Exploring the effects of infertility on pregnancy and perinatal outcomes -a two sample Mendelian Randomisation study

Infertility is a common reproductive disorder affecting approximately 12% of people globally. Some studies have identified the association between infertility and several adverse pregnancy and perinatal outcomes (APPOs). However, these associations may be confounded by maternal factors, which increase the risk of infertility and at least one or more APPOs or ART-related outcomes, making it difficult to determine whether infertility itself is causally related to these adverse outcomes. To address these challenges, Mendelian Randomisation (MR) can be used to estimate the causal effect by leveraging genetic variants as instrumental variables (IVs) for genetic liability to infertility. A recent genome-wide association study (GWAS) has identified genetic variants associated with any/all causes of female infertility, anovulatory female infertility, anatomical infertility, including polycystic ovary syndrome or uterine leiomyomas and female infertility of unknown cause. This provides data for genetic instruments of female infertility that can be used in two-sample MR. The primary aim of this study is to use two-sample MR to determine the effect of genetic liability to all-cause (any) female infertility on the following APPOs: hypertensive disorders of pregnancy (HDP), gestational hypertension, pre-eclampsia (PE), gestational diabetes mellitus (GDM), pregnancy loss, stillbirth, preterm birth, very preterm birth, small gestational age (SGA), large gestational age (LGA), low birth weight, high birth weight. The secondary aim is to explore the following sub-types of female infertility on the same APPOs: 1) anatomical female infertility (including tubal, uterine, and cervical origins), 2) anovulatory female infertility (including polycystic ovary syndrome, endometriosis and uterine leiomyomas), 3) unknown cause of female infertility (defined by exclusion of known causes of infertility) and 4) idiopathic female infertility defined by inclusion of diagnostic codes for idiopathic infertility.