Scientific background

Pregnancy and Microbiome
    

The human microbiota is a new emerging knowledge that has been explored by the scientists in this present days. Improvement in technologies to detect the microbiome with DNA sequencing helps to culture the non-cultivated microorganism.[1] It is said that the microbiome is important to health and body function.[2] But did you know that the microbiome can actually determine whether the mother will give early delivery or not? This interaction between the microbiome and pregnancy as well as the pregnancy outcome is an interesting topic for researchers, but also for those who think of becoming pregnant or let’s say for a woman in general.

Pregnancy and microbiome
http://www.the-scientist.com/? articles.view/articleNo/40600/title/the-Body-s-Ecosystem/

Every healthy individual has a very different and unique microbiome in different parts of their body. I’m going to explain about microbiome and pregnancy, therefore I divided the region into a proximal maternal site (placenta, amniotic fluid, meconium) and distal site (oral cavity, intestine, vagina).[3]

Proximal site.

The placenta, as we know, is an organ which works as a connection between mother and fetus. It is known that the placenta sometimes contains microbes and is associated with preterm labour.[1] Aagaard et al. used 16S ribosomal DNA sequence and found that the placenta is mostly dominated with non-pathogenic Firmicutes, Tenericutes, Proteobacteria, Bacteroides and Fusobacteria, which have more similarity with oral cavity of non-pregnant women than the urinary tract microbiomes.[4]

Amniotic fluid also has an important effect on pregnancy. The traditional dogma about the sterilized condition is now debatable. Recent studies have discovered there is 30%-50% a microbial invasion in amniotic fluid undetected by cultivation-based method. This microbiome causes an increase of white blood cells, thus leads to inflammation, and is correlated to gestational age and time of delivery. This means inflammation can trigger preterm birth.[3]

Another way to study a microbiome in an intrauterine environment is through meconium or early stools of the newborn. The studies of meconium revealed the diversity of microbial DNA were linked to gestational age. This microbiome is likely originated from amniotic fluid because during last semester, when the fetus swallows a large amount of amniotic fluid.[3]

Distal site.

The oral cavity has an enormous microbiome, that consit of more than 700 micro-organisms. Interestingly, periodontal disease is thought to cause intrauterine infection. A study showed periodontal disease can increase the incidence of preterm birth up to 2-7 times.[2]                   

If we looked into intestines, gut microbial changes in pregnancy depend on the stage of pregnancy itself. A study that was conducted in Finland, showed that the microbiome in the first trimester is similar to the one of healthy people. Towards the third trimester a shift takes place, the microbiome becomes less diverse and has increased amounts of Proteobacteria and Actinobacteria. There is a relative abundance of Streptococcus after the third trimester until one month after delivery [5]

The vaginal microbiome is ought to have a significant relation to pregnancy. The biodiversity in the vaginal microbiome is less compared to gastrointestinal and oral microbiota. Despite that, the vaginal microbiome has a rich diversity Lactobacillus spp. Lactobacilli, a lactic-acid producing bacteria, are postulated to protect the vaginal ecosystem, with a certain mechanism.[2] The typical lactobacilli in healthy vaginas usually consist of L. crispatus, L. gasseri, L. iners, or L. jensenii.[6] Some authors said the L. iners are dominant in older maternal age.[7] The small presentation of vaginal bacteria are composed of anaerobic bacteria, comprise of Prevotella, Gardnerella vaginalis, Sneathia, and Atopbium vaginae.[6] Intriguingly, studies have found that the vaginal microbiome in non-pregnant women is different from a pregnant woman. In pregnant women, the microbiome is more stable and less diverse during pregnancy. While in non-pregnant women, the composition changing fluctuated throughout age, hormonal changes, infection, and sexual behavior.[1]

Microbiome in pregnant women
https://www.frontiersin.org/articles/10.3389/fmicb.2016.01031/full

After we learned about the microbiome, the next question is how can these microbiomes contribute to preterm birth? The prematurity itself has been linked to multiple factors, one of which is the microbiome. While relatively the major microbiome is non-pathogenic, disruption of balance in their ecosystem (eg. Dysbiosis) would increase the risk of inflammation.[8] Dysbiosis is a shift in a microbiotas composition and is usually associated with several effects leading to disease.[9] A study has found that during pregnancy, vaginal microbiome shifts from one Lactobacillus to another species, but rarely to anaerobes.[4] In one longitudinal study was showed that during pregnancy, L. crispatus is more dominant and L. gasseri is more prominence in the first  trimester.[7] Many factors contribute to this changes such as hormone fluctuations and menstrual flow, changes in the cervix and vaginal secretion and changes in sexual activity. The rising of estrogens in pregnancy leads to in a deposition in vaginal glycogen thus resulting Lactobacilli proliferation. It is postulated that Lactobacilli in pregnant women have an important role in initial upper gastrointestinal microbiome of newborn and protect them from ascending infection that may cause preterm birth.[1]

As I previously mentioned, the intrauterine infection can prompt preterm birth. Ureaplasma, species of Firmicutes phylum were culprits of perinatal infection a long time ago. Ureaplasma from amniotic fluid in 16-20 week gestation has been found related to histologic chorioamnionitis and preterm birth. Nevertheless, the exact mechanism of Ureaplasma still controversial.[10] It has been said that the ascending infection both from vagina and placenta can cause inflammation, this can manifest into preterm premature rupture of membranes (PPROM) and preterm delivery.[11] The human placenta can express Toll-like receptors (TLRs) 2,4,10 and it is found increased in the presence of TLR-2 and 10 agonists. Also, the endocervix and ectocervix are able to produce cytokines pro-inflammation IL6 and IL8 in response to lipopolysaccharide (LPS) of bacteria.[11] One study detected 16S ribosomal DNA of amniotic fluid samples from preterm labour women had a high level of IL-6 and contained Leptotrichia or Fusobacterium.[6]

People used to believed that newborn’s first contact with the microbiome occurred after delivery. However, in 2008 Jimenez et al. orally inoculated pregnant mice with Enterococcus faecium, and then found this bacterium in the meconium of the mice offspring. This means the maternal bacteria can enter the gastrointestinal tract of the fetus.[9] The process of labor plays an important role for the infant’s early microbial colonization and is influenced by maternal the microbiota, delivery mode, genetic, and other factors. Infants with normal delivery, acquire microbes that are similar with the maternal vaginal microbiome, while caesarean-delivered infants resembling those microbiomes found on the maternal skin. There is also a different microbiome in term of gestational age. Preterm infants have more predominance of  Proteobacteria, and a lack of healthy infant’s microbiome, Bifidobacterium and Lactobacillus. In the first year of life, infants begin to develop their own microbiome, with changes of feeding pattern will determine their gut microbiota.[2] Exclusively breastfeeded infants decrease the prevalence of Firmicutes phylum.[7] They also contained higher Bifidobacteria, which is believed to improve immune function. After six months, babies will introduce with complimentary food and will likely cause shifting of the intestinal microbiome with a chance of gastrointestinal infection. As a matter of fact, during the first 2-3 years, microbiomes are a dynamic entity with each diet change.[2] Bacteroides species were found on the introduction of vegetables.[7]

The maternal microbiome set infant's microbiome
http://www.nature.com/nm/journal/v23/n3/fig_tab/nm.4299_F1.html

There are a lot of factors that can influence microbiomes throughout our life. For instance, environmental exposure, diet and nutrition, health status, and stress are components that have an impact on preterm birth and others pregnancy complication.[6] Nutrition is important in pregnant women. Both low and high body mass index (BMI) is related to preterm birth and gestational hypertension and influence the maternal microbiome’s composition. The diet in the western country, which is high in simple carbohydrates, fats, and animal protein, has reported increasing the prevalence of Clostridium innocuum, Eubacterium dolichum, Cantenibacterium mitsuokai and Enterococcus spp. and decrease of Bifidobacteria and Bacteroidetes.[2]

Some behaviors are known to affect pregnancy outcome. In context of smoking, the number of cigarettes smokes daily increased the risk of preterm birth. It also affects the oral microbiome. Poor oral hygiene can accumulate more pathogenic bacteria and form a biofilm. This process will reduce the biodiversity of the oral cavity and cause dental caries or periodontal disease. Smokers are common to have more persistent periodontal pathogens and then produce pro-inflammatory  response to this.[2]         

Mental stress can form a complex neuroendocrine-immune response, with increasing of pro-inflammatory cytokines and cortisol. Even if this action protects from infection, acute inflammation increase the chances to preterm birth. In low-income African American women, exposure to stress is correlated with bacterial vaginosis during pregnancy, and this also explains a racial disparity in bacterial vaginosis epidemiology.[2]

The microbiome shapes our life way earlier than we thought. The exact mechanism of how this rich microbiomes affect pregnancy and parturition remains unclear. Further investigation of the complex maternal microbiome may help to improve pregnancy outcome, and therefore neonatal and infant health in the future.

Reference :

[1]    C. Fox and K. Eichelberger, “Maternal microbiome and pregnancy outcomes,” Fertil. Steril., vol. 104, no. 6, pp. 1358–1363, 2015.

[2]    A. L. Dunlop, J. G. Mulle, E. P. Ferranti, S. Edwards, A. B. Dunn, and E. J. Corwin, “Maternal Microbiome and Pregnancy Outcomes That Impact Infant Health,” Adv. Neonatal Care, vol. 15, no. 6, pp. 377–385, Dec. 2015.

[3]    J. Neu, “The microbiome during pregnancy and early postnatal life,” Semin. Fetal Neonatal Med., vol. 21, no. 6, pp. 373–379, 2016.

[4]    K. Aagaard et al., “A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy,” PLoS One, vol. 7, no. 6, 2012.

[5]    O. Koren et al., “Host remodeling of the gut microbiome and metabolic changes during pregnancy,” Cell, vol. 150, no. 3, pp. 470–480, 2012.

[6]    I. Solt, “The human microbiome and the great obstetrical syndromes: A new frontier in maternal-fetal medicine,” Best Pract. Res. Clin. Obstet. Gynaecol., vol. 29, no. 2, pp. 165–175, 2015.

[7]    A. L. Prince, D. M. Chu, M. D. Seferovic, K. M. Antony, J. Ma, and K. M. Aagaard, “The perinatal microbiome and pregnancy: Moving beyond the vaginal microbiome,” Cold Spring Harb. Perspect. Med., vol. 5, no. 6, pp. 1–23, 2015.

[8]    M. Malecki, V. Schildgen, and O. Schildgen, “The Microbiome, Parturition, and Timing of Birth: More questions than answers,” Epidemiology, vol. 77030, pp. 1107–1114, 2011.

[9]    M. Nuriel-Ohayon, H. Neuman, and O. Koren, “Microbial changes during pregnancy, birth, and infancy,” Front. Microbiol., vol. 7, no. JUL, pp. 1–13, 2016.

[10] J. Romano-Keeler and J.-H. Weitkamp, “Maternal influences on fetal microbial colonization and immune development,” Pediatr. Res., vol. 77, no. 1–2, pp. 189–195, 2015.

[11] A. L. Prince, K. M. Antony, J. Ma, and K. M. Aagaard, “The Microbiome and Development : A Mother ’ s Perspective,” Semin. Reprod. Med., vol. 77030, no. 212, pp. 14–22, 2014.