As eager as one may be to greet a newborn, an early arrival is never good. Preterm birth (PTB) — when an infant is born before 37 weeks of gestation — is a serious problem across the globe. With an estimated 15 million cases annually, spontaneous preterm birth (SPTB) is the leading cause of death in infants under the age of five years. Of the numerous risk factors linked to PTB, ascending bacterial infections of the uterine cavity account for the vast majority of spontaneous preterm births. Therefore, the cervicovaginal microbiome has received increased scrutiny in recent years.
Preterm birth, in brief
PTB is a challenging issue worldwide with a prevalence of 5% in northern Europe to 18% in some African countries. In addition to increasing the risk of morbidity and mortality, long-term complications may include both psychological and physical disabilities to neonatal life.
Because of the differences in underlying pathophysiology and clinical presentation, PTB is commonly divided into spontaneous PTB and indicated PTB. The former includes the spontaneous onset of labor and preterm pre-labor rupture of membranes, whereas the latter is explained by cesarean delivery or induction of labor because of maternal or fetal complications. Spontaneous PTB is of particular concern, since a significant proportion occurs at extremely low gestational age, and mortality and morbidity are high.
Though the pathogenesis of PTB is poorly understood, numerous risk factors can affect fetal developmental plasticity, gestational age, or birth outcome.
These include both environmental and clinical factors: toxins, high fat diet, family history of PTB, low education, low socioeconomic status, short pregnancy interval, early (<16 years) or late (>36 years) pregnancy, tobacco or alcohol consumption, high stress, hypertension, obesity or underweight, infection, short cervix, uterine anomaly, and prior miscarriage.
And now add to the list, the host cervicovaginal microbiota and levels of generated metabolites that are now known to regulate the maternal and fetal immune interaction as well as the birth outcome.
The microbiome and preterm birth
A normal cervicovaginal microbiota in women of reproductive age is generally dominated by Lactobacillus species. In contrast, an abnormal microbiota is characterized by a low abundance of lactobacilli with an overgrowth of anaerobic bacteria, such as Gardnerella vaginalis, Prevotella spp., Bacteroides spp., and Mollicutes. Lactobacilli prevent the overgrowth of pathogens by various mechanisms such as hydrogen peroxide and lactate production, leading to a reduced vaginal pH.
It is widely accepted that intrauterine infection and inflammation are important causative factors of spontaneous PTB, which is thought to be due to pathogen ascension from the vagina.
For example, in early pregnancy, an increase in pathogenic microbiota provides permissible colonization and metabolic signatures of bacterial vaginosis (BV), which is strongly linked to the risk of PTB. Bacterial vaginosis (BV) is characterized by a depletion of lactobacilli, an overgrowth of pathogens, and the induction of pro-inflammatory cytokines.
Multiple studies have tried to characterize the relationship between the cervicovaginal microbiome and spontaneous PTB. However, a 2022 review of the evidence observed that the results diverge depending on ethnicity. Notably, one study found that lactobacilli depletion was more common and species diversity was higher in African American women than in white women. African American women have a higher rate of BV-related microbiota than white women. But interestingly, a deficit of Lactobacillus and higher species diversity was seen as a risk factor for PTB primarily in white women and not in African American women.
Briefly, a few of the significant findings gathered in the review:
- Lactobacillus crispatus was strongly linked to full-term pregnancies, whereas other microbial communities were associated with PTB in a 2020 study.
- An Australian cohort (mostly white women) who subsequently delivered at term had higher amounts of Lactobacillus crispatus, Lactobacillus gasseri, or Lactobacillus jensenii DNA in their vaginal swabs.
- In a study from India, a protective role of L. crispatus and L. gasseri in reducing the risk of PTB was observed.
- The microbiota of women who experienced PTB had higher richness and diversity and higher Mollicutes prevalence when compared to those of women who delivered at term in another study.
Mechanisms of microbiota protection
It is widely accepted that the dominance of Lactobacillus spp. in the healthy vaginal tract promotes vaginal homeostasis and prohibits the colonization and growth of adverse microorganisms.
The protective role of Lactobacillus spp. is exerted through several mechanisms, such as the creation of an acidic environment by reducing vaginal pH through the production of lactate, the production of bioactive compounds, competition for nutrients and adhesion sites, and modulation of host immunity.
For example, microbiota dysbiosis directly affects the production of microbiota metabolites, and the presence of metabolites at higher or lower levels impacts metabolic function including PTB. These metabolites include short-chain fatty acids, polyamines, polyphosphates, and peptides. The other mechanisms listed above are acknowledged actions that may contribute to the protective benefit of Lactobacillus spp in PTB.
A role for probiotics?
Despite several clinical trials and meta-analyses, it is still not clear if modulation of maternal and neonatal microbiota with probiotic supplementation affects the risk of preterm birth and its complications.
Evidence supports the hypothesis that maternal dysbiosis could act as a trigger for preterm birth. One study suggested that supplementation with probiotics in late pregnancy could modify the vaginal microbiota by counteracting the decrease of Bifidobacterium and the increase of Atopobium, a dysbiosis linked with more than 70% of cases of bacterial vaginosis, which in turn can lead to preterm birth. In addition, supplementary probiotics following antibiotic treatment can lower the vaginal pH to an optimal value hence promoting the restoration of the vaginal microbiota, thereby modulating the inflammatory cascade commonly observed in preterm birth.
However, results on the use of probiotics to prevent preterm births are inconclusive.
A 2019 review found that using probiotics during pregnancy neither decreased nor increased the risk of preterm birth before 34 weeks or before 37 weeks.
Another systematic review and meta-analysis conducted in 2018 also found no decisive evidence that taking probiotics or prebiotics during pregnancy either increases or decreases the risk of preterm birth. The authors concluded that taking probiotics or prebiotics during pregnancy to prevent preterm birth or newborns and maternal adverse pregnancy outcomes is still not supported by evidence.
(Nonetheless, there is encouraging evidence that alteration of the microbiota with probiotics in the preterm infant can reduce the incidence of necrotizing enterocolitis (NEC) in premature infants.)
While the mechanisms underlying PTB are many, evidence suggests that microbiota dysbiosis plays a role. The mechanisms are not clear but the protective role of Lactobacillus spp. in PTB has been observed in some studies. Probiotic interventions targeting bacterial vaginosis and elimination of infection in women at risk for PTB appear to be beneficial.
Yet the consumption of probiotics during pregnancy to prevent preterm birth is still not supported by the bulk of the evidence. More detailed investigations on the types of probiotics, the characteristics of individual women, and the length of administration are required.
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