Science Proves That Vaginal Wash From Mother Starts the Creation of Baby's Immune System

Clin Perinatol. Author manuscript; available in PMC 2012 Jun 1.

Published in final edited form as:

PMCID: PMC3110651

NIHMSID: NIHMS284291

Cesarean versus Vaginal Delivery: Long term infant outcomes and the Hygiene Hypothesis

Josef Neu

^a Professor of Pediatrics, Sectionalization of Neonatology, University of Florida; Gainesville, Florida

^b Director, Neonatology Fellowship Training Program, University of Florida, Gainesville, Florida

Jona Rushing

^c Young man, Department of Obstetrics and Gynecology, Segmentation of Maternal Fetal Medicine, University of Florida, Gainesville, Florida

Keywords: microbiota, mode of commitment, hygiene hypothesis

INTRODUCTION

In the United States the rate of cesarean delivery (CD) has risen 48% since 1996, reaching a level of 31.viii% in 2007. ¹ This tendency is reflected in many parts of the world, with the well-nigh populous state in the earth, China, approaching l%² and some private clinics in Brazil budgeted fourscore% ³. While a pregnant number of CD are preformed for obstetrical indications, some are simply due to maternal request and may incur several risks for the child. Well known among these risks are neonatal low due to general anesthesia, fetal injury during hysterotomy and/or delivery, increased likelihood of respiratory distress even at term, and breastfeeding complications. Concurrent with the trend of increasing CD, there has been an epidemic of both autoimmune diseases such every bit blazon i diabetes, Crohn's disease, and multiple sclerosis and allergic diseases, such every bit asthma, allergic rhinitis, and atopic dermatitis^{four , 5}. The occurrence of these diseases is higher in more than affluent, Western, industrialized countries. Several theories have emerged that suggest environmental influences are contributing to this phenomenon. Most notably, the "hygiene hypothesis" suggests that an overly clean surroundings, especially in early on childhood, may contribute to the development of several babyhood diseases. It was first proposed by Strachan, who observed an inverse correlation between hay fever and the number of older siblings. ^half-dozen This was subsequently extended by others from the allergies to autoimmune diseases such as type 1 diabetes. ^v Whether the increase in CD incidence is also causally related will exist addressed in this review.

The interplay between the emerging microbial ecology of the gastrointestinal tract and the developing mucosal immune organization serves equally a backdrop for a relationship between CD and the emergence of some of these diseases. With the highly immunoreactive intestine serving as the largest surface area of the body that is exposed to the environment, especially a vast array of luminal microbes and antigens, it is intriguing to speculate that the intestinal ecology interaction during early development of the immune system may relate to these diseases. One intriguing component of this relates to the early development of the intestinal microbiota, the developing immune system and the early influence of cesarean versus vaginal delivery (VD) on these phenomena. The immune arrangement undergoes major development during infancy and is highly related to the microbes that colonize the intestinal tract.^{7 - 9} It has been suggested that dissimilar initial exposures depend on mode of delivery (VD vs. CD). The microbes that "seed' the intestine during either CD or VD may pb to changes in long term colonization and subsequent altering of allowed development (Fig. 1). Here we will provide background nigh the human microbiota, its relationship to the developing allowed system, and the relationship of way of delivery on the colonization of the infant intestine, development of the allowed system, and subsequent babyhood allergies, asthma and autoimmune diseases.

THE Human MICROBIOTA

The human torso, consisting of about 100 trillion cells, carries about ten times as many microorganisms in the intestines. ^{10 - 12} Information technology is estimated that these gut flora have effectually 100 times as many genes in amass every bit in that location are in the man genome.^xiii The metabolic activities performed by these bacteria resemble those of an organ, leading some to liken gut bacteria to a "forgotten" organ. ¹² Microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful, pathogenic leaner, regulating the evolution of the gut, and producing vitamins for the host (such equally biotin and vitamin K). ¹⁴ Excitement about the potential of harnessing the intestinal microbiota for therapeutic purposes and health is reflected by the popularity of pro- and prebiotics and fifty-fifty such seemingly esoteric therapies as human fecal transplantation. ^fifteen

Not all the species in the gut accept been identified because nearly cannot be cultured, ^ten and identification is difficult. An effort to improve describe the microflora of the gut and other body locations using newly developed not-culture based technologies^xvi has been initiated and termed the "Man Microbiome Projection"¹⁷. This project has a mission of generating resources enabling comprehensive characterization of the human microbiota and analysis of its role in human wellness and disease. Although the human intestine is the site where most studies are being focused, other sites such as the skin, bladder, oral cavity and vagina harbor distinct microbial populations and are likely to as well play major roles in wellness and disease¹⁶.

INTESTINAL MICROECOLOGY OF THE FETUS AND NEWBORN

Almost current literature suggests that the gastrointestinal tract of a normal fetus is sterile. During nativity and chop-chop thereafter, bacteria from the mother and the surrounding surround colonize the baby's gut. It is obvious that exposure at nativity would differ by fashion of delivery. What long term sequelae or touch on this difference in exposure may have on the child has yet to be adamant.

Some recent research work suggests colonization may begin even earlier. While the paradigm has been that babies' intestines are sterile until birth, recent work found a microbial community already domicile in the meconium of some babies born prematurely.¹⁸ It has as well been shown that amniotic fluid of mothers with preterm labor contains a large and diverse spectrum of bacterial rDNA. ²⁰ While a baby is in utero, it typically swallows 400 to 500 milliliters of amniotic fluid per twenty-four hour period at term, and the hypothesis that intra-amniotic infection is the driving force behind preterm labor is one beingness widely studied in obstetrics.^nineteen Whether the microbes or microbial components swallowed in the amniotic fluid stimulate an inflammatory response driving preterm birth remains to be evaluated. The effect these organisms have on the developing immune organisation, aside from their role in preterm labor, also raises interesting questions.

Currently, very few studies have investigated the development of the human being microbiota subsequently birth using non-culture based techniques. In a step toward greater systematic investigation of babies built-in at term, Palmer et al.²¹ evaluated the developing microbiota of infants during the outset year after birth using microarray techniques to discover and quantify the small subunit ribosomal RNA (SSU rRNA) gene sequences of near currently recognized species and taxonomic groups of bacteria; this was washed along with sequencing of cloned libraries of PCR-amplified SSU rDNAto profile the microbial communities in fourteen salubrious full-term infants during the first year after nascence. To investigate possible origins of the baby microbiota, the researchers too profiled vaginal and milk samples from nearly of the mothers besides as stool samples from all of the mothers, most of the fathers, and two siblings. The investigators found that the limerick and temporal patterns of the microbial communities varied widely from baby to babe, just the distinct features of each baby's microbial customs were recognizable for intervals of weeks to months. The strikingly parallel temporal patterns from a set of dizygotic twins suggested that incidental environmental exposures play a major function in determining the distinctive characteristics of the microbial community in each babe. Past the end of the first year of life, microbial ecosystems in each baby, although even so distinct, had converged toward a profile characteristic of the adult gastrointestinal tract. Of involvement, Bifidobacteria were not found in these infants using these techniques. This could be highly significant in that information technology may debunk the big amount of attention this microbe has received equally a potentially important microbe that may be harnessed as a probiotic. On the other hand, this could be a technical problem that nonetheless needs to exist solved using these newly developed methodologies.

Although a few studies accept monitored the bacterial communities in preterm infants, our picture of the intestinal microbiota nonetheless remains limited. To make up one's mind whether noncultured bacteria represent an important function of the community in premature babies' abdominal ecosystems, Magne et al.²² used 16S rRNA genes and PCR-based electrophoretic profiling of 288 clones obtained from the fecal samples of 16 preterm infants. These were classified into 25 molecular species. The mean number of molecular species per babe was 3.25 and ranged from i to eight. The researchers found loftier interindividual variability. The main bacterial groups encountered belonged to the Enterobacteriaceae family unit and the genera Enterococcus, Streptococcus, and Staphylococcus. The preterm infants were colonized by anaerobes and only four bifidobacteria (again seeming to minimize these taxa during evolution). The researchers did not determine the relative impacts of commitment fashion, sex, gestational age, birth weight, age at sampling, feeding modes, and antibiotic therapies. They concluded that species diversity was low and interindividual variability was high in the feces of preterm infants, every bit revealed by sequences of 16S rRNA genes and PCR-temporal temperature gradient gel electrophoresis profiles (TGGE). The intestinal ecosystem of these preterm infants had no typical characteristic.

In summary, whether the fetal intestinal ecosystem is sterile at the time of nascency remains a question. This may be the instance in some infants, merely non necessarily in others, especially preterms. This may in plough play a role in the initiation of preterm labor. Nevertheless, the species diversity does announced to be low in most infants shortly after birth, merely this increases with environmental exposure. Very petty is currently known virtually the specific emergence of the microbial ecology of infants during the first year afterward birth and how this specifically relates to development of immunity and subsequent health and affliction.

FUNCTIONS OF THE INTESTINAL MICROBIOTA

A comprehensive review of the functions of the intestinal microbiota is beyond the scope of this review, but here we wish to focus on the immunologic functions because of their importance in development of the immune organization and possible pathogenesis of several known allergic and autoimmune diseases. Intestinal bacteria are primal in promoting the early development of the gut's mucosal immune arrangement, both in terms of its physical components and office and proceed to play a role afterwards in life in its operation. The bacteria stimulate the lymphoid tissue associated with the gut mucosa to produce antibodies to pathogens. The immune system recognizes and fights harmful bacteria, but leaves the helpful species alone, a tolerance developed in infancy, and sometimes termed the "old friends" hypothesis. ²³ (Figure 2) This hypothesis appears to exist a synthesis of the hygiene hypothesis that proposes that the office of these microorganisms that have evolve with humans provide an essential function in the establishment of the immune organization wherein the microorganisms and the host have evolved a co-dependence: the virtually relevant organisms are those that co-evolved with mammals. These microorganisms are interacting with other modern environmental changes that likewise pb to enhanced inflammatory responses such as inappropriate nutrition, obesity, psychological stress, vitamin D deficiency, pollution (dioxins), and perhaps even cesarean commitment. The range of chronic inflammatory disorders that is afflicted is potentially larger than usually assumed and include allergies, autoimmunity, inflammatory bowel disease, but also vascular disease, some cancers, depression/anxiety and perhaps neurodegenerative disorders and type 2 diabetes.

"The Onetime Friends Hypothesis"

Common organisms interact with dendritic cells in the GI tract, leading to increased maturation of dendritic cells. When in that location is interaction with these organisms once more, the dendritic cells increase Treg maturation; not Th1 or Th2. This increases the baseline amount of anti-inflammatory cytokines, producing a Bystander Suppression. Another effect of the increased number of mature dendritic cells is as they interact with self antigens, they increment the number Treg specific to these antigens. This is referred to as Specific Suppression. Together these two arms lead to tolerance of both cocky antigens also as those of helpful gut organisms.

Basic laboratory based research is supplementing the epidemiologic studies. Recent findings accept shown that gut bacteria play a role in the expression of Toll-similar receptors (TLRs) in the intestines. TLRs are 1 of the two classes of pattern recognition receptors (PRR) that provide the intestine the ability to discriminate between pathogenic and commensal bacteria. These PRRs identify the pathogens that have crossed the mucosal barrier and trigger a set up of responses that accept action confronting the pathogen, involving 3 main immunosensory cells: surface enterocytes, M cells and dendritic cells.²⁴ The other class of PRRs are known as the nucleotide-binding oligomerization domain/caspase recruitment domain isoforms (NOD/Card), which are cytoplasmic proteins that recognize endogenous or microbial molecules or stress responses and form oligomers that actuate inflammatory caspases. This would result in the cleavage and activation of important inflammatory cytokines and/or activate the NF-κB signaling pathway to induce the product of inflammatory molecules. ²⁴

Bacteria can influence the miracle known as oral tolerance, in which the immune system is less sensitive to an antigen (including those produced by gut bacteria) once it has been ingested. This tolerance, mediated in part by the gastrointestinal allowed arrangement and in part by the liver, tin can reduce overreactive immune responses like those found in allergies and machine-allowed disease.²⁵

There are several antenatal and perinatal events that might too affect the evolution of the intestinal microbial ecology. Therapy with wide-spectrum antibiotics is a mutual practice for mothers who go into premature labor or who have a CD. This treatment tin reduce the biodiversity of the fecal microbiota and may be a cistron in the cause of necrotizing enterocolitis. ^{26 , 27} Studies in mice show that intestinal commensal microbiota have an influence on early on postnatal allowed development via interactions with abdominal Price like receptors, which in turn are likely to influence the evolution of the mucosal immune system and mucosal-related diseases.²⁸ Other studies suggest that specific microbes may induce regulatory T-cell evolution. For case, a prominent human commensal, Bacteroides fragilis, directs the development of Foxp3(+) regulatory T cells (Tregs) with a unique "inducible" genetic signature. ²⁹ Monocolonization of germ-gratis animals with B. fragilis increases the suppressive chapters of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3(+) T cells in the gut. This consequence appears to be mediated past an immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis, which mediates the conversion of CD4(+) T cells into Foxp3(+) Treg cells that produce IL-10 during commensal colonization. Functional Foxp3(+) Treg cells are as well produced past PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg consecration and IL-10 expression. These studies as well show that PSA is not only able to forbid, only also cure experimental colitis in animals and therefore demonstrate that B. fragilis Treg lineage differentiation pathway in the gut to actively induce mucosal tolerance.²⁹

VAGINAL VS. CESAREAN DELIVERY

During vaginal delivery, the contact with the maternal vaginal and abdominal flora is an of import source for the start of the babe's colonization. During CD, this straight contact is absent, and non-maternally derived environmental bacteria play an important role for infants' intestinal colonization.³¹ Some authors have suggested that the composition of the very first human microbiota could have long lasting effects on the intestine in breast fed infants. For example, Gronlund, et al ³² showed that the master gut flora in infants born by cesarean delivery may be disturbed for upwardly to half dozen months after nascency. Another study using culture based techniques showed that the way of delivery was associated with differences in abdominal microbes 7 years later delivery. ³³ The clinical relevance of these changes is unknown, and even longer follow-upward is needed to establish how long-lasting these alterations of the primary gut flora tin can be.

Nevertheless, there is accumulating show that abdominal bacteria play an important part in the postnatal evolution of the allowed system. ³⁰ Thus, if the intestinal flora develops differently depending on the way of delivery, the postnatal development of the immune organisation might also be different. Available epidemiological information testify that atopic diseases announced more than often in infants later on cesarean delivery than after vaginal delivery.^{34 - 37} The composition of enteric microbiota in early days of life seems, therefore, to be a very of import factor for achieving and maintaining good wellness in the years to come up. Information technology follows that it is cardinal to identify more thoroughly the abdominal ecosystem of the newborn.

Although there is an increasing body of testify that the intestinal microbiota play an essential role in the postnatal development of the immune system, the mechanisms remain poorly understood. Malamitsi-Puchner et al.³⁸ constitute that only vaginal delivery promotes the product of diverse cytokines implicated in neonatal immunity. Hallstrom et al. ³⁹ constitute a link between cesarean delivery, disturbed abdominal colonization, and, possibly, occurrence of necrotizing enterocolitis (NEC) in preterm infants. Although the epidemiological studies demonstrated that constituent cesarean commitment provides an increased risk for allergic diseases in later babyhood, confounding factors could too play intermediate roles. Data bachelor from several studies indicate a delayed onset of lactation with cesarean section.^{xl , 41} Thus, many infants born by cesarean commitment also lacked the early back up of breast milk every bit stimulator for a physiological intestinal flora. Both the nonphysiological commencement of colonization and the missing early dietary support by delayed offset of lactation might result in these long-lasting effects.

Babies are born with immunological tolerance that is instructed by the mother past preferential consecration of regulatory T lymphocytes⁴², which might allow the baby to go colonized past this showtime inoculum. The mechanism is via substantial numbers of maternal cells crossing the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal anti-maternal immunity and persist at to the lowest degree until early machismo. However, but a subset (if any) of the microbes to which the newborn is initially exposed will permanently colonize bachelor niches and contribute to the distinctive microbiota harbored past the body habitats of adults. ²¹ As more and more deliveries featherbed the vagina, babies may not exist exposed to these microbes at nativity. Differences in commitment mode have been linked with differences in the intestinal microbiota of babies.^{31 , 32 , 43 , 44} Initial communities may serve equally a direct source of protective or pathogenic bacteria very early on in life.

Another contempo study⁴⁵, offers a detailed look at the early on stages of the body's colonization by microbes. Babies born vaginally were colonized predominantly by Lactobacillus, whereas cesarean delivery babies were colonized by a mixture of potentially pathogenic bacteria typically found on the peel and in hospitals, such as Staphylococcus and Acinetobacter, suggesting babies born by CD were colonized with pare flora in lieu of traditionally vaginal type of bacterium.

The outcome of way of delivery on development of babyhood disease has but recently begun to be explored (Table 1). The effect appears to be most robust in the area of immune mediated diseases. CD has been associated with a significant increased rate of asthma, particularly in females, and allergic rhinitis, merely non atopic dermatitis.⁴⁶ This increase was even more apparent when accounting for the factors surrounding the CD. The take chances of asthma was increased by 60% in females who underwent a repeat cesarean without ruptured membranes versus those babies with ruptured membranes and/or labor prior to CD.⁴⁶

Tabular array 1

Cesarean Delivery Associated Childhood Diseasesi , 2
Allergic Rhinitis
All Cesareans	one.37 (1.14-1.63)
Echo Cesareans Only	1.78 (1.34-2.37)
Asthma
All Cesareans	1.24 (1.01-one.53)
Female	1.53 (1.10-2.10)
Female & Repeat Cesarean three	one.83 (1.13-ii.97)
Celiac Illness	1.eighty (1.13-2.88)
Diabetes Mellitus (Type one)	1.19 (1.04-ane.36)
Gastroenteritis 4	ane.31 (1.24-ane.38)
Gastroenteritis AND Asthma	1.74 (one.36-two.23)

Children born past CD are likewise significantly more likely to suffer from celiac affliction and to be hospitalized for gastroenteritis.⁴⁷ No association has been establish between CD and Crohn'south affliction or ulcerative colitis. However, while preterm nascence has been implicated in the evolution of inflammatory bowel disease, style of delivery has not ⁴⁸

Type I Diabetes Mellitus has been on the rise in recent decades, mirroring the rise in CD.⁴⁹ Meta-analysis found a xix% increase in Blazon I DM in cesarean children when controlling for confounders such as gestational age, maternal age, and nascency weight. ^fifty A recent retrospective written report of children in Scotland failed to evidence such an association. ⁵¹ However, it is important to bespeak out that the Scotland study had a very small number of subjects (n=361) compared to the meta-analysis (due north=9938) and the charge per unit of CD was simply fourteen% in the Scottish study (much below the U.s. boilerplate).

SUMMARY AND CONCLUSIONS

While CD is necessary in modern obstetrics, the process appears to shift a baby'due south kickoff bacterial customs. A better agreement of this early colonization, which is besides influenced by events such as breast-feeding, may atomic number 82 to medical practices for establishing healthy bacterial colonization. The causal relationship betwixt CD, the shift in microbiota and many babyhood diseases continues to be studied. Yet, in that location are several issues with the studies we accept reviewed here.

Information technology is impossible to lump CD into ane category without delineating the indication for CD. It stands to reason that a fetus delivered subsequently abort at 8 centimeters dilation after a long labor would be exposed to a much dissimilar microbial environment than a fetus that undergoes CD for maternal request prior to rupture of membranes. Information technology is naïve to call up that the fetus is but exposed to microbes every bit the head passes through the vaginal introitus onto the perineum and to ignore the constant exposure to vaginal flora after rupture of membranes. Sonntag et al ⁴⁸ failed to show a relationship between manner of delivery and inflammatory bowel disease. However, the boilerplate age of a subject in this study was 42 years old. Indication for CD in the late 1960'southward, prior to common use of external fetal monitoring, is strikingly different than modern obstetrical indications. The intrapartum exposures of these subjects is most probable vastly different than a more than gimmicky cohort. Future studies must be more meticulous in categorizing CD to fully understand the effect of CD on colonization and childhood disease.

The part of antepartum and intrapartum antibiotics must besides be accounted for in hereafter studies. What consequence, if any, these take on the microbiota of the fetus and/or subsequent development of disease is unknown. Nigh 20% of women in the United states are colonized with Group B Streptococcus and will subsequently receive intrapartum antibiotics. Standard of care also dictates that antibiotics be administered prior to cesarean delivery and to mothers in preterm labor and/or with premature prolonged rupture of membranes. Given all of this, the exposure to antenatal antibiotics is significant. Dominguez-Bello ⁴⁵ noted a divergence in fetal colonization based on mode of delivery. Nevertheless, none of their vaginally delivered patients received antibiotics and the cesarean cases received cephalosporin "several hours" prior to incision which is non the recommended grade in the United states. Whether this exposure accounts for the deviation, or if fetuses who receive antibiotics per standard guidelines in the The states show a unlike colonization pattern, is an important research surface area to explore.

The link between mode of commitment and subsequent childhood pathology is an important one. This becomes even more important as maternal want for primary cesarean commitment is on the rising and rates of vaginal nascency after cesarean (VBAC) are failing in this country. This new information about colonization differences with differing modes of commitment seems to be taking the hygiene hypothesis to an entirely new level.

Footnotes

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110651/

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