Changes in Microbiota of Amniotic Fluid Might be Critical to Predict Spontaneous Preterm Births

Introduction:

Is there something that affects more individuals worldwide than cancer, (either directly or through someone we know)? The answer is pregnancy. There are many complications that can arise throughout pregnancy, with spontaneous preterm labor affecting 5-18% of pregnancies. Preterm labor is childbirth that happens before a healthy delivery date, where the baby is not fully developed to survive on its own. Depending on where you live, preterm labor can be considered a death sentence not just for the infant, but for the mother as well. Infants who survive are more at risk for infection and health issues the earlier they were born (Romero et al. 2014). Logically and morally, it is imperative for civilisations to decrease the amount of pregnant women who go into preterm labor so as to decrease risk to mother and child.

Testing the amniotic fluids for infection is one method to identify at risk pregnant women. Combs et al have established that the extent of the inflammatory response has an impact on increased neonatal mortality. When bacteria are detected in the foetal circulation system, the mother’s body initiates an inflammatory response (Urushiyama et al. 2017).  Microbes that induce inflammatory agents and response would be the most important to target in DNA analysis (Combs et al. 2014). Thus the identification and detection of microbes in the womb that create other waste products that are known to cause developmental issues can help facilitate shorter hospital stays after birth (Romero et al. 2014).

Several microbe genera have been discovered in healthy non-pregnant women, most being natural for maintaining proper conditions in the reproduction organs (Feitas et al. 2017). It has been observed that pregnant women have a decreased abundance and variety of microbes than their nonpregnant counterparts (Feitas et al. 2017). This lower abundance and variety can be associated with the unique environment that is created in the womb in order to maintain a healthy fetus. Pregnant women with varying levels in inflammation due to infection also showed differing vaginal microbiomes when compared to each other (Urushiyama et al. 2017). If a vaginal microbiome profile is created for pregnant women, is it possible to screen women for being at risk for preterm labor and taking preventative action in ensuring that we decrease mortality and health deficiencies for their children.

Central Question:

Is there a way to identify a specific range of bacteria that can indicate risk of a mother going into preterm labor? Multiple studies are trying to compile a specific list of bacteria present in pregnant women with and without infections in hopes of knowing which infections will be most likely to put the mother and child at risk of a preterm birth.

Findings and evidence:

The top 28 species and their abundance found present across healthy, infected (0-IV being stages of placental inflammation), and environmental specimens. The 11 most dominant species in Stage III (†) were almost non-existent in Stage0-I, while the seven most dominant species in Blank (§) were not dominant in Stage III and 40 miCAM samples (indicated by a pink bar). H. influenzae (‡), which was dominant in one sample in Blank (N16), was dominant in some samples in Stage III and Stage II. DOI: 10.1038/s41598-017-11699-8

Combs et al, Freitas et al, and Urushiyama et al have identified the different species most abundant in pregnant women with infections and healthy pregnant women. Figure 1 identifies the most prevalent species in pregnant women with chorioamnionitis (an infection of the membranes surrounding the unborn child in the womb) and healthy women. There were 3 major stages of infection defined, stage 0-1 being minimal, stage II being intermediate, and stage III being severe. The red boxes indicate women who had stage III infection, yellow boxes are stage II, and blue boxes indicate stage 0-1. As seen in the figure, the most common bacteria found across stage III are not found in such intensity or even at all in some stage II and stage 0-1 patients. The results of Urushiyama et al suggests that there is differing diversity in microbiota between stages of infection.

Freitas et al establishes the microbiome of healthy pregnant women and compares it to non-pregnant women. Urushiyama et al and Freitas et al compare to their results to already established studies, confirm that all results are similar between the chosen studies, and find that a small range of bacteria are present in pregnant women with amniotic infections. For the pregnant women, it has been established that those with infections are at higher risk of preterm labor, as some test subjects actually demonstrated in multiple studies, including Freitas etal, Urushiyama et al, and Combs et al. Combs et al find the importance of the inflammatory response as being more important than infection as a potential cause for preterm labor in pregnant women, indicating that microbiota that create an inflammatory response are a likely cursor to preterm labor.  Combs et al also supports Ureaplasma species to be particularly present in pregnant women with amniotic infections, likely in part to the fact that they are mainly associated with bacterial vaginosis in women. It has been established that women with this infection type have a high chance of passing it to the immunocompromised newborn. Identifying other bacteria and further understanding of the interactions within the uterus will be a major factor in pre diagnosing women that are risk of going into preterm labor.

Future Studies:

There are important factors that need to be identified, such as which women are most at risk for microbial colonization and infection, which identified microbes can cause inflammation, and when should an infection be tested for during pregnancy. Identifying the women most likely at risk for preterm birth, either due to genetic predisposition or environmental factors, would be paramount as it can help develop the best preventative courses for infection causing microbes. Knowing which microbes create the most disturbance can allow medical scientists to either identify or create a treatment to eradicate the infective agents. By identifying the last two, we can also make prenatal care for pregnant women more efficient.

Reproductive health is important for the sake of future generations and current ones, understanding when pregnancies have difficulties can lower complications in the future. Mapping out the unique vaginal microbiome of pregnant women in both healthy and infected states could potentially even lead to studies that could use microbes to ease pregnancy issues that arise in expecting mothers.

Further Reading:

Despite our medical advances, the US is one of the top 10 countries with the most preterm births. For more information on this subject try out these articles:

National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications (Blencowe et al 2012)

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000 (Liu, Li et al 2012)

For general information provided by leading health organizations:

Preterm Birth (CDC Maternal and Infant Health)

Preterm Birth (WHO)

References:

  • Combs CA, Gravett M, Garite TJ, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol 2014;210:125.e1-15. https://doi.org/10.1016/j.ajog.2013.11.032
  • Freitas, A. C., Chaban, B., Bocking, A., Rocco, M., Yang, S., Hill, J. E., … Yudin, M. (2017). The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women. Scientific Reports, 7, 9212. http://doi.org/10.1038/s41598-017-07790-9
  • Romero, R., Dey, S. K., & Fisher, S. J. (2014). Preterm Labor: One Syndrome, Many Causes. Science (New York, N.Y.), 345(6198), 760–765. http://doi.org/10.1126/science.1251816
  • Urushiyama, D., Suda, W., Ohnishi, E., Araki, R., Kiyoshima, C., Kurakazu, M., . . . Hata, K. (2017). Microbiome profile of the amniotic fluid as a predictive biomarker of perinatal outcome. Scientific Reports, 7(1). http://doi.org/10.1038/s41598-017-11699-8