Abstract
The syndrome of spontaneous preterm birth (sPTB) presents a challenge to mechanistic understanding, effective risk stratification, and clinical management. Individual associations between sPTB, self-reported ethnic ancestry, vaginal microbiota, metabolome, and innate immune response are known but not fully understood, and knowledge has yet to impact clinical practice. Here, we used multi–data type integration and composite statistical models to gain insight into sPTB risk by exploring the cervicovaginal environment of an ethnically heterogenous pregnant population (n = 346 women; n = 60 sPTB < 37 weeks’ gestation, including n = 27 sPTB < 34 weeks). Analysis of cervicovaginal samples (10–15+6 weeks) identified potentially novel interactions between risk of sPTB and microbiota, metabolite, and maternal host defense molecules. Statistical modeling identified a composite of metabolites (leucine, tyrosine, aspartate, lactate, betaine, acetate, and Ca2+) associated with risk of sPTB < 37 weeks (AUC 0.752). A combination of glucose, aspartate, Ca2+, Lactobacillus crispatus, and L. acidophilus relative abundance identified risk of early sPTB < 34 weeks (AUC 0.758), improved by stratification by ethnicity (AUC 0.835). Increased relative abundance of L. acidophilus appeared protective against sPTB < 34 weeks. By using cervicovaginal fluid samples, we demonstrate the potential of multi–data type integration for developing composite models toward understanding the contribution of the vaginal environment to risk of sPTB.
Highlights
The syndrome of spontaneous preterm birth is a major cause of neonatal death and morbidity globally [1]
Consideration of how vaginal microbiota profiles may contribute to pathophysiological pathways that lead to spontaneous preterm birth (sPTB) has been limited
To address these knowledge gaps, we explored whether increased risk of sPTB was directly associated with the cervicovaginal metabolic profile, alterations to the host response, and the presence of specific bacteria with a holistic strategy
Summary
The syndrome of spontaneous preterm birth (sPTB) is a major cause of neonatal death and morbidity globally [1]. A healthy vaginal ecosystem and term birth has been described as a Lactobacillus-dominated microbiome, with microbiota metabolites playing important roles in inhibition of bacterial and viral infections [14, 20] — e.g., Lactobacillus crispatus contributes to low pH by secreting the metabolite D-lactate [21]. BV does not explain all sPTB, conferring only a 2-fold increase in risk [24], and not all sPTB deliveries present a microbial profile dominated by L. iners [11] This is apparent among Black women, where mixed bacterial vaginal communities are common even before pregnancy [9, 12, 25, 26], but a relative lack of lactobacilli does not appear to explain the higher rate of sPTB in a US study of Black women [10]. Knowledge of the vaginal microbiota alone seems insufficient to develop sPTB prediction tools, and a much greater understanding of the vaginal microbiota and the environment within which it lives (i.e., maternal host response) is clearly needed
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