Fetal fraction and beyond: Expanding the scope of noninvasive prenatal testing

Abstract

The discovery of placental cell-free DNA (cfDNA) in the maternal bloodstream led to the development of noninvasive prenatal testing (NIPT). Currently, NIPT is available worldwide and is implemented in the Netherlands as part of a national prenatal screening program. Fetal fraction is defined as the proportion of placental cfDNA in the maternal circulation and is routinely measured in NIPT as a quality parameter. As placental cfDNA originates from apoptotic placental cells, fetal fraction may provide information on placental health. This thesis is based on the hypothesis that impaired placentation in early pregnancy results in lower amounts of placental cfDNA in the maternal circulation, leading to a lower fetal fraction and an increased risk of placenta-related adverse pregnancy outcomes later in pregnancy. The aim of this thesis was to evaluate the potential of fetal fraction in NIPT to predict adverse pregnancy outcomes. The thesis consists of two parts. In Part I, the clinical relevance of fetal fraction to predict adverse pregnancy outcomes is investigated. In Part II, the perspectives of pregnant women and obstetric healthcare professionals and ethical considerations on expanding the scope of NIPT to prediction of adverse pregnancy outcomes are explored. In Part I, the association between fetal fraction and adverse pregnancy outcomes was explored through a systematic review and a retrospective cohort study, which suggested that a low fetal fraction is associated with an increased risk of adverse pregnancy outcomes. Consecutively, a nationwide retrospective cohort study was performed, including over 56,000 pregnancies. In this study, a decrease in fetal fraction was associated with an increased risk of hypertensive disorders of pregnancy, small for gestational age neonates, spontaneous preterm birth, and diabetes, after adjustment for relevant confounders. In a follow-up analysis, the added prognostic value of fetal fraction on top of established first-trimester clinical parameters was statistically significant, but limited. In addition, the association between low fetal fraction and fetal chromosomal aberrations was assessed in a systematic review, showing an increased risk of trisomy 13, trisomy 18, monosomy X, and triploidy in case of a low fetal fraction, but not of trisomy 21. Variability in fetal fraction measurement between laboratories and methods was also evaluated, demonstrating substantial inter-method and inter-laboratory variability. In Part II, an interview study and an online questionnaire showed that pregnant women and obstetric healthcare professionals generally expressed a positive attitude towards expanding the scope of NIPT to prediction of adverse pregnancy outcomes. Perceived benefits included the possibility to take preventive actions, while concerns included potential stress and anxiety following a high-risk result. Ethical analysis showed the tensions between autonomy-aimed screening for fetal aneuploidies and health gain-aimed screening for adverse pregnancy outcomes. In conclusion, a low fetal fraction in NIPT is associated with an increased risk of adverse pregnancy outcomes. Although its added prognostic value is limited, fetal fraction may be of interest because it is readily available in early pregnancy. Future research could focus on combining fetal fraction with other cfDNA characteristics, while taking ethical considerations and stakeholder perspectives into account.