Theses Doctoral

Exploring racial disparity in stillbirth rates through structural racism and methylation of stress-related genes: From systemic to epigenetic

Leisher, Susannah Hopkins

Problem to be addressed: Stillbirth is a major public health problem. The stillbirth burden is on a par with newborn deaths. The stillbirth rate measures not only a substantial portion of the global and national burden of mortality, but also equity and quality of care for women’s and children’s health. Reducing the numbers of these deaths requires an understanding of why they occur, yet approximately one-third of stillbirths are unexplained, even in settings with high-quality autopsy and placental examination, while deaths considered to be explained are usually ascribed to single, proximal causes. An important limiting factor for efforts to reduce the large and inequitable stillbirth burden has been insufficient research into conditions that could inform prevention strategies and reduce inequity.1 2

Substantial evidence exists for associations between structural racism, maternal stress, and adverse pregnancy outcomes, yet research focusing on stillbirth is sparse, particularly at the ends of the causal spectrum—macro-level structural conditions and mechanisms. Several studies have called for research on possible biological mechanisms by which racism, racism-related stress, and stillbirth may be associated, including epigenetic mechanisms.3-6 The most recent review of causes of racial disparities in stillbirth rates in the U.S. recommended that researchers take a multi-domain approach, considering not just individual-level risk factors, which have been relatively well-studied, but also upstream factors such as institutional racism, and biological mechanisms such as epigenetic modification.

The objective of this dissertation was to explore evidence that could help to explain persistent racial disparities in stillbirth. The specific aims were:

1. To review the literature on racial disparity in stillbirth rates;
2. To assess whether structural racism can help to explain racial disparity in stillbirth rates in New York City; and
3. To assess whether maternal stress is associated with stillbirth, whether stress is associated with methylation of stress-related genes, whether methylation is associated with stillbirth, and whether there is evidence that methylation of stress-related genes mediates associations between stress and stillbirth.

Materials and methods used: For Aim 1, we carried out a scoping review of the literature in five databases (PubMed, Scopus, Cinahl, Embase, PsycInfo) to identify all reports including stillbirth rates stratified by race in the U.S., mapping exposures and effect modifiers (“domains of analysis”) and authors’ comments on racial disparity in stillbirths (“domains of explanation”) into one of eight domains (race, genetic, fetal, maternal, family, community, healthcare system, and structural). We defined Stillbirth Disparity Ratios (SDRs) as the ratio of the stillbirth rate in a racial/ethnic minority group to the stillbirth rate in white individuals. Selected SDRs were extracted from each report, as were all SDRs for Black/white comparisons.

For Aim 2, we modelled associations between four measures of structural racism and stillbirth in all non-Hispanic (NH) Black and white singleton births in New York City between 2009 and 2018. Exposures were four Public Use Microdata Area (PUMA)-level measures of structural racism (Indices of Dissimilarity, Isolation, and Concentration at the Extremes (ICE), and an Educational Inequity Ratio) constructed from U.S. Census American Community Survey data. Using multilevel logistic regression, we first tested for interaction between race and structural racism in relation to stillbirth. For structural racism measures that interacted with race, we estimated odds ratios for stillbirth separately in 221,925 NH Black and 325,058 NH white births. Race-specific models were further stratified by maternal age.

For Aim 3, we assessed associations between maternal stressors and stillbirth in 183 non-anomalous full-term singleton births (63 stillbirths and 120 livebirths) from the U.S. Stillbirth Collaborative Research Network. Measuring maternal stress with two hypothesized stressors, an Index of Significant Life Events and an Index of Disadvantage, we assessed associations between maternal stressors and stillbirth in our sample, and then whether maternal stressors and stillbirth were associated with differential methylation of 1,191 CpGs on five stress-related genes (BDNF, FKBP5, HSD11B2, IGF2, and NR3C1). Finally, we assessed whether methylation mediates associations between stressors and stillbirth.

Conclusions reached: For Aim 1, we found 95 reports presenting stillbirth rates stratified by race/ethnicity in the U.S. We found evidence of increased risk of stillbirth in Black as compared to white births in the majority of the 83 reports with the necessary data. Among the 1143 Black-white SDRs that we extracted, the median SDR was 1.67, with 74% of SDRs showing evidence of disparity. Family and community factors, healthcare system factors, and structural factors were commonly used as domains of explanation (20-38% of reports), but rarely (family/community, structural, 4-5%) or never (healthcare system) used in analysis. The most commonly used domains of analysis—fetal and maternal factors including gestational age, maternal age, education, and prenatal care—do not appear able to explain the observed racial disparities. Gaps in the literature include a paucity of studies examining the possible role of health system, community, and structural factors in Black-white disparity in stillbirth rates, and limited data on other types of racial disparities in stillbirth rates, including Hispanic and Native American births.

For Aim 2, we found that structural racism as measured by ICE and Isolation was associated with stillbirth in NH Black but not NH white mothers. This would seem consistent with our hypothesis that structural racism may help to explain racial disparity in stillbirth rates; however, the associations we observed were not in the expected direction. Specifically, NH Black mothers living in PUMAs with a high concentration of privilege had 90% greater odds of stillbirth in comparison to those living in PUMAs with a high concentration of disadvantage (ICE quintile 5 vs 1), and NH Black mothers living in PUMAs that were the most isolated had 40% lower odds of stillbirth in comparison to those living in PUMAs that were the least isolated (Isolation tertile 3 vs 1). We suggest that while the measures we used (ICE and Isolation) do help to explain the Black-white disparity in stillbirth rates, our results raise questions about the way these measures operationalize structural racism, meriting further investigation.

For Aim 3, we found that having two or more vs no items in the Index of Disadvantage (“Disadvantage”) was associated with more than fourfold greater odds of stillbirth (95% CI 1.58, 12.93). We found no association between the Index of Significant Life Events and stillbirth. We found that 32 out of 1,191 CpGs on five stress-related genes were differentially methylated with respect to stillbirth, and six CpGs were differentially methylated with respect to Disadvantage. Methylation at two CpGs on IGF2 and one on HSD11B2 (cg02097792, cg12283393, and cg19413291, respectively) mediated the association between Disadvantage and stillbirth.

Research on causes is a critical component of stillbirth prevention and reducing the inequitable distribution of this public health burden. Limited understanding of causes at both “ends of the spectrum”, from upstream distal factors to mechanisms, has likely contributed to slow progress on prevention.7 8 This dissertation contributes to science and public health by providing researchers with data to support new lines of inquiry, e.g., into associations between structural racism and stillbirth, and for methylation as a mechanism of effect, that should help to improve our understanding of causes. Our research may also support health policy makers who now have additional data to illustrate the adverse health outcomes of structural racism in the U.S. Finally, it may help the parents and other family members of stillborn babies who continually seek to understand “why”.

Geographic Areas


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More About This Work

Academic Units
Thesis Advisors
Factor-Litvak, Pam
Ph.D., Columbia University
Published Here
December 7, 2022