By Anne M. Estes, PhD, Illustrations by Cara Gibson, PhD

In recent years, there has been much discussion about the impact of our high cesarean rate and downstream affects on the baby, short and long and term. Dr. Maria Dominguez-Bello and her colleagues have been leading the way in attempting to determine if "seeding" the cesarean delivered newborn's microbiome with the parent's vaginal microbiome. Today, Dr. Dominguez-Bello released a paper showing promise in understanding microbiome transmission in newborns. Regular contributor, Dr. Anne M. Estes reviews this just published research and helps both professionals and consumers to understand the potential impact and these new findings. What are you currently telling families about this nascent idea when you discuss this? - Sharon Muza, Community Manager, Science & Sensibility.

Study findings: Swabbing an infant born via cesarean section with a gauze incubated in mother's vagina prior to surgery transfers a portion of the vaginal microbiome to the infant.

Conducting a "vaginal microbiome transfer" by swabbing cesarean section delivered infants with vaginal fluids may transfer the maternal vaginal bacteria that infants would normally acquire during vaginal birth to a c-section baby. The initial results of a small, four infants, "proof of principle" experiment (a proof of principle study is where a small scale study is conducted to determine that an idea works before beginning a larger scale study) released today in Nature Medicine by Dr. Maria Gloria Dominguez-Bello and colleagues demonstrates partial microbiome transfer from a gauze incubated in the mother's vagina to the c-section infant [1]. The microbiome transferred is maintained in and on the infant throughout the first 30 days of life. This work is a step-forward in transmitting the vaginal microbiome to c-section infants; however, much remains to be done before this practice is routinely implemented widespread clinically.

Concerns with Cesarean Sections

Babies delivered via c-section are more likely to have non-communicable diseases such as diabetes, allergies, asthma, and obesity, than vaginally born infants [2]. Why infants born via c-section are more likely to have these health issues is unknown. Birth is a complex activity, with many physiological changes occurring over a period of time. One hypothesis is that c-section babies do not receive beneficial microbes from the vagina during birth as do vaginally born babies [3, 4].

Infants acquire bacteria quickly upon leaving the womb. The microbiome of vaginally born infants are most similar to the vaginal microbiome of their mothers. In contrast, the microbiome of c-section infants is most similar to that of skin bacteria [5-7] and bacteria found in the delivery room[8]. This difference in the microbiome persists over time [5-7], including into adulthood [9], and may influence immune system development. Colonization of the appropriate microbes for a given host at the appropriate time seems to educate the baby's immune system to distinguish between pathogens and foreign matter and non-threatening substances. Many of these non-communicable diseases are diseases of inflammation and autoimmune issues where the immune system is unnecessarily activated. Thus, colonization with microbes from the mother may be important.

Can we inoculate c-section babies with vaginal microbes?

To determine if the vaginal microbiome could be transferred to a c-section delivered infant, an 8 cm x 8 cm square of sterile gauze was folded into a fan shape and then folded in half and inserted in the vagina (Figure 1, Left) [1]. Unlike Europe, in the U.S., antibiotics are given prophylactically 1 hour prior to performing a c-section. Gauze was inserted in the vagina when antibiotics were given. Immediately after birth, the infant's mouth, face, and the rest of the body was swabbed with the vaginal secretion-soaked gauze (Figure 1, right). Microbiome samples were taken at several body sites of the mother and infant, including skin, anus (representing digestive system microbiome), and oral. Body site samples were compared to each other and that of the gauze to determine if bacteria were transmitted from vaginal fluids to the infants.

Figure 1. Vaginal Microbiome Transfer preparation. (L) Folded saline-moistened sterile gauze incubates within the mother for ~ 1 hr for colonization by vaginal flora. (R) At birth, microbiome colonized gauze is applied to the infant's face and body.

Dominguez-Bello and her colleagues found that the microbiome of infants swabbed with the vaginal-fluid soaked gauze were more similar to their mothers and to vaginally born infants than unswabbed c-section infants. Antibiotic use did not seem to alter the vaginal communities of mothers undergoing c-section after one hour. Both vaginally born infants and c-section babies swabbed with vaginal secretions had a similar development process with anal bacteria changing from beingLactobacillus dominated to Bacteroidetes dominated. Such changes in the microbiome community were not seen in the unswabbed c-section infants. These results suggest that swabbing infants with vaginal secretions transmits vaginal bacteria [1].

Incomplete transmission

Although swabbed infants were more similar to vaginally delivered infants than c-section infants, this transmission was incomplete. Lactobacillus was not maintained on the skin of swabbed infants as it was on vaginally born infants. Anal bacteria were also in lower abundance in swabbed infants than vaginally born. Whether this incomplete transmission is due to issues with the gauze picking up and transmitting the full vaginal microbiome in the short time of swabbing or other factors such as antibiotic use cannot be determined with this small sample set of four infants.

What is a Healthy Vaginal Microbiome?

Although the vaginal microbiome is lower in diversity than the microbiome of the digestive system, making it easier to study, there are still many unknowns. Jacques Ravel, Professor and Associate Director for Genomics at the Institute for Genome Sciences in Baltimore, Maryland, suggests that vaginal microbiome transfers may be risky at this time due to the lack of knowledge about the function of the vaginal microbiome in general and specific bacterial members of the community. Research from the Ravel lab demonstrates that vaginal microbiome communities can vary with ethnicity and still be considered healthy. For example, the absence of Lactobacillus was previously considered a sign of bacterial vaginosis. To ensure that patients did not have bacterial vaginosis, only patients with a vaginal pH < 4.5, with no signs of vaginosis, and Group B Streptococcus negative were used in the study by Domenguez-Bello et al.

"What is the function of the vaginal microbiome?"" Dr. Ravel asked. "Does the vaginal microbiome play a role in delivery? At this time we do not know." The vaginal microbiome, especially those dominated by Lactobacillus seems to be most protective against sexually transmitted diseases including HIV, but other bacteria may provide similar functions to Lactobacillus in some vaginal microbiomes. Additionally, not all Lactobacillus species may have the same function. Dr. Ravel agreed that this study by Dominguez-Bello and colleagues suggests that vaginal bacteria can be transferred to c-section infants. However, he cautions that investigators need to better determine which bacterial species were present in the mothers prior to transfer and that the function of the vaginal microbiome should be better understood. Finally, long term health monitoring of both vaginal and c-section born infants is necessary to fully understand the interaction between microbiome communities and health. Dominguez-Bello and her colleagues are in the midst of conducting a longer term and larger study.

Should We "Seed" Babies Born By Cesarean?

The idea of "seeding" a c-section infant with vaginal microbes is an attempt to transmit microbes from the mother that the infant would normally have gotten during vaginal birth. However, as with other human microbiome work, scientists are just beginning to learn about the members of the vaginal microbiome, their roles, and how microbial communities interact with their human host. What is the role of these bacteria in the vagina? What is a "healthy" vaginal microbiome? How does the role of human genetics, such as ethnicity, factor into vaginal microbiome health?

The study by Dominguez-Bello is a "proof of principle". Swabbing vaginal secretions on c-section born infants partially transmits the vaginal microbiome. However, work remains to be done to ensure transmission of all members of the vaginal microbiome. Larger studies with a diversity of women and with better identification of the bacterial species present are needed. A deeper understanding of the function of the vaginal microbiome and its community members is essential. Finally, as the authors of the study mention, birth is a complex process. Microbial transmission may be only one part of the puzzle surrounding differences between vaginal and c-section infant health outcomes.

Should Parents Consider Vaginal Swabbing?

As with any medical decision, there are trade-offs. While we do not know what a healthy vaginal microbiome looks like, we do know that c-section babies are more frequently colonized by environmental bacteria such as skin and hospital-acquired bacteria. We do know that infants born via c-section are more likely to have non-communicable diseases. Is this true of all c-section infants? No, some do not. Do all vaginally born infants avoid these non-communicable diseases? No, some do not. What accounts for this variation in long term health? Would inoculating c-section babies at birth increase overall health outcomes? It most likely depends on the vaginal microbiome that is being transmitted, how well it becomes established, and how it is maintained through a healthy lifestyle. Certainly before considering vaginal swabbing, mothers should know what potential pathogens they may pass on to their infants. For example, mothers colonized with Group B Streptococcus (GBS) should discuss vaginal swabbing with their OB and pediatrician before attempting this since GBS can cause meningitis.

Many people worry about needing a c-section and having their infants miss out on potentially beneficial bacteria or pick up hospital-acquired infections. Certainly, like in all ecosystems, organisms that colonize first are more likely to be able to outcompete later arriving organisms. The vaginal microbiome transfer is one way to ensure that the mother's vaginal microbiome is more likely to colonize her c-section baby than environmental microbes. What particular vaginal microbiome is ideal for any given infant's health is a question that will take a long time to answer.

Here is a video - The Healthy Truth About Traditional Childbirth from the Smithsonian Channel of Dr. Dominguez-Bello swabbing a newborn born by cesarean with inoculated gauze.

While this study is just a small first step in understanding this complicated issue, the results seem promising and have the potential to change protocols for those newborns born by cesarean. Continued research needs to be conducted, but the significance of these findings should not be overlooked. While we work to reduce the number of cesareans performed, we also must look at ways to mitigate the impact on those babies who are delivered surgically. This is a great first step. - SM

References

1. Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI et al: Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 2016, advance online publication.
2. Sevelsted A, Stokholm J, Bønnelykke K, Bisgaard H: Cesarean section and chronic immune disorders. Pediatrics 2014, 135.
3. Dominguez-Bello MG, Blaser MJ: Asthma: Undoing millions of years of coevolution in early life? Science Translational Medicine 2015, 7(307):307fs339-307fs339.
4. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N: Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010, 107.
5. Bäckhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, Li Y, Xia Y, Xie H, Zhong H et al: Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host & Microbe 2015, 17(5):690-703.
6. Azad MB, Konya T, Persaud RR, Guttman DS, Chari RS, Field CJ, Sears MR, Mandhane PJ, Turvey SE, Subbarao P et al: Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. BJOG: An International Journal of Obstetrics & Gynaecology 2015.
7. Madan JC, Hoen AG, Lundgren SN, et al.: Association of cesarean delivery and formula supplementation with the intestinal microbiome of 6-week-old infants. JAMA Pediatrics2016:1-8.
8. Shin H, Pei Z, Martinez KA, Rivera-Vinas JI, Mendez K, Cavallin H, Dominguez-Bello MG: The first microbial environment of infants born by C-section: the operating room microbes. Microbiome 2015, 3(1):1-6.
9. Goedert JJ, Hua X, Yu G, Shi J: Diversity and Composition of the Adult Fecal Microbiome Associated with History of Cesarean Birth or Appendectomy: Analysis of the American Gut Project. EBioMedicine 2014, 1(2-3):167-172.

Tags