Increasing understanding of causes of stillbirth: Is the effect of maternal stress on stillbirth mediated by methylation of stress-related genes?

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PROJECT SUMMARY/ABSTRACT The burden of 2.6 million stillbirths a year places stillbirth on a par with neonatal mortality as a major global public health issue. In the U.S., the stillbirth rate of 6.0 per 1000 total births has consistently exceeded the infant mortality rate, and is higher than the stillbirth rates of 25 other high-income countries. Moreover, there is high racial inequity, with Black families facing a stillbirth rate more than double that of whites. There has been persistent global inattention to stillbirth prevention, and the United Nations’ goal of 12 stillbirths per 1000 births by 2030 is unlikely to be met. The CDC’s vital statistics report on mortality excludes stillbirths, and the CDC only began reporting on causes of stillbirth in 2014. One barrier is limited knowledge on causes. The wide range of stillbirth rates, from 1.3 in Iceland to 43.1 in Pakistan, demonstrates that most stillbirths are not inevitable, yet one-third of stillbirths are unexplained. A recent review of 489,089 stillbirths found a pooled estimate of 32% of stillbirths “unexplained” in high-income countries—nearly 400 times higher than the rate of unexplained infant deaths in the U.S. Limited understanding of causes reduces opportunities for prevention. Stress holds promise as a possible cause, with epidemiological evidence of an association with stillbirth, but no studies have yet assessed biological plausibility. One potential mechanism is epigenetic silencing of stress-related genes through DNA methylation. Using a nested case-control design with data from a racially diverse population-based cohort, the NICHD-founded Stillbirth Collaborative Research Network (SCRN), this study will assess whether the effect of maternal stress on stillbirth is mediated by methylation of stress-related genes. Study aims are to: (1) test models for the effect of stress (as measured by socioeconomic status, childhood maltreatment, and significant life events) on stillbirth in the SCRN population (663 stillbirths, 1,439 live births) and a subgroup of 66 non-anomalous full-term stillbirths and 132 livebirths; (2) use causal mediation analysis to assess evidence for mediation by methylation of stress-related candidate genes in placental tissue; (3) carry out exploratory assessment of modification of these effects by race/ethnicity; and (4) use an agnostic approach to further assess mediation by epigenome-wide methylation. By demonstrating biological plausibility, the study could contribute to knowledge of preventable causes, highlight the role of stress in inequity in stillbirth rates, generate new hypotheses, and inform the development of interventions at individual and policy levels to reduce stillbirth numbers. The proposed aims will directly contribute to the NICHD’s goals of improving pregnancy outcomes and identifying exposures to explain fetal loss, as well as the high-priority research area of addressing the burden of stillbirth. The proposed training plan will be delivered within Columbia University, one of the world’s preeminent research universities, providing the applicant with skills in epigenetics, bioinformatics, and advanced methods that will, with an outstanding sponsor team, ensure successful completion of the study and the applicant’s transition to a career as an independent researcher focused on stillbirth prevention.