Abstract
Objective
This study aims to evaluate the impact of cesarean section delivery on the neonatal intestinal microflora compared to vaginal deliveries.
Design
A mini-review.
Methods
A comprehensive search strategy was implemented, primarily using PubMed, to identify relevant studies published in English within the past 10 years. Selected studies were appraised by three independent reviewers using JBI critical appraisal and data extraction forms. Four articles were included in the analysis, encompassing systematic reviews and a retrospective cohort study. Primary and secondary outcome data were combined across these studies.
Results
Selected studies revealed consistent trends in bacterial colonization differences between cesarean and vaginal deliveries. Vaginally delivered infants exhibited higher populations of beneficial bacteria such as Bifidobacterium, Lactobacillus, and Bacteroides. Cesarean-delivered infants, on the other hand, showed greater colonization of Enterococcus, Klebsiella, Clostridium, Staphylococcus, Streptococcus, and Corynebacterium. Statistically significant differences were observed in two studies. All articles explored the potential health implications of these microbiome differences, with associations found between cesarean deliveries and various health outcomes.
Conclusion
This review demonstrates that cesarean section delivery influences the composition of the neonatal gut microbiota. The presence of certain bacterial species more prevalent in vaginally delivered infants, such as Bifidobacterium, is associated with improved infant health, while species found in cesarean-delivered infants, such as Clostridium, increase the risk of certain infections. Recognizing the increased health risks for cesarean-born infants enables clinicians to implement early screening, treatment, or prevention strategies, potentially reducing future morbidity and mortality.
Introduction
Cesarean sections
Over the past few decades, cesarean sections have become increasingly more common. The number of births worldwide that occurred by c-section has risen from 7% in 1990 to 21% in 2018 (Organization 2023). This growing prevalence is likely due to the improved ability to safely deliver fetuses in circumstances that would otherwise be dangerous for both the mother and the fetus, such as fetal malpresentation, placental abnormalities, maternal comorbidities, or fetal intolerance to labor. Although these procedures have been performed for many years, modern anesthesia and improved surgical techniques over time have facilitated further reduction of risk. As a result, this widespread implementation has contributed to a 38% decrease in maternal mortality from 2000 to 2017 (Betran et al. 2021). This ultimately establishes c-sections as a viable and essential alternative for high-risk pregnancies.
Nonetheless, c-sections present a host of challenges and differences from vaginal births, the main discrepancy being the fetus’s avoidance of exiting through the birth canal. Vital physiologic changes occur during this process that are interrupted or prevented when a cesarean section is performed. Many of these fetal adaptations to life outside the womb are set in motion by specific characteristics of passing through the vaginal vault such as pressure, oxygen delivery, and temperature. For example, fetuses are more slowly and progressively exposed to the cold environment outside their mother’s bodies during a vaginal delivery, allowing for the enactment of catecholamine release, proper control of blood flow to the skin, and induction of shivering thermogenesis (Lubkowska et al. 2020). Another illustration of the importance of natural initiation of physiologic processes is how infants born by c-section are more likely to develop transient tachypnea due to increased fluid remaining in their lungs, as maternal hormones released during vaginal labor are responsible for activating proper reabsorption of fluid (World Health Organization 2021). This further supports the significant role that specific environmental factors play in the fetuses’ transition to independent function. So, although c-sections are a viable and crucial option for high-risk pregnancies, there are many benefits to delivering vaginally that cannot be replicated through c-sections.
The consequences that an individual born via a cesarean delivery may be faced with later in life are a topic that has been more widely researched. Previous studies have identified an association between delivery via c-section and the rate of metabolic conditions later in life such as obesity and diabetes mellitus (Kristensen & Henriksen 2016). This suggests that an infant’s endocrine physiology is significantly altered by c-section, resulting in repercussions long after birth. An increased hazard ratio has also been observed for autoimmune conditions such as asthma, allergies, juvenile idiopathic arthritis, celiac disease, and inflammatory bowel disease in children who were delivered by c-section (Yuan et al. 2016). This reveals that cesarean deliveries can also have a negative effect on the immunological development of the infant. However, the pathophysiologic explanation behind why each of these relationships exists is still not well understood, yet important to understand in order for it to be adequately addressed or even prevented.
Fetal intestinal flora
Altered fetal bacterial exposure based on the mode of delivery is a proposed underlying etiology for the sequela experienced by individuals born by cesarean section. When an infant is born vaginally, there is vertical transmission of the vaginal and rectal microbiome to the infant, with the dominant species including actinobacteria, bifidobacteria, and Bacteroidetes. However, when an infant is born by c-section, exposure to these sources of bacteria no longer occurs, resulting in the infant’s gut flora becoming a closer reflection of the mother’s skin microbiome. In this case, Firmicutes as well as other bacteria such as Staphylococcus and Clostridiumwould become the dominant species (Lyu et al. 2021). This demonstrates a stark difference in the gut microbiota of the infant based on the delivery method and subsequent transfer of microorganisms. It is also believed that the initial colonization of the infant’s intestinal flora may influence the future microbial profile of the infant (Shaterian et al. 2021). These preliminary species that are established at birth could possibly have an impact on the infant’s life lasting much longer than infancy. As a result, the delivery method can have an early, yet persistent effect on the infant’s microbiome and calls into question what consequences this may have on their health as they grow into adulthood and throughout their life.
The microbiome is thought to have a notable role in several aspects of an infant’s development. It has been shown that Bifidobacterium are essential to the development of intestinal epithelial cells (Lyu et al. 2021). Since the concentration of this particular species in the microbiome of infants born by c-section is decreased, this suggests that the development of this epithelium could be stunted. As this tissue determines digestive and absorptive function, the observed delay in the growth of this bacteria could have a variety of impacts on the infant’s gastrointestinal health. It is also thought that the gut microbiome is related to both immune function and metabolism (Pan et al. 2021). Being that the infants born by c-section have a completely different composition of microbiota than those vaginally delivered, it is plausible that the microbiome could be responsible for the increased risk of conditions such as diabetes, obesity, and atopic conditions experienced by these individuals due to the subsequent alterations in normal cellular function. The extent to which these discrepancies in microbiota exist needs to be further evaluated in greater detail in order to elucidate the consequential long-term effects that may threaten the infant’s current and future health.
Thus, the primary purpose of this mini-review is to determine if cesarean sections have a negative impact on the neonatal gut microbiome compared to vaginal deliveries. Additionally, the subsequent risk of developing certain disease states will also be evaluated. If a relationship can be identified between the method of delivery and resultant fetal intestinal flora, awareness of future health consequences may be enhanced. This would allow specific differences in the flora that are affecting the infant’s health to be identified. As a result, appropriate screening may be implemented in order to facilitate prompt diagnosis, treatment, or even prevention of these later manifestations. These findings ultimately have the power to reduce further morbidity and mortality associated with the observed increased prevalence of metabolic, endocrine, and autoimmune conditions in individuals born by c-section.
Methods
Inclusion criteria
This review aimed to synthesize qualitative findings from existing literature exploring the impact of cesarean section delivery on the neonatal gut microbiome. While the data collection approach was systematic, the analysis employed a narrative synthesis due to heterogeneity of the studies, and different measurement scales.
This review consists of studies which evaluated human subjects, including both neonates and young children. Subjects of any age group were considered, as this study focuses on both short- and long-term effects. Articles that examined participants who developed metabolic, gastrointestinal, and immunologic diseases were included. Individuals born by cesarean sections served as the intervention of interest for this review. Studies were selected which included a control group consisting of individuals delivered vaginally, in order to serve as a comparison, to a group of individuals delivered via cesarean section. The studies that were selected must either have acknowledged the primary or secondary outcomes of this review. The primary outcome of this study was to determine if there is a measurable difference in the diversity of beneficial species of gut bacteria among infants born via cesarean versus vaginal delivery. The long-term health sequelae of children of cesarean births were examined as a secondary outcome.
Search strategy
Electronic bibliographies were used exclusively, with the primary resource used to find sources being PubMed. These inquiries were completed between 28 July and 5 August 2022. The advanced search setting was used and the following MeSH terms were used: (‘cesarean section’ AND ‘neonate’ OR ‘infant’ AND ‘microbiome’ OR ‘microbiota’) (Appendix I). The search was further refined to articles published within the past 10 years. Filters were then applied to restrict the search to studies that were either systematic reviews, meta-analyses, or randomized clinical trials (RCTs), which ultimately narrowed the search to only 35 articles.
Study screening and selection
Once the search was narrowed to the 35 articles, the abstracts were screened for articles that included differences in the microbiome of neonates born via cesarean section versus vaginal delivery. Articles were automatically omitted if they were not in English or if the full text could not be accessed. The full text of the remaining articles was then read independently by three reviewers and articles were chosen which had data that correlated delivery methods to health outcomes. Exclusions were made if an article included neonates with serious birth defects, gestational diabetes, or traumatic births. Additionally, studies with health outcomes that could be linked to any genetic or identifiable external factors were ruled out.
Critical appraisal
After screening each article to ensure that it met all inclusion criteria and aligned with the topic in question, more critical analysis was performed. In order to determine if the article included robust research, factors such as type of study, sample size, level of evidence, use of randomization or blinding, and type of statistical analysis performed were taken into account. Systematic reviews and cohort studies that had a sample size of less than 20 participants were excluded. Due to the limited amount of current research on the topic, all of the articles that were selected were either retrospective or prospective cohort studies or systematic reviews, so the use of randomization and blinding became irrelevant. Articles that included obvious selection bias or confounding were limited where possible. Any disagreements between reviewers were resolved by discussion, consensus, and the use of a third reviewer’s opinion.
Data extraction
In order to determine the relationships between the selected articles, specific aspects from each study were reviewed and tabulated. These categories included population characteristics, study design, methods used to measure and analyze outcomes, general conclusions about the overall relationship between cesarean section and intestinal bacterial diversity, and any additional observed health consequences associated with these findings. After these components were assessed, screening was done to identify any duplicated data that could have been gathered from multiple publications of any of the studies. If any overlap in the data was identified, two reviewers identified and re-evaluated the articles which the data had come from in order to exclude one of the articles in which the duplicated study was included.
Data synthesis
To address the primary outcome, the data presented in each article regarding the differences in the microbiota of neonates were compiled into a narrative synthesis which analyzed the types of bacteria present according to delivery method. The secondary outcome was addressed by observing the combined rates of the chronic disease identified across all articles in the subset of individuals delivered via cesarean section and comparing that to the rates of occurrence in the vaginally delivered control groups. The rates of long-term health complications were further organized into categories of obesity, asthma, type I diabetes, food allergies, celiac disease, and allergic rhinitis.
Results
Study inclusion
The results of the search are presented in a PRISMA flow diagram (Fig. 1). After searching the databases as outlined above, 126 articles were found. Next, duplicates were removed, which left 111 articles to be screened for the additional criteria of being published within the last 10 years as well as only systematic reviews, meta-analyses, or RCTs. Of these, 76 were excluded. This resulted in 35 full-text articles which were assessed for eligibility. After reviewing the full text of these articles, 31 were excluded as they did not meet the remaining inclusion criteria (Appendix II). Articles were excluded for reasons such as their outcomes did not match with the outcomes of the review, or if the articles did not include samples of participants delivered by cesarean section and samples of participants delivered vaginally. After these exclusions, four articles remained, which were all included in the review (Appendix III).
Search results and study selection and inclusion process.
Citation: Microbiota and Host 1, 1; 10.1530/MAH-23-0006
Methodological quality
Tables 1 and 2 summarize the critical appraisal results of the included studies. Each of the four articles was included after their methodological quality was assessed. There were, however, a few issues that were identified. Out of the three systematic reviews, the likelihood of publication bias was only mentioned in one article. The other two articles did not address whether or not publication bias was present or if any steps were taken to ensure that there was no bias present. Another concern was identified, regarding the single cohort study used in this review. The article was unclear as to whether there were strategies in place that were utilized to address incomplete follow-up. However, it did not mention any difficulty with participant adherence. Due to this being the only cohort study used in this review, there were no articles which clearly stated their methods in place for attrition concerns. The methodological quality of the three systematic reviews was assessed using the JBI Critical Appraisal Assessment Tool for Systematic Reviews and the cohort study was assessed using the JBI Critical Appraisal Assessment Tool for Cohort Studies.
Critical appraisal of eligible systematic reviews.
| Review 1 | Review 2 | Review 3 | Total % | |
|---|---|---|---|---|
| 1. Is the review question clearly and explicitly stated? | Y | Y | Y | 100 |
| 2. Were the inclusion criteria appropriate for the review question? | Y | Y | Y | 100 |
| 3. Was the search strategy appropriate? | Y | Y | Y | 100 |
| 4. Were the sources and resources used to search for studies adequate? | Y | Y | Y | 100 |
| 5. Were the criteria for appraising studies appropriate? | Y | U | Y | 66 |
| 6. Was critical appraisal conducted by two or more reviewers independently? | U | Y | Y | 66 |
| 7. Were there methods to minimize errors in data extraction? | Y | Y | Y | 100 |
| 8. Were the methods used to combine studies appropriate? | Y | Y | Y | 100 |
| 9. Was the likelihood of publication bias assessed? | Y | NA | U | 25 |
| 10. Were recommendations for policy and/or practice supported by the reported data? | Y | Y | Y | 100 |
| 11. Were the specific directives for new research appropriate? | Y | Y | Y | 100 |
Review 1: Słabuszewska-Jóźwiak et al. (2020); Review 2: Montoya-Williams et al. (2018); Review 3: Shaterian et al. (2021).
Critical appraisal of eligible cohort study.
| Pan et al. (2021) | % | |
|---|---|---|
| 1. Were the two groups similar and recruited from the same population? | Y | 100 |
| 2. Were the exposures measured similarly to assign people to both exposed and unexposed groups? | Y | 100 |
| 3. Was the exposure measured in a valid and reliable way? | Y | 100 |
| 4. Were confounding factors identified? | Y | 100 |
| 5. Were strategies to deal with confounding factors stated? | Y | 100 |
| 6. Were the groups/participants free of the outcome at the start of the study? | Y | 100 |
| 7. Were the outcomes measured in a valid and reliable way? | Y | 100 |
| 8. Was the follow-up time reported and sufficient to be long enough for outcomes to occur? | Y | 100 |
| 9. Was follow-up complete, and if not, were the reasons to loss to follow-up described and explored? | Y | 100 |
| 10. Were strategies to address incomplete follow-up utilized? | Y | 100 |
| 11. Was appropriate statistical analysis used? | Y | 100 |
Characteristics of included studies
Each of the studies included in this review examined differences in neonatal gut microbiota and/or secondary health outcomes for infants born via cesarean section as compared to those vaginally delivered. Table 3 summarizes the characteristics from each article and Appendix IV may be referenced for a comprehensive review of additional information extracted from each of the sources. Of the four articles, three were systematic reviews, one of which was a narrative review, while one was a retrospective cohort study. In total, this systematic review pools findings from 123 studies. The sample size of each individual study varied from as little as 7 participants to over 2.5 million participants. Studies performed or used in the selected sources originated from various locations across the world, including Europe, Asia, North America, and Australia. Three of the studies’ primary outcome measures focused on the neonatal gut microbiome composition itself, which utilized microbial sequencing technology in order to detect each of the species contained within samples from various sources, primarily infant stool. One study’s primary outcome, as well as the secondary outcomes from all included studies, directed focus toward the development of secondary health consequences. These were measured using pooled odds ratios, as well as heat maps that predicted vitamin and carbohydrate metabolism levels.
Characteristics of included studies.
| Study | Study design | Population | Sample size | Intervention | Comparison | Outcome measures | Measurement points | |
|---|---|---|---|---|---|---|---|---|
| Primary | Secondary | |||||||
| Montoya-Williams et al. (2018) | SRN | Newborns and children delivered via CS | 88 articles | CS infant | VD infant | Composition of gut microbiota | Observed health consequences | Microbial sequencing and speciation from various sample sources (fetal stool, meconium, amniotic fluid) |
| Pan et al. (2021) | RCS | CS vs VD | 82 newborns | CS | VD | Structure of intestinal microbiota | Predicted function of intestinal microbiota | Primary: Microbial sequencing and speciation from stool samples (t-test and Wilcoxon signed rank test) |
| Secondary: predicted carbohydrate and vitamin metabolism level, analyzed via heatmap of (KEGG) pathway level 2 | ||||||||
| Shaterian et al. (2021) | SR | Infants born via CS | 7 articles | CS | VD | Composition of gut microbiota | Observed health consequences | Various techniques to sequence microbiome from stool samples |
| Słabuszewska-Jóźwiak et al. (2020) | SRM | Newborns and children delivered via CS | 27 studies | CS | VD | Development of respiratory diseases, asthma, obesity, T1D | Difference in neurologic development | Pooled odds ratios for cesarean sections and each observed health consequence |
CS, cesarean section; RCS, retrospective cohort study; SR, systematic review; SRM, systematic review and meta-analysis; SRN, systematic review (narrative); T1D, type 1 diabetes; VD, vaginal delivery.
Review findings
Four studies (n = 4) were selected to investigate if there is a measurable difference in the diversity of species of gut bacteria among infants born via cesarean versus vaginal delivery. Two systematic reviews and one retrospective cohort study examined the composition of the gut microbiota while one systematic review focused on the long-term health outcomes of cesarean versus vaginal delivery. Appendix IV provides a more thorough extraction and critical appraisal of data.
Cesarean effects on neonatal microbiome
Among the articles that studied microbiome composition, various sequencing techniques were utilized on samples from primarily infant stool in order to identify specific microbial species. Pan et al. studied gut microbiota using sequencing on stool samples of the gene which encodes the 16S rRNA. Measurements taken on day 3 of life in a cohort of 82 neonates showed no significant difference (P > 0.05) in Escherichia–Shigella levels between cesarean and vaginally birthed neonates. However, increased amounts of Bifidobacterium, Lactobacillus, and Bacteroides were found in vaginally delivered neonates, while cesarean-delivered infants were found to have higher concentrations of Staphylococcus, Streptococcus, and Corynebacterium, both of which findings were statistically significant (P < 0.05). When the studies were repeated at 30–42 days of life, a statistically significant difference between microbiome composition remained. While both groups showed a prominent population of Bifidobacterium, Escherichia–Shigella, and Bacteroides, vaginally delivered infants had a large concentration of Lactobacillus and cesarean-delivered infants showed a stable population of Staphylococcus.
Montoya-Williams et al. synthesized articles which studied intestinal microbiomes using a variety of methods and sample sources. The review found that while no consensus has been found as to if there is a difference in the richness or diversity of the neonatal gut microbiota between vaginally and cesarean-delivered infants, there is a substantial body of evidence supporting a difference in the composition of the microbiome. The impact of the delivery method on this distribution is evidenced by the findings that the bacterial populations which appear in infant’s intestinal flora appear to mirror the typical species that populate either the vagina, such as Lactobacillus, Bifidobacterium, and Bacteroides, or the skin, such as Klebsiella, Enterococcus, Corynebacterium, Propionibacterium, and Clostridium.
The review conducted by Shaterian et al. examined cross-sectional and cohort studies that used various extraction and sequencing techniques to identify bacterial populations from stool samples that were collected at various times throughout the first year of the babies’ lives, comparing the different microbiota at each time stage. During the first week of life, statistically significant differences were seen in the most prevalent species for each group. Higher colonization means of the species Bacteroides (VD group = 11.1, CS group = 0.75), Bifidobacterium (VD group = 20.1, CS group = 15.5), and Enterobacter (VD group = 8.8, CS group = 4.6) were found in vaginally delivered infants, whereas Clostridium (VD group = 3.9, CS group = 7.7), Lactobacillus (VD group = 10.9, CS group = 15.5), Staphylococcus (VD group = 0.5, CS group = 11.7), and Enterococcus (VD group = 2.6, CS group = 6.9) were more populous in cesarean delivered infants at this stage of life. At 3 to 6 months of life, Bifidobacterium and Staphylococcus colonization rates showed no statistically significant difference, while Clostridium (VD group = 18.2, CS group = 32.9) and Bacteroides (VD group = 23.1, CS group = 14) showed continued statistically significant differences in concentration. Table 4 summarizes the general trends of bacterial colonization for each population.
Overall trends in microbiome bacterial concentrations for vaginal versus cesarean-delivered neonates (Montoya-Williams et al. 2018, Pan et al. 2021, Shaterian et al. 2021).
| Bacterial genera | Vaginal | Cesarean |
|---|---|---|
| E. coli | = | = |
| Bifidobacterium | + | − |
| Lactobacillus | + | − |
| Bacteroides | + | − |
| Enterococcus | − | + |
| Klebsiella | − | + |
| Clostridium | − | + |
| Staphylococcus | − | + |
| Streptococcus | − | + |
| Corynebacterium | − | + |
=, no significant difference in population within the gut microbiota; +, increased population within the gut microbiota comparatively; −, decreased population within gut microbiota comparatively.
Cesarean secondary health outcomes
Each of the studies included a section that examined secondary health outcomes (Table 5). Pan et al. examined carbohydrate and vitamin metabolism of intestinal microbiota for each population using the Heatmap of Kyoto Encyclopedia of Genes and Genomes pathway level 2, which showed higher levels of metabolism and biodegradation in the vaginally delivered infant population. As a result, the specific species found in infants delivered vaginally were found to be protective against milk allergies and obesity. Słabuszewska Jóźwiak et al. performed a meta-analysis using pooled odd ratios for cesarean sections and each observed health consequences. These calculations showed cesarean section being a potential risk factor for respiratory tract infections (pooled OR=130, P = 0.001), asthma (pooled OR = 1.23, P < 0.00001) as well as obesity (pooled OR = 1.35, P < 0.00001) in infants delivered via this method. Shaterian et al. found that Bifidobacterium, bacteria seen primarily in the vaginal microbiome, was seen to be a protective factor in immune health, whereas Clostridium difficile, found more commonly in skin flora, can lead to infantile gastroenteritis. Montoya-Williams et al. found strong associations of increased respiratory morbidity, relative hypothermia, and increased risk of ICU admission in infants born via cesarean section. Later on in childhood, this study saw a higher incidence of autoimmune conditions such as asthma, allergic rhinitis, food allergies, celiac disease, and type I diabetes. Furthermore, many of the bacterial species found in the gut microbiome of vaginally delivered neonates were found to be protective against some of these conditions, including asthma and obesity.
Discussion
Our review aimed to elucidate the impact of cesarean section delivery on the neonatal gut microbiome and subsequent health outcomes, drawing from a pool of 123 studies. The stringent inclusion criteria, ensuring the reliability and relevance of our findings, resulted in the analysis of four articles, which provided consistent and high-quality data. However, we acknowledge the substantial exclusion of articles and recognize the potential limitations this imposes on the generalizability of our findings.
In neonates delivered by cesarean section, the composition of the gut microbiota was found to be significantly different than of those delivered vaginally. Two systematic reviews and one cohort study analyzed the types and proportions of the bacteria species present. These findings demonstrated that in infants delivered by c-section, the microbiota composition more closely mirrored the mother’s skin flora compared to the vaginal–rectal flora which was seen in the vaginally delivered neonates. These studies, along with a third systematic review, also analyzed secondary health outcomes and showed that these neonates delivered by cesarean section had an increased risk of developing conditions such as diabetes mellitus, obesity, and immunologic conditions. The differences in the microbiota have been analyzed as a potential factor in the increased risk that is seen in these neonates for these health conditions.
Overall trends were seen in the results of this study when combining the data from each article on microbiota composition. Bifidobacterium, Lactobacillus, and Bacteroides species were generally determined to be significantly decreased in those neonates delivered by cesarean section (Montoya-Williams et al. 2018, Pan et al. 2021, Shaterian et al. 2021). However, the review conducted by Shaterian et al. found that Lactobacillus species were increased in the cesarean-delivered neonates. One possibility for this difference could be due to the fact that this review examined a number of cohort studies that used multiple extraction and sequencing techniques to analyze the bacteria present in the microbiotas. This could have potentially increased the chance for error due to a lack of consistency in the technique being used throughout the studies included in the review. The rest of the results of this review were, however, in agreement with the other two articles. The data from all three of these articles demonstrated an increased quantity of multiple species, including Enterococcus, Corynebacterium, and Clostridium, in the neonates delivered by cesarean (Montoya-Williams et al. 2018, Pan et al. 2021, Shaterian et al. 2021). This shows that the delivery method has a significant impact on the microbiome of the neonatal gut and that the composition, especially in regards to these species, is affected when not exposed to the vaginal flora as it is during vaginal delivery.
Each article included in this study analyzed secondary health outcomes associated with delivery by cesarean section. All four studies demonstrated that there was an increased incidence of developing obesity in childhood in the neonates delivered by cesarean compared to those delivered vaginally (Montoya-Williams et al. 2018, Słabuszewska-Jóźwiak et al. 2020, Pan et al. 2021, Shaterian et al. 2021). These results strongly support that there is a higher likelihood of the development of obesity in this subset of children. This was the only secondary health outcome that all four articles examined. The remaining outcomes analyzed in this review including asthma, type 1 diabetes, celiac disease, and allergic rhinitis each had data contributed from only three of the articles. This is largely due to the fact that the cohort study by Pan et al. only included data on obesity and food allergies. Although not every article addressed each health outcome, the combined results still showed a significant correlation between the neonates delivered by cesarean section and the development of these secondary conditions.
The effect that certain species in the gut microbiota have on the intestinal cellular structure has been established in previous studies. One of these species, Bifidobacterium, has been determined to have a significant impact on the development of intestinal epithelial cells, which are crucial for digestion and absorption. As well as having an impact on digestive health, Shaterian et al. found that Bifidobacterium was also seen to be a protective factor in immune health. The results of this review established that the quantity of Bifidobacterium in the neonatal microbiota delivered by cesarean section was significantly lower, specifically in the first week of life. With this decreased population, the epithelial development would be stunted, thus influencing the immune and digestive systems of the cesarean-born neonate, ultimately increasing the likelihood that they will develop long-term health sequelae compared to those delivered vaginally. The Clostridium species has also been shown to potentially have a negative effect on the gastrointestinal system. Shaterian et al. found that an imbalance of this species can lead to gastroenteritis. The results of this review demonstrated that, compared to vaginally delivered neonates, there is an increased colonization of Clostridium in those delivered by cesarean. These observed differences in the composition of the microbiota have demonstrated a distinctly negative impact on neonatal intestinal development when compared to the composition of those delivered vaginally, increasing the risk of specific future health conditions.
These results have identified a subset of children who may be at increased risk for developing some specific health conditions, including obesity, type I diabetes, and other autoimmune or atopic conditions. By recognizing this high-risk group, earlier screening may be performed, which will hopefully result in swifter treatment of such issues before greater complications arise. Future studies can be aimed at realizing effective strategies to mitigate the risk or even prevent the development of these conditions altogether by addressing the differences in the gut microbiota. For example, early administration of probiotics which focus on the bacterial species an infant delivered by cesarean section is deficient in could be a potential treatment to be studied. Furthermore, this increased risk should encourage clinicians to begin incorporating these findings into their patient education. When discussing risks and benefits with a patient who is considering an elective c-section, the patient should be aware that the probability of these health outcomes is slightly higher than with a vaginal birth so they may make a fully informed decision.
The strengths of this study include the large population which resulted from compiling articles that drew from a total of 123 studies. This ultimately allowed for the ability to draw stronger conclusions. These were conducted in a variety of locations, spanning almost every continent. This degree of diversity increases the generalizability of findings to many individuals of different origins, races/ethnicities, ages, or gestational ages at the time of delivery. Additionally, the exclusion criteria of only selecting high-quality study designs, such as systematic reviews or cohort studies with a large sample size, were carefully chosen to produce more meaningful results. Lastly, the data utilized in this review are very recent, as each of the studies selected was conducted in the past 4 years.
The exclusion of 119 articles was meticulously executed to uphold the integrity and quality of our review, ensuring that only studies meeting our predefined criteria were considered in the final analysis. Despite the limited number of studies analyzed, the retained articles presented consistent, robust data, substantiating our conclusions. These articles were subjected to rigorous analysis and were deemed to be of high quality and directly relevant to our research question, providing valuable insights into the impact of delivery mode on the neonatal gut microbiome and subsequent health outcomes.
We transparently acknowledge the limitations associated with drawing conclusions from a smaller subset of articles. Our conclusions are cautiously formulated, reflecting the available data from the four included studies, and we advocate for their interpretation considering the significant exclusion of articles. The findings from our review should be viewed as a valuable addition to the existing body of literature, providing insights while recognizing the need for further research to validate and potentially expand upon our findings.
This review was limited by elements related to the study design. Although inclusion criteria for this review were chosen to remain broad in order to obtain a robust selection of studies to review, more specific criteria could have been chosen in order to ensure that the scope of the study was more refined. A way to achieve this could have been to select only one or two specific secondary health outcomes to examine, such as asthma or obesity. Another weakness was the use of both systematic reviews and cohorts. If only one type of study was used, rather than a combination of both, results could have been compiled and further analyzed. Furthermore, the selection of an article that was a narrative systematic review impeded the ability to conduct any additional statistical analyses. Great difficulty was also encountered when conducting database searches. This was likely due to poor indexing of the topics, as many trials of modifying the language used in inquiries were required to refine the data to such a specific topic.
We acknowledge the limitations associated with methodologies such as 16S, which are incapable of distinguishing between pathogenic and nonpathogenic strains within a bacterial genus/species. For instance, while 16S can identify the presence of E. coli, it cannot distinguish between pathogenic strains, such as Shiga toxin-producing E. coli, and nonpathogenic strains. This limitation potentially impacts the interpretation and applicability of the findings, as the nuanced differences in pathogenicity between individual bacterial species and strains cannot be discerned. Future research employing methodologies capable of distinguishing between bacterial strains will be crucial to further elucidate the impact of cesarean section delivery on the neonatal gut microbiome and subsequent health outcomes.
Number of references for each secondary health outcome.
| Study | Obesity | Asthma | Type I diabetes | Food allergies | Celiac disease | Allergic rhinitis |
|---|---|---|---|---|---|---|
| Montoya-Williams et al. (2018) | 1 | 1 | 1 | 1 | 1 | 1 |
| Pan et al. (2021) | 1 | 0 | 0 | 1 | 0 | 0 |
| Shaterian et al. (2021) | 1 | 1 | 1 | 1 | 1 | 1 |
| Słabuszewska-Jóźwiak et al. (2020) | 1 | 1 | 1 | 0 | 1 | 1 |
| Total references | 4 | 3 | 3 | 3 | 3 | 3 |
Conclusion
This review ultimately found that the delivery method affects the neonatal gut microbiota composition, which further exposes infants delivered by cesarean section to an increased risk of developing certain health conditions. These findings have profound significance in pediatric medicine, as they demonstrate an opportunity for clinicians to implement increased monitoring of children born via c-section for these health sequelae that were specifically identified. Furthermore, health care in general may be affected, as the identified relationship, if proper screening and early treatment or prevention strategies are enacted, has the potential to reduce future morbidity and mortality for at-risk individuals. The implications of our findings suggest a discernible impact of cesarean section delivery on the neonatal gut microbiome, with potential subsequent health implications. However, we emphasize that these findings should be interpreted with caution, considering the limited number of articles analyzed. Future research endeavors might explore this topic by employing a broader inclusion criterion, providing additional insights and potentially validating the findings presented herein.
Further research still needs to be conducted to explore potential maternal confounding variables such as administration of antibiotics, maternal dietary habits, or gastrointestinal disorders that may have occurred or played a role during the pregnancy in greater detail. It seems plausible that each of these factors could easily alter bacterial content and diversity in the developing neonate. These clarifications will allow for a more definitive and direct relationship between delivery method and intestinal microbiota to be drawn.
We recognize the necessity to delve deeper into the demographic details of the populations studied in the included articles. The studies analyzed encompassed a wide range of sample sizes, from as few as 7 to over 2.5 million participants, originating from various global locations, including Europe, Asia, North America, and Australia. However, the demographic details such as age, gender, socioeconomic status, and health status of the participants were not thoroughly explored in our initial review. These factors can significantly influence the neonatal gut microbiome and subsequent health outcomes, thereby warranting a detailed exploration.
In conclusion, our review, while based on a limited number of studies, provides valuable insights into the relationship between cesarean section delivery, neonatal gut microbiome alterations, and potential health outcomes. We advocate for the cautious interpretation of our findings and emphasize the necessity of further research to substantiate and expand upon our conclusions, ensuring a comprehensive understanding of the topic.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Acknowledgements
We express our heartfelt gratitude to the faculty and staff of Physician Assistant Program and College of Health Professions for their everyday support, constructive feedback and suggestions during the manuscript preparation. We would also like to extend our appreciation to our families and friends for their unwavering moral support and patience during the entirety of this research project. In the spirit of scholarly research, we also thank the anonymous reviewers for their constructive comments that helped enhance the quality of the manuscript.
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