Is the womb sterile in uncomplicated pregnancies?

Recent studies have challenged the century-old notion that the human fetal environment is sterile and that the neonate's microbiome is acquired during and after birth. A recent study published in the Journal of Science Translational Medicine reported the presence of unique commensal placental microbiome from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla.

Research has shown that seeding of healthy microbiome at birth is crucial for human health in later life. Another study published in September issue of American Journal of Obstetrics and Gynecology does not support the existence of microbiomes within the healthy fetal milieu, and this concept of ‘sterile womb’ have implications in the development of practices like ‘vaginal seeding’ after cesarean births.

The researchers from Norway and Sweden randomly sampled amniotic fluid from study cohort of uncomplicated pregnancies at term from 1 of the three sites included in the Preventing Atopic Dermatitis and Allergies in children (PreventADALL) study. The amniotic fluid from 65 pregnancies was collected under sterile conditions, ten samples were from women undergoing elective, planned cesarean section and 14 were from women who had prior rupture of membranes.

Women with ruptured membranes have more than 10-fold higher concentration of prokaryotic DNA (16S rRNA) gene copies/mL. More than 50% samples of amniotic fluid from ruptured membranes cohort showed bacterial growth in anaerobic cultures, while all samples from women who had intact membranes were sterile.

The bacteria identified on culture were vaginal commensals and/ or intrauterine pathogens including Streptococcus agalactiae, Peptoniphilus harei/ asaccharolyticus, Lactobacillus reuteri/crispatus/vaginalis, and Prevotella amnii/bivia.

The authors concluded that in uncomplicated pregnancies, fetal development occurs in a sterile environment and fetal microbiome is seeded following rupture of membranes. Understanding the timing of the first microbial colonization in fetus could help the researchers in a better understanding of the origin of many diseases.

Abstract

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Endometrial microbiome plays a key role in implantation and pregnancy rates in IVF patients.

Clinical pearls:

• Different bacterial species were detected between vagina and endometrial cavity of the same subjects.
• The microbiota in the endometrial cavity is labelled as Lactobacillus-dominated microbiota (>90% Lactobacillus spp.) or a non-Lactobacillus-dominated microbiota (<90% Lactobacillus spp. with >10% of other bacteria). 
• The composition of endometrial microbiome is not regulated by the hormonal cycle and non-Lactobacillus-dominated microbiota during the receptivity phase correlates with significant decrease in implantation, on-going pregnancy, pregnancy and live birth rates. 

It has been believed since last 50 years that uterine cavity and endometrium is sterile and devoid of microbial habitat in the absence of infection. The sterile womb paradigm was coined by the French pediatrician Henry Tissier and postulated that human infants develop in a sterile environment. [1]

Recent advances in genomics and bioinformatics have led to identifying microbiota in many body organs that were previously thought to be sterile by use of 16S rRNA gene-based bacterial detection and identification techniques. By using this newer advances in microbiology it has been proved that upper genital tract harbors a distinct set of microbiome and is differs considerably in health and disease states.

A study published in the December issue of American journal of Obstetrics and Gynecology (ACOG)  by Moreno et al,[2] not only demonstrated that endometrium harbors microbes and endometrial microbiome has a lot in common with vaginal microbiome.  The study further demonstrated that like vaginal microbiome, the endometrial flora is also divided into Lactobacillus dominant (LD) and non-Lactobacillus dominant (NLD) communities.

The researchers obtained paired samples from vagina and endometrial cavity in 13 fertile women in both receptive and prereceptive phases of the same menstrual cycles. (n=52). To study the hormonal influence on endometrial microbiome during the preparation of endometrium for implantation samples of endometrial aspirate collected from 22 fertile women.

Finally, to study the impact of altered endometrial microbiome on reproduction, the endometrial aspirate was assessed by implantation, miscarriage, ongoing pregnancy, and live birth rates in 35 infertile women undergoing IVF by endometrial receptivity array (ERA).

The study results showed that:

Different bacterial species were detected between vagina and endometrial cavity of the same subjects.

The microbiota in the endometrial cavity is labelled as Lactobacillus-dominated microbiota (>90% Lactobacillus spp.) or a non-Lactobacillus-dominated microbiota (<90% Lactobacillus spp. with >10% of other bacteria). 

The composition of endometrial microbiome is not regulated by the hormonal cycle and non-Lactobacillus-dominated microbiota during the receptivity phase correlates with significant decrease in implantation, on-going pregnancy, pregnancy and live birth rates.

This pilot study has opened the doors for many basic, translational and clinical studies in future. It has also drawn our attention to the fact that reproductive success does not solely rely on endometrial histology and gene expression.

Linda C. Giudice, MD, PhD, Distinguished Professor and reproductive endocrinologist at the University of California San Francisco said in an accompanying editorial “The ongoing revolution in technology, science, multiple omics, and multidimensional data analysis has opened the window of implantation to a greater level of scrutiny. It is time to further investigate the endometrial microbiome and expand research to its virome, fungome, epigenome, and metabolome to increase our understanding the biology of this dynamic tissue and to develop targeted therapies of endometrial disorders that underlie infertility and poor pregnancy outcomes and affect women’s health more broadly. We are indeed on the threshold to transform clinical reproductive medicine and improve reproductive outcomes with precision and personalization for individual patients.”

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[1] https://www.ncbi.nlm.nih.gov/pubmed/23976878/ accessed on 8 December 2016

[2] Moreno, I., Codoñer, F.M., Vilella, F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016; 215: 684–703

Microbirthing: The " Vaginal Seeding" is growing fad, but thin evidence concerns physicians!

Every 4^th baby in UK is born by Caesarean Section. Parents of the Caesar babies are requesting a procedure called as ‘microbirthing’ or ‘vaginal seeding’.

Vaginal seeding involves taking a swab from mother’s vagina and swabbing it over babies face, eyes, mouth and skin immediately after caesarean birth.

This article is based on recent editorial in BMJ (BMJ 2016; 352:i227) by Cunnington A.J. et al “Vaginal seeding” of infants born by caesarean section. How should health professionals engage with this increasingly popular but unproved practice?

Our body is colonized with millions of microbes, collectively called as microbiota. They outnumber our cells by 10:1. The microbiota varies according to parts of our body and also person to person. As described by microbiology professor Graham Rook at University College London, we are designed to live in nature’s biodiverse ecosystem encountering our old microbial friends as part of our early immune education.

During the process of vaginal birth, specific species of good bacteria are transferred to the baby during and immediately after birth via the birth canal, immediate skin-to-skin contact and breastfeeding. This is the seeding of the baby's microbiome. The process heralds the training of baby’s immune system to recognize between ‘good’ and ‘bad’ bacteria and protect the neonate from diseases now and also in future.  Large epidemiological studies and reviews have concluded that babies delivered by C-section have moderately high risk of obesity, asthma, and autoimmune diseases, these  diseases being associated with alteration in microbiota.

For babies entering this world via a C-section, this microbial transfer from the mother to baby is interfered with or bypassed completely. According to the latest research if the baby is not seeded with mother’s bacteria, it can have significant health consequences. Dr Rodney R Dietert, Professor of Immunotoxicology at Cornell University says “Over the past 20-30 years, we've seen dramatic increases in childhood asthma, type 1 diabetes, coeliac disease, childhood obesity. We've also seen increases in Caesarean delivery. Does Caesarean cause these conditions? No. What Caesarean does is not allow the baby to be seeded with the microbes. The immune system doesn't mature, and the metabolism changes. It's the immune dysfunction and the changes in metabolism that we now know contribute to those diseases and conditions.”

So, many researchers advocate that even if vaginal birth is not possible, immediate skin to skin contact and breast feeding should be initiated.

A new documentary “MICROBIRTH” warns how our children are born could have serious repercussions for their lifelong health. “Microbirth” is a new sixty minute documentary looking at birth in a whole new way: through the lens of a microscope. Investigating the latest scientific research, the film reveals how we give birth could impact the lifelong health of our children. http://microbirth.com

In spite of all the hypotheses, we lack scientific proof at present. The newborn may be at risk of developing infection, being exposed to vaginal commensals that the mother maybe harboring without any symptoms. These include group B streptococcus (the most common cause of neonatal sepsis), herpes simplex virus, Chlamydia trachomatis, and Neisseria gonorrhoeae (the last two, causes of ophthalmia neonatorum). These pathogens may also be transferred on a vaginal swab, potentially voiding the protection offered by elective caesarean section.

Clinically we are aware of only one clinical trial going on, called as Potential Restoration of the Infant Microbiome (PRIME) trial. That study is expected to be completed in February, 2019.It is looking at the neonatal microbiota according to mode of birth, the women being screened beforehand for potential pathogens.

Dr. Cunnington, who is the lead author of the article, affirms the lack of sufficient evidence to put vaginal seeding into routine practice. Studies need to be sufficiently large, randomized and need follow up of many years before a recommendation can be made.  

In a statement Dr Cunnington says: "Demand for this process has increased among women attending hospitals in the UK - but this has outstripped professional awareness and guidance. At the moment we're a long way from having the evidence base to recommend this practice. There is simply no evidence to suggest it has benefits - and it may carry potential risks." He also believes in fully informing the risks and harm of this simple procedure to the patients who are demanding it.

He also emphasizes that there are other ways of   influencing baby’s microbiota at birth and “Encouraging breast feeding and avoiding unnecessary antibiotics may be much more important than worrying about transferring vaginal fluid on a swab.”

References:

http://www.criver.com/about-us/eureka/blog/april-2014/early-immune-education

http://articles.mercola.com/sites/articles/archive/2014/12/27/seeding-baby-microbiome.aspx

http://www.actionbioscience.org/genomics/the_human_microbiome.html

http://www.nytimes.com/2013/08/29/science/human-microbiome-may-be-seeded-before-birth.html?_r=0

http://www.huffingtonpost.co.uk/toni-harman/microbirth-babys-mircobiome_b_4947959.html

https://clinicaltrials.gov/show/NCT02407184?link_type=CLINTRIALGOV&access_num=NCT02407184