Phenome-Wide Analysis of Short- and Long-Run Disease Incidence Following Recurrent Pregnancy Loss Using Data From a 39-Year Period

Background It is unclear how recurrent pregnancy loss (RPL) impacts disease risk and whether there is a difference in risk between women with or without a live birth before RPL (primary versus secondary RPL). We investigated the disease risk following RPL, and whether there was a difference between primary and secondary RPL. Methods and Results Using population-wide healthcare registries from Denmark, we identified a cohort of 1 370 896 ever-pregnant women aged 12 to 40 years between 1977 and 2016. Of this cohort, 10 691 (0.77%) fulfilled the criteria for RPL (50.0% primary RPL). Average follow-up was 15.8 years. Incidence rate ratios were calculated in a phenome-wide manner. Diagnoses related to assessment and diagnosis of RPL and those appearing later in life were separated using a mixture model. Primary RPL increased the risk of subsequent cardiovascular disorders, including atherosclerosis, cerebral infarction, heart failure, and pulmonary embolism, as well as systemic lupus erythematosus, chronic obstructive pulmonary disease, anxiety, and obsessive-compulsive disorder. Women with secondary RPL had no increased risk of cardiovascular disorders. However, we observed an increased risk of gastrointestinal disorders such as irritable bowel syndrome and intestinal malabsorption, as well as mental disorders and obstetric complications. Conclusions RPL is a risk factor for a spectrum of disorders, which is different for primary and secondary RPL. Screening following RPL explains some associations, but the remaining findings suggest that RPL influences or shares cause with cardiovascular disorders, autoimmune disorders, and mental disorders. Research into the pathophysiology of RPL and later diseases merits further investigation.