Mediation analysis quantifying the magnitude of stillbirth risk attributable to small for gestational age infants

Abstract

Many risk factors for stillbirth are linked to placental dysfunction, which leads to suboptimal intrauterine growth and small for gestational age infants. Such infants also have an increased risk for stillbirth. This study aimed to investigate the effect of known causal risk factors for stillbirth, and to identify those that have a large proportion of their risk mediated through small for gestational age birth. This retrospective cohort study used data from all births in the state of Queensland, Australia between 2000 and 2018. The total effects of exposures on the odds of stillbirth were determined using multivariable, clustered logistic regression models. Mediation analysis was performed using a counterfactual approach to determine the indirect effect and percentage of effect mediated through small for gestational age. For risk factors significantly mediated through small for gestational age, the relative risks of stillbirth were compared between small for gestational age and appropriate for gestational age infants. We also investigated the proportion of risk mediated via small for gestational age for late stillbirths (≥28 weeks). The initial data set consisted of 1,105,612 births. After exclusions, the final study cohort constituted 925,053 births. Small for gestational age births occurred in 9.9% (91,859/925,053) of the study cohort. Stillbirths occurred in 0.5% of all births (4234/925,053) and 1.5% of small for gestational age births (1414/91,859). Births at ≥28 weeks occurred in 99.4% (919,650/925,053) of the study cohort and in 98.9% (90,804/91,859) of all small for gestational age births. Of the ≥28-week births, stillbirths occurred in 0.2% (2156/919,650) of all births and 0.8% (677/90,804) of the small for gestational age births. Overall, increased odds of stillbirth were significantly mediated through small for gestational age for age <20 years, low socioeconomic status, Indigenous ethnicity, birth in sub-Saharan and North Africa or the Middle East, smoking, nulliparity, multiple pregnancy, assisted conception, previous stillbirth, preeclampsia, and renal disease. Preeclampsia had the largest proportion mediated through small for gestational age (66.7%), followed by nulliparity (61.6%), smoking (29.4%), North-African or Middle Eastern ethnicity (27.6%), multiple pregnancy (26.3%), low socioeconomic status (25.8%), and Indigenous status (18.7%). Sensitivity analysis showed that for late stillbirths, the portions mediated through small for gestational age remained very similar for many of the risk factors. Although small for gestational age is an important mediator between many pregnancy risk factors and stillbirth, mitigating the risk of small for gestational age is likely to be of value only when it is a major contributor in the pathway to fetal demise.