Fetal fraction of cell-free DNA in noninvasive prenatal testing and adverse pregnancy outcomes: a nationwide retrospective cohort study of 56,110 pregnant women - 08/01/24

Doi : 10.1016/j.ajog.2023.12.008

Ellis C. Becking, MD ^a, Peter G. Scheffer, MD, PhD ^a, Jens Henrichs, PhD ^b, Caroline J. Bax, MD, PhD ^c,^d, Neeltje M.T.H. Crombag, PhD ^a, Marjan M. Weiss, PhD ^e, Merryn V.E. Macville, PhD ^f, Diane Van Opstal, PhD ^g, Elles M.J. Boon, PhD ^h, Erik A. Sistermans, PhD ^d,^h, Lidewij Henneman, PhD ^d,^h, Ewoud Schuit, PhD ⁱ, Mireille N. Bekker, MD, PhD ^a,^⁎
^a Department of Obstetrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
^b Department of Midwifery Science, VU University Medical Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
^c Department of Obstetrics and Gynaecology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
^d Amsterdam Reproduction and Development research institute, Amsterdam University Medical Centers, Amsterdam, the Netherlands
^e Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
^f Department of Clinical Genetics, GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
^g Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
^h Department of Human Genetics, VU University Medical Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands
ⁱ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

^∗Corresponding author: Mireille N. Bekker, MD, PhD.

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Abstract

Background

Noninvasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In noninvasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Given that fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation.

Objective

This study aimed to assess the association between the fetal fraction and adverse pregnancy outcomes.

Study Design

We performed a retrospective cohort study of women with singleton pregnancies opting for noninvasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing [TRIDENT]-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as <10th percentile, corresponding to a fetal fraction <2.5%.

Results

The cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with increased risk of hypertensive disorders of pregnancy (adjusted odds ratio, 2.27 [95% confidence interval, 1.89–2.78]), small for gestational age neonates <10th percentile (adjusted odds ratio, 1.37 [1.28–1.45]) and <2.3rd percentile (adjusted odds ratio, 2.63 [1.96–3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (adjusted odds ratio, 1.02 [1.01–1.03]). No association was found for fetal congenital anomalies (adjusted odds ratio, 1.02 [1.00–1.04]), stillbirth (adjusted odds ratio, 1.02 [0.96–1.08]), or neonatal death (adjusted odds ratio, 1.02 [0.96–1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was <10th percentile.

Conclusion

In early pregnancy, a low fetal fraction is associated with increased risk of adverse pregnancy outcomes. These findings can be used to expand the potential of noninvasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures.

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Becking. Fetal fraction in noninvasive prenatal testing and adverse pregnancy outcomes. Am J Obstet Gynecol 2023.

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Key words : adverse pregnancy outcomes, cell-free DNA, cell-free DNA screening, cell-free fetal DNA, fetal fraction, gestational diabetes, hypertensive disorders of pregnancy, noninvasive prenatal testing, pregnancy complications, small for gestational age neonates, spontaneous preterm birth

Plan

	The authors report no conflict of interest.
	This work was supported by a grant from the Netherlands Organisation for Health Research and Development (No. 43002014). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or the decision to submit the report.
	Cite this article as: Becking EC, Scheffer PG, Henrichs J, et al. Fetal fraction of cell-free DNA in noninvasive prenatal testing and adverse pregnancy outcomes: a nationwide retrospective cohort study of 56,110 pregnant women. Am J Obstet Gynecol 2023;XX:x.ex–x.ex.