meta-analysis was designed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. It included all observational studies that reported low -ff levels after the performance of non-invasive prenatal testing (NIPT) as part of the screening for chromosomal abnormalities and their association with adverse pregnancy outcomes, namely the subsequent development of hypertensive disorders of pregnancy, gestational diabetes, preterm birth, and the detection of small for gestational age fetuses or growth-restricted fetuses. The Medline (1966–2041), Scopus (2004–2024), Clinicaltrials.gov (2008–2024), EMBASE (1980–2024), Cochrane Central Register of Controlled Trials CENTRAL (1999–2024) and Google Scholar (2004–2024) databases were used in our primary search along with the reference lists of electronically retrieved full-text papers. The date of our last search was set at February 29, 2024.

Results

Our search identified 128 potentially relevant studies and,overall, 8 studies were included in the present systematic review that enrolled a total of 72,507 patients. Low ff of cfDNA cfDNA was positively associated with HDP (OR 1.66, 95% CI 1.34, 2.06, I-square test: 56%). Low ff of cfDNA was positively associated with GDM (OR 1.27, 95% CI 1.03, 1.56, I-square test: 76%). Furthermore, low ff levels were positively associated with SGA/FGR (OR 1.63, 95% CI 1.32, 2.03, I-square test: 0%). Low ff levels were positively correlated with the risk for PTB but the association did not manage to reach a statistical significant level (OR 1.22, 95% CI 0.89, 1.67, I-square test: 66%).

Conclusion

Our study suggests that low ff is associated with increased risk of adverse perinatal outcomes, including PE/PIH, GDM, and SGA/FGR. However, the relationship between ff and PTB remains unclear due to conflicting evidence. It should be emphasized that further research is needed to reveal the underlying mechanisms behind the association of low ff with adverse pregnancy outcomes and explore its potential role in an overall prenatal screening, which could potentially not be limited to detecting aneuploidies.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. 1st Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 80 Aven., 2-4, Lourou Str., 11528, Athens, Greece

    Ioakeim Sapantzoglou, Maria Giourga, Vasileios Pergialiotis, Rafail Mantzioros, Dimitrios Papageorgiou, Panagiotis Antsaklis, Mariana Theodora, Nikolaos Thomakos & Georgios Daskalakis

  2. School of Medicine, European University of Cyprus, Address: 6, Diogenous Str.Egkomi, 2404, Nicosia, Cyprus

    Maria Anastasia Daskalaki

Authors
  1. Ioakeim Sapantzoglou
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Contributions

Ioakeim Sapantzoglou: co-designed the project and co-wrote the manuscript; Maria Giourga: co-designed the project and co-wrote the manuscript; Vasilios Pergialiotis: supervised the project, wrote and revised the manuscript; Rafail Mantzioros: co-wrote the manuscript;Dimitrios Papageorgiou: co-wrote the manuscript; Maria Anastasia Daskalaki: supervised the project and revised the manuscript; Panagiotis Antsaklis: co-designed the project and revised the manuscript; Mariana Theodora:: co-designed the project and revised the manuscript; Nikolaos Thomakos: supervised the project and revised the manuscript; Georgios Daskalakis: supervised the project and revised the manuscript.

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Correspondence to Ioakeim Sapantzoglou.

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Sapantzoglou, I., Giourga, M., Pergialiotis, V. et al. Low fetal fraction and adverse pregnancy outcomes— systematic review of the literature and metanalysis. Arch Gynecol Obstet (2024). https://doi.org/10.1007/s00404-024-07638-4

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