The Role of Nutrient Supplements in Female Infertility: An Umbrella Review and Hierarchical Evidence Synthesis

Background and Objectives: Nutrient supplements are commonly used to improve fertility outcomes by women with infertility trying to conceive spontaneously or utilising medically assisted reproduction (MAR). However, despite their widespread use and perceived safety, there is a lack of clear guidance on the efficacy and safety of these supplements for female infertility. The aim of this umbrella review was to identify the best available and most recent evidence on the efficacy and safety of nutrient supplements for female infertility to provide evidence-based guidance for clinicians and reproductive couples. Methods: Five electronic databases were searched for umbrella reviews, meta-analyses, and systematic reviews of randomised controlled trials on nutrient supplements for female infertility, published from August 2017 to January 2024. The primary outcomes were live birth, and clinical and biochemical pregnancy rates. Secondary outcomes were adverse effects including miscarriage and ectopic or multiple pregnancy. Quality assessment was performed using the A MeaSurement Tool to Assess systematic Reviews Version 2.0 (AMSTAR 2), and the certainty of evidence for outcomes were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, where possible. Results: Four meta-analyses were included. Multiple micronutrients and antioxidants increased live birth rates in women utilising MAR and/or trying to conceive spontaneously compared to placebo, standard or no treatment (odds ratio (OR) 2.59 and 1.81 respectively) with very low certainty evidence. L-carnitine, coQ10, melatonin, myo-inositol, NAC and vitamin D increased clinical pregnancy rates in women with PCOS and/or undergoing MAR compared to placebo, standard or no treatment (odds ratio (OR) 11.14, 2.49, 1.66, relative risk (RR) 1.52, OR 2.15, and 1.49 respectively) with very low certainty evidence. Vitamin D did not increase biochemical pregnancy rates in women utilising MAR with very low certainty evidence. NAC, vitamin D, and pooled antioxidants had no effect on miscarriage rates or multiple pregnancy rates in women trying to conceive spontaneously or utilising MAR, with low to very low certainty evidence. Pooled antioxidants had no effect on ectopic pregnancy rates in women trying to conceive spontaneously or utilising MAR, with low certainty evidence. Conclusions: The available evidence is insufficient to recommend nutrient supplementation to improve female infertility in women trying to conceive naturally and those utilising MAR. However, there is currently no indication that these nutrients pose any risk of significant harm. Registration: PROSPERO (CRD42022365966) 20 October 2022.