Strengths and limitations:
Our study is unique in its size and breadth, including over one million individuals, stretching as far back as 1939. The size of the study allowed us to calculate a precise estimate for the familial risk of PA. While the UPDB allows for population-level results, we were able to collect data at the individual level using birth and death certificates as well as electronic medical records. This allowed for careful inclusion of cases, stratification of separate pregnancies for each individual, and the ability to address confounding environmental and clinical risk factors. We used a novel alternative method for evaluating heritability, the “ego-driven” risk analysis, which allowed for adjustment of clinical confounders as well as evaluating familial risk using the relatives as the study population rather than the individual. One limitation to generalizability is that our cohort arises from a population of individuals living in a single state in the US. While the state’s current population resulted from a smaller founder population in the 1800s, recent genetic investigations have revealed a similar proportion of genetic heterogeneity to the rest of the US population.19 The inclusion of all cases of PA in research is often limited by under-reporting and reliance on the subjective judgement of health care professionals. We attempted to mitigate this limitation by including cases of “antepartum bleeding” while excluding placenta previa in our case definition. While there might be causes of antepartum bleeding independent of PA, like cervical or vaginal bleeding, PA is the most common leading cause of vaginal bleeding throughout pregnancy.1,7 Our results revealed a trend towards the null with the inclusion of “antepartum bleeding”: from 20% estimated heritability to 18%. While we attempted to adjust for all known risk factors for PA in our heritability analyses, one possible confounding factor includes shared environments in family pedigrees, which could have led to an overestimation in our risk.