Methods:
The familial risk of PA was estimated through this retrospective cohort study using the Utah Population Database (UPDB), which is a genealogic database of over 11 million individuals spanning up to 17 generations. The UPDB contains individual-level medical and demographic information, linked to official statewide birth and death records dating back to the 1900s. 17 This study was approved by the Institutional Review Board at the University of Utah and the Utah Resource for Genetic and Epidemiologic Research, which oversees studies performed using UPDB data.
Cases of PA and controls were ascertained from birth certificates (1939 – 2020), maternal death certificates (1904 – 2020), and fetal death certificates (1978 – 2020), inpatient medical records, and International Classification of Diseases (ICD) codes (1996 – 2020) from the University of Utah Health Sciences Center. While PA can occur at any time point in pregnancy, this diagnosis is often confirmed at the time of delivery and more mild cases of placental abruption are often missed on official medical records. Diagnosing PA antepartum is challenging because of the poor sensitivity of ultrasound imaging and uncertainty on the clinicians’ part to confirm the diagnosis prior to delivery. Frequently, a suspected diagnosis of PA will be based on recurrent antepartum bleeding in the absence of a more obvious explanation. Therefore, many cases are not captured within our data sources. For this reason, we included “antepartum bleeding” in the case definition. Pregnancies affected by placenta previa, multifetal gestations, cases with inadequate demographic information allowing pedigree linkage, or cases that were listed as gestational carriers were excluded. Controls were 3:1 matched to cases based on age, parity, number of eligible female relatives in the UPDB, and availability of eligible first-degree relatives (FDRs), second-degree relatives (SDRs), or third-degree relatives (TDRs) for analyses.
Statistical analysis included relatives of all PA cases and controls. Demographic and clinical variables were compared using Pearson’s Chi-squared test for categorical variables and Wilcoxon rank sum test for continuous variables. Clinical variables described were restricted to the index pregnancy, i.e., the pregnancy affected by PA, for cases. Familial risk of PA was estimated using generalized linear mixed-effect regression for FDRs, SDRs, and TDRs, clustering around cases and controls to account for non-independence of observations within families. The analysis included all cases and controls with at least one eligible relative in the UPDB. Family members of controls were used as the reference group in all analyses. Variables adjusted for in the primary analysis included age, year of pregnancy, race, ethnicity, education level, and parity. A stratified analysis was performed estimating familial risk of PA stratified by the number of pregnancies affected by placental abruption (at least 1 vs. 2 or more vs. 0). A sensitivity analysis was performed excluding cases coded as “antepartum bleeding,” which excluded 50.4% of cases.
A secondary analysis was performed, which included cases and controls with available data in the medical record to adjust for clinical risk factors. This analysis was performed using an alternative familial risk statistical method, referred to as an “ego-driven” familial analysis as opposed to “relative-driven”. Ego-driven familial risk analyses estimate the risk of PA for a case and control depending on whether a family member was affected. The method allows for adjusting for important clinical risk factors and medical comorbidities because they are only required to be available for the case or control, as opposed to all the relatives in the analysis. Familial risk of PA using this method was estimated using conditional logistic regression, adjusting for all demographic characteristics and potentially confounding clinical risk factors complicating the pregnancy affected by PA. These risk factors included smoking, drug use, diabetes, uterine anomaly, hypertension, or pre-labor rupture of membranes (PROM) complicating the pregnancy affected by PA, and a history of cesarean delivery in prior pregnancies. Maternal drug use was noted to be co-linear with smoking and was not adjusted for in multivariable analysis. Clinical risk factors were selected based on prior published work evaluating risk factors for PA1,5,7,8 and our univariate analyses. Statistical analyses were carried out using R version 4.2.2 [R Core Team, Vienna, Austria].18