MYPP trial: Myo-inositol supplementation to prevent pregnancy complications in women with polycystic ovary syndrome, study protocol for a multicenter, double-blind, randomized controlled trial

IntroductionPregnant women with polycystic ovary syndrome (PCOS) have an increased risk of gestational diabetes mellitus (GDM), preeclampsia and preterm birth, and their offspring are more likely to have an abnormal birth weight and require hospitalization. Current preventive strategies to reduce the rate of pregnancy complications associated with PCOS have ineffective. Myo-inositol supplementation has shown promising clinical benefit in preventing adverse outcomes in individuals with obesity and PCOS-related disorders. Recent randomized controlled trials using daily supplementation with 4 grams of myo-inositol during pregnancy estimated a relative reduction of up to 65% for GDM and preterm delivery.(1-7) These studies included both obese patients and patients with normal body weight. From these trials, post-hoc analysis suggested similar, or even greater, reductions in the sub group of women with PCOS.(8) However, no randomized controlled trials have been conducted to evaluate the potential benefit of myo-inositol supplementation in preventing pregnancy complications in these women. Methods and analysisThis is a prospective, multicenter, double-blind, randomized controlled trial to study the clinical effectiveness and cost-effectiveness of myo-inositol supplementation to prevent pregnancy among women with PCOS. Recruitment will set out to include 464 individuals with PCOS between 8+0 and 16+0 weeks of pregnancy, who are then randomized in a 1:1 ratio to either the intervention group that will receive 4 grams myo-inositol added a standard recommended dose of folic acid, divided over two daily sachets of sugary powder throughout pregnancy; or into the control group that will receive similar looking sachets containing no supplement other than the routinely recommended dose of folic acid. Regular multivitamin use (without inositols) will be allowed for both groups. The primary endpoint is the incidence of the composite outcome of either GDM, preeclampsia and/or preterm birth. Secondary endpoints include indicators of maternal physical and mental well-being, maternal health-related quality of life, neonatal outcomes, breastfeeding practices and breastmilk composition. Trial results will be analysed according to the intention-to-treat principle. A full economic evaluation will be performed. Ethics and disseminationThe study protocol has been approved by the Medical Ethics Committee of the Erasmus MC University Medical Centre Rotterdam. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted to peer-reviewed journals. Trial registration numberNTR-NL7799 Strengths and limitations of this studyO_LIThis will be the first prospective randomized controlled trial, aimed specifically at women with polycystic ovary syndrome (PCOS), to estimate the potential of myo-inositol supplementation in preventing common pregnancy complications associated with PCOS. C_LIO_LIThe double-blinded randomized multicenter design enables unbiased interpretation and generalisability of results. C_LIO_LIThis study will provide novel recommendations on myo-inositol supplementation as a safe nutritional intervention aimed to improve pregnancy outcomes among women with PCOS. C_LIO_LIInclusion of individuals of diverse ethnic backgrounds may prove a limitation given the relative homogeneous population of the Netherlands; the estimated effect sizes, compared with previous studies upon which our power calculations were based, may also vary across sub populations e.g. women with obesity and different PCOS phenotypes. C_LIO_LIRecruitment and compliance in this patient group may lead to self-selection of participants with higher educational, or socio-economic backgrounds. This needs to be taken into account to estimate the impact of implementation. C_LI