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