MYPP-trial: Myo-inositol Supplementation to Prevent Pregnancy Complications in Women with Polycystic Ovary Syndrome: a multicentre double-blind randomised controlled trial

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is a heterogeneous condition, characterised by metabolic disturbances, insulin resistance and hyperandrogenism. Pregnancies in women with PCOS have an increased risk of gestational diabetes mellitus, preeclampsia and preterm birth, and their offspring have an increased risk of aberrant birth weight and hospitalization. After pregnancy, PCOS is thought to have an impact on breastfeeding success and breastmilk composition.
Current strategies to improve pregnancy outcome among women with PCOS have not demonstrated significant risk reduction. Myo-inositol is a commonly used dietary supplement with a favourable effect on glucose metabolism and insulin sensitivity. Optimal intake of myo-inositol is associated with a decrease in glucose, lower insulin and lower testosterone levels in women with PCOS. Among women with PCOS-related disorders (e.g. in women with obesity), myo-inositol supplementation in pregnancy has been shown to have clinical benefits in preventing adverse pregnancy outcomes in a number of clinical trials, by reducing the risk of gestational diabetes mellitus, hypertensive complications and preterm birth.

The MYPP-trial will be the first randomised prospective trial aimed specifically at pregnant women with PCOS, to evaluate the potential effectiveness of myo-inositol supplementation as a nutritional intervention to prevent all three pregnancy complications associated with PCOS (i.e. GDM, preeclampsia and preterm birth). Secondary objectives are to evaluate the impact of supplementation on maternal (mental) and neonatal health, breastfeeding practices and breastmilk composition. In addition, a full cost-effectiveness analysis will be performed.
Women with a diagnosis of PCOS and a singleton pregnancy between 8+0 and 16+0 weeks of gestational age are eligible. Participants randomly allocated to the intervention group will receive 4 grams myo-inositol added to their routinely recommended folic acid supplement, divided over two daily sachets of sugary powder throughout pregnancy. The control group will receive similar looking sachets of supplements containing only the standard dose of folic acid without the added myo-inositol supplement, as part of the current standard-of-care recommendation. In addition to receiving supplements, participants will be asked to complete three questionnaires, provide blood and urine samples once each trimester of pregnancy, and routine ultrasound scanning will be performed to assess fetal growth. All study visits will be aligned with routine antenatal care appointments. Additionally, subjects can choose to participate in research on the impact of myo-inositol supplementation on breastfeeding and take part in the MYPP biobank.
The results of this study will provide important novel recommendations for PCOS patients on the importance of optimising life-style and nutrient intake to improve pregnancy outcome.

Based on previous clinical trials among pregnant women with PCOS-related disorders (e.g. in women with obesity) we expect daily intake of myo-inositol, as a safe nutritional intervention during pregnancy, will result in a 35% reduction in the composite outcome of GDM, preeclampsia and preterm birth among women with PCOS.

Women with a diagnosis of PCOS will be included after confirmation of a viable singleton pregnancy by ultrasound between 8+0 and 16+0 weeks of gestational age.
After inclusion participants will be allocated at random to either the intervention group or the control group and will receive supplementation up until delivery. Participants will be followed-up until 6 weeks postpartum.
The primary outcome (i.e. the number of pregnancies complicated with either gestational diabetes, and/or preeclampsia and/or preterm birth) will be scored ultimately one week postpartum (as to include postpartum preeclampsia). Maternal and neonatal data will be collected until 6 weeks postpartum.
We will seek permission for follow-up of breastfeeding mothers until 6 months postpartum and seek permission for additional follow-up of children until school-age to monitor the long-term effects on development, metabolic changes and epigenetic changes (subject to additional protocols and funding).

Participants randomly allocated to the intervention group will receive 4 grams myo-inositol added to their routinely recommended folic acid supplement, divided over two daily sachets of sugary powder throughout pregnancy. The control group will receive similar looking sachets of supplements containing only the standard dose of folic acid without the added myo-inositol supplement as part of the current standard-of-care recommendation.