Cesarean Delivery: Increasing the Risk of Obesity?

Peri Schaut

Abstract
Although delivery by cesarean section has been an alternative mode of giving birth for centuries, it has always posed risks for both the mother and the infant. Today, with the increasing rates of cesarean delivery worldwide, researchers are looking at both immediate and long-term risks for individuals delivered by cesarean section. Current research has introduced a new long-term risk factor for cesarean-delivered individuals: obesity. This paper reviews the association between cesarean delivery and future risk of obesity, emphasizing the differences in gastrointestinal microbiota between individuals delivered vaginally and individuals delivered by cesarean section as the possible underlying mechanism of this association. I begin this review with a brief history of cesarean delivery, as well as a description of the increasing rates of cesarean sections worldwide and the known risks of cesarean section to both mother and child. Next, I review current research assessing the strength of the association between cesarean delivery and obesity. Specifically, I evaluate the perspective of some researchers that confounding variables are responsible for the association, as well as factors that may influence the strength of the correlation. Next, I address the challenges of confounding variables and age of assessment, suggesting that these aspects be considered in future research methods. In the next section, I explain the hygiene hypothesis, a possible mechanism underlying the association between cesarean delivery and obesity. In conclusion I determine that the association between cesarean delivery and obesity may have a strong influence on the future of cesarean sections. This review may be useful for medical professionals as well as mothers contemplating the decision to have an elective cesarean section as it discusses a new risk associated with cesarean delivery, supported by researchers in the medical field.

Cesarean Delivery
Cesarean delivery
Also known as cesarean section or C-section, this method of delivering an infant is a surgical procedure involving an incision through the maternal abdomen and a second incision in the maternal uterus to extract the infant from the 4 mother .

Cesarean sections, although relatively common as a mode of delivery in the 21st century, were originally performed as a means to retrieve an infant from a dying or dead mother. The operation was initially not intended to maintain the mothers life until the 19th century, when advances in medicine allowed both mother and infant to survive the procedure. Although the operation has historically been performed to preserve the health of the mother, the health of the fetus has been the current focus in decisions for the procedure. Since the introduction of heart monitors in the 1970s, fetal monitoring of heart rate has allowed for detection of signs of distress. This ability to detect for fetal distress has increased the rates of cesarean delivery as a preventative measure to avoid complications such as brain damage due to lack of oxygen1. 1

Today, cesarean rates are increasing worldwide. In the United States, the cesarean rate increased by 53% from 1996 to 2007, reaching the highest reported cesarean rate of 32%2 (Figure 1). In England, between 1990 and 2008, there has been a 100% increase in births delivered by cesarean section. Based on the known risks of cesarean deliveries for both mother and child, the World Health Organization recommends that the cesarean section rate remain under 15%. Yet many countries report rates above the WHO recommendation, such as China with a 60% cesarean section rate, Brazil with a 47% cesarean section rate, and England with a 23.8% cesarean section rate3.
Figure 1: Cesarean Delivery Rates: United States, 1991-20072

Apgar Score
A scale used to evaluate a newborns health, giving the infant a rating of 0, 1, or 2 on five characteristics: skin color, heart rate, muscle tone, and 5 reflexes .

With the increasing rates of cesarean delivery worldwide, it is important for medical professionals to be aware of the risks associated with cesarean section and to inform mothers considering elective cesarean section of both short- and long-term risks. Compared to vaginal delivery, cesarean delivery is associated with the highest rates of infant mortality and morbidity, as well as an increased risk of low Apgar scores at one minute after birth, difficulty breathing, hypoglycemia, and a longer period spent in the neonatal intensive care unit3. Although short-term risks of cesarean delivery to the mother and infant are consistently recognized by physicians and communicated with mothers, long-term complications are less often considered6. Cesarean delivery has been associated with long-term complications of offspring such as lower immune response, leading to an increased risk of asthma, neuroendocrine disorders, metabolic disorders, and diabetes6-7. In addition, recent research has proposed that cesarean delivery is also associated with an increased risk of offspring obesity; however, some researchers believe that this association is the result of confounding variables. This paper will review the association between cesarean delivery and future risk of obesity, emphasizing the differences in microbiota composition between individuals delivered vaginally and individuals 2

delivered by cesarean section as an underlying mechanism of this association.

Current Research
BMI
Body Mass Index is an indirect measure of body fat calculated from a persons 8 weight and height .

Childhood Overweight and Obesity

For children of the same age and sex, a child with a BMI at th or above the 85 percentile and th below the 95 percentile is considered overweight, while a child with a BMI at th or above the 95 percentile is 9 considered obese .

In the United States, in addition to increasing cesarean rates, more than one-third of adults are obese and the obesity rates among children have nearly tripled since 19809. Obesity is associated with many chronic conditions such as inflammation, type II diabetes, hepatic steatosis, and cardiovascular disease10. Given the rise in obesity rates and cesarean rates, scientists have recently begun speculating an association between cesarean delivery and future risk of obesity. Although some studies have found confounding variables to be responsible for the association, many studies have controlled for such variables and have still concluded that an association exists. This section discusses the proposed confounding variables, specifically maternal prepregnancy BMI, and associated factors such as socioeconomic status, sex, and age, ultimately favoring the research supporting the association between cesarean delivery and obesity. Confounding Variables Some researchers argue that there is no association between cesarean delivery and obesity but that positive correlations are a result of confounding variables. A Brazilian study concluded that young adults, who had been born by cesarean delivery, had a 58% higher prevalence of obesity than young adults who had been delivered vaginally. This prompted Fernando C. Barros and his researchers to analyze three Brazilian birth cohorts to determine if cesarean deliveries lead to increased risk of obesity in childhood, adolescence, and early adulthood. Initial analyses suggested that individuals born by cesarean section had about a 50% higher prevalence of obesity. However, after adjusting for possible confounding variables, such as family income, type of payment for delivery (covered by health care, private health insurance, private practice), maternal age, smoking during pregnancy, maternal education, maternal prepregnancy weight, maternal height, and birth weight, the association was no longer significant11. Maternal Prepregnancy BMI One study suggested that the confounding variable responsible for the association between cesarean delivery and offspring obesity was maternal prepregnancy BMI. In a retrospective cohort study, epidemiologist Kelli Flemming, along with other researchers, surveyed fifth grade students and their parents looking for an association between cesarean delivery and childhood obesity. After controlling for a range of possible confounding variables, the study showed no causal association between cesarean delivery and obesity in children in fifth grade. This study suggests that maternal prepregnancy weight may be the confounding variable responsible for this association since obese mothers are more likely to have a required cesarean

Adult Overweight and Obesity

An adult who has a BMI between 25 and 29.9 is considered overweight, and a BMI of 30 or higher is 9 considered obese .

section due to increased soft tissue, complications during labor, and fetal macrosomia. Overweight and obese prepregnancy weight is associated with childhood obesity and may be responsible for the association between cesarean delivery and obesity, as other studies may have not adjusted for maternal prepregnancy BMI12. Despite this claim that maternal prepregnancy BMI is responsible for the association12, other research suggests that an association exists even after controlling for this variable. In a prospective cohort study led by Dr. Susanna Y. Huh of Boston Childrens Hospital, researchers examined the relationship between mode of delivery and obesity in children at three years of age. Of the 1,255 live births, 22.6% were delivered by cesarean section and 77.4% by vaginal birth. Controlled variables included measures of obesity included maternal pre-pregnancy BMI, birth weight for gestational age, breastfeeding duration, and skinfolds. The mean maternal pre-pregnancy BMI was higher for mothers who had cesarean sections than those who had vaginal deliveries. Infants born by cesarean delivery had a higher mean BMI at age three and greater skinfold measurements. Furthermore, infants delivered by cesarean section were more likely to be overweight by age three than children delivered vaginally. Overall, the researchers found that at age three, children delivered by cesarean section had twice the likelihood of obesity, as well as higher BMI and skinfold measurements, than children delivered vaginally13. Despite claims that confounding variables11, such as maternal prepregnancy BMI12, are responsible for the association between cesarean delivery and risk of obesity, this study ensures control over potentially confounding variables such as maternal BMI and still concludes that an association exists. Influential Factors Socioeconomic Status Some research suggests that there are influential factors that may strengthen or weaken the association between cesarean delivery and obesity, such as socioeconomic status. In Brazil, cesarean delivery is associated with high economic status, and cesarean section rate has increased from 15% in 1970 to 50% in 2011. Researchers from University of Rio Grande do Sul and University of Sao Paulo assessed two Brazilian cohort studies from different socioeconomic backgrounds for the association of cesarean delivery and increased BMI and obesity in school children. One cohort was born in a wealthy city, and the other cohort was born in a less wealthy city. The obesity rate in the wealthy city, Ribeirao Preto, was 13.0% and 2.1% in the less wealthy city of Sao Luis. After adjusting for confounding variables such as maternal education, smoking during pregnancy, duration of breastfeeding, birth weight, and, only in Sao Luis, pre-pregnancy maternal weight, the association between cesarean delivery and obesity remained significant in the wealthy city of Ribeirao Preto7. This suggests a socioeconomic factor that

may influence, but is not responsible for, the association between cesarean delivery and risk of obesity. Sex One study led by researchers at the College of Public Health at East Tennessee State University examined the relationship between cesarean delivery and the risk of overweight and obesity in sixth grade children. Taking into account possible confounding variables, the study found that children delivered by cesarean section were twice as likely to be overweight or obese than vaginally delivered children. This study further examined the association in relation to males and females, discovering that males delivered by cesarean section were at an increased risk for overweight and obesity, while females delivered by cesarean section were at an increased risk for overweight only14. This research suggests that the strength of the association between cesarean section and obesity may differ depending on sex. Age Other research proposes that age may influence the strength of the association between cesarean delivery and obesity. In a study led by Zhengcun Pei, full-term infants were recruited and associations between cesarean delivery and being overweight or obese were assessed at age 2, 6, and 10 years. The researchers found a greater likelihood of obesity at 2 years in the cesarean delivery group compared to the vaginal delivery group, but not at 6 years or 10 years, concluding that cesarean delivery may increase the risk of obesity in early childhood but that this risk diminishes with age15. In a meta-analysis at the Imperial College London, researchers evaluated the effect of cesarean section and vaginal delivery on offspring BMI by analyzing studies that had reported birth characteristics and long-term follow-up. Analysis of these fifteen studies led to the conclusion of a strong association between cesarean delivery and overweight and obesity in adulthood. However, this research found a reduced association between cesarean delivery and BMI in older subjects, suggesting that exposure to environmental factors throughout life increases with age, concealing the association in older subjects3. Once again, this study suggests that the strength of the association decreases with age.

Challenges and Opportunities

Controlling Confounding Variables Recent studies have raised considerable debate surrounding the association between cesarean delivery and obesity in offspring7, as some studies have concluded that an association exists while others have not. Based on the previously discussed research, I argue that there is an association between cesarean delivery and obesity. Although some studies have proposed that confounding variables, specifically maternal prepregnancy BMI, are responsible for the association11-12, another study

controlled specifically for maternal prepregnancy BMI and concluded that children delivered by cesarean section had double the risk of obesity as compared to children delivered vaginally13. I suspect that the discrepancies in results are a result of differences in methods, specifically in the controlled variables. Future research is needed to determine whether the association is causal or reflective of confounding variables, such as the rising rates of cesarean deliveries3. Consideration of Age at Assessment In addition, I argue that age influences the strength of the association between cesarean delivery and obesity. Based on the two studies presented reflecting age differences15, 3, I suspect that the association is weakened with increasing age. However, it is unclear as to what age the association is strongest or weakest. I suggest that future studies evaluate their cohorts at the same age or ages in order to obtain a series of results with similar conditions. This will allow researchers to determine the age or ages that individuals are at the greatest risk of obesity as a result of cesarean section.

The Mechanism Underlying the Association

The Hygiene Hypothesis Although the research assessing the association between cesarean delivery and obesity is fairly new, researchers are currently speculating the possible mechanisms underlying the association1. Some researchers propose a biological mechanism that underlies the association between cesarean delivery and offspring obesity. Figure 2: Vaginal Delivery vs. Cesarean Delivery and Exposure to This mechanism is known as Vaginal Microflora16-17 the hygiene hypothesis, and suggests that infants delivered vaginally gain direct exposure to maternal microbiota in the vaginal and intestinal tracts, whereas infants delivered by cesarean section are exposed to nonmaternal, environmental bacteria (Figure 2). This difference in initial acquisition of infant bacteria may impact gut microbiota diversity and composition, causing long-term complications for cesareandelivered individuals6. There is supporting evidence for the hygiene hypothesis as studies have

shown an association between the bacterial microbiome and obesity, as well as other metabolic disorders7. Human gut microbiota is proven to influence host metabolism as they impact insulin resistance, inflammation, and adiposity, extracting energy from the diet as well as influencing the bodys metabolism as a whole10. Altered microbiome composition may lead to overweight and obesity through the following mechanisms: (1) microbiota can convert indigestible food into absorbable nutrients, increasing available energy; (2) microbiota can influence gut gene expression, which can increase free fatty acids and adiposity; and (3) microbiota may cause obesity through inflammation by activating lipopolysaccharides15. Tests have shown that the relative abundance of two dominant groups of bacteria in the gut, Bacteroidetes and Firmicutes, differs between lean and obese individuals; gut microbiota of obese individuals contains a lower proportion of Bacteroidetes, which are protective factors against overweight and obesity6, and a higher 3: Relative Abundance of Bacteroidetes and Firmicutes in Obese proportion of Firmicutes than Figure and Lean Individuals19 lean individuals12, 18 (Figure 3). In addition to obesity, other diseases, such as neonatal necrotizing enterocolitis, inflammatory bowel disease, and vaginosis, have been associated with disturbances in the microbiome. Given an evolutionary perspective, it makes sense for humans to benefit from the bacterial microbiome, which consists of over 100 trillion microbial cells, ten times more than the number of human cells. These microbial cells provide individuals with many metabolic functions that human cells lack6. Nevertheless, there may be solutions to restore a disturbed microbiome. One study concluded that infants delivered by cesarean section that were breastfed had increased proportions of Bacteroidetes, as breastfeeding was associated with more diversity and an overall greater abundance of gut microbiota20. I propose that in future studies, researchers looking at infants delivered by cesarean section compare the effects of breast milk versus infant formula on the composition of the microbiome of cesarean-delivered infants to determine if breastfeeding is a solution to reducing the risk of obesity in infants delivered by cesarean section. I also suggest that future research investigates other methods to restore an abnormal microbiome, such as the use of probiotics or skin-to-skin contact. However, such interventions must be studied in controlled experiments comparing mode of delivery and long-term outcomes of microbiome composition in relation to obesity risk6.

Future Directions
Based on the current research presented, I argue that an association between cesarean delivery and future overweight and obesity does exist. I also suspect that the association weakens with increasing age, as individuals are continuously exposed to microbiota throughout life. However, I believe that further research is needed in order to determine whether the association is causal or reflective, and at what age the correlation is strongest. I anticipate that with further research, the risk of obesity will become one that must be presented to mothers considering elective cesarean delivery. Given the rise of obesity rates as well as the numerous diseases and conditions associated with being obesity, I suspect that this risk may be a heavily weighted factor for many mothers in making a decision about cesarean or vaginal delivery. It is therefore crucial that health care providers inform mothers considering cesarean delivery of the many risks of cesarean section to not only the mother, but the infant as well, including the risk of obesity if future research continues to support the association.

Acknowledgments
This work was reviewed by Amanda Schmitt and Jenny Ji Jung at Northeastern University.

References
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13. Huh, S. Y., et al. Delivery by caesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch Dis Child 97, 610-616 (2012). Web. 14. Wang, L., Alamian, A., Southerland, J., Wang, K., Anderson, J., Stevens, M. Cesarean section and the risk of overweight in grade 6 children. Eur J Ped 172, 1341-1347 (2013). Web. 15. Pei, Z. MSc, Heinrich, J. PhD, Fuertes, E. MSc, et al. Cesarean delivery and risk of childhood obesity. J Ped (2014). Image. Web. 16. Richardson, Leland G.K. Cesarean vs. vaginal delivery: differences in early gut flora and immune system development. (2013). Image. Web. 17. Neu, J. MD, Rushing, J. MD. Cesarean versus vaginal delivery: long term infant outcomes and the hygiene hypothesis. Clin Perinatol 38(2), 321331 (2011). Web. 18. Ley, E.R., et al. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022-1023 (2006). Web. 19. Zimmer, C. The human lake. Discover Magazine (2011). Image. Web. 20. Azad, B. M., et al. Impact of cesarean section delivery and breastfeeding on infant gut microbiota at one year of age. Allergy, Asthma & Clinical Immunology 10 (2014). Web.

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