Researchers also confirmed that the fetal microbiome is transmitted from the mother. These findings open the door to potential interventions during pregnancy to stimulate the fetal microbiome when a premature birth is expected, to help the baby grow faster and be better equipped to tolerate early life infection risk. The study was published in the journal JCI Insight.
“Our study provides strong proof that a complex microbiome is transmitted from the mother to the fetus,” says senior author Patrick Seed, MD, PhD, Associate Chief Research Officer of Basic Sciences at Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago, and Research Professor of Pediatrics, Microbiology and Immunology at Northwestern University Feinberg School of Medicine.
“Unlike other studies relying only on next generation DNA sequencing, we validated our sequencing results with microscopy and culture techniques, to resolve a decades long controversy about the existence of a fetal microbiome.
Now we can pursue ways to boost the development of fetal immune system and metabolism by stimulating mom’s microbiome. Our findings point to many promising opportunities for much earlier intervention to prevent future disease.”
Now we can pursue ways to boost the development of fetal immune system and metabolism by stimulating mom’s microbiome. The image is in the public domain.
The human microbiome is estimated to consist of over a trillion bacteria in a single person, with 10 times the number of microbial cells to every human cell.
Research has established that specific microbiome characteristics play causal roles in obesity, allergy, asthma, diabetes, autoimmune disease, depression and a variety of cancers.
“Establishing a dynamic microbiome in the fetus leads us to suspect that controlled exposure to microbes trains the developing immune system and metabolism,” says Dr. Seed. “We need more research to better understand the mechanisms involved and how we can intervene to improve children’s health at the start of life and beyond.”
Living on and within each person are complex ecological communities of microbes, or microbiota (Turnbaugh et al., 2007). Consisting of bacteria, fungi, and archaea, these microbiota live in relative symbiotic harmony with their hosts.
The collective genomes of these microbes are known as the microbiome. Scientists now understand that each person’s unique collection of traits are actually the result of complex interactions between human and microbiota processes, creating one composite, ‘human supraorganism’ (See table 1).
The symbiotic relationship between humans and microbes has evolved over millions of years, allowing each to thrive in their biophysical environment. Rapid changes in human lifestyles over the past 100 years, including profound alterations in modern-day birthing practices (Epstein, 2010), have the potential to transform our microbiome with unknown implications for health and predisposition to disease (Cho & Blaser, 2012).
Definitions of Commonly Used Terms
|Human microbiome: the collective genomes of the microbiota (composed of bacteria, bacteriophage, fungi, protozoa and viruses) that live inside and on the human body|
|Genomes: the complete set of genetic material present in a cell or organism.|
|Microbiota: the community of commensal, symbiotic and pathogenic microorganisms that share our body space|
|Species diversity: the number of species present and the abundance of each within a select body site|
The first major microbial colonization of newborns occurs at birth, when newborns are ‘seeded’ with their mothers’ microbiota (Backhed et al., 2015). Medicalization of birth in many developed nations has changed the quality and quantity of contact between mothers and babies, altering this initial microbiome composition and formation (Backhed et al., 2015; Epstein, 2010).
The newest evidence on factors in the labor and birth environment (e.g. route of birth, vaginal exam frequency, antibiotic use) that may influence the maternal and newborn microbiome, and identify relevant practice implications and considerations for labor and birth nurses is presented.
Colonization and establishment of the newborn microbiome is a process that likely begins prior to birth, as microbes have been isolated from the placenta, fetal membranes, amniotic fluid, and umbilical cord blood (Aagaard et al., 2014; Oh et al., 2010). Although traditionally the intrauterine environment has been considered sterile, a recent study investigating the microbial composition of placental basal plates (peripheral surface of the placenta on the maternal side) identified both gram positive and gram negative bacteria in 54% of those giving birth preterm and 26% of those giving birth at term (Stout et al., 2013).
Similarly, Aagaard et al. (2014) sequenced the bacterial species of placentas following normal term pregnancies and found a variety of bacteria in low abundance including Escherichia coli, Prevotella tannerae, and Bacteroidetes, suggesting that the placenta may harbor its own commensal flora.
Although the presence of bacteria in the intrauterine environment has traditionally been associated with perinatal complications such as preterm birth, (Gregory, 2011), future research is needed to explore the function of this newly discovered microbiome, its role in perinatal health processes, and the initial establishment of the newborn microbiome.
The mechanisms by which bacteria translocate into the intrauterine cavity are not yet clear. Several theories have been proposed including hematogenous translocation from the oral cavity and gastrointestinal (GI) tract, supported by the finding that non-pathogenic microbiota similar to those found in the oral cavity (e.g. Firmicutes, Proteobacteria) and GI tract (e.g. Enterococcus, Streptococcus) have been isolated from the placenta and amniotic cavity (DiGiulio, 2012; Solt, 2015).
Vaginal microbes have also been isolated in intrauterine samples (Witkin, 2014) suggesting that organisms from the vagina may ascend into the intrauterine cavity from the vaginal canal. Further research is needed to explore a potential prenatal maternal-fetal exchange of microbes.
The gut and vaginal microbiomes are the primary sources from which the initial transfer of microbes to the newborn is likely to occur, and research suggests that pregnancy may influence these maternal microbiome environments (Nuriel-Ohayon, Neuman, & Koren, 2016).
A recent study of 24 pregnant women between 18 and 40 weeks sought to characterize the composition and dynamics of the vaginal microbiome during pregnancy and found that species diversity and richness decreased throughout pregnancy with an overall dominance of Lactobacillus species as well as Clostridiales, Bacteroidales, and Actinomycetales orders (Aagaard et al,. 2012).
These findings suggest that the microbiome signature of pregnancy is dynamic and changes throughout gestation although the factors that promote such changes are not yet fully understood (Aagaard et al., 2012).
Gut microbiota in pregnant women with gestational diabetes also appear to change significantly across gestation, with an increased abundance of disease associated microbes including Actinobacteria and Proteobacteria in the third trimester (Koren et al., 2012). Germ-free mice, when inoculated with these third trimester bacterial samples, demonstrated a greater presence of inflammation, increased fat storage, and insulin resistance (Koren et al., 2012).
It is possible that gestational changes in the microbiome may occur as a natural mechanism to prepare for the initial transfer of microbes to newborns. This transfer of microbes from mother to newborn may have implications on the transition of newborns to the extrauterine environment. Much more research, however, is needed to understand the physiologic role of microbes during gestation and its impact on nursing care practices for women and newborns.
Implications of Route of Birth
Vaginal birth remains the most common method of birth and is achieved by 68% of women in the United States (Martin, Hamilton, Osterman, Driscoll, & Mathews, 2017).
The vaginal microbiome is a mutualistic environment of organisms that are dependent on environmental conditions and host factors that promote homeostasis in the vagina and inhibit growth of bacteria that have been associated with preterm labor and chorioamnionitis (Hyman et al., 2014).
Lactobacillus spp. dominate the vaginal landscape and inhibit the growth of pathogenic bacteria by creating an acidic environment and competing for nutrients (Huang, Fettweis, Brooks, Jefferson, Buck, 2014). Additionally, periodic hormonal cycles and continual sloughing of epithelial cells contribute to the maintenance of healthy vaginal flora.
Vaginal bacterial communities differ by ethnic group. A study of 1290 women identified significantly different microbiome profiles between African American women and women of European ancestry (Huang, 2014).
Specifically, African American women demonstrated a higher pH, greater variety of vaginal genus-level profiles dominated by anaerobic species, and smaller communities of protective species specifically lactobacilli (Huang, 2014).
Lactobacilli produce an acidic vaginal environment, a protective factor for development of potentially harmful organisms in the vagina.
A vaginal microbiome with a higher pH and greater diversity of anaerobic species also contributes to a higher incidence of sexually transmitted infections and growth of other organisms associated with adverse pregnancy outcomes including preterm birth (Huang, 2014; Dunlop et al, 2015).
Children born via cesarean compared to those born vaginally are more likely to develop immune-related disorders like asthma/allergies (Black, Bhattacharya, Philip, Norman, & McLernon, 2016; Kristensen & Henriksen, 2016), inflammatory bowel disease (Kristensen & Henriksen, 2016), and obesity (Bernardi et al., 2015; Li, Zhou, & Liu, 2013; Mueller et al., 2015).
Although not all of these associations are shown consistently in all studies (Bernstein et al., 2016; Black et al., 2016), these findings have led some researchers to speculate that alterations in microbiome seeding of newborns following cesarean birth may play some role in these associations between chronic disease and route of birth (Dominguez-Bello et al., 2016; Goedert, Hua, Yu, & Shi, 2014).
Adults born via cesarean birth have fecal microbiome/microbiota that are distinctly different than those of adults born vaginally (Goedert et al., 2014). Cesarean birth results in a gut microbiome that is less similar to that of the mother compared to vaginal birth (Backhed et al., 2015), and is more likely to include skin and oral microbes, and bacteria from the operating room (Backhed et al., 2015).
It appears that any contact between the unborn fetus and the mothers’ vaginal microbiome (for example, through rupture of membranes in labor) results in early microbial seeding and potential long-term health benefits for the newborn.
In a study of 18 maternal/newborn dyads, the microbiome of mothers and babies in three groups were compared: newborns born vaginally, newborns born via cesarean with standard post-op treatment, and newborns born via cesarean who were exposed to maternal vaginal fluids immediately following birth (Dominguez-Bello et al., 2016).
Within two minutes of birth, newborns in the last group had their mouth, face, and body swabbed with a gauze pad that had been incubated for an hour in their mothers’ vagina. These gut, oral, and skin microbiome of these newborns were more similar to vaginally-born newborns than to other newborns who experienced the standard cesarean birth. This similarity persisted through one month of life, when the study ended.
These findings are consistent with population-based studies showing that children born via elective cesarean birth (no labor) are at higher risk for health problems like asthma compared to children who had some exposure to their mother’s vaginal microbiome during labor, even if labor ended in cesarean (Kristensen & Henriksen, 2016).
Cesarean birth as currently practiced in most hospitals in the United States has additional implications on neonatal microbiome seeding. In conventional cesarean birth practices, newborns do not experience skin-to-skin with their mother until several hours following birth, during which time the newborn is handled by healthcare providers, receives a bath, and touches various operating room and recovery room surfaces.
Family-centered cesarean birth, or skin-to-skin cesarean birth, is a new option that involves immediate skin-to-skin contact between the newborn and mother in surgery. However, this new cesarean protocol has not been widely adopted in hospitals due to safety concerns around the mother’s ability to hold her newborn while on an operating room table and concerns related to postpartum hemorrhage and infection (Posthuma et al., 2016).
In a recent study comparing conventional cesarean birth to skin-to-skin cesarean birth, investigators did not see increases in either of these adverse outcomes, but did find that skin-to-skin treatment was associated with a decrease in both neonatal admission to the neonatal nursery and neonatal work-ups for infection (Posthuma et al., 2016).
Another implication of cesarean birth on neonatal microbiome seeding is early exposure to antibiotics in women having cesarean. Almost all women having cesarean birth receive intrapartum antibiotics to decrease their risk of post-operative infection (Smaill & Grivell, 2014).
These powerful intravenous antibiotics are quickly transmitted to the fetus through the placenta, and are thus in active circulation in both mother and newborn at time of birth, with unknown implications on microbiota transfer.
Cesarean birth may also influence the neonatal microbiome seeding process via delayed breastfeeding initiation. Compared to newborns born vaginally, newborns born via cesarean are nearly half as likely to initiate breastfeeding before hospital discharge (Prior et al., 2012) and are more likely to have breastfeeding difficulties (Karlstrom, Lindgren, & Hildingsson, 2013).
Thus, microbiota transmission via breastfeeding is delayed or eliminated in many cesarean-born babies. Antibiotics given to almost all women having cesarean birth lower the counts in breastmilk of Bifidobacterium species, which are known to prevent infection and provide anticarcinogenic capabilities to the newborn (Quigley, O’Sullivan, Stanton, et al 2013). Therefore, cesarean birth appears to decrease both the quantity and quality of human breastmilk, limiting an essential source of new microbial communities for the newborn.
Cesarean birth more often results in separation of the mother and newborn for several hours following birth with implications for neonatal microbiota seeding. Planned cesarean birth is associated with nearly twice the rate of newborn transfers to the neonatal intensive care unit and diagnosis of pulmonary disorders like transient tachypnea of the newborn as planned vaginal birth (Kolas, Saugstad, Daltveit, Nilsen, & Oian, 2006).
Although typically these problems do not involve long-term nursery stays, this early exposure of newborns born via cesarean birth to nursery environments instead of maternal-focused environments potentially increases the influence of cesarean mode of birth on optimal early newborn microbiota formation.
Ann & Robert H. Lurie Children’s Hospital of Chicago
Vita Lerman – Ann & Robert H. Lurie Children’s Hospital of Chicago
The image is in the public domain.
Original Research: Open access
“Fetal exposure to the maternal microbiota in humans and mice”. Patrick Seed et al.
JCI Insight doi:10.1172/jci.insight.127806.