Sunday, April 23, 2017

Sonoma Medicine

The magazine of the Sonoma County Medical Association

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UNINTENDED CONSEQUENCES?
Cesarean Section and Long-Term Child Health

Mark Sloan, MD

In 1971,
the year I graduated from high school, 6% of American children were born by cesarean section. By 2013 the cesarean rate had risen to 32.7%—a five-fold increase in little more than four decades. As a pediatrician, I witnessed that increase firsthand and, in general, welcomed it. I’d been in enough tense delivery room situations early in my career to see the increase as a positive change. More cesareans meant safer births for more babies, I thought. What could be bad about that?

I witnessed another trend firsthand during those decades: as the 1980s gave way to the 1990s and 2000s, the number of children with chronic inflammatory and autoimmune disorders steadily climbed. More and more of my young patients were diagnosed with asthma. Type 1 diabetes, previously a disease of school-aged children and teenagers, began to strike at younger ages than before—as young as 11 months in one memorable case. And although I didn’t see much of it, inflammatory bowel disease was becoming more common across the country.

The rising incidence of inflammatory diseases in younger-than-usual children spurred a search for causative factors in pregnancy and early infancy, when the fetus and newborn are particularly sensitive to environmental insults. One obvious environmental trend was the increasing cesarean section rate, which roughly paralleled the increase in disease. Scientists began to wonder: could the two somehow be connected?

Concerns about a possible link between cesarean section (CS) and chronic inflammatory diseases in childhood date to the early 1990s, after the Soviet Union disintegrated and previously isolated Eastern European countries opened to travel. As public health researchers fanned out across the old Soviet bloc, they noticed something odd: an “asthma gradient” that ran from east to west, with asthma much more prevalent in industrialized western countries than in the more rural, formerly socialist nations to the east. A child living in Sweden, for example, was significantly more likely to have asthma than a child living in Estonia—only a couple of hundred miles away.1 A lot of analysis and a little out-of-the-box thinking eventually led to an unorthodox theory.

Researchers noted that while CS rates in Western European countries had risen sharply since the 1970s, those in the countries of the former Soviet bloc had remained low and relatively stable. Variation in national CS rates roughly matched the variation in asthma prevalence.

At about the same time the importance of the newborn gut microbiota to immune system development—and the idea that mode of delivery exerted a strong influence on the composition of the microbiota—were coming under scrutiny. Could the dots be connected? Could at least some of the asthma gradient—and by extension some of the variation in prevalence of other chronic inflammatory diseases—be explained by differences in Cold War birthing practices?

While the issue remains far from settled, current evidence appears to support a link between CS and a mild-to-moderately increased risk of diseases related to immune system malfunction. This article examines three of those diseases: asthma, type 1 diabetes and inflammatory bowel disease.

Asthma

Asthma is by far the most common chronic inflammatory disease of childhood and, with millions of American children afflicted by this disease, a pressing public health issue. As noted above, its prevalence has increased disproportionately in industrialized, more affluent nations compared with poorer and more rural countries. Asthma has been linked to a number of environmental factors, including air pollutants, indoor allergens, dampness and mold. To date, more than 30 research papers have examined a possible cesarean section-asthma (CS-A) link.

Initial studies found a strong association between CS and asthma. In a retrospective birth cohort, for example, Xu (2001) found that Finnish adults with current asthma were three times more likely to have been born by CS than by vaginal delivery (VD).2 Methodological problems dogged this and other early research: the failure to adjust for prematurity and a history of maternal asthma, known risk factors for both CS and child asthma, significantly clouded interpretations of the data. However, separate meta-analyses by Bager3 and Thavagnanam4 in 2008 arrived at similar, if less robust, conclusions: CS was associated with a 20% increase in risk of child asthma.

The majority of studies published since 2010—more statistically rigorous than their predecessors—have found a significant CS-A association. Recent retrospective birth cohort studies in Sweden5 and Denmark6—involving a combined 2.2 million mother-child couplets—found that, similar to the 2008 meta-analyses, CS babies were about 20% more likely to be diagnosed with asthma in childhood than were vaginally born infants.

Problems with CS-A research persist, however. Asthma, particularly in infants and young children, can be difficult to differentiate from viral respiratory infections, a source of confusion that can lead to both over- and under-diagnosis. Diagnostic criteria can differ significantly between studies as well: health questionnaires or parental recall are used by some researchers; hospital admission or pharmacy registries by others.

Virtually all studies on the subject of CS and future child health are retrospective epidemiological studies, and so are more subject to bias and confounding than prospective studies. For example, significant factors like maternal smoking, a family history of asthma, and socioeconomic status may or may not have been accurately recorded in decades-old birth registries.

Finally, while epidemiological studies can show that an association exists, they cannot prove causation. Prospective studies with meticulous record keeping would provide a clearer picture, but the gold standard of medical research—a randomized controlled study allocating women to either cesarean or vaginal birth—is obviously impossible.

Diabetes and IBD

Type 1 diabetes mellitus (T1D) is a progressive autoimmune disorder in which a T-cell-mediated autoimmune process targets and destroys pancreatic beta cells. The etiology of T1D remains elusive; genetic susceptibility and a number of environmental factors have been implicated.

The number of children living with T1D has increased dramatically in the last quarter century. During the 1990s the global incidence of T1D rose an estimated 2.8% per year.7 The 2009 EURODIAB study predicted a doubling of new cases in European children between 2005 and 2020.7 In the United States, the prevalence of T1D increased 21.1% between 2001 and 2009.8

The dramatic surge in new cases of T1D suggests that as yet unidentified environmental factors are to blame. The increase has been particularly steep among the very young (<4 years old), a trend that again led researchers to examine the prenatal and perinatal periods for possible answers. In 1992, Dahlquist was the first to demonstrate an association between T1D and CS.9

A 2008 meta-analysis of 20 studies demonstrated a 20% increased risk of T1D in CS-born children after adjustment for gestational age, birth weight, maternal diabetes and other potential confounders.10 Since 2010, research in Canada, Germany and Australia has found similarly increased risks. Support for a CS-T1D association hasn’t been universal, however: a recent Swedish study found that the association nearly disappeared when siblings were used as controls.11 Still, the discussion among many diabetes experts has shifted from whether a CS-T1D association exists to exploring possible mechanisms for that association.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder consisting of two major phenotypes: Crohn’s disease and ulcerative colitis. The etiology of these diseases is multifactorial, involving complex interactions of genes, the immune system, the gut microbiota and environmental factors. As is true for asthma and type 1 diabetes, the incidence and prevalence of IBD have risen significantly in the last 25 years.

Although not as well studied as the CS-A and CS-T1D associations, a half-dozen studies in Europe and Australia since 2009 have consistently demonstrated a mild-to-moderate increase in risk of IBD for CS-born children. A recent Danish national cohort study found the risk, adjusted for a number of possible confounders, to be increased by 29%.12

Possible Mechanisms

Hypothetically, if a causal link does exist between CS and at least some cases of chronic immune system disorders, what might be the mechanism(s)? Leading theories include (1) changes in the neonatal gut microbiota induced by CS, (2) inadequate immune system priming due to the absence or shortening of labor, and (3) other factors for which CS may simply be a marker.

Neonatal gut microbiota.
The bacteria that colonize the neonatal intestine are known to play a major role in the development of the mammalian immune system. In experiments with germ-free mice, failure to normally colonize the gut at birth leads to severe defects in gut-associated lymphoid tissue, cell-mediated immunity, and antibody production.13

CS alters the gut microbiota by allowing bacteria from the skin and hospital environment to colonize the lower intestine, rather than the bacteria normally acquired from the maternal birth canal and perianal area in a vaginal birth. These abnormal bacteria suppress TH-1 activity and promote a pro-inflammatory TH-2 response, which in turn can lead to increased mucosal permeability, a situation that makes it easier for pathogens, endotoxins and food antigens to enter the neonate’s bloodstream.13

Such disturbance of the gut microbiota can last months or even years—a critical period in immune system development—and may predispose a child to chronic inflammatory and autoimmune disorders.13

Absence or shortening of labor. The absence or shortening of labor in a cesarean section appears to affect a number of hormones that are known to play a role in stimulating the immune system at birth. In a vaginal birth, fetal hypoxia resulting from uterine contraction leads to a significant stress response, which in turn leads to very high catecholamine and cortisol levels in the neonate. These stress hormones play a key role in activation of the neonatal hypothalamic-pituitary-adrenal axis. A delay in HPA maturation could alter the early development of the immune system.14

In addition, the cord blood of babies born by elective CS (i.e., before onset of labor) has been found to be lower in neutrophils, lymphocytes and natural killer cells than that of their VD counterparts. Leukocyte activity is diminished as well; overall immune system function is hampered. Differences in lymphocyte function between CS and VD babies have been detected as late as one year of age.14

Although speculative at this point, it is possible that CS may also cause epigenetic alterations in the newborn that predispose to inflammatory disease later in life. Animal studies have shown that neonatal stress can lead to permanent epigenetic alteration via DNA methylation. A small Swedish study found that human infants delivered by elective CS had significantly elevated cord blood leukocyte methylation compared with VD newborns.15 While the significance of these findings is unclear at present, it does suggest that the newborn epigenome is sensitive to perinatal influences.

Other factors. One factor for which CS may be a marker is antibiotics, which are known to cause marked and long-lasting alteration in the gut microbiota in infancy. As antibiotics are a routine part of a cesarean birth, it is possible that they (or other, as yet unidentified, iatrogenic factors), rather than the CS per se, may be responsible for at least some of the association between CS and chronic diseases.

Another factor is breastfeeding. Breast milk contains antibodies, leukocytes, probiotic bacteria and other immunologically active substances. CS is associated with lower rates of successful breastfeeding, which may contribute to delayed or abnormal immune system development.16

Disease Burden

If cesarean section does have a causal relationship with a number of chronic inflammatory disorders—and to reiterate, this has not been proven—how much disease could it actually cause?

Take asthma as an example. In a 2008 meta-analysis of 26 epidemiologic studies, Bager estimated that 1–4% of asthma cases could be attributable to CS.3 Approximately 7 million American children currently have asthma. Using Bager’s figures, CS could be responsible for between 70,000 and 280,000 cases.

A 25% reduction in the U.S. cesarean rate (i.e., returning to 2001 levels) could mean 20,000 to 70,000 fewer cases of asthma over an 18-year period. If the cesarean rate were reduced to the WHO-recommended level of 15% of all births, the reduction in disease could be proportionally greater.

Prevention of a relatively few cases of asthma may not be the whole story, however. Unaddressed in Barger’s analysis is the issue of disease severity in children who were destined to develop asthma regardless of mode of delivery. If CS does put children at risk to develop the disease, it follows that it could also worsen the disease in children whose asthma is primarily due to genetic or other factors. It’s possible that a reduction in cesarean sections could mean less severe disease for those CS-born children who would have developed asthma in any case.

Conclusion
While cesarean section has saved untold numbers of lives en route to becoming a nearly routine alternative to vaginal birth in the early 21st century, it may be accompanied by unintended consequences that are only now becoming evident.

A significant majority of recent research studies has found that an association exists between CS and a mild-to-moderately increased risk of several chronic inflammatory diseases in childhood, including asthma, type 1 diabetes, and inflammatory bowel disease. The extent to which CS may contribute to the overall burden of these and other diseases is unclear at present.

In emergent cases, that additional risk is worth taking, but a note of caution is warranted in elective situations as researchers seek to fully understand the impact of CS on the developing immune system. To quote Dr. Jose Saavedra of the Johns Hopkins Bloomberg School of Public Health, “The increasing recognition of cesarean section as a risk factor for chronic conditions that manifest themselves far beyond the perinatal period should foster increased awareness of these risks, and serve as additional argument against non-medically indicated cesarean section.” ::

Dr. Sloan, who teaches pediatrics at the Santa Rosa Family Medicine program, serves on the SCMA Editorial Board.

Email: markpsloan@gmail.com

References
1. von Mutius E, “Global etiology of asthma,” Annales Nestle, 60:45-55 (2002).
2. Xu B, et al, “Cesarean section and the risk of asthma and allergy in adulthood,” J Allergy Clin Immunol, 107:732-733 (2001).
3. Bager P, et al, “Cesarean delivery and risk of atopy and allergic disease: meta-analyses,” Clin Exp Allergy, 38:634-642 (2008).
4. Thavagnanam S, et al, “Meta-analysis of the association between cesarean section and childhood asthma,” Clin Exp Allergy, 38:629-633 (2008).
5. Bråbäck L, et al, “Confounding with familial determinants affects the association between mode of delivery and childhood asthma medication: a national cohort study,” Allergy, Asthma & Clin Immunol, 9:14 (2013).
6. Sevelsted A, et al, “Cesarean section and chronic immune disorders,” Pediatrics, 135:e92-98 (2014).
7. Vehik K, Dabelea D, “The changing epidemiology of type 1 diabetes,” Diab Metab Res Rev, 27:3–13 (2011).
8. Dabelea D, et al, “Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009,” JAMA, 311:1778-86 (2014).
9. Dahlquist G, Kallen B, “Maternal-child blood group incompatibility and other perinatal events increase the risk for early-onset type 1 diabetes mellitus,” Diabetologia, 35:671-675 (1992).
10. Cardwell CR, et al, “Cesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: meta-analysis of observational studies,” Diabetologia, 51:726-735 (2008).
11. Khashan A, et al, “Mode of obstetrical delivery and type 1 diabetes: a sibling design study,” Pediatrics, 134:104 (2014).
12. Bager P, et al, “Cesarean section and offspring’s risk of inflammatory bowel disease: national cohort study,” Inflamm Bowel Dis, 18:857-862 (2012).
13. Torrazza R, Neu J, “The developing intestinal microbiome and its relationship to health and disease in the neonate,” J Perinatol, 31:S29-S34 (2011).
14. Cho C, Norman M, “Cesarean section and development of the immune system in the offspring,” Am J Obstet Gynecol, 208:249-254 (2013).
15. Almgren M, et al, “Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant,” Am J Obstet Gynecol, 211:502.e8 (2014).
16. Prior E, et al, “Breastfeeding after cesarean delivery: a systematic review and meta-analysis of world literature,” Am J Clin Nutrition, 95:1113–35 (2012).

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