Long-term health assessment of children following first trimester progesterone treatment in the PRISM trial

Background Miscarriage, affecting approximately 15% of clinically recognised pregnancies, is a significant concern for women and their partners. Currently, there are limited effective treatments available for miscarriage prevention in women experiencing complications during early pregnancy. The PRogesterone In Spontaneous Miscarriage (PRISM) trial was a randomised, placebo-controlled trial that evaluated progesterone treatment to prevent miscarriage among women with early pregnancy bleeding. The trial demonstrated an increase in live birth rate in women with at least one previous miscarriage but not in those without. Despite this, there remains hesitancy among some clinicians to use progesterone due to fears of potential long-term harm due to the limited available data on the long-term health outcomes of children. This cohort of children born on the PRISM trial provides a unique opportunity to acquire high-quality comparative data for both the progesterone and placebo groups. Aim The aim of this study is to compare the health outcomes of children born to women who took progesterone during early pregnancy with those who received a placebo. Objectives The objectives are to compare the following between the progesterone and placebo groups: 1) Health-related quality of life (HRQoL) outcomes using the Health Utilities Index (HUI3). 2) HRQoL outcomes using the EuroQol (EQ-5D-Y-3L version). 3) Incidence of neurodevelopmental disorders (Autism Spectrum Disorder [ASD], Attention Deficit Hyperactivity Disorder [ADHD], dyslexia, dysgraphia, dyspraxia, dyscalculia, Obsessive-Compulsive Disorder [OCD], anxiety, and depression). Methods This prospective observational study will follow children born to women who participated in the PRISM trial. Eligible participants are women who had a live birth during the trial and had previously consented to future follow-up. We will obtain necessary ethical approvals and contact these women to invite participation in the follow-up study. Participants will complete a health questionnaire for their child, capturing data on HRQoL and diagnosed neurodevelopmental disorders. The primary outcome is the HUI3 multi-attribute utility score. The key secondary outcome is valuation of health outcomes using the EQ-5D-Y-3L health questionnaire. Other secondary outcomes are the incidence of ASD, ADHD, dyslexia, dysgraphia, dyspraxia, dyscalculia, OCD, anxiety, and depression. Sensitivity analyses will incorporate data from electronic health records to account for non-respondents. Timeline The study will be completed over an 18-month period. Impact The study will provide comprehensive data on the long-term neurodevelopmental outcomes of children exposed to progesterone in early pregnancy, with the ability to detect clinically significant differences in HUI3 and EQ-5D-Y-3L scores between the progesterone and placebo groups. Additionally, the study will provide robust data on the incidence of neurodevelopmental disorders, addressing current concerns and informing clinical practice. The study will be presented at national and international conferences and published in high-impact peer-reviewed journals. The findings will be pivotal in guiding recommendations by key health bodies, such as the Association of Early Pregnancy Units (AEPU), the Royal College of Obstetrics and Gynaecology (RCOG), and NICE. Results will be shared with patients and the public through collaborations with organisations including the Miscarriage Association and Tommy s Charity.