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

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $41,640

## Abstract

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 deli...

## Key facts

- **NIH application ID:** 10067819
- **Project number:** 1F31HD103336-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Susannah Hopkins Leisher
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,640
- **Award type:** 1
- **Project period:** 2020-09-03 → 2022-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067819

## Citation

> US National Institutes of Health, RePORTER application 10067819, Increasing understanding of causes of stillbirth: Is the effect of maternal stress on stillbirth mediated by methylation of stress-related genes? (1F31HD103336-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067819. Licensed CC0.

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