A phenome-wide analysis of short- and long-run disease incidence following Recurrent Pregnancy Loss using data from a 39-year period

Abstract

Background: Pregnancy loss is one of the most frequent pregnancy complications. It is unclear how recurrent pregnancy loss (RPL) impacts disease risk later in life and if later disease risk is different in women with or without a live birth prior to RPL (primary vs. secondary RPL). We sought to investigate if women have an increased risk of disease following RPL, and if there was a difference between primary and secondary RPL. Methods: Using population-wide health care registry databases from Denmark we identified a cohort of 1,370,896 women between 12 and 40 years in the period January 1, 1977, to October 5, 2016 who had been pregnant. Each woman was followed on average for 15.8 years. Of these, 10,691 (0.77%) women fulfilled the criteria for RPL (50.0% had primary RPL). Relative Risk Ratios (RR) were calculated in a phenome-wide manner for diagnoses with a cumulative incidence proportion ≥0.1% in women with RPL. Diagnoses related to assessment and diagnosis of RPL and those appearing later in life were separated using a Mixture Model. Results: In the full cohort of pregnant women, 0.77% (10,691) fulfilled the criteria for RPL (50.0% primary RPL). Compared to women without RPL, primary RPL increased the risk of subsequent cardiovascular disorders, including atherosclerosis (RR=2.45, 1.65-3.51 95% Uncertainty Interval (UI)), cerebral infarction (RR=1.87, 1.43-2.4 95% UI), heart failure (RR=1.97, 1.44-2.63 95% UI), and pulmonary embolism (RR=1.82, 1.32-2.46 95% UI). Women with secondary RPL had an increased risk of obstetric complications, e.g. placenta previa (RR=3.76, 2.9-4.8 95% UI), premature rupture of membrane (RR=2.55, 2.21-2.91 95% UI), intrapartum hemorrhage (RR=2.8, 1.77-4.31 95% UI), gestational hypertension (RR=2.2, 1.67-2.87 95% UI), and puerperal sepsis (RR=2.54, 1.8-3.5 95% UI). We also noticed associations to autoimmune, respiratory, gastro-intestinal and mental disorders in both subtypes. Conclusion: Our findings show that RPL is a risk factor for a spectrum of disorders. This can in part be due to increased screening following RPL, but it also suggests that RPL may directly influence or share etiology with a number of diseases later in life. Research into the pathophysiology of both pregnancy loss and later diseases merits further investigation.

The impact of early pregnancy complications on completed family size—A nationwide, registry‐based cohort study with 40 years of data

“…Our conclusion that consecutive pregnancy losses have a larger impact than the total number of pregnancy losses is consistent with a recent publication from our group where consecutive pregnancy losses had a much larger effect on chance of live birth in the next pregnancy than the total number of pregnancy losses experienced 27 . The observation that women with three or more consecutive pregnancy losses have a reduced completed family size adds to the growing evidence that there are maternal and/or pathophysiological causes underlying the condition that put these women at risk beyond random chance, also of risk of disease later in life 6,10,13,14,16 . We believe that the clear results of our study were possible because of the very large sample sizes we could work with, but independent replication studies of consecutive pregnancy losses in other populations are clearly needed.…”

“…However, we did not specifically study trends of selective fertility in the present cohort and therefore we do not know if the decrease in number of live‐born children is due to infertility, continued adverse pregnancy outcomes, or if couples stop trying. Lastly, our study represents a population average, but individual disease trajectories, social circumstances, and lifestyle will explain a considerable proportion of individual‐level variance that we could not capture 10,28,29 . Specifically, smoking and body mass index were not registered before 1991 and 2003, respectively, and are only registered in pregnancies ending in a birth, i.e.…”

“…It is well documented that previous pregnancy losses decrease the likelihood of live birth in the next pregnancy, especially among women with recurrent pregnancy loss 6–8 . New studies have also highlighted that the number of consecutive pregnancy losses has a greater importance than the total number of pregnancy losses, both in terms of chance of live birth in the next pregnancy and later maternal health 9,10 . However, no studies have quantified the effect of pregnancy losses on the total number of live‐born children.…”

“…Adverse pregnancy outcomes are associated with an increased risk of numerous diseases later in life. For instance, pregnancy loss is associated with cardiovascular disease (both in the woman and her first‐degree relatives), 13,14 autoimmune, respiratory, gastrointestinal, and mental disorders, 10 type two diabetes mellitus, 6 as well as obstetric complications, especially among women who experienced recurrent pregnancy loss after giving birth to a boy, 10,15 but not cancer 16 . Previous stillbirth is associated with dementia 17 .…”

Leveraging electronic health records to identify risk factors for recurrent pregnancy loss across two medical centers: a case-control study

“…Computational methods provide the opportunity to mine this data and uncover patterns within patient populations. Previous projects analyzing EHR data to study RPL have investigated disease incidence after RPL 36 and characterized lifetime phenotypic associations of idiopathic RPL 15 . The first study included 10,691 RPL patients from Denmark, and reported an increased risk of cardiovascular and gastrointestinal disorders later in life, for primary and secondary RPL patients respectively 36 .…”