AFFIRM: prediction of Adverse pregnancy outcome by Fetal Fraction Measurement in NIPT

BACKGROUND AND RATIONALE One in eight pregnancies is complicated by small for gestational age neonates (SGA), preeclampsia (PE), preterm birth (PTB), or gestational diabetes mellitus (GDM). These complications have a life-long impact on both the mother and child with an associated burden on general health care costs. Identifying pregnant women at risk for these adverse pregnancy outcomes at an early gestational age allows for timely interventions and tailored pregnancy management to prevent complications. Although many first-trimester risk stratification models have been developed, no one method is universally applied as performance of these models is at best acceptable. In non-invasive prenatal testing (NIPT), cell-free fetal DNA in the blood of the pregnant woman is analyzed to screen for fetal aneuploidies. As this cell-free fetal DNA is derived from placental cells undergoing apoptosis, the amount of cell-free DNA released in the maternal circulation reflects placental health and maternal pregnancy adaptation. Indeed, several small-scaled studies have shown an association between the fetal fraction (FF) of cell-free DNA (i.e. the amount of placental-derived cell-free DNA in relation to the amount of cell-free DNA of maternal origin in the blood of the pregnant mother) and placenta-related adverse pregnancy outcomes. The primary aim of our project is to study the value of FF in the risk stratification of adverse pregnancy outcomes. OBJECTIVES 1. To determine the association between FF and adverse pregnancy outcomes, such as SGA, PE, PTB, and GDM 2. To determine the additional value of adding FF to existing prognostic models for adverse pregnancy outcomes 3. To determine the clinical impact and cost-effectiveness of using FF in the prediction of adverse pregnancy outcomes 4. To assess the perspectives and needs of pregnant women and professionals regarding early prediction of adverse pregnancy outcomes using NIPT 5. To explore the implications for the normative framework for prenatal screening: under what conditions can early prediction of adverse pregnancy outcomes (prevention-aimed) be responsibly incorporated in NIPT-screening for fetal chromosomal anomalies (reproductive autonomy-aimed)? 6. To develop an implementation roadmap for the future use of FF in NIPT in the early prediction of adverse pregnancy outcomes DESIGN AND METHODS In the Netherlands, NIPT is performed within a governmentally supported implementation study (TRIDENT-2) and available for all pregnant women. With an uptake of about 42%, 73,000 tests are performed each year and the FF is uniformly measured in all NIPT laboratories as a sample quality parameter. To determine the association between FF and adverse pregnancy outcomes (obj. 1) we will draw and analyze data from already in place TRIDENT-2 databases and the national prenatal and perinatal registries Peridos and Perined. We will then determine the additional value of adding FF to existing prognostic models (obj. 2) through internal and external validation. A health technology assessment (HTA) will be conducted to determine the clinical impact and cost-effectiveness of using FF in the prediction of adverse pregnancy outcomes (obj. 3). To consequently assess the perspectives and needs of pregnant women and professionals regarding early prediction of adverse pregnancy outcomes using NIPT (obj. 4), we will organize a stakeholders meeting, perform focus groups, and conduct semi-structured interviews. Based on this information, we will develop questionnaires to perform a discrete choice experiment. When changing the scope of NIPT from a reproductive autonomy-aimed test to (also) a prevention-aimed test it is essential to think about the conditions for responsibly offering such screening. We will explore the implications for the normative framework for prenatal screening (obj. 5) through literature research and conceptual and ethical analysis by method of wide reflective equilibrium. Expecting to have established a multifaceted and complete perspective of using FF in the risk stratification of adverse pregnancy outcomes, we will finally develop a road map for implementation (obj. 6), that will be offered to all stakeholders and policy makers in the Netherlands. The project is highly feasible since we will use the well-organized and national network for prenatal screening that has been collaborating together with the NIPT consortium since 2011. Our project team represents all relevant areas of expertise necessary to perform this study. Our proposal has the support of the NIPT consortium, KNOV, and NVOG. We build on former ZonMw projects (TRIDENT, RESPECT). ANTICIPATED RESULTS We will deliver a ready-to-use NIPT-based risk stratification model for adverse pregnancy outcomes together with a multifaceted perspective of broadening the NIPT-based prenatal screening from enabling reproductive choices to risk stratification to improve fetal-maternal health and a road map for future implementation.