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Published in final edited form as: Am J Obstet Gynecol MFM. 2024 Jan 19;6(3):101291. doi: 10.1016/j.ajogmf.2024.101291

The role of neighborhood deprivation in the cervicovaginal microbiota

Heather H Burris 1,2,3,*, Nancy Yang 4, Valerie Riis 5, Linda Valeri 6, Eugenia C South 7, Jacques Ravel 8, Michal A Elovitz 5,9
PMCID: PMC10948309  NIHMSID: NIHMS1962317  PMID: 38246324

Abstract

Background:

Lactobacillus-deficient cervicovaginal microbiota is associated with spontaneous preterm birth and is more common among Black individuals. Persistent racial segregation in the United States has led to differential neighborhood exposures by race that can affect pregnancy outcomes. The extent to which neighborhood exposures may explain racial differences in the cervicovaginal microbiota is unknown.

Objective:

We sought to determine if neighborhood deprivation, defined as material community deprivation, is associated with a Lactobacillus-deficient cervicovaginal microbiota in a prospective cohort of pregnant individuals. Our hypothesis is that racial differences in neighborhood deprivation may explain the higher prevalence of Lactobacillus-deficient cervicovaginal microbiota in Black birthing people.

Design/Methods:

We analyzed data from Motherhood & Microbiome, a prospective pregnancy cohort enrolled from prenatal clinics in a single hospital system 2013–2016 in which a Lactobacillus-deficient cervicovaginal microbiota was previously shown to be associated with spontaneous preterm birth. We geocoded addresses to obtain census tract neighborhood deprivation data from the Brokamp Nationwide Community Deprivation Index that uses weighted proportions of poverty, income, public assistance, lack of health insurance, and vacant housing. Generalized linear mixed models quantified associations of deprivation with the cervicovaginal microbiota accounting for geographical clustering by census tract and potential confounders. Due to different distributions of neighborhood deprivation and the cervicovaginal microbiota, we performed race-stratified models. Mediation analyses quantified the extent to which deprivation may contribute to racial differences in the cervicovaginal microbiota.

Results:

Higher neighborhood deprivation was associated with a Lactobacillus-deficient cervicovaginal microbiota. Per standard deviation increment of deprivation, participants had 28% higher adjusted odds (aOR 1.28, 95% CI: 1.04–1.58) of a Lactobacillus-deficient microbiota. Black participants had higher odds of a Lactobacillus-deficient microbiota than White participants (aOR 4.00, 95% CI: 2.05, 8.26), and mediation analysis revealed that deprivation accounted for 22% (P=0.046) of that disparity.

Conclusion:

Neighborhood deprivation was associated a Lactobacillus-deficient cervicovaginal microbiota and may partially explain Black-White disparities in the cervicovaginal microbiota. Mechanistic studies to explore how environmental exposures modify the cervicovaginal microbiota are warranted to identify novel opportunities for future interventional strategies to prevent preterm birth. As these findings demonstrate a potential biologic impact from neighborhood conditions, policies that drive urban planning should be explored to improve pregnancy outcomes.

Keywords: Cervicovaginal microbiota, cohort study, mediation analysis, neighborhood deprivation, pregnancy, preterm birth, racial disparities, spontaneous preterm birth, vaginal microbiome

Tweetable statement:

Neighborhood deprivation may contribute to racial disparities in Lactobacillus-deficient vaginal microbiota

Graphical Abstract

graphic file with name nihms-1962317-f0001.jpg

INTRODUCTION

Preterm birth (PTB) disproportionately affects non-Hispanic Black families in the United States with Black infants born preterm 50% more often than White infants.1 Race is a social construct that serves as a proxy for numerous exposures in life that differ by race due to racism.2,3 While Black populations in the US have higher rates of PTB, recent research has demonstrated that racial disparity in PTB is largely environmental, as opposed to genetic, in origin.4–6 Racial segregation has led to differential environmental stressors by race.7 However, how environmental stressors, such as neighborhood deprivation, that differ by race, lead to racial differences in PTB risk remains unknown.

Neighborhood deprivation indices are summary measures of multiple area-level factors that indicate resources in a neighborhood and often include poverty rates, educational attainment, and other factors such as housing and employment.8 Adverse neighborhood exposures, which can track with deprivation, including violent crime, have been shown to be associated with PTB and low birth weight risk in prior studies.9–13 However, these studies do not measure molecular biomarkers or mechanisms by which neighborhoods may contribute to PTB risk.

The cervicovaginal microbiota is clustered into distinct Community State Types (CSTs) based on the dominating species of bacteria.14 CST IV, which is characterized by a paucity of Lactobacillus species and dominance of anaerobes, such as Gardnerella vaginalis, is associated with spontaneous PTB (sPTB) and may be mechanistically involved in sPTB via cervical epithelial barrier disruption.15–17 In a previously conducted, prospective, race-matched, nested, case-control study, Motherhood & Microbiome (M&M), 48% of participants with sPTB had Lactobacillus-deficient cervicovaginal microbiota compared to just 35% among term births.18 While environmental stressors increase risk of PTB19–24 and animal evidence supports the concept that environmental stressors can affect the vaginal microbiota,25 it is unclear whether or how exposures might modify the vaginal microbiota in humans. In humans, low socioeconomic position8,26–28 and stress29 have been shown to be associated with bacterial vaginosis which is a clinical condition consistent with Lactobacillus-deficient cervicovaginal microbiota (CST IV), suggesting that environmental stressors may affect the microbiota, perhaps via inflammation and immunomodulation.30

We aimed to perform the first study to explore the possible associations of neighborhood deprivation, defined as material community deprivation, with a Lactobacillus-deficient cervicovaginal microbiota (CST IV) and to explore the extent to which higher levels of neighborhood deprivation among Black individuals contribute to racial disparities in colonization with a Lactobacillus-deficient cervicovaginal microbiota.

MATERIALS AND METHODS

Study population

We analyzed data from the prospective cohort, Motherhood & Microbiome (M&M)18 following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.31 M&M is a prospectively enrolled pregnancy cohort of singleton gestations with births from April 23, 2014 to March 3, 2017 during the course of prenatal care at Penn Medicine in Philadelphia; details are published elsewhere.18,32–36 A flow diagram demonstrating the derivation of the analytic dataset is presented in Supplemental Figure 1. The Institutional Review Board of the University of Pennsylvania approved the study (IRB # 818914) and participants signed informed consent.

Exposure – Neighborhood Deprivation

To obtain neighborhood deprivation levels, individual addresses were geocoded using ArcGIS (10.5.1) to link to a nationwide material community deprivation index that included census tract 2015 American Community Survey data.37 The index ranges from 0 to 1 (higher indicating more deprivation) and includes median household income, the fraction of residents who were below the poverty line, completed high school, received public assistance income or food stamps, and the fraction of vacant housing.38

Outcome – Lactobacillus-deficient cervicovaginal microbiota

As previously reported, the composition of the cervicovaginal microbiota was characterized using 16S rRNA gene sequencing from swabs obtained at 16–20 weeks’ gestation.14,18,39–41 Samples from each sPTB case and four race-matched full-term controls were analyzed. Briefly, PCR amplification of the V3-V4 regions of the 16S rRNA gene which were sequenced.42 CSTs were assigned using VALENCIA, a novel nearest centroid classification algorithm based on the classification of over 13,000 vaginal microbiota datasets.43 CST IV is characterized by a paucity of Lactobacillus and over-representation of a wide array of anaerobic bacteria. Since in this manuscript, the word community could be conflated with neighborhood exposures, we henceforth use Lactobacillus-deficient microbiota instead of CST terminology where appropriate.

Covariates

Covariates were obtained with questionnaires and medical record review. Race and ethnicity were self-reported and then combined into mutually exclusive race/ethnicity categories. Individuals with racial/ethnic identities other than non-Hispanic Black and White were combined into a single “other” category due to small numbers.

Statistical analysis

We performed descriptive and bivariate analysis to compare average neighborhood deprivation index among participants with and without Lactobacillus-deficient cervicovaginal microbiota. In other words, we compared individuals with CST IV to those with all other CSTs. We also analyzed bivariate associations of each outcome with quartiles of deprivation. We performed generalized linear mixed effects regression models to account for geographic clustering of individuals within census tracts to model associations of deprivation with the odds of Lactobacillus-deficient cervicovaginal microbiota compared to Lactobacillus-dominant microbiota, adjusting for variables including age, parity, insurance, and race/ethnicity. These variables were chosen a priori because of their associations with sPTB. We also performed race-stratified models due to large differences in both neighborhood deprivation and Lactobacillus-deficient cervicovaginal microbiota to determine whether associations were similar among non-Hispanic Black (Black) and non-Hispanic White (White) individuals. We tested for interaction to determine if associations by race differed statistically. Stratification and interaction testing assess differential response to a variable which may imply differential susceptibility. In contrast, causal mediation analysis methods can quantify the extent to which a variable may explain an association between exposures and outcomes, often from different doses of exposure.44 Causal mediation methods address confounding between the exposures and outcomes, exposures and mediators, as well as mediators and outcomes.45 We used mediation methods to quantify the extent to which neighborhood deprivation might explain racial disparities in Lactobacillus-deficient cervicovaginal microbiota. All analyses were done using R version 4.2.2 (2022-10-31 ucrt).

RESULTS

Neighborhood deprivation varied across Philadelphia (Figure 1) and was higher among Black compared to White individuals (Figure 2). In the analytic dataset, the majority of individuals identified as Black, and most participants were not privately insured (Table 1). We compared participants included and excluded from the present study due to either missing neighborhood deprivation (n=17) or lack of microbiota data (n=1312); only a subset of M&M participants were chosen to have microbiota analyzed for the original study.18 Included M&M participants were more likely to have sPTB, be overweight or obese, and identify as Black compared to those excluded (Supplemental Table 1).

Figure 1.

Figure 1.

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Neighborhood deprivation across Philadelphia, 2015

Figure 2.

Figure 2.

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Black-White disparities in neighborhood deprivation, Motherhood & Microbiome (M&M) (n=424 Black and n=111 White participants)

Table 1.

Characteristics of Motherhood & Microbiome (M&M) pregnancy cohort, Philadelphia, PA, 2013–2017.

Overall (n=581) Lactobacillus-deficient cervicovaginal microbiota (CST IV) (n=224) Lactobacillus-dominant cervicovaginal microbiota (Other CSTs) (n=357)
Characteristic n (%) n (%) n (%) P
Age (years) <0.001
  < 25 178 (30.6) 87 (38.8) 91 (25.5)
 25 – <35 302 (52.0) 113 (50.4) 189 (52.9)
 > 35 101 (17.4) 24 (10.7) 77 (21.6)
Race/Ethnicity <0.001
 Non-Hispanic Black 424 (73.0) 199 (88.8) 225 (63.0)
 Non-Hispanic White 111 (19.1) 13 (5.8) 98 (27.5)
 Othera 46 (7.9) 12 (5.4) 34 (9.5)
Private insurance 274 (47.2) 70 (31.3) 204 (57.1) <0.001
Body mass index (kg/m2)
 < 25 197 (33.9) 61 (27.2) 136 (38.1) 0.005
 25 – < 30 162 (27.9) 60 (26.8) 102 (28.6)
 > 30 222 (38.2) 103 (46.0) 119 (33.3)
Nulliparous 245 (42.2) 87 (38.8) 158 (44.3) 0.23
Smoked in pregnancy 47 (8.1) 24 (10.7) 23 (6.4) 0.09
Neighborhood Deprivation, mean [SD] 0.47 [0.16] 0.53 [0.13] 0.44 [0.17] <0.001
Birth outcome 0.02
 Term 421 (72.5) 148 (66.1) 273 (76.5)
 Spontaneous preterm 03 (17.7) 49 (21.9) 54 (15.1
 Medically indicated preterm 57 (9.8) 27 (12.1) 30 (8.4)
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BMI, body mass index; CST, Community State Type characterizing the vaginal microbiota

a

Other race/ethnicity: Hispanic (n=23); non-Hispanic Asian (n=21); Other, not specified (n=2)

In bivariate analysis, with each increase in deprivation quartile, the proportion of participants with Lactobacillus-deficient microbiota increased (Figure 3). Mean neighborhood deprivation levels were also higher among those with Lactobacillus-deficient microbiota (0.53, SD 0.13) than those with Lactobacillus-dominant microbiota (0.44, SD 0.17) (p<0.0001) (Table 1). Generalized linear mixed effects models accounting for clustering by census tract revealed similar findings; per SD increment of deprivation, participants had 73% higher odds of Lactobacillus-deficient microbiota (unadjusted OR 1.73, 95% CI: 1.46–2.06) (Table 2). In models adjusted for age, parity, BMI, race, and insurance, associations attenuated but persisted; per standard deviation increment of neighborhood deprivation, participants had 28% higher odds of Lactobacillus-deficient microbiota (aOR 1.28, 95% CI: 1.04–1.58) (Table 2). Point estimates were similar in race-stratified models but lacked statistical significance with confidence intervals crossing 1 (Black participants: aOR 1.25 [0.99–1.59], White participants: aOR 1.33 [0.71–2.49]). We did not detect interaction between race and deprivation on the outcome of Lactobacillus-deficient microbiota in unadjusted (P=0.894) or adjusted models (P=0.996).

Figure 3.

Figure 3.

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Proportion of Motherhood & Microbiome (M&M) participants (n=581) with a Lactobacillus-deficient cervicovaginal microbiota (CST IV) in each quartile of neighborhood deprivation

Table 2.

Unadjusted and adjusted associations of neighborhood deprivation with Lactobacillus-deficient cervicovaginal microbiota (CST IV) in Motherhood & Microbiome (M&M); estimates are per standard deviation increment of deprivation.

Model OR (95% CI)
 All participants (n=581)
  M1 : unadjusted 1.73 (1.46, 2.06)
  M2: age, parity, BMI, insurance 1.43 (1.18, 1.74)
  M3: M2 + race/ethnicity 1.28 (1.04, 1.58)
 Race-stratified models
  Non-Hispanic Black (n=424)
   M1 : unadjusted 1.34 (1.07, 1.67)
   M2: age, parity, BMI, insurance 1.25 (0.99, 1.58)
  Non-Hispanic White (n=111)a
   M1 : unadjusted 1.28 (0.73, 2.24)
   M2: age, parity, BMI, insurance 1.33 (0.71, 2.49)
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a

Robust standard errors instead of random effect for lack of convergence

BMI, body mass index; CST, Community State Type

As previously published, there were racial disparities in Lactobacillus-deficient cervicovaginal microbiota;18 in adjusted models, Black participants had 4-fold higher odds of Lactobacillus-deficient cervicovaginal microbiota compared to White participants (aOR 4.00, 95% CI: 2.05, 8.26). When neighborhood deprivation was introduced to the adjusted model, the association between race and Lactobacillus-deficient cervicovaginal microbiota was attenuated (aOR 2.99, 95%CI: 1.39, 6.40). We then tested for whether there were significant mediation and found that 22% of the association between non-Hispanic Black race/ethnicity and Lactobacillus-deficient cervicovaginal microbiota was mediated by neighborhood deprivation differences between Black and White participants (p=0.046).

COMMENT

Principal Findings

In a racially diverse cohort of pregnant individuals, we found neighborhood deprivation is associated with a Lactobacillus-deficient cervicovaginal microbiota, known to confer increased risk for sPTB. Importantly, we found that racial differences in neighborhood deprivation may partially explain racial disparities in the presence of Lactobacillus-deficient cervicovaginal microbiota.

Results in the Context of What is Known

Our study is consistent with others that have shown that neighborhood is important with respect to reproductive health, specifically PTB risk.9–13 However, to our knowledge, no previous study has linked neighborhood to the cervicovaginal microbiota. Multiple reports have previously established that individuals colonized with vaginal microbiota that lack Lactobacillus dominance are at higher risk for PTB15,16,18,46 and are more likely to identify as Black.14,18,47 In one of the first studies to describe cervicovaginal microbiota, Ravel et al investigated the vaginal microbiome of 396 non-pregnant, reproductive-age women in Atlanta and Baltimore and found that Lactobacillus was the dominant genus for most people.14 They reported significant racial differences in microbial profiles; Lactobacillus-dominance was found in 89.7% of White individuals, but only 61.9% of Black individuals. These results were similar to a study by Zhou et al, which demonstrated racial differences in the vaginal microbiota of 75 White and 69 African American menstruating individuals from five centers across North America.47 Specifically, anaerobic species dominated the vaginal microbiota more often among Black (32%) than White (8%) subjects. Environmental contributes to microbiota differences were not examined. M&M is the first pregnancy cohort large and racially diverse enough to test rigorously if racial differences in the likelihood of colonization with a Lactobacillus-deficient microbiota in pregnancy may be due to environmental exposures. Adding to the evidence that environmental exposures can affect the cervicovaginal microbiota, we recently reported that air pollution was also associated with a Lactobacillus-deficient cervicovaginal microbiota.48 However, overall there is a paucity of data exploring how exposures might influence the cervicovaginal microbiota and contribute to adverse pregnancy outcomes.

There is evidence that other aspects of the human microbiome are environmentally responsive. Rosenfeld postulated that environmental exposures could lead directly to changes in the gut microbiota, or could change host immunologic and inflammatory status, making it more or less welcoming to specific bacterial species or genera.49 Multiple animal studies demonstrate gut microbiota disruption in response to arsenic,50–54 lead,55–57 and particulate matter.58,59 A study of 44 healthy adults in Chicago demonstrated that lower neighborhood socioeconomic status was associated with reduced diversity of the gut microbiota.60 Hierarchical linear regression models revealed that as socioeconomic status of an individual’s residential census tract decreased, so did the alpha-diversity of the microbiota. Furthermore, neighborhood socioeconomic status explained 12–18% of the variability in the diversity of the gut microbiota.

Research in animal models suggests that environmental stress during pregnancy (a risk factor for human PTB19–24) can affect vaginal microbiota composition. In a pregnant mouse model, stressed dams (fox odor, restraint, constant light, saturated bedding, and novel object exposure) had significantly lower vaginal Lactobacillus abundance compared to control dams.25 Providing support for this finding in humans, low socioeconomic position26–28 and stress29 have been shown to be associated with Lactobacillus-deficient cervicovaginal microbiota. Amabebe and Anumba proposed that stress-induced cortisol production alters the vaginal microenvironment through changes to NF-κB mediated cytokine activity interrupting the balance of Lactobacillus and anaerobes.30 Area-level exposures such as neighborhood deprivation61 may alter vaginal microbiota through immune modulation. In a previous analysis of M&M, we found that individuals with both high perceived stress and low β defensin-2 levels (an innate immune marker) had increased odds of sPTB.62 Collectively, these findings suggest that lived experiences and environmental exposures may modify the cervicovaginal microbiota. If replicated and validated, then reducing the harmful exposures and/or targeting the microbiome-host interactions may prove to be a new strategy to reduce PTB.

Clinical Implications

Given persistent racial disparities in many adverse pregnancy outcomes, including sPTB, it is necessary to understand how lived experiences drive biological pathways that contribute to sPTB. Clinically, Black race has been used as a risk factor for PTB.63 However, given that socioeconomic position and race often determine where Americans live, it follows that environmental exposures differ by race.6,7,64–68 Longstanding residential segregation has led to Black families disproportionately living in neighborhoods with higher concentrations of deprivation and is one striking example of structural racism.69,70 Historically and continuing today, certain policies in the United States have contributed to residential segregation.71 Practices such as redlining result in systematic disinvestment in predominantly Black neighborhoods. The impact of this practice on reproductive health is now evident with higher PTB rates in historically redlined neighborhoods.72,73 Reducing racial disparity in PTB and other adverse pregnancy outcomes will require mitigating harmful and supporting beneficial exposures in predominantly Black neighborhoods. Revealing how environmental stressors can impact biological pathways should serve as further impetus to policymakers to implementing policies and practices that serve to reduce disparities and adverse outcomes outside of standard medical care. Policies such as the Earned Income Tax Credit or other efforts to relieve neighborhood deprivation could be explored.

Research Implications

Many unanswered questions remain about the link between environmental stressors from neighborhood conditions and the cervicovaginal microbiota. From a translational perspective, there are opportunities to delineate mechanistic pathways between environmental exposures and reproductive tract function. Such exploration would enable the development of therapeutics to interrupt pathophysiologic processes to improve outcomes for individuals who come into pregnancy with lifetimes of environmental exposures. From a public health policy perspective, additional research on the impact of environmental interventions on health are needed to prioritize resource allocation to improve outcomes.

Strengths and Limitations

Strengths include the use of multilevel modeling to account for area-level and individual-level factors in addition to using a prospectively enrolled cohort with molecular phenotyping (microbiota). Rigorous collection of covariates allowed for confounder adjustment. Limitations include threats to generalizability given the use of a single site. While our data link one composite, area-level variable – neighborhood deprivation – to the cervicovaginal microbiota, we did not examine the multitude of other environmental factors to which people are exposed before and during pregnancy. There are key assumptions inherent to mediation methods if causal inference is desired. Specifically, one assumption is “sequential ignorability” which means that the preexisting covariates and the treatment are independent of all potential values of the outcome and mediating variables.74 It also requires that the observed mediator is independent of all potential outcomes given the observed treatment and pretreatment covariates. Since we are not confident that the sequential ignorability assumption holds in our analysis, we do not claim that deprivation is truly on the causal pathway between self-identified race and the vaginal microbiota. We recognize that it may be a proxy for a set of variables could be causal. Our sample size may have lacked power; statistical significance was not reached in race-stratified models but point estimates were similar compared to the primary analysis demonstrating significant associations of deprivation with Lactobacillus-deficient microbiota. Nor did we detect significant interaction between race and deprivation on the microbiota. Together, this means that likely, regardless of race, neighborhood deprivation is associated with the cervicovaginal microbiota.

Conclusions

We found that neighborhood deprivation is associated with a cervicovaginal microbiota characterized by a paucity of Lactobacillus species, a known risk factor for sPTB. Neighborhood deprivation may partially explain racial disparities in the cervicovaginal microbiota. More research is needed to explore causal links between neighborhood environment and biologic changes that contribute to PTB risk. Such findings could have substantial urban planning policy implications for cities working toward birth outcome equity.

Supplementary Material

1
Download video file (94.6MB, wmv)
2

Supplemental Figure 1. Analytic cohort development, Motherhood & Microbiome (M&M)

3

AJOG at a Glance:

A. Why was this study conducted?

Lactobacillus-deficient cervicovaginal microbiota has been previously shown to be associated with spontaneous preterm birth and to be more common among Black pregnant people. The extent to which racial differences in neighborhood conditions may contribute to the disparity in Lactobacillus-deficient cervicovaginal microbiota is unknown.

B. What are the key findings?

In a Philadelphia-based study, census tract neighborhood deprivation was associated with a Lactobacillus-deficient cervicovaginal microbiota.

C. What does this study add to what is already known?

Mediation analysis revealed that neighborhood deprivation may contribute to racial disparities in the cervicovaginal microbiota.

Funding

This work was supported with funds from NIH (R01NR014784, PI Elovitz & R01HL157160, mPIs South & Burris); the Department of Pediatrics at the Children’s Hospital of Philadelphia (Burris).

Footnotes

Disclosure statement

M.A.E. is a consultant with equity in Mirvie, San Francisco, CA. None of the authors have potential conflicts of interest to disclose.

Meeting Presentation

This study was presented as a poster presentation at the Society for Maternal-Fetal Medicine SMFM’s 40th Annual Pregnancy Meeting, Dallas, TX, February 3–8, 2020

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