Study design and population
We conducted an extended pedigree analysis of stillbirth using the Utah Population Database (UPDB). The UPDB contains genealogy information linked to Utah fetal death and live birth certificates, and hospital records databases. Request for permission to use family structure data was approved by the Utah Resource for Genetic and Epidemiologic Research (RGE), the UPDB data use oversight committee. This study was approved by the Institutional Review Board of the University of Utah.
The UPDB genealogy record extends up to as many as 17 generations. It also includes approximately 5.8 million individuals with family relationship data dating back at least 3 generations.16 Stillbirth cases were identified using electronic Utah fetal death records that were available between 1978 and 2019. We used previously suggested nomenclature for stillbirth, defined as the birth of an infant with no signs of life (Apgar scores of 0 and 0) at ≥ 20 weeks’ gestation.17 Gestational age was used as reported on birth and fetal death certificates. The 1978 revision of the birth and fetal death certificates used the last menstrual period (LMP) for gestational age determination with addition of a correction based on the physician’s judgement if the LMP was unknown or incorrect.18 This system was utilized until the 2003 revision, when the National Center for Health Statistics utilized the best obstetric estimate for gestational age reporting on vital statistics records. This method uses the last menstrual period dating with correction as needed if estimated gestational age by ultrasound differs significantly from menstrual dates.19 Controls were identified as singleton live birth(s) and without reports of stillbirth, miscarriage, or pregnancy termination (as indicated in the Utah birth certificates). Controls were 2:1 matched to cases based on maternal age at stillbirth/ delivery, stillbirth or live birth-year, and minimum pedigree information (those with informative vs uninformative relationship data in their pedigrees).20 Extended pedigrees of parents of stillbirth cases and controls included biological first-degree relatives (FDR; parents, full-siblings, and children), second-degree relatives (SDR; grandparents, full aunts/uncles, nieces/nephews, and half-siblings) and third-degree relatives (TDR; cousins from full aunts/uncles, grandnieces/ grandnephews from full siblings, great aunts/uncles, great grandchildren, and half-nieces/ nephews from half-siblings). The inclusion criteria for cases, controls, and parent’s relatives were based on maternal age 13-40 years old and paternal age ≥13 years old between 1978 and 2019, and knowledge of offspring and parental sex. We restricted records to 13-40 years old mothers at the time of offspring death/birth-year, because maternal age >40 years is strongly associated with unexplained stillbirth.21,22