Objective To determine if stillbirth aggregates in families and quantify its familial risk using extended pedigrees. Design State-wide matched case-control study. Setting Utah, United States. Population Stillbirth cases (n=9 404) and live-birth controls (18 808) between 1978 and 2019. Methods Using the Utah Population Database, a population‐based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardized Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR), and third-degree relatives (TDR) of parents with a stillbirth and live-birth were estimated using logistic regression models. Results We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR≥2.00 and P-value<0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI: 1.11-1.33), and 1.15-fold (95% CI: 1.08-1.21) higher stillbirth odds compared to FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI: 1.02-1.47), 1.38-fold (95% CI: 1.17-1.62), 1.17-fold (95% CI: 1.05-1.30) higher stillbirth odds compared to those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI: 0.98-1.28), 1.09-fold (95% CI: 0.96-1.24), and 1.15-fold (95% CI: 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. Conclusions We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine its genetic architecture.

Objective: To estimate the association between chronic hypertension and perinatal mortality and evaluate the extent to which this risk is impacted by preterm delivery. Design: Cross-sectional analysis. Setting: US, 2015-2018. Population: Singleton births from 20-44 weeks’ gestation. Main outcomes and measures: We derived the risk of perinatal mortality in relation to chronic hypertension from fitting log-linear Poisson models with robust variance. Risk ratios (RR) and 95% confidence intervals (CI) were estimated after adjusting for confounders. The impact of misclassifications and unmeasured confounding biases were assessed. Causal mediation analysis was performed to quantify the impact of preterm delivery on the association. Results: Of the 15,090,678 singleton births, perinatal mortality was 22.5 per 1000 births in chronic hypertensive pregnancies compared to 8.2 per 1000 births in normotensive pregnancies (adjusted RR 2.05, 95% CI 2.00, 2.10). Corrections for exposure misclassification and unmeasured confounding biases substantially increased the risk estimate. Although, causal mediation analysis revealed that most of the effect of chronic hypertension on perinatal mortality was mediated through preterm delivery, the perinatal mortality rates were highest at early term, term, and late term gestations, suggesting that a planned early term delivery at 37-386/7 weeks may optimally balance risk in these pregnancies. Additionally, 87% (95% CI 84, 90) of perinatal deaths could be eliminated if preterm deliveries, as a result of chronic hypertension were prevented. Conclusions: Chronic hypertensive pregnancies are associated with increased risk for perinatal mortality. Planned early term delivery and targeting modifiable risk factors for chronic hypertension may reduce perinatal mortality rates.

Mini Commentary – BJOG

Objective: To estimate the causal impact of small for gestational age (SGA) births on caesarean delivery, with and without trial of labour (TOL); and to quantify how much of the association is mediated through gestational age at delivery. Design: Cross-sectional analysis. Setting: Para 2 women who delivered non-anomalous, singleton live births from 22-44 weeks’ gestation in the US (2015-2018). Main outcomes and measures: Caesarean delivery with and without TOL. The exposure was SGA births (sex-specific birthweight <5th and <3rd percentiles for gestational age), and AGA births (10-89th percentile). We performed causal mediation analysis to determine the impact of gestational age at delivery (22-33, 34-36, 37-38, 39-40 and ≥41 weeks) as intermediate. Results: Of the 3,755,798 subjects, compared to AGA (29.6%), caesarean risks were higher for SGA <5th (34.3%) and SGA <3rd (36.4%) percentiles. For SGA <5th percentile, the adjusted excess risk of caesarean delivery without TOL had a “U” shaped association, with increased risk at preterm gestations, nadir at 39-40 weeks, and increased thereafter. The decomposition analysis revealed the driver of this excess risk was SGA births. The risk of caesarean delivery with TOL was highest <34 weeks’ gestation and was primarily an interaction effect. As gestation advanced, SGA births contributed proportionately greater to the risk. Associations were stronger for SGA <3rd percentile. Conclusions: Exposure to SGA drives high rates of prelabour caesareans and contributes to high risks of caesarean deliveries after TOL at >41 weeks gestation; a different mechanism drives high rates of caesareans after TOL at preterm gestations.