Polycystic ovarian syndrome and metformin use in pregnant woman. Possible reduction of fetal loss. A cohort study in the Clinical Practice Research Datalink.

Date of Approval: 
2020-11-20 00:00:00
Lay Summary: 
Polycystic ovary syndrome (PCOS) is a common condition that affects how a woman's ovaries work. Some features of PCOS are irregular periods, which mean that the ovaries do not regularly release eggs; and insulin resistance which means that the cells are more resistant to insulin, the hormone regulating blood glucose level, leading to a high blood glucose level. This might lead to difficulty in getting pregnant. Furthermore, once pregnant, women with PCOS present an increased risk of baby loss (miscarriage) and of too early birth (preterm birth). Metformin is licensed in the United Kingdom to treat type 2 diabetes. Just as in diabetic patients, it might also lower insulin resistance and blood sugar levels in women with PCOS. Metformin is not licensed for treating PCOS in the UK, however as many women with PCOS have insulin resistance, it is used "off-label" in certain circumstances to encourage fertility. However, not all medical guidelines are recommending the use of metformin in PCOS pregnant women. This study will investigate, if exposure to metformin during pregnancy can reduce the risk of miscarriage and preterm birth, among women with PCOS, in the Clinical Practice Research Datalink.
Technical Summary: 
Among women with polycystic ovary syndrome (PCOS), the aim of this study is to describe metformin treatment pattern, the frequency of general practitioner visit, the occurrence of gestational diabetes mellitus, and the pregnancy outcomes; and to compare pregnancies exposed to metformin as opposed to pregnancies unexposed to metformin, in terms of miscarriage and preterm live birth. This study will be a cohort of all eligible pregnancy episodes among women with PCOS. The time scale will be the gestational age, and the last menstrual date (LMP) will be the index date. Pregnancies will be followed from the LMP date, through the earliest of: end of pregnancy, or mother’s death. The outcomes will be retrieved via the CPRD Pregnancy Register, while the mother’s comorbidities and treatment via CPRD Gold. Metformin exposure will be defined as a time-varying variable classifying pregnancy into exposed or unexposed at every time point of the follow-up. A survival approach by the multistate methodology will be implemented. It will investigate the time until one composite outcome and elaborates standard survival analysis to event histories analyses. Pregnancies will be entered at the time of estimated LMP as index date in state 0 if exposed to metformin or state 1 if unexposed; and will be censored at the 260th day of pregnancy as they are no longer at risk for preterm birth or miscarriage. Depending on the exposure status, pregnancies can move between the state 0 and 1. Finally, a pregnancy will be terminated by any of outcome of competing events (state 2, absorbing state): miscarriage, preterm live birth, elective termination of pregnancy, mother´s death, or any other adverse pregnancy outcome (stillbirth, unspecified loss, ectopic, molar, blighted ovum). Adjusted hazard ratio (Cause specific HR and Subdistribution HR for competing setting) for the outcomes and the competing events will be displayed.
Health Outcomes to be Measured: 
Treatment patterns of metformin; Frequency of general practitioner visits (GP); Gestational diabetes mellitus; Pregnancy outcomes; Miscarriage; Preterm live birth.
Application Number: 

Caroline Foch - Chief Investigator - Merck Healthcare KGaA (Merck Group)
Caroline Foch - Corresponding Applicant - Merck Healthcare KGaA (Merck Group)
Emmanuelle Boutmy - Collaborator - Merck Healthcare KGaA (Merck Group)
Kerstin Brand - Collaborator - Merck Healthcare KGaA (Merck Group)
Michael Batech - Collaborator - Merck Healthcare KGaA (Merck Group)
Patrice Verpillat - Collaborator - Merck Healthcare KGaA (Merck Group)

Practice Level Index of Multiple Deprivation;Pregnancy Register