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

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”

Evaluating quality of contraceptive counseling: An analysis of the method information index

The Method Information Index (MII) is calculated from contraceptive users\u27 responses to questions regarding counseling content-whether they were informed about methods other than the one they received, told about method-specific side effects, and advised what to do if they experienced side effects. The MII is increasingly reported in national surveys and used to track program performance, but little is known about its properties. Using additional questions, we assessed the consistency between responses and the method received in a prospective, multicountry study. We employed two definitions of consistency: (1) presence of any concordant response, and (2) absence of discordant responses. Consistency was high when asking whether users were informed about other methods and what to do about side effects. Responses were least consistent when asking whether side effects were mentioned. Adjusting for inconsistency, scores were up to 50 percent and 30 percent lower in Pakistan and Uganda, respectively, compared to unadjusted MII scores. Additional questions facilitated better understanding of counseling quality

Seeking order amidst chaos: a systematic review of classification systems for causes of stillbirth and neonatal death, 2009-2014.

BACKGROUND: Each year, about 5.3 million babies die in the perinatal period. Understanding of causes of death is critical for prevention, yet there is no globally acceptable classification system. Instead, many disparate systems have been developed and used. We aimed to identify all systems used or created between 2009 and 2014, with their key features, including extent of alignment with the International Classification of Diseases (ICD) and variation in features by region, to inform the World Health Organization's development of a new global approach to classifying perinatal deaths. METHODS: A systematic literature review (CINAHL, EMBASE, Medline, Global Health, and PubMed) identified published and unpublished studies and national reports describing new classification systems or modifications of existing systems for causes of perinatal death, or that used or tested such systems, between 2009 and 2014. Studies reporting ICD use only were excluded. Data were independently double-extracted (except from non-English publications). Subgroup analyses explored variation by extent and region. RESULTS: Eighty-one systems were identified as new, modifications of existing systems, or having been used between 2009 and 2014, with an average of ten systems created/modified each year. Systems had widely varying characteristics: (i) comprehensiveness (40 systems classified both stillbirths and neonatal deaths); (ii) extent of use (systems were created in 28 countries and used in 40; 17 were created for national use; 27 were widely used); (iii) accessibility (three systems available in e-format); (iv) underlying cause of death (64 systems required a single cause of death); (v) reliability (10 systems tested for reliability, with overall Kappa scores ranging from .35-.93); and (vi) ICD alignment (17 systems used ICD codes). Regional databases were not searched, so system numbers may be underestimated. Some non-differential misclassification of systems was possible. CONCLUSIONS: The plethora of systems in use, and continuing system development, hamper international efforts to improve understanding of causes of death. Recognition of the features of currently used systems, combined with a better understanding of the drivers of continued system creation, may help the development of a truly effective global system.The Mater Research Institute, University of Queensland, AustraliaThis is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12884-016-1071-

Classification systems for causes of stillbirth and neonatal death, 2009-2014: an assessment of alignment with characteristics for an effective global system.

BACKGROUND: To reduce the burden of 5.3 million stillbirths and neonatal deaths annually, an understanding of causes of deaths is critical. A systematic review identified 81 systems for classification of causes of stillbirth (SB) and neonatal death (NND) between 2009 and 2014. The large number of systems hampers efforts to understand and prevent these deaths. This study aimed to assess the alignment of current classification systems with expert-identified characteristics for a globally effective classification system. METHODS: Eighty-one classification systems were assessed for alignment with 17 characteristics previously identified through expert consensus as necessary for an effective global system. Data were extracted independently by two authors. Systems were assessed against each characteristic and weighted and unweighted scores assigned to each. Subgroup analyses were undertaken by system use, setting, type of death included and type of characteristic. RESULTS: None of the 81 systems were aligned with more than 9 of the 17 characteristics; most (82 %) were aligned with four or fewer. On average, systems were aligned with 19 % of characteristics. The most aligned system (Frøen 2009-Codac) still had an unweighted score of only 9/17. Alignment with individual characteristics ranged from 0 to 49 %. Alignment was somewhat higher for widely used as compared to less used systems (22 % v 17 %), systems used only in high income countries as compared to only in low and middle income countries (20 % vs 16 %), and systems including both SB and NND (23 %) as compared to NND-only (15 %) and SB-only systems (13 %). Alignment was higher with characteristics assessing structure (23 %) than function (15 %). CONCLUSIONS: There is an unmet need for a system exhibiting all the characteristics of a globally effective system as defined by experts in the use of systems, as none of the 81 contemporary classification systems assessed was highly aligned with these characteristics. A particular concern in terms of global effectiveness is the lack of alignment with "ease of use" among all systems, including even the most-aligned. A system which meets the needs of users would have the potential to become the first truly globally effective classification system.The Mater Research Institute of the University of Queensland, AustraliaThis is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12884-016-1040-

Stillbirths: ending preventable deaths by 2030

Efforts to achieve the new worldwide goals for maternal and child survival will also prevent stillbirth and improve health and developmental outcomes. However, the number of annual stillbirths remains unchanged since 2011 and is unacceptably high: an estimated 2·6 million in 2015. Failure to consistently include global targets or indicators for stillbirth in post-2015 initiatives shows that stillbirths are hidden in the worldwide agenda. This Series paper summarises findings from previous papers in this Series, presents new analyses, and proposes specific criteria for successful integration of stillbirths into post-2015 initiatives for women’s and children’s health. Five priority areas to change the stillbirth trend include intentional leadership; increased voice, especially of women; implementation of integrated interventions with commensurate investment; indicators to measure effect of interventions and especially to monitor progress; and investigation into crucial knowledge gaps. The post-2015 agenda represents opportunities for all stakeholders to act together to end all preventable deaths, including stillbirths

Characteristics of a global classification system for perinatal deaths: a Delphi consensus study.

BACKGROUND: Despite the global burden of perinatal deaths, there is currently no single, globally-acceptable classification system for perinatal deaths. Instead, multiple, disparate systems are in use world-wide. This inconsistency hinders accurate estimates of causes of death and impedes effective prevention strategies. The World Health Organisation (WHO) is developing a globally-acceptable classification approach for perinatal deaths. To inform this work, we sought to establish a consensus on the important characteristics of such a system. METHODS: A group of international experts in the classification of perinatal deaths were identified and invited to join an expert panel to develop a list of important characteristics of a quality global classification system for perinatal death. A Delphi consensus methodology was used to reach agreement. Three rounds of consultation were undertaken using a purpose built on-line survey. Round one sought suggested characteristics for subsequent scoring and selection in rounds two and three. RESULTS: The panel of experts agreed on a total of 17 important characteristics for a globally-acceptable perinatal death classification system. Of these, 10 relate to the structural design of the system and 7 relate to the functional aspects and use of the system. CONCLUSION: This study serves as formative work towards the development of a globally-acceptable approach for the classification of the causes of perinatal deaths. The list of functional and structural characteristics identified should be taken into consideration when designing and developing such a system.This project was initially undertaken as part of the Harmonized Reproductive Health Registries project through the Norwegian Institute of Public Health in Partnership with the Mater Medical Research Institute, Brisbane, Australia, and in collaboration with the Department of Reproductive Health and Research, WHO.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by BioMed Central

Care in subsequent pregnancies following stillbirth: An international survey of parents

Objective: To assess the frequency of additional care, and parents' perceptions of quality, respectful care in pregnancies subsequent to stillbirth. Design: Multi-language web-based survey. Setting: International. Population: 2,716 parents, from 40 high- and middle-income countries. Methods: Data were obtained from a broader survey of parentsâ experiences of stillbirth. Data were analyzed using descriptive statistics and stratified by geographical region. Subgroup analyses explored variation in additional care by gestational age at index stillbirth. Main outcome measures: Frequency of additional care, and perceptions of quality, respectful care. Results: The majority (66%) of parents conceived their subsequent pregnancy within one year of stillbirth. Additional antenatal care visits and ultrasound scans were provided for 67% and 70% of all parents, respectively, although there was wide variation across geographical regions. Care addressing psychosocial needs was less frequently provided, such as visits to a bereavement counsellor (10%) and access to named care provider's phone number (27%). Compared to parents whose stillbirth occurred at 29 weeks' gestation or less, parents whose stillbirth occurred at 30 weeksâ gestation or greater were more likely to receive various forms of additional care, particularly the option for early delivery after 37 weeks. Around half (47-63%) of all parents felt that elements of quality, respectful care were consistently applied, such as spending enough time with parents and involving parents in decision-making. Conclusions: Care in pregnancies subsequent to stillbirth appears inconsistent. Greater attention is required to providing thoughtful, empathic, and collaborative care in all pregnancies following stillbirth. Training for health professionals is needed