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The Microbiome and the Risk of Preterm Birth

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Lactobaccili species microbes
Lactobacilli species, a beneficial Gram-positive, anaerobic, rod-shaped bacteria that normally inhabits the cervicovaginal space.

The findings of recent investigations into spontaneous pre-term birth at Penn Obstetrics and Gynecology are shedding new light on the clinical ability to predict preterm birth and to develop diagnostic techniques that accurately identify women at risk for the condition early in pregnancy. Importantly, these studies link factors in the cervicovaginal microbiome to preterm births among African-American women, underpinning the finding of a racial disparity for these events in the United States.

Iatrogenic and spontaneous preterm birth (sPTB) are leading causes of neonatal morbidity and mortality in the United States that together exceed $26 billion in healthcare costs annually.

Infants that survive preterm birth are at increased risk for a spectrum of lifelong health concerns, including breathing problems and vision loss, as well as cerebral palsy, intellectual delays and other neurocognitive issues.

Spontaneous preterm birth—or birth occurring at <37 weeks of gestation—has been called an enigma because within the many explanations for its etiology are contradictions that continue to escape simple explanation.

It is known, for example, that sPTB occurs at significantly higher rates in African-American women than among their non-African American peers, and that African-American women of higher socio-economic status (SES) have a higher rate of PTB than white women of lower SES. However, the risk of adverse birth outcomes does not extend to American women of similar SES, or to women of African descent elsewhere in the world. Compounding these issues is an insufficient understanding of the pathology of sPTB, though many factors, including lifestyle, infectious agents, inflammation and more recently, genetics, have been suspected culprits.

sPTB Research at the Perelman School of Medicine

With the discovery at the Perelman School of Medicine and elsewhere that certain types of bacteria and immune factors within the cervical-vaginal space increase the risk of sPTB, a marked transformation is taking place in sPTB research. As a result, investigators at Penn Medicine appear to be closing in on preventatives for the condition.

Led by, Michal Elovitz, MD, and published in Nature Commentary, recent research at Penn Medicine is helping physicians understand, better predict and better diagnose preterm birth and take the necessary precautions to prevent it early in pregnancy—particularly for African American women who are more at-risk.

Studying the Cervicovaginal Microbiome

The Director of the Maternal and Child Health Research Center at Penn Medicine, Dr. Elovitz recently reflected on the investigation’s beginnings and its findings.

“About eight years ago, I started thinking outside of the world of obstetrics,” Dr. Elovitz said. “Specifically about what other thematic areas had arisen in science that might be important in the world of obstetrics.”

What sparked Dr Elovitz’s interest was the microbiota, the populations of symbiotic bacteria that inhabit many regions of the body. The collective genomes, or microbiome, of these populations, have been studied for more than a decade at Penn Medicine as part of a multi-center National Institutes of Health (NIH) research initiative known as the Human Microbiome Project, which seeks to determine how different microbial communities across body sites influence health and disease. 

Studies have found an association between the cervicovaginal microbiota and the incidence of bacterial vaginosis (BV) in African-American women has been recognized for some time. Like sPTB, BV affects African-American women disproportionately by comparison to other female populations in the US. These reports found that the vaginal microbiome in disease is characterized by a decrease in lactobacillus, a bacterial species generally considered beneficial, and by a greater profusion and diversity of facultative and anaerobic organisms, there is a higher risk of acquiring HIV and other sexually transmitted infections, among other diseases.

Does the Cervical Vaginal Microbiome play a role in Spontaneous Preterm Birth (sPTB)?

In the absence of elaboration on the association between the microbiota of the cervical vaginal space and its potential role in preterm birth, Dr. Elovitz formed a collaboration with other microbiologists and immunologists to spearhead a research study at Penn Medicine. Sampling vaginal swabs from the cervicovaginal microbiota of 2,000 pregnant women to establish the bacteria that make up the cervicovaginal microbiota, the investigation sought to identify, if possible, communities of bacteria associated with preterm birth. 

The data—the largest sample of cervicovaginal microbiota in pregnant women to date—was collected at several points over the course of pregnancy. The first, collected at 16-20 weeks gestation, was of particular interest to researchers because early pregnancy is the time when preventative interventions would be most likely to be effective.

The study found that seven bacterial taxa in the cervicovaginal space were associated with sPTB in all women, with five of these taxa associated with sPTB in African-American women. A second study, from the Maternal and Child Health Research Center at the Perelman School of Medicine (published in Anaerobe in 2019), further linked one of the bacterial species, Mobiluncus mulieris, to molecular and functional changes in the cervical epithelial barrier thought to contribute to the pathogenesis of sPTB. In the large cohort, M mulieris was identified as highly associated with sPTB. 

The immune system is also involved in sPTB, according to Dr. Elovitz.

“In African-American women who experienced sPTB, we found lower levels of an innate immune system factor called peptide β-defensin-2,” Dr. Elovitz said. “Further, we discovered that β-defensin-2 acts to modulate the risk of sPTB for some—but not all—of the bacterial taxa in the cervicovaginal space.” These interactions led the investigators to consider the possibility of an intricate interaction between risk modulators (e.g., β-defensin-2 and the lactobacilli) pathogenic factors, and sPTB risk.

Are Microbiome-based Therapies Next?

In identifying specific signatures combining both immune and microbial factors associated with sPTB, the Penn study has major implications for the clinical management of pregnant women, and addresses a long-held belief that the lack of Lactobacillus spp.-dominated cervicovaginal microbiota is strongly associated with adverse pregnancy outcomes.

However, further research is needed, according to Dr. Elovitz.

“While these findings are a good start to unraveling the interactions that exist in the cervicovaginal environment between immune factors, the microbiota and the risk of sPTB, further study is needed to explore other factors thought to contribute to increasing or reducing the risk of sPTB,” she said.

These new studies, she concluded, would likely involve therapies that modulate the local host immune response or modify the existing microbial communities (or a combination of such therapies) and may hold promise to help reduce the effects of sPTB.

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