Symptoms and General Pathology

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Neoplasms

Syndrome

Diabetes, Gestational

Diabetes Mellitus

Pre-Eclampsia

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Micronutrients

All Drugs and Chemicals

Hematinics

Vitamins

Other Dietary Supplements

Inositol

Folic Acid

Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Inositol (Myo-inositol and D-chiro-inositol at 40:1 ratio) plus Folic acid before spontaneous conception until delivery.

Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Folic acid before spontaneous conception until delivery.

Daily oral supplementation before spontaneous conception until delivery:

Myo-Inositol: 1100 mg D-chiro-inositol: 27.6 mg Folic acid: 400 mcg

Inositol + Folic acid

Daily oral supplementation before spontaneous conception until delivery:

Folic acid: 400 mcg

Folic acid

Antonio Simone Laganà, M.D.

Simone Garzon, M.D.

Fabio Ghezzi, M.D.

Massimo Franchi, M.D.

Antonella Cromi, M.D.

Polycystic ovarian syndrome (PCOS) is a heterogeneous, multifaceted and complex disorder characterized by insulin resistance (IR), hyperinsulinemia, and hyperandrogenism leading ovarian disfunction and infertility. Given the central pathogenic role of IR in the endocrine, reproductive, and metabolic disturbances of PCOS, several pharmacological and non-pharmacological approaches have been proposed to counteract the hyper insulinemic IR typical of the syndrome. Two Inositol stereoisomers, Myo-Inositol (MI) and D-chiro-inositol (DCI), captured the attention of researchers for their insulin-sensitizing actions, which configure them as proper candidates for the treatment of PCOS.

Very few studies reported on spontaneous clinical pregnancy rates, none were powered for this outcome, and none reported on the clinically relevant outcome of live birth. Therefore, data about clinical pregnancy rate, live birth rate, and miscarriage rate comparing inositols with placebo are limited.

Nevertheless, regarding infertility the primary outcomes that should be considered are clinical pregnancy rate, miscarriage rate and live birth rate. Although many studies showed improved hormonal and metabolic profile and improved ovulation rate and higher quality and number of oocyte retrieved in Assisted Reproductive Technology (ART) in PCOS women after inositols administration, data about clinical pregnancy rate, live birth rate, and miscarriage rate are limited with several concerns regarding interpretation of the studies.

Furthermore, independently by the effect on PCOS related infertility, few data are available about the role of inositol on obstetrics outcomes of pregnancies conceived after treatment with inositol and/or orally supplemented during pregnancy. Considering that the combination of MI and DCI alleviate many of the metabolic dysregulations typical of PCOS thanks to insulin-sensitizing actions, it is plausible consider a beneficial effects on pregnancy complications such as gestational diabetes and preeclampsia.

Randomized multi centre double-blind controlled trial

The patients, care provides, investigators and outcome assessors are blinded for the treatment: Inositol + Folic acid versus Folic acid alone. The treatment allocation is identified by code number before the study start, and will be revealed only after data analysis.

Effects of Oral Inositol Supplementation on Obstetrics Outcomes in PCOS Women

Effects of Oral Inositol Supplementation on Obstetrics Outcomes in Polycystic Ovary Syndrome Women After Spontaneous Conception

Gestational diabetes prevalence: number of women that develop gestational diabetes diagnosed based on oral glucose tolerance test (OGTT) cut-off (92 - 180 - 153 mg/dl).

Preeclampsia prevalence: number of women that develop preeclampsia diagnosed based on blood pressure higher than 140/90 mmHg after 20 week of gestation plus 24h proteinuria higher that 300mg.

Universita di Verona

Università degli Studi dell'Insubria

Principal Investigator

Heart and Blood Diseases

Rare Diseases

Premature Birth

Eclampsia

Metabolic Diseases

Glucose Metabolism Disorders

Hypertension

Hypertension, Pregnancy-Induced

Obstetric Labor, Premature

Obstetric Labor Complications

Hypoglycemic Agents

Insulin

Insulin, Globin Zinc

Myo-inositol is a naturally occurring substance, with a structure quite similar to glucose, which forms an essential component of the cell membrane and is known to support several cellular processes in all living organisms. It is present in nature in high abundance and can be found in many food products. Myo-inositol was historically considered part of the vitamin-B complex and can safely be used as a dietary supplement. In humans, it is synthesized de novo from glucose-6-phosphate in many tissues, mainly in the kidney. Under normal circumstances, the kidneys produce large quantities of myo-inositol, estimated at about 4 grams of endogenous production per day. Myo-inositol has been shown to have a physiological role in supporting the effects of insulin in all living beings. It fulfils a second messenger role in the insulin signalling pathway by enhancing the translocation of GLUT-4 receptors on the plasma membrane and thereby facilitates the intra-cellular uptake of glucose.

Folic acid supplements are part of routine pregnancy care and frequently used as background supplements in previous trials on myo-inositol supplementation in pregnancy.

Participants randomly allocated to the intervention group will receive 4 grams myo-inositol added to their routinely recommended 0.4 mg folic acid supplement, divided over two daily sachets of sugary powder throughout pregnancy.

Myo-inositol and routinely recommended folic acid

The control group will receive similar looking sachets of supplements containing only the standard dose of 0.4 mg folic acid without the added myo-inositol supplement as part of the current standard-of-care recommendation.

Routinely recommended folic acid

Rebekka Bout - Rebel, MSc

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.

MYPP-trial: Myo-inositol Supplementation to Prevent Pregnancy Complications in Women With Polycystic Ovary Syndrome.

MYPP-trial: Myo-inositol Supplementation to Prevent Pregnancy Complications in Women With Polycystic Ovary Syndrome: a Multicentre Double-blind Randomised Controlled Trial

To evaluate the cost-effectiveness of the nutritional intervention from a societal perspective, all resources used in maternity and neonatal care are recorded using questions derived from the Medical Consumption Questionnaire (MCQ).

To evaluate the patient perspective, questions derived from the EQ-5D-5L and the Productivity Cost Questionnaire (PCQ) are incorporated in the study questionnaire

GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.

Preeclampsia as defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP).

Preterm birth is internationally defined as any birth before 37 completed weeks of gestational age.

The BDI-II-NL measures characteristic attitudes and symptoms of depression and contains 21 items, subdivided in cognitive, affective and somatic factors. Patients rate themselves on these depressive symptoms by endorsing the most relevant statement (ranging in four steps of intensity from minimal to severe) covering a time frame of the past 2 weeks.

he EQ-5D-5L records the patient's self-rated health, and a descriptive system. The descriptive system distinguishes five health domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The PCOSQ is the only existing validated, disease-specific, health related quality of life assessment questionnaire. As stated in the new evidence-based PCOS guidelines, this questionnaire could be clinically useful to highlight PCOS features causing greatest distress and was developed to evaluate the effect of treatment in clinical trials in PCOS.

* The incidence of Small-for-gestational-age (SGA): babies in the two study arms; birth weight ≤10th percentile or two standard deviations below the mean birth weight for gestational age, using Dutch Perinatal Registry birth weight reference charts.
* The incidence of Large-for-gestational-age (LGA) babies in the two study arms: birth weight ≥90th percentile for gestational age, using Dutch Perinatal Registry birth weight reference charts.
* The incidence of NICU admission in the two study arms, including reason for admission and time to discharge or transfer to another unit.
* The incidence of Neonatal hypoglycaemia in the two study arms:

ZonMw: The Netherlands Organisation for Health Research and Development

Erasmus Medical Center

Associate Professor

Metformin

Metformin 1000 mg x 2 per day. Orally. From inclusion (before gestational week 12) to delivery. Verbal and written diet and lifestyle advices at inclusion to the study

Placebo, 2 tablets x 2 daily.Orally. From inclusion (that is before gestational week 12) to delivery. Verbal and written diet and lifestyle advices at inclusion to the study

Placebo

Eszter I Vanky, MD, PhD

To investigate the effect of metformin on pregnancy complications and pregnancy outcome in the II. and III. trimester of pregnancy in women with polycystic ovary syndrome.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effects of Oral Inositol Supplementation on Obstetrics Outcomes in PCOS Women	NCT03585738	Polycystic Ovar...	Inositol + Foli... Folic acid	18 Years - 40 Years	Università degli Studi dell'Insubria
MYPP-trial: Myo-inositol Supplementation to Prevent Pregnancy Complications in Women With Polycystic Ovary Syndrome.	NCT05524259	Gestational Dia... Preeclampsia Preterm Birth Polycystic Ovar...	Myo-inositol an... Routinely recom...	18 Years -	Erasmus Medical Center
MYPP-trial: Myo-inositol Supplementation to Prevent Pregnancy Complications in Women With Polycystic Ovary Syndrome.	NCT05524259	Gestational Dia... Preeclampsia Preterm Birth Polycystic Ovar...	Myo-inositol an... Routinely recom...	18 Years -	Erasmus Medical Center
Metformin in Pregnant PCOS Women	NCT00159536	Polycystic Ovar...	Metformin Placebo	18 Years - 45 Years	Norwegian University of Science and Technology
Effects of Oral Inositol Supplementation on Obstetrics Outcomes in PCOS Women	NCT03585738	Polycystic Ovar...	Inositol + Foli... Folic acid	18 Years - 40 Years	Università degli Studi dell'Insubria
Metformin in Pregnant PCOS Women	NCT00159536	Polycystic Ovar...	Metformin Placebo	18 Years - 45 Years	Norwegian University of Science and Technology
MYPP-trial: Myo-inositol Supplementation to Prevent Pregnancy Complications in Women With Polycystic Ovary Syndrome.	NCT05524259	Gestational Dia... Preeclampsia Preterm Birth Polycystic Ovar...	Myo-inositol an... Routinely recom...	18 Years -	Erasmus Medical Center

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