Association of insulin resistance with in vitro fertilization outcomes in women without polycystic ovarian syndrome: potential improvement with metformin treatment

Abstract

Study question: What is the association between insulin resistance (IR), metformin treatment, and the outcomes of IVF in IR infertile women without polycystic ovarian syndrome (non-PCOS)?

Summary answer: IR among non-PCOS infertile women was associated with worse IVF outcomes compared to insulin-sensitive (IS) infertile women, and metformin treatment prior to embryo transfer (ET) was associated with improved reproductive outcomes.

What is known already: Endometrium insulin-mediated glucose uptake is essential in human embryo implantation, decidualization, and pregnancy. IR has been described as a risk factor for spontaneous abortion in women undergoing IVF. While this condition has been studied in the context of PCOS and its association with poorer reproductive outcomes, with Metformin proposed as a possible treatment, there is a lack of studies examining the role of IR in non-PCOS infertile women.

Study design, size, duration: Observational, multicenter, retrospective cohort study with clinical data from private fertility centers in Spain collected between January 2015 to November 2023. From 1659 patients a total of 1033 women met all the inclusion criteria and had available data for analysis.

Participants/materials, setting, methods: The study included non-PCOS infertile women between 18 and 45 years old, with a BMI ≤30 kg/m2, available oral glucose tolerance test (OGTT) results, and an indication for IVF and ET using donated oocytes. The study population was stratified based on OGTT results in IS women (n = 718) and in IR women (n = 315). Among IR patients, we identified 198 who were not exposed to metformin at their first ET and 117 who were Metformin-exposed prior to their first ET. IVF outcomes, including biochemical pregnancy, biochemical miscarriage, clinical pregnancy, clinical miscarriage, and live birth rates were evaluated as primary outcomes in IS and not exposed IR groups. The association between metformin exposure and IVF outcomes among IR patients was assessed as secondary outcomes.

Main results and the role of chance: The prevalence of IR in non-PCOS infertile women was 30.5%. Compared to the IS group, unexposed IR women had a higher risk of clinical miscarriage [26.3% vs 17.6%; adjusted relative risk (aRR)=1.439 (1.078-1.921); P = 0.013] and lower live birth rates [9.6% vs 24.5%; aRR=0.422 (0.269-0.663); P < 0.001]. Alternatively, IR patients exposed to Metformin had a higher risk of clinical pregnancy [53.9% vs 35.9%; aRR = 1.467 (1.137-1.892) P = 0.003], lower risk of clinical miscarriage [13.7% vs 26.3%; aRR = 0.481 (0.288-0.804), P = 0.005], and higher live birth rates [40.2% vs 9.6%; aRR = 4.069 (2.445-6.774), P < 0.001] than unexposed IR patients.

Limitations, reasons for caution: Due to its retrospective nature, the inherent limitations of this pilot study are the potential heterogeneity and confounding factors among the study groups.

Wider implications of the findings: The findings of this study provide valuable insights into the role of the endometrial environment on reproductive outcomes in the context of IR among non-PCOS infertile women. Nevertheless, future prospective studies with larger sample sizes are essential to corroborate these findings to broader populations.

Study funding/competing interest(s): This project was supported by the Spanish Ministry of Universities through the Formacion de Profesorado Universitario Program (FPU21/01178) awarded to A.B.A, the Instituto de Salud Carlos III, cofounded by the European Social Fund (ESF) 'Investing in your future' through the Miguel Servet Program (CP20/00120) awarded to H.F. and (CP19/00149) awarded to I.C. and Sara Borrell Contract (CD23/00157) awarded to A.C. The authors have no conflicts of interest to disclose.

Trial registration number: N/A.

Keywords: IVF outcomes; assisted reproduction; infertility; insulin resistance; metformin; oocyte donation.