Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery

Michal A Elovitz,Amy G Brown,Pawel Gajer,Johanna B Holm,Jacques Ravel,Valerie Riis,Michael S Humphrys

doi:10.1038/s41467-019-09285-9

Michal A Elovitz, Amy G Brown + Show 5 more

Open Access

https://doi.org/10.1038/s41467-019-09285-9

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Abstract

Failure to predict and understand the causes of preterm birth, the leading cause of neonatal morbidity and mortality, have limited effective interventions and therapeutics. From a cohort of 2000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Using innovative Bayesian modeling of cervicovaginal microbiota, seven bacterial taxa were significantly associated with increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of β-defensin-2 lowered the risk of sPTB associated with cervicovaginal microbiota in an ethnicity-dependent manner. Surprisingly, even in Lactobacillus spp. dominated cervicovaginal microbiota, low β-defensin-2 was associated with increased risk of sPTB. These findings hold promise for diagnostics to accurately identify women at risk for sPTB early in pregnancy. Therapeutic strategies could include immune modulators and microbiome-based therapeutics to reduce this significant health burden.

Highlights

Failure to predict and understand the causes of preterm birth, the leading cause of neonatal morbidity and mortality, have limited effective interventions and therapeutics
Single Married Insurance Private Medicaid Nulliparous Gestational diabetes Pre-gestational diabetes Chronic hypertension History of spontaneous preterm birth (sPTB)/2nd trimester loss Cervical length screening performed at Level II Ultrasounda Cervical length at Level II, median (IQR) Cerclage Vaginal bleeding—first trimester Vaginal bleeding— second trimester Vaginal bleeding—third trimester Gestational age at delivery in weeks, median (IQR)
The findings address a long-held belief that not having Lactobacillus spp.dominated cervicovaginal microbiota is strongly associated with adverse pregnancy outcomes

Summary

Introduction

Failure to predict and understand the causes of preterm birth, the leading cause of neonatal morbidity and mortality, have limited effective interventions and therapeutics. From a cohort of 2000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Even in Lactobacillus spp. dominated cervicovaginal microbiota, low β-defensin-2 was associated with increased risk of sPTB. There have been a few studies that have examined the relationship between cervicovaginal microbial communities and sPTB18–22 Definitive conclusions from these studies are difficult to establish as phenotyping of sPTB is heterogenous, the number of sPTB cases is significantly limited and methodology is variable. To overcome sample size limitations, misclassification of cases and methodological differences, we conducted a study involving a prospective cohort of 2000 women with singleton pregnancies called Motherhood & Microbiome (M&M) and tested associations of cervicovaginal microbial communities and local immunological features with sPTB.

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