Effect of a Nonoptimal Cervicovaginal Microbiota and Psychosocial Stress on Recurrent Spontaneous Preterm Birth

Abstract

Objective While select cervicovaginal microbiota and psychosocial factors have been associated with spontaneous preterm birth, their effect on the risk of recurrence remains unclear. It is also unknown whether psychosocial factors amplify underlying biologic risk. This study sought to determine the effect of nonoptimal cervicovaginal microbiota and perceived stress on the risk of recurrent spontaneous preterm birth. Study Design This was a secondary analysis of a prospective pregnancy cohort, Motherhood and Microbiome. The Cohen's Perceived Stress Scale (PSS-14) was administered and cervical swabs were obtained between 16 and 20 weeks of gestation. PSS-14 scores ≥30 reflected high perceived stress. We analyzed cervicovaginal microbiota using 16S rRNA sequencing and classified microbial communities into community state types (CSTs). CST IV is a nonoptimal cervicovaginal microbial community characterized by anaerobes and a lack of Lactobacillus. The final cohort included a predominantly non-Hispanic Black population of women with prior spontaneous preterm birth who had recurrent spontaneous preterm birth or term birth and had stress measurements (n = 181). A subanalysis was performed in the subset of these women with cervicovaginal microbiota data (n = 74). Multivariable logistic regression modeled adjusted associations between CST IV and recurrent spontaneous preterm birth, high stress and recurrent spontaneous preterm birth, as well as high stress and CST IV. Results Among the 181 women with prior spontaneous preterm birth, 45 (24.9%) had high perceived stress. We did not detect a significant association between high stress and recurrent spontaneous preterm birth (adjusted odds ratio [aOR] 1.67, 95% confidence interval [CI]: 0.73–3.85). Among the 74 women with prior spontaneous preterm birth and cervicovaginal microbiota analyzed, 29 (39.2%) had CST IV; this proportion differed significantly among women with recurrent spontaneous preterm birth (51.4%) compared with women with term birth (28.2%) (p = 0.04). In models adjusted for race and marital status, the association between CST IV and recurrent spontaneous preterm birth persisted (aOR 3.58, 95% CI: 1.25–10.24). There was no significant interaction between stress and CST IV on the odds of spontaneous preterm birth (p = 0.328). When both stress and CST IV were introduced into the model, their associations with recurrent spontaneous preterm birth were slightly stronger than when they were in the model alone. The aOR for stress with recurrent spontaneous preterm birth was 2.02 (95% CI: 0.61–6.71) and for CST IV the aOR was 3.83 (95% CI: 1.30–11.33). Compared to women with neither of the two exposures, women with both high stress and CST IV had the highest odds of recurrent spontaneous preterm birth (aOR = 6.01, 95% CI: 1.002–36.03). Conclusion Among a predominantly non-Hispanic Black cohort of women with a prior spontaneous preterm birth, a nonoptimal cervicovaginal microbiota is associated with increased odds of recurrent spontaneous preterm birth. Adjustment for perceived stress may amplify associations between CST IV and recurrent spontaneous preterm birth. Identification of modifiable social or behavioral factors may unveil novel nonpharmacologic interventions to decrease recurrent spontaneous preterm birth among women with underlying biologic risk. Key Points

Vaginal Microbiome Composition in Early Pregnancy and Risk of Spontaneous Preterm and Early Term Birth Among African American Women

“…This agreement is more remarkable as that cohort was restricted to women with a prior history of sPTB who received progesterone therapy in the subsequent pregnancies that comprise their cohort ( Callahan et al., 2017b ). Also, in a study restricted to women with a prior sPTB, vaginal CST IV was found to be a significant risk factor for a recurrent sPTB ( Gerson et al., 2020 ). Conversely, studies that have considered substantial numbers of cases of PTB among AA women did find particular taxa that increased the risk of PTB, whereas our study did not.…”

Colonization at birth with human CST IV cervicovaginal microbiota alters development and increases neonatal mortality in mice

“…A nonoptimal CST IV cervicovaginal microbiome is common in Black women and has been associated with negative maternal-child health outcomes, including obstetric complications, spontaneous preterm birth, and neonatal morbidity and mortality (Brown et al, 2018(Brown et al, , 2018Callahan et al, 2017;DiGiulio et al, 2015;Elovitz et al, 2019;Fettweis et al, 2019;Florova et al, 2021;Gerson et al, 2020a;Hočevar et al, 2019;Ravel et al, 2011;Romero et al, 2014;Tabatabaei et al, 2019Tabatabaei et al, , 2019Zhou et al, 2007). This underlying biological risk is further amplified by a variety of environmental factors that contribute to a high risk in utero environment, including, but not limited to, obesity, diabetes and consumption of a diet that deficient in dietary fibers (Brookheart et al, 2019;Danese and Lewis, 2017;Gerson et al, 2020b;Shivakoti et al, 2020). While these maternal environmental perturbations alter the composition of the microbiota transferred from mother to offspring, the possibility that prenatal exposure to these risk factors may impact developmental processes that support offspring response and adaptation to postnatal colonization remains unclear.…”

“…During pregnancy, Black women are more likely to harbor CST IV microbiota that have been associated with increased incidence of obstetric complications, inflammation in the intrauterine environment, spontaneous preterm birth, and neonatal morbidity (Brown et al, 2018(Brown et al, , 2018Callahan et al, 2017;DiGiulio et al, 2015;Elovitz et al, 2019;Fettweis et al, 2019;Florova et al, 2021;Gerson et al, 2020a;Hočevar et al, 2019;Ravel et al, 2011;Romero et al, 2014;Tabatabaei et al, 2019Tabatabaei et al, , 2019Zhou et al, 2007). The risk associated with CST IV may be further amplified by a variety of environmental factors that promote chronic and systemic inflammation, including maternal stress and trauma, infection, and consumption of a high-fat, low-fiber diet (Brookheart et al, 2019;Danese and Lewis, 2017;Gerson et al, 2020b;Shivakoti et al, 2020).…”

Interactions between Perceived Stress and Microbial-Host Immune Components in Pregnancy

“…[4][5][6] High perceived stress during pregnancy has also been associated with obstetrical complications, such as gestational diabetes mellitus, preterm birth, gestational hypertension, preeclampsia and complications for the infant, such as being small for gestational age. [7][8][9][10][11] The way that stress is experienced and expressed and the resulting physical and mental health effects is highly individualized, and may be influenced by culture. The data-driven Woods-Giscombe's Superwoman schema explains that Black women feel an obligation to manifest strength and independence, suppress emotions, including reporting perceived stress, succeed despite limited resources, and help others, 12 but the combined effects of structural inequities and chronic experienced stress explain poorer health.…”

“…[16][17][18] There is increasing evidence that the microbiota-gut-brain axis, that encompasses interactions between the neurological, endocrinological and immunological systems, is associated with mental health disorders and obstetrical complications. 10,[19][20][21][22][23][24] The microbiota that reside in the gastrointestinal system can be influenced by lifestyle (e.g., diet, exercise), residential location and home environment (e.g., rural versus urban), and medication use (e.g., antibiotics). 25 Disruptions in the gut microbial ecosystem have been associated with both intestinal and systemic diseases (e.g., IBS, diabetes, depression).…”