Microbiome and Long-Term Health Considerations

Abstract

All the tissues of our body are formed by cells, but there are at least 1–10 times more microbes than cells in it, which coexist in balance and help us maintain our health. Most of them are found in the intestine; through their interaction with the food, they produce a great variety of functions related to nutrition and the functioning of the nervous, immune, and cardiovascular systems through their influence on gene programming, among others. It is now known that there are periods in life that are more sensitive and have greater long-term impacts that depend on the proper functioning of this large number of microbes in the human body. Pregnancy, birth, and the first 2 years of the life of a human are crucial stages that can predispose a person to health or disease, and in this chapter, we will be able to delve into the role played by cesarean section as a way of birth in this regard.

1. Introduction

Cesarean section surgery has reached such high rates that, in many places, it is the main method of birth with a significant participation of surgeries by maternal choice. In general, the indications for performing it have been made more flexible with the justification of being an increasingly safer procedure. However, it is necessary to ask: is being born by cesarean section safer for the mother and the baby than vaginal birth? Are there long-term risk periods that are not being considered when making decisions?

The answers to these questions will be answered in this chapter and will allow more accurate decisions to be made, thinking about long-term health and the development of the individual’s full potential and not simply considering short-term risks and complications.

The evolution of medications, anesthetic procedures, hospital technology for surveillance, patient safety protocols, and the rapid solutions to complications during surgeries have made cesarean section also a safe surgical procedure for the mother with respect to the risks during this procedure or in the postoperative period. However, a greater risk of maternal morbidity and mortality has been described when compared to vaginal birth (VD), increasing this risk proportionally in each subsequent pregnancy with a greater number of previous cesarean sections.

When compared to vaginal birth, women with a previous cesarean section have a 40–96% greater risk of complications with placentation such as acretism, placenta previa, and abruption that are associated with hemorrhages, hysterectomies, massive blood transfusions, disseminated intravascular coagulation, admission to intensive care, the poor prognosis for premature babies and higher maternal and neonatal mortality [1]. The anatomical changes with each previous surgery make the current procedure more difficult and require greater skills and experience from the surgeon. Fetal complications, such as breathing problems, immaturity, and the need for intensive care, are also higher for babies born by cesarean section (CD) compared to those born vaginally (VD). Other more common activities in CDs, whose long-term impact is still unknown, are increased use of antibiotics, maternal separation immediately after birth, and delay in the start of breastfeeding.

The number of cesarean sections is considered a medical intervention indicator of maternal health. A very low rate probably indicates inadequate availability and a very high rate indicates excessive use. However, care must be taken in the interpretation of these rates, and preferably consider the variations between private and public practice, or between wealth quintiles that can mask the differences in averages in a region or nation [2]. Both sides of medical care are related to increased maternal and neonatal morbidity and mortality. On the one hand, not having access to an emergency cesarean section, when it is essential, and on the other hand, being exposed to an excess of medical interventions, often carried out by routine protocols or habits that will imply greater possibilities of adverse effects, medical errors, and acute complications.

On the other hand, different pathologies related to the immune system, such as infections, chronic diseases such as inflammatory diseases, allergies and metabolic, digestive and respiratory tract and diseases and neoplastic problems, can be considered multifactorial as they do not have a direct cause-effect relationship with a single etiological factor or antecedent of the person, however, increasing studies from different areas of science like the ones displayed in Figure 1, are paying attention to the perinatal event and its epidemiological relationship with the risk of developing pathology throughout the individual’s life. The most studied variables have been during the gestational period, such as nutrition and maternal stress, or during infancy, such as the type of attachment the baby develops with its caregivers and the type of infant feeding. The role of the relatively short birth period has only more recently begun to be studied. It is recognized that fetal complications during pregnancy and birth, such as low birth weight, growth restriction, and prematurity, may also be related to long-term health problems, but what effect can CD have on the vast majority of healthy mothers and babies in the long term, simply because of the way the birth was conducted?

Figure 1.

Representation of some of the different specialties of science that have expressed interest in contributing research aimed at understanding the physiological processes of the first 1000 days of people’s lives, which includes the time of gestation, birth, and the first 2 years of life.

When compared with VD, it has been observed in different systematic reviews and meta-analyses that birth by cesarean section CD is epidemiologically associated with a greater risk of diseases such as upper respiratory tract infections, asthma, obesity [3, 4], autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) [5, 6] and acute lymphoblastic leukemia [7]. As the main explanation for these differences in the way of giving birth, it has been found that the microbes in the intestine of the CD newborn were different from the VD, and these interact poorly with the host’s immune system at a crucial moment in its development, as they are the first hours of life.

The interest and quality of studies that try to demonstrate and understand these epidemiological relationships have been variable. For example, in the systematic review and meta-analysis of 61 studies that analyzed just over 20 million human births [5], where they identified that the quality of the studies was high in 82% of the cohort studies and in 50% of the cases and controls, they concluded that being born by cesarean section, regardless of whether it was emergency or elective, was significantly associated with ASD and ADHD.

Considering type 1 diabetes as another example, a Danish cohort study that differentiated cesarean section (CS) with and without labor analyzed the national records of 4400 young people under 15 years of age with a diagnosis of childhood type 1 diabetes and found a higher risk index in participants who had pre-labor cesarean section (PLCS) when compared to VD while there was no difference with those born by intrapartum cesarean section [8]. However, later studies, one in the Australian population [9] and another in the German population [10], did not find a significant difference so it was suggested that the microbiota may not be involved in type 1 diabetes.

The importance of differentiating cesarean sections with or without labor in studies is attributed to different factors. It can be suspected that PLCS performed either by medical indication or at maternal request could be related to psychological factors such as stress that indicate a certain genetic vulnerability and therefore a possible association with psychiatric or neurodevelopmental disease of the offspring. On the other hand, an ILCS can be performed with or without emergency, the latter in cases of true maternal compromise such as preeclampsia/eclampsia, fetal compromise such as cases of severe fetal stress, or finally, acute complications with danger for both such as cases of placental abruption. These cases of ILCS with true emergency may in themselves imply an adverse long-term prognosis for the baby.

The general objective of this chapter will be to summarize the evidence published so far that explains the differences in health according to the single variable of the form of birth. It will be specified when the research is in animal models to avoid confusion since studies in humans represent an ethical and methodological challenge understandable by the theme.

It will be explained below how the beginning of the microbiota in the early stages of life can influence the brain and other systems, conditioning the greater risk for long-term health. The role played by normal stress will also be mentioned in labor and hormonal imprinting, but we will also try to conclude why not all of us respond in the same way.

To fulfill the purpose of summarizing the existing information on the influence of cesarean section on the long-term health of the individual’s life, the terms and concepts related to caesarea, cesarean section, microbiome, microbiota, epigenetic, long-term health were searched, labor delivery and trial of labor delivery in the databases PubMed, Web of Science, Scopus, lilacs, and Ebsco. The bibliography was reviewed, especially regarding studies in humans, but some studies in animals were also included due to their relevance and usefulness for the problem under study.

2. Human microbiome and its impacts on health

The human intestinal microbiota refers to more than 100 trillion cells that each person houses, mainly in the intestine, and that includes between 100 and 1000 symbiotic microbial species co-evolving with their host and establishing a complex ecosystem [11]. Bacteria comprise most of this biomass and diversity, although archaea, eukaryotes, and viruses are also present in smaller quantities and will be sensitive to the type of nutrition and the changes we make throughout life. On the other hand, the human microbiome refers to the genes that these microbiota cells harbor, so as it is a broader term, it should not be used interchangeably. The diversity of this bacterial genome or microbiome is much greater than the diversity of the human genome itself. Our genes differentiate us from the rest, even though two random people will be 99.9% identical to each other in terms of their genome, but the microbiome defines us with its much greater quantity and diversity.

It is said that each person can be 80–90% different in terms of the microbiome of just their hand or intestine [12], thus leaving a much more specific imprint on each one. This microbiome is inherited through different generations and can evolve or change for better or worse, depending on the habits and customs of each generation. Furthermore, an unhealthy diet, stress, use of antibiotics, smoking, excessive alcohol consumption, and exposure to toxins or pollutants can lead to a decrease in good bacteria, an increase in pathogenic bacteria, and an imbalance in the intestinal microbiome (GM, gut microbiome). This is known as dysbiosis, which could trigger a series of events such as interruption of the metabolic process, epigenetic changes, increased oxidative stress, inflammation, and progression toward disease. This sequential chain of events is currently better understood in relation to major mental disorders such as schizophrenia, autism spectrum disorder, bipolar disorder, and major depressive disorder [13].

2.1 Changes in the microbiota depending on the route of birth

The GM participates in physiological processes such as host defense through various mechanisms including immunomodulation; other processes are the homeostasis of the body, metabolism of amino acids and glutathione, detoxification of dangerous substances, synthesis of vitamins and good metabolites that help digest the very important fiber in the diet that would otherwise be impossible.

Digestion of this fiber from foods such as fruits, vegetables, and legumes results in the production of short-chain fatty acids that carry out the important functions of energy production, intestinal mucosal protection, metabolic control, anti-inflammatory effect, and impact on the immune system [10].

Therefore, the first research that found changes in the intestine microbiota of newborns according to CD versus VD birth, form drew the attention of the scientific community to the role that the short intrapartum period may play in the health of the individual as mediated by their microbiota. In DV infants, the intestine microbiota resembled the vaginal microbiota of their mothers, whereas, in CD infants, they showed a composition similar to their mothers’ skin microbiota [14]. These findings initiated a series of multidisciplinary investigations that have led to a better understanding of the role of the microbiome, which will be summarized below.

Good bacteria such as lactobacilli and bifidobacteria that predominate in the VDs help break down food, absorb nutrients, care for the integrity of the gut, and help with its maturation. Bifidobacteria play an important role in the development of the immune system, produce vitamins, reduce atopic dermatitis and rotavirus infections, and improve lactose intolerance; their abundance indicates better responses to vaccination and lower risk of obesity and allergies [15].

A reduction in Bifidobacterium and Bacteroides species has been found as a consistent sign in babies born by CS [16, 17, 18], and it has been reported that cesarean section allows colonization of the microbiota by nosocomial opportunistic bacterial pathogens, such as Enterococcus, Enterobacter, and Klebsiella. It was also observed that this pronounced difference detected at 4 days of life was corrected after the first 3 weeks of life, matching the microbiota of babies born vaginally and also resembling the maternal microbiota [5, 7] and new differences between CS and VD individuals are reported in their microbiota between 2 and 7 years old [19, 20, 21].

Currently, the findings of two investigations suggest the possibility of vertical transmission of the newborn’s microbiota from various places in addition to the vagina [22]. A study in which they found no difference between the microbiota of babies born by cesarean section without labor (PLCD pre-labor cesarean delivery) and those born by emergency cesarean section (ECS), which was assumed to have exposed the babies to the hormonal response of labor and maternal vaginal flora [23]. The other study found that the microbiota of babies did not recover after orally administering 3 ml of a solution with maternal vaginal bacteria compared to a group that was administered only sterile water and the VD control group [24]. These findings question the value of vaginal seeding and suggest that other maternal sources may play a more important role in neonatal GM colonization.

2.2 Human microbiome and correlation with epigenetics

The cell cycle is the cycle of life, we are all products of repeated cycles of cellular reproduction since the beginning of life. A cell always originates from another cell at the same time that it receives all of its genetic information in each cycle. Genetic information is contained in the chromatin of the cell nucleus, which contains the association of DNA, RNA, and proteins constituting the genome.

The expression of genes conditions the division and differentiation of cells regulated by nuclear proteins that induce and coordinate the basic processes of the cycle. This reproduction and generation of new cells that replace dead ones allow the growth and development of all living beings.

It is considered that within a year, a person regenerates their entire weight in cells except neurons. During this division, cells can differentiate or specialize thanks to the programming of their phenotype and their genetic and epigenetic regulation.

Epigenetics is understood as the study of the mechanisms that regulate the expression of genes associated with physiological and pathological processes but without the modification of the genomic DNA sequence [25]. These epigenetic modifications are considered a form of adaptation that will regulate the expression of the modified genes depending on environmental stimuli and in a way that may even be reversible. The two best-known categories of these epigenetic modifications are DNA methylation and histone modification [11].

From the first moments of life, there is a microbial connection between the mother and her offspring. Each mother transmits a microbiota that she inherited from her ancestors, and that in turn she will surely pass on to her babies with some modifications caused by her own lifestyle. It is suspected that this transmission can originate vertically from different areas of the mother’s body and by different mechanisms and that birth is a determining factor in this transmission.

The GM of the newborn produces metabolites by interacting with the nutrients in the food it receives. These substances, products of the microbiota, actively participate in functions of the nervous system and immune system and in general in metabolism, in addition to epigenetically modifying the individual’s genes. This relationship between environment—microbiota—epigenetics and gene expression or inhibition continues to be studied with great interest and is increasingly better understood by the scientific community. Activities throughout life such as adequate nutrition, a healthy lifestyle, exercise, and non-exposure to toxins and pollutants are directly related to the prevention of diseases. However, the first 1000 days of human life have been highlighted as a period that is especially sensitive to the influence that the environment has on genes. In this important period of time, the way of birth is a very important variable to take into account, and that remains under the scrutiny of researchers.

There is a close, complex, and dynamic relationship between the intestinal microbiota and the immune system. Epigenetic modifications are the mechanism by which the microbiota and the immune system communicate, relate, and strengthen each other. The micronutrients used in the methylation of epigenetic changes originate from the biosynthesis processes of intestinal bacteria during the biochemical process of dietary fermentation [9].

If we analyze the relationship with the microbiome but from the already established pathology, we have evidence that shows epigenetic mechanisms as a key factor in mental disorders and immunological memory. Epigenetic alterations have a determining role in the pathogenesis of mental disorders such as schizophrenia, autism, bipolar disorder, and depression [10]. The questions that spontaneously arise would be: did these epigenetic modifications occur in the face of continued exposure to a single risk factor? Do the effects of several of them add up to finally trigger the disease? Can an isolated risk factor such as shape be sufficient to increase the risk of developing a disease?

2.3 Microbiome-related signaling system

The intestine is considered to communicate and relate directly with the brain and may produce extraintestinal effects. It is a signaling system with two-way effects that connects mainly through the vagus nerve, the enteric nervous system, and the central nervous system. Signal transmission can be by various neuronal, immune-mediated, or even metabolite-mediated pathways detected by chemoreceptors in the vagus nerve, which also promote the generation of neurotransmitters.

Thanks to these mechanisms, intestine microbes have come to be considered master regulators of CNS function. Intestine microbiota also participates in the production of acetate propionate n-butyrate (SCFA, acetate, propionate, and n-butyrate), which are critical components in the function of the microbiota-intestine-brain axis and are also an important source of human energy [10].

In the human body, we have microbes that are good for the host and more harmful microbes. Depending on the microbiota, when interacting with nutrients it also produces metabolic byproducts that help the host or others that can cause harm. Some products of bacterial fermentation such as short-chain fatty acids, vitamin B12, folate, choline, methionine, and inflammatory cytokines have useful effects by participating in the regulation of the permeability of the blood-brain barrier, optimizing mitochondrial function, synthesis of neurotransmitters, neuroprotection, immune modulation, and reprogramming of the cellular epigenome.

Harmful bacteria produce toxins, cytokines, and dysbiosis by increasing the permeability of the intestinal barrier. The integrity of the intestinal barrier is crucial in the pathophysiology of different diseases including mental disorders since it prevents the translocation of pro-inflammatory and pathogenic factors into the blood, which subsequently alters the functions of the blood-brain barrier as well [10].

There are perinatal factors that can alter gastrointestinal functions and the intestinal microbiome in terms of its abundance and diversity. Among the known factors are maternal diet and weight, use of antibiotics and/or probiotics; gestational age, weight, and sex of the baby; the mode of birth (VD and CD); type of immediate feeding of the baby and early experiences such as stress caused by painful and repeated procedures, loud noises and lights in the neonatal intensive care (NICU), infections, inflammation, and mother-baby separation [26].

These perinatal factors influence regulating the gut-brain axis with inflammatory and immune responses, mainly through changes in the expression of genes that influence health later in life. As represented in Figure 2, the degree of impact could depend on the sum of adverse or protective factors and the moment in life they take place or persist, explaining the possibility of even reversing certain epigenetic changes.

Figure 2.

Graphic description of the importance of some events such as breastfeeding and its influence on reversing or modifying the expression of previously activated or inactive genes, thus preventing possible long-term adverse health effects such as those reported in individuals born by cesarean section. Cesarean section can modify the intestinal microbiota of newborns, causing, through different mechanisms, a negative effect on the immune, nervous, and endocrine systems and therefore a greater possibility of long-term disease.

3. Brain differences depending on the type of birth

The brain remodels throughout life, but the first two postnatal weeks are characterized by remarkable plasticity, during which new synapses are actively formed and remodeled. In the first experiments carried out with mice, changes, and differences in the brain were reported between those born by VD compared to those born by CD. In the early neonatal period, it was found that those born by cesarean section had a significantly lower level of expression of the Ucp2 protein that promotes neuronal differentiation, axonal growth, and synapse formation in the hippocampus, thus corroborating that these mice had smaller neurons and fewer synapses than the VD [27, 28] in adult life they presented deficits in their spatial memory and alterations in their behavior.

This uncoupling protein 2 (Ucp2) is highly expressed in microglia and plays a fundamental role in it. Many more synaptic connections are established in the newborn brain than at other stages of life. These connections are gradually purged through the process of synaptic pruning [29]. Synaptic pruning is just one of the multiple functions of microglia, which is considered the set of immune cells that live in the brain and play an important role in its healthy homeostasis [30].

Moreover, it is considered that microglia perform a bidirectional function by supporting the survival of some neuronal cells and eliminating excess components from others [31]. This diversity of functions manifests itself in different phases of development, from regulating neurogenesis, cell survival, maturation or elimination of synapses, and maintenance of neuronal circuits [32].

In addition, in animal models, it has been observed that microbiota deficiencies are related to alterations in myelination and changes in plasticity at the level of the prefrontal cortex, which is a key region involved in a range of neuropsychiatric problems such as depression, schizophrenia, and autism. It was observed that these changes can be reversed again by colonizing with conventional microbiota as long as it is carried out within the critical window period of early development. The prefrontal cortex is considered more susceptible than other brain regions to intestinal microbial influence to undergo changes in myelination in a dynamic way even until adulthood [33].

Initial suggestions of the impact of CD on gut-brain axis communication signals as a functional model explaining the effect on microglia and brain development [34] have also progressed in human studies. Brain magnetic resonance imaging was analyzed in three cohorts of children of different ages, and it was found that those born by cesarean section had less white matter development and also significantly less functional connectivity during early childhood. Myelination of those born by cesarean section was considered to catch up with those born vaginally when the growth curve reached a plateau after the first 5 years of life and after having been influenced by factors such as breastfeeding, diet, and socioeconomic factors that could help compensate for initial differences caused by cesarean sections.

The complex interaction between microbes, endocrine system and nervous system and its influence on the development and maintenance of higher cognitive functions is currently recognized. This bidirectional interaction is achieved in different ways, which include the production of neurotransmitters and metabolites, the vagus nerve, hormonal metabolism, regulation of the blood-brain barrier, and function of the immune system [35].

Studies in humans have already indicated that the type of birth is related to neurocognitive development and, in the long term, immunological and metabolic health, highlighting the importance of GM at birth [35, 36, 37]. It is known that the alteration of the hypothalamus-pituitary-adrenal axis (HPA) is one of the pathways that links cesarean section with future disease. Reports indicate that CD babies have suboptimal cortisol concentrations in response to pain [38] and that the labor event itself initiates endocrine, physiological, and biochemical processes relevant to the neonatal immune system and its response to stress. Lower levels of inflammatory and stress markers as well as an elevation in the growth factor have been demonstrated in babies born by Cesaresera before labor contractions (PLCS) when compared with babies born vaginally, and these differences are not significant if the cesarean was during delivery (ILCD) [37].

There are growing interest in host-microbe interactions to regulate brain networks related to psychiatric disorders. It is known that microbes modulate the HPA axis throughout life and that stress affects the microbiome-gut-brain axis through its influence on the HPA axis.

HPA axis dysfunction with excessive or blunted reactivity to stressors and circadian rhythm abnormalities with altered cortisol production is linked to problems in cognitive functions, aging, systemic inflammation, and immune system dysfunction. Stress can modify the signaling system in the gut-brain axis and also influence health, hence the importance of avoiding it or carrying out strategies to reduce it during pregnancy, birth, and early ages. Accompaniment during labor, adequate management or addressing of pain, and early contact between parents and children are effective in reducing stress in the mother and baby [22]. In relation to the early life of the baby, exposure to stressors can also generate changes in the chemical structure of cytokines located in gene regulatory regions that condition the addition of methyl groups and, through epigenetics, thus contribute to neurological development disorders [39].

Furthermore, to continue learning about the physiology of these complex relationships, animal studies will continue to be an important basis for progress. For example, an animal study demonstrated that the microbiome is necessary for the regulation of genes related to myelin [30]. It is now known that continuous myelination of the prefrontal cortex (PFC) can have dynamic changes influenced by environmental stimuli and that this myelination can vary mainly in critical phases of neurological development.

The PFC is a key region involved in a wide range of neuropsychiatric pathologies such as depression, schizophrenia, and autism, and hence there is great interest in improving the understanding of the mechanisms with which GM participates. Post-mortem human studies analyzed the gene expression of the CPF of schizophrenic patients and observed abnormal regulation of genes related to myelination, which has suggested that this pathology could be the result of a defect in neurodevelopment [40]. More recent studies in post-mortem humans have identified the reduction in the expression of new genes in the pyramidal neurons of the dorsolateral prefrontal cortex and also the anterior cingulate cortex related to the severity of dementia in these patients [41]. Evidence of other pathologies and their relationship with the route of birth is presented below.

3.1 Obesity and cesarean section

Of the metabolic disorders, the example of the risk of overweight and obesity due to cesarean birth alone will be presented below. Meta-analyses and systematic reviews that evaluated the impact of cesarean section more than 10 years ago already reported its association with obesity and overweight in the offspring [42]. Subsequently, controversy arose between studies that on the one hand confirmed the risk relationship at some infant ages and others that did not find it in others during infancy. New publications that included subgroup analyses confirm that there is an increased risk of developing childhood obesity with elective cesarean section or without labor (PLCS) when compared to VD. The maternal decision for CS is attributed to fear of labor pain [43].

Moreover, the increased risk of childhood obesity is attributed to differences in newborn GM of PLCS when compared to VD, but the role of exposure to labor stress hormones is also mentioned. It is proposed that lower fetal cortisol levels in PLCS could be the cause of metabolic disturbances at birth and obesity later in life, which also coincides with the adipose tissue dysfunction found in experimental studies [44] and its paradoxical relationship with growth hormone (GH). Currently, a new systematic review confirms that the risk of obesity also in adults is increased in CD [45], and in a recent publication, the CHILD study from Canada, which included just over 3000 mother-baby pairs, confirms a greater risk of being overweight at 1 year of age, especially in PLCD males [46].

3.2 Autism spectrum disorders and mode of birth

Autism spectrum disorders (ASDs) are constantly increasing in incidence in several countries and place a heavy burden on individuals, families, and society. Genetic studies reveal a strong genetic influence, but that alone does not explain the cause in many cases. It is currently believed that both genetic, epigenetic, and environmental risk factors interact and play a role.

In addition, evidence indicates prenatal maternal factors such as obesity, stress, gastrointestinal symptoms, infections, smoking, addictions, pollutants, toxins, etc., trigger a state of inflammation and immune activation in the mother that in turn alters the GM of the baby. This altered GM produces inappropriate metabolites that influence epigenetically, generating a greater risk of mental illnesses in the offspring, among which are ASDs [10]. But what role do interventions such as cesarean section play in the short period of birth, and what would be their influence on long-term sequelae?

If only the VD or CD route of birth is taken into account, the positive association between cesarean section (CS) and ASD described in different epidemiological studies [47] has been strengthened as confounding variables continue to be ruled out. For example, gestational age at birth and prematurity may be important in the positive association between cesarean section (CS) and (ASD). Therefore, in a study carried out in five countries that analyzed the association of premature birth and that also identified emergency cesarean sections (ECS) and planned cesarean sections (iLCS), they analyzed a study sample that included almost 5 million babies from singleton pregnancies that survived their first year of life, just over 670,000 were born with CS, and there were 31,073 children with ASD. They found that both ECS and iLCS were consistently associated with a modest increased risk of ASD from gestational weeks 36 to 42 compared with vaginal delivery [48].

In the United States, a parallel increase in ASD is estimated along with that of CDs and labor inductions. CDs increased from 5% in 1970 to 32% in 2015, and inductions from 9.6% in 1990 to 27.1% in 2018. In the 1980s, it was estimated that less than 1 in 1000 children had ASD, and this figure increased to 1 in every 54 by 2016.

A recent retrospective study published by the state of California, USA, that included nearly 1.5 million low-risk pregnancies and births between 1992 and 2012 comparing induced and uninduced VD and CD to labor and found that the risk-adjusted probability of ASD increased by 7% (AOR = 1, 7, 95% CI = 1.01, 1.14) for induced VD, 26% non-induced CD (AOR = 1.26, 95% CI = 1.19, 1.33) and 31% in CD after induction (AOR = 1.31, 95% CI = 1.18, 1.45) when compared to non-induced VD to labor [49].

Similarly, another meta-analysis that included 35 studies confirms a higher risk of ASD (OR = 1.25, P < 0.001) and ADHD (OR = 1.11, P < 0.001) in CD offspring compared to VD [47]. Neither of the last two mentioned studies differentiate between iLCD and PLCS. The importance of labor for both mother and fetus should make us change the simplistic view of only two birth options, vaginal or abdominal.

The importance of labor and its long-term effects are still poorly understood to justify adding in future studies and registries the difference between births without labor, that is, birth by planned cesarean section or by maternal choice, which we will group simply as pre-labor cesarean section (PLCS). And thus be able to contrast them with the other modes of cesarean section such as in-labor non-emergency cesarean section and planned in-labor cesarean section, in addition to vaginal births [50]. The reason for making these differences is to learn more about the long-term effects. A cesarean section during non-emergency labor such as those indicated for failure to progress or arrest in labor may not present the same risk as emergency cesarean section due to acute fetal distress or failed operative delivery.

Mental disorders may be the best-studied example regarding the relationship with differences in the composition and function of the GM of both the mother and the newborn. Diversity in maternal intestine microbiota may increase the risk of ASD in their children. It has now been proven that mothers of ASD children share similar microbiota profiles, and ASD children also exhibit unique bacterial biomarkers when compared to healthy children [51]. Although the etiology of disorders such as autism spectrum disorders (ASD) can be complex and multifactorial, both genetic and environmental factors influence its development together mediated by epigenetic modifications. Exposure to environmental risk factors during pregnancy such as nutritional deficiencies (vitamin D and folate) and toxins (sodium valproate, Bisphenol-A) and intrapartum factors such as cesarean delivery leave epigenetic marks through alteration in DNA methylation.

New strategies based on nutrition and lifestyle are being investigated to reduce the negative effects on behavior of disorders such as AED or aggression in other types of mental problems [52, 53]. The existence of a complex relationship between nutrition, genes, and the brain is known. An adequate diet and regular physical activity directly influence brain health, mood, and cognitive functions throughout life.

Research continues with the aim of improving methylation and correcting epigenomic deficiencies with personalized diets based on the genetic or epigenetic profile of each person, adapting with specific supplements to reinforce the 1-carbon metabolism [54]. 1-carbon metabolism comprises a series of interconnected metabolic pathways that includes the methionine and folate cycles fundamental in cellular function, synthesis of DNA, polyamines, amino acids, creatine, and phospholipids. The methionine and folate cycles contribute to the formation of S-adenosylmethionine, which is the universal donor of basic methyl reactions of epigenetic mechanisms that regulate gene expression [55].

The usefulness of GM remodeling as a way to versatilely regulate communication and behavior between the intestine and the brain is also viewed with great interest with the intention of exploring new treatments. Novel techniques of genetic manipulation of intestinal microbes and specific degradation of proteins in bacteria, in addition to advances in optogenetics and chemogenetics, are trying to decipher the gene-microbiome-phenotype communication of complex neuropsychiatric diseases and thus aspire to new, more personalized therapeutic strategies and precises interventions. This field of microbiome research will allow progress from simple initial associative links to causal and mechanistic knowledge of adult pathology related to early-life dysbiosis [56].

3.3 Cesarean section without labor and other considerations

PLCS, in which the baby was not exposed to the hormonal stress of labor and transmission of the ideal microbiota, could be considered the most unfavorable way for the baby to be born. However, few studies differentiate between cesarean section with and without labor contractions, and even fewer detail its duration and whether there was a maternal or fetal emergency that conditions the need for it.

In a recent study that determined levels of inflammatory, stress, and growth biomarkers, newborns born by cesarean section without labor (PLCS, pre-labor C-section) were compared with babies born by cesarean section during labor (iLCS, in-labor cesarean section) and VD, and significant differences were found suggesting that labor has an important effect on the immune system and stress levels regardless of whether the birth was concluded by cesarean section or vaginally [57].

It has been reported that PLCS could be related to the decreased T cell receptors at birth with an increased risk of early onset acute lymphoblastic leukemia (ORprelaborCD=1.66, 95% CI: 1.13-2.43) [58]. The reason is believed to be the PLCS baby’s lack of exposure to the effects of stress hormones released during labor. Although another study replicated this increased risk in both PLCS and emergency cesarean sections [59], a more recent systematic review and meta-analysis of observational studies report that PLCS (pre-labor C-section) increases the risk in offspring more than emergency cesarean section (ECS, emergency C-section) [7, 60].

A study that directly used obstetric records to record the time of onset of labor and the reason for cesarean section in the UK population of babies born on average in the year 1989 when cesarean sections accounted for only 12% of births compared just over 1000 children with LLA and their controls and classified them as PLCS if the medical history indicated that labor had not started before CS. They found that the majority of PLCS were elective/planned due to previous CS, breech presentation, or placenta previa, and 23% were ECS with diagnoses of fetal distress. They found no significant evidence that CS in general increases the risk of childhood LLA [61]. For a better interpretation of the emerging studies, it would be important to consider possible generational changes in the microbiota. That is, with exposure to new lifestyles, differences in diets, and contact with new antibiotics, for example. We can infer that the microbiome of new grandmothers, mothers, and daughters will also be modified and therefore also the epigenetic expressions.

Changes in genetic expression can be dynamic, reversible, stable, or heritable to new generations thanks to the plasticity of the phenotype effect of epigenetic programming [62]. The cumulative effect of exposure to new good or bad environmental factors will probably be responsible for each member of the offspring responding with health or disease, giving this plasticity and/or reversibility to the epigenome.

From a more general and integrative view, recent analysis of the diverse and sometimes confusing information to date reported in systematic reviews and meta-analyses concludes that the early age at the time of ALL diagnosis suggests a hereditary component but that exposures to other factors in uterus and during early childhood may be a determining factor in the increased risk and should be considered a relevant time window. Risk factors were evaluated in 196 meta-analyses, 35 systematic reviews, and 17 pooled analyses, classified by window of exposure, strength of evidence, and magnitude of childhood LLA risk. Cesarean section, maternal diabetes, paternal age, and increased birth weight showed an association with childhood LLA; other modifiable factors also related to variable risk of strength in their association with LLA were exposure to pesticides, high intake of coffee and cola, infertility treatments, paternal smoking, maternal age over 25 years, and postnatal exposure to ionizing radiation to benzene and living near oil stations. An inverse or protective relationship was found with factors such as breastfeeding, taking vitamins and folic acid, living with pets, or living in the countryside [63].

4. Role of labor

Spontaneous and physiological labor is considered to be a complex neurohormonal process that generates brain neurochemical modifications in both the mother and the baby, which adapts and programs them in a special and different way when compared to babies who were not exposed to labor. During labor, differences are created that would be impossible to reproduce artificially. Hormonal levels in both mother and baby reach higher levels than at any other time in life. Actions as simple as separation from the mother after childbirth can impact the beginning of attachment, bonding, breastfeeding, and the neurodevelopment of the newborn [64].

4.1 Childbirth as a neuroendocrine event

Motherhood involves neurochemical, morphological, and functional changes that facilitate the initiation of appropriate maternal behaviors and the survival of newborns. Specifically, childbirth is a physiological event, not just a mechanical one, in which a complex and sensitive neuroendocrine synchronization is carried out that achieves the necessary changes for both the mother’s body and that of the baby to achieve the miracle of birth.

It is known that the maternal hypothalamic-pituitary-adrenal (HPA) axis adapts and attenuates its responses during pregnancy and lactation to psychological and physical stressors. In this way, it helps to avoid the adverse effects of stress in both the mother and the offspring by reducing their excessive exposure to glucocorticoids and facilitating more appropriate metabolic and immune responses [65]. Depending on the severity of the stressful phenomenon will be the level of HPA deregulation and its duration even throughout life [66].

Physiological birth functions for the fetus as a necessary phenomenon of stress level or eustress [67] that causes a massive sympathoadrenal activation that will help with the adaptation of the newborn to the new environment dependent on the oxygen of the air it breathes by increasing blood flow, activating CNS, regulating cytokines and promoting lung maturity, developing sense of smell, and facilitating attachment to the mother.

After birth, keeping the newborn with its mother balances stress thanks to the vagal stimulation caused by being in skin-to-skin contact and initiating suction to the mother’s breast early.

The baby that is born without having been exposed to labor does not participate by emitting signals of lung maturation, nor is it exposed to eustress, the deprivation of which can leave an important imprint on the functioning of its HPA axis. We do not know the role that this plays in the development of their sense of smell, in the recognition of their mother, in breastfeeding, or in the levels of adiponectin, a hormone involved in fat metabolism and which is apparently decreased in births without work of childbirth [68].

4.2 Skin-to-skin contact between mother and baby

Skin-to-skin contact (SSC) between mother and baby, according to UNICEF, is described as placing the newborn naked or with a diaper or cap on the mother’s bare skin and only covering the exposed back with a towel or sheet. It is recommended immediately after birth for at least an hour in all women or until after their first feeding at the breast, and if they are still eating, they should continue until they finish feeding; it is also advisable to implement it at any time thereafter and for any period of time.

This period after birth, which lasts approximately 2 hours, has been called the critical or sensitive period due to the importance it represents for the development of attachment behaviors and the beginning of early breastfeeding [69].

Skin-to-skin contact (SSC) reduces crying in babies, helps conserve energy, adjusts acid-base balance, maintains temperature, improves interaction between mother and baby, facilitates crawling behavior and more effective suction; in the mother, it reduces cortisol levels and increases maternal attention to the baby and promotes vocal communication and achieves greater lactogenesis. In the long term in the baby it promotes emotion regulation, stress reactivity, and social and cognitive development [70, 71, 72].

Facilitating SSC in just minutes (immediate SSC) after CD or within the first hour of life (early SSC) can help reduce time to first breastfeeding, reduce formula supplementation in the hospital, improve mother-baby bonding and maternal satisfaction also does not imply disadvantages or other risks [73].

A recent randomized clinical trial has shown that postpartum EFS of full-term infants influences the composition and volatility of the gut microbiota in early infancy in addition to its age in late infancy. Three possible mechanisms of action were proposed: first, natural physical contact through SSC and care; the second was breastfeeding; and the third was the de-stressing effect of SSC, which can function as a buffer and influence the volatility of the microbiota [74].

5. Offset the disadvantages of cesarean section

The negative effects mentioned so far of CD and mainly PLCS can be compensated thanks to the fact that the microbiota and its effect on the brain, immune, and metabolic system can be partially or completely reversed depending on how early corrective measures are implemented. These measures can be environmental, such as the type of diet, upbringing, and maternal habits. On the other hand, one should avoid adding other grievances or bad habits during the gestation period, perinatal period, early parenting, and the rest of development.

Breastfeeding may be the most important factor that modifies or restores the intestinal microbiota after birth. Breastfed infants with CSD have demonstrated partial restoration of gut microbiota compared to formula-fed infants with CSD [75].

5.1 Use of antibiotics

The antibiotics routinely used by the mother to prevent subsequent infections in CD may also play an important role in the most critical period of acquisition of the baby’s intestinal microbiome. Babies born by VD whose mothers received prophylactic antibiotics prior to birth were also characterized by an altered microbiome with low numbers of bacteroids during the first month of life [9], so delaying their administration until after umbilical cord clamping could help reduce this negative impact.

There is a study with just over 55000 women in which no differences in wound infections were found when comparing the administration of prophylactic antibiotics before or after cord clamping [76]. This new evidence is relevant to evaluate protocols for the use of prophylactic antibiotics taking into account the impact on the baby in the long term.

5.2 Breastfeeding

Pointing out the short- and long-term maternal benefits, as well as the nutritional and protective importance of unique characteristics of breast milk [77], is beyond the scope of this chapter, so only some long-term aspects for babies will be mentioned. Epidemiological studies indicate that early and exclusive breastfeeding is associated with higher IQ values and cognitive functioning in childhood and adolescence, and it has been demonstrated by magnetic resonance imaging that breast milk promotes healthy neuronal growth and better development of the white matter of the brain thanks to better general myelination [78, 79].

It should be noted that breast milk serves as a rich source of bacterial species with its own microbiome and that it represents a crucial role in the introduction of these beneficial bacterial species to the baby’s gastrointestinal tract from birth and at least for the first 1000 days of life. As illustrated in Figure 2, breast milk is a determining factor that influences the composition and maturation of the baby’s intestinal microbiota, helping to prevent negative health outcomes in more advanced stages of life [80]. Studies comparing breastfed and formula-fed infants suggest vertical transmission from mother to child through breastfeeding and this contribution to infant microbial seeding could be one of the pathways through which the human milk microbiota impacts the child’s health [15, 81, 82].

It is known that cesarean section can affect breastfeeding by prolonging the time for the baby to feed for the first time at the mother’s breast, and is related to a lower incidence of exclusive breastfeeding by increasing the probability of supplementation. Limited mobility and postoperative pain or treatment of complications may also influence the maternal decision [83]. Early onset of breastfeeding is a consistent and significant predictor of prolonged breastfeeding [84]. However, maintaining its exclusivity can be a challenge if there are problems with latching on to the breast [85], misinformation, or lack of professional help, so achieving prolonged breastfeeding beyond the first 6 months deserves more attention.

Currently, there are also studies evaluating the different uses and benefits of prebiotics and probiotics as an alternative to restore the intestinal microbiota and prevent or even reverse the negative effects of dysbiosis, including the effects of antibiotics on the microbiota [86]. Breastfeeding counteracts the risks of dysbiosis in the newborn and achieves its epigenetic modulation effect both due to its content of nutrients and substances and due to the reparative effect of the microbiota itself, providing its rich source of microbes [87]. The oligosaccharides provided by HM are a crucial determinant for the genetics of the baby and can be balanced with other factors that can also shape GM such as the way of birth, race, and vitamin D levels. On the other hand, symbiotic intervention stands out as a safe and effective way to modulate the microbial environment by producing organic acids that improve the epithelial barrier function of the intestine [88].

The success of breastfeeding has implications for health for the rest of the individual’s life, so pursuing it should be a priority and common interest of everyone related to maternal and neonatal care. Doing and supporting more research in lactation and human milk (HM) is vital to understanding and improving global health. The remaining challenges are to address low breastfeeding rates and reduce inequalities to improve population health; Increase awareness about the benefits, difficulties, and complexities of breastfeeding among health professionals and the public; study and support alternative modes of feeding with HM such as expressed milk, donor milk, and shared milk; better understand the variability of MH composition and its mechanisms on health [89].

5.3 Evolution of the cesarean section technique

With the aim of encouraging the mother and father to be more active participants in the birth of their baby instead of passively going through the surgical event, a team of doctors published their experience at Queen Charlotte’s Hospital in London in 2008, which they called a natural cesarean section. This cesarean section included the parents being able to see the baby immediately upon leaving the mother’s womb by slowly extracting it to make it more capable of initiating breathing without assistance, immediately placing it skin-to-skin with the mother, promoting maternal attachment, and if the father requested it, he could make the second cut to the umbilical cord [90].

In a similar way, they used transparent plastic surgical covers so that the mother could see through them at the Brigham and Women’s Hospital in Boston, which they called a gentle cesarean. On the other hand, to return to the importance of early mother-baby contact, the Memorial Hospital of Rhode Island, affiliated with Brown University in 2009 implemented its gentle cesarean delivery pilot program in low-risk patients. This program was based on minimizing extraneous conversations between caregivers, music of the patient’s choice, delaying cord cutting for at least 30 seconds, immediate SSC, supporting breastfeeding, and avoiding mother-baby separation unless indicated or at the request of the mother. Their success in maternal satisfaction and the absence of morbidity allowed them to perform the procedure also in unscheduled and urgent cesarean sections in 2011 [91].

In the traditional CS of the Leiden University Center, the first moment of bringing the mother together in skin-to-skin contact with her baby was until the anesthetic recovery in the postoperative period until they decided to evaluate the so-called family-centered cesarean section (FCS), which was increasingly implemented in many hospitals to improve maternal satisfaction and early attachment to the mother. At that time, there were controversies about the safety of the procedure regarding the risk of hypothermia, infections, or respiratory distress, so they set out to evaluate the safety of FCS and began their pilot study in 2014 in healthy, low-risk mothers using a hot air system to cover the mother, and also raised the temperature of the surgical room. They detected an increase in neonatal admissions (21 vs. 7%) in the FCS group, which they attributed to SpO2 monitoring, but there was actually no greater respiratory morbidity or hypothermia [92].

Later studies did not report greater risks when comparing FCS with planned CS [93] and instead concluded that the time of SSC was longer and there were higher breastfeeding rates [94]. These FCS did not take into account long-term health effects on the baby or possible differences with cesarean sections in labor (iLCS).

Perioperative anxiety may also have physiological implications in relation to sympathoadrenal activation with circulatory effects that may increase the risk of surgical complications. Furthermore, a holistic surgery technique that takes care of the emotional and psychological needs of the mother and her partner can make the birth experience more human and extraordinary. Health personnel who care for women during a cesarean section should not forget that although it is a surgical procedure, it is still above all, a “birth” and not just a “surgery,” Capogna mentions in his book [95]. You can help achieve a warmer environment during cesarean sections by avoiding cold temperatures in the surgical room and having dimmer lights. Promoting maternal support, SSC, mother-baby attachment, and early breastfeeding have short and long-term benefits. There is scientific evidence outlining the benefits of music in helping with pain and anxiety during VD and CD.

In Mexico, the experience of a private hospital was reported with its humanized cesarean section protocol that began in 2011, with a convenience sample of 150 women, with a requirement for inclusion to have been in trial labor. The main reasons for cesarean sections were secondary arrest at dilation, failure of labor progression, and non-reassuring fetal status during monitoring. High-risk women were included: 39.3% of the participants had at least one previous cesarean section, 8% had a hypertensive disorder, 5% had pelvic presentations, 5% were premature, and 2% had twins, and there were also diabetics, one woman with uterine dehiscence, one with abruption placenta, and one with eclampsia. Immediate SSC was performed in 88% of cases. The protocol included the management of maternal stress and anxiety through accompaniment by a trusted family member, music therapy, and a setting with dim light and warm temperature control; SSC was also carried out immediately and permanently during surgery and recovery period in addition to supporting the initiation of breastfeeding within the first hour of life.

With these actions, great maternal satisfaction was achieved, but above all, a high prevalence of breastfeeding in the first hour and prolonged for at least 6 months [96]. This study was characterized by achieving a change in attitude in the team of doctors and nurses that was sufficient to be able to apply the protocol without alterations to the infrastructure. Thus, it was possible to reduce maternal stress, keep mother-baby united by practicing SSC, and initiate breastfeeding during the first hour of life, even in patients classified as high risk. It was recognized that in order to increase the rates of prolonged breastfeeding, it is important to reinforce the maternal intention to breastfeed with adequate information but, above all, with support to resolve difficulties in latching on for the first feedings and correcting myths and misinformation that may arise.

6. Discussion

The considerations presented in this chapter have the main limitation in that they are the result of the analysis of the evidence carried out by the author and represent only a summary of it with the best intention of understanding the different mechanisms involved and the role they play during the first bacterial colonization of the newborn host and its impact on immune system programming and hormonal imprinting with long-term effects.

A series of intertwined events have been described that are of great importance to the long-term physical and mental health of the individual. The description of these events has been described linearly for better understanding, although they are not necessarily carried out that way. Aspects have been mentioned from global health during pregnancy, the birth period, and early childhood habits, but the role of a main variable has been highlighted, which would be the way of birth via VD and CD, but in no way has the intention been to generate alarm but rather to raise awareness to adopt the necessary preventive measures.

We can now summarize that the microbiota is acquired mainly at birth but that it will develop, mature, change, and evolve throughout life, permanently interacting through different pathways with different systems, mainly the immune, endocrine, and nervous systems. The microbiota of each individual is more extensive than their own cells, and, like them, they contain their own genome, which is even much more specific and can make more precise differences than the genes themselves in each person. This microbiome has the ability to modify the function or expression of its host’s genes without affecting its structure through a mechanism called epigenetics. There are still doubts about how and from where future mothers transmit their own microbiome, which in turn they acquired from their mothers but which they surely modified in diversity throughout their own lives through their own habits, especially food but also lifestyle exposure to other environmental factors such as toxins, pollutants, tobacco, alcohol, stress, which affects the quantity and variety of your intestinal microbiome, which is known as dysbiosis, conditioning epigenetic changes and effects on metabolic processes, increased oxidative stress, inflammation, and other mechanisms that favor the development of diseases.

It is possible to recognize then that the first 1000 days of life of individuals are crucial to acquire their own microbiota, mature their microbiome, and initiate the first and very important interactions with the other systems of the organism that will program them to function in a certain way in the long term, which conditions the individual’s ability to acquire or resist certain diseases at another stage of their life. It is also possible to highlight the concept of epigenetic plasticity, which means that the changes or predisposition acquired in a period as critical and sensitive as the perinatal period can also be reversed or modified in other sensitive, although less critical, periods and even during the rest of life of the person, which means that not all people develop the aforementioned pathology. The protective role of breastfeeding and other factors such as adequate nutrition during pregnancy, avoiding excess stress in mothers, and promoting skin-to-skin contact between the mother and her baby as soon as possible and for as long as possible are highlighted, ensuring non-separation between them. These simple actions alone and, even better, together can help restore the microbiota and its epigenetic functions.

Therefore, in the face of the growing epidemic of cesarean sections, many of them not necessary or performed without having attempted prior labor, of which we continue to be unaware of its extent, many will wonder if they or their descendants were born by cesarean section, why they have not started having problems? Or how much greater risk will they have for having made this decision? The simple answer is that an individual is different, and so is his response. Remember that most of the health problems mentioned may have a genetic component, but in reality, there are many factors that can influence their onset; it is true that some factors have more strength and influence on the risk, but in the end, they very likely to develop a health problem that will depend on the balance between the protective and harmful factors that we add and the strength or sensitivity of each of us.

7. Conclusions

A lot of the published evidence has been gathered and synthesized regarding the relationships that the form of birth may have with the development of diseases in other stages of the life of the newborn individual. An attempt has been made to establish the differences between some of the types of cesarean section, such as that with or without having started labor, and its counterpart, which is being born vaginally. It has not been possible to obtain evidence that clarifies the long-term effects of other types of cesarean sections, such as those that are performed after labor has begun but without being in a real emergency with danger to the life of the mother or the baby and in the absence of evidence has not been delved into different types of vaginal birth, such as that achieved naturally or physiologically, referring to the mother who began and continued her labor and birth without medications or the DV that was initiated and augmented with medications. The effect of other medications such as anesthetics, antibiotics, or other interventions such as the use of suction cups or forceps was not addressed.

Therefore, from this review, we can conclude that the variables that participate and can influence the development of long-term diseases are many and different in each person and that the pathologies mentioned by themselves are considered to have a multifactorial cause, which will continue to be a great challenge to take into account to obtain future studies of methodologies with greater scientific value or statistical power. No specific conclusions are made regarding the risks and types of diseases to which people born by cesarean section are exposed, but reading this chapter allows the reader the opportunity to raise awareness that these mainly epidemiological relationships exist, that there is still much to understand about the mechanisms and that when in doubt it will always be better to act with caution, adequately justify the interventions and avoid routine interventions, approaching the first 1000 days of life for what it is: a period that is actually critical and very sensitive for people.

Conflict of interest

The authors declare no conflict of interest.

Notes/Thanks/Other declarations

Dedicated to Guille and all the people who, in one way or another, have experienced cancer or the mental illness of a loved one closely. Before, it was believed that with some hereditary problems, we were destined to experience them, and there was nothing that could be done. Now we know, thanks to a better understanding of epigenetics, that a lot depends on ourselves, so let us get to work with everything that is available in our hands to improve, prevent, and have better health.

Abbreviations

HPA	hypothalamic-pituitary-adrenal
SSC	skin-to-skin contact
PLCS	pre-labor C-section
iLCS	in-labor cesarean section
ASD	autism spectrum disorders
ADHD	attention-deficit/hyperactivity disorder
GM	gut microbiome