Nearly 1 in 5 children worldwide1 and 1 in 3 children in the United States2 are born by cesarean delivery. When indicated, cesarean deliveries are lifesaving procedures to mother and child. Concerns regarding the safety of cesarean delivery have traditionally focused on immediate risks to mother and newborn, such as increased risks of pulmonary embolism and surgical infections in the mother and increased risk of respiratory distress in the newborn. In recent years, interest—and literature—regarding the potential long-term health impacts of this common surgical intervention have grown. One of the most consistent findings in this expanding field is that birth by cesarean delivery is associated with a higher risk of childhood obesity. Two meta-analyses3,4 summarizing data from 24 studies have reported an increased risk of obesity for individuals born by cesarean delivery (pooled odds ratios, 1.33; 95% CI, 1.19-1.48 and 1.22; 95% CI, 1.05-1.42), with little difference for risk of obesity during childhood vs adolescence and some evidence that the elevated risk persists in adult life (odds ratio, 1.50; 95% CI, 1.02-2.20).4
Despite the consistency of this literature, a key question remains: are these results reflective of a causal relation or are they due to residual confounding? In the absence of a randomized trial to answer this question, clever study design and analysis of observational studies must be leveraged to address this important problem. Three main strategies have been used to address this issue: statistical adjustment for shared risk factors for cesarean delivery and childhood obesity, most critically prepregnancy body mass index; comparison of weight status of siblings discordant in mode of delivery; and comparison of weight status of individuals born by vaginal delivery with those born by cesarean delivery after differentiating between elective and nonelective procedures and/or procedures performed before or after the onset of labor. Separating elective procedures performed before the onset of labor from other cesarean deliveries can also provide insights into one of the proposed mechanisms underlying this association: differences in infant gut microbiome resulting from differences in exposure to maternal vaginal secretions.
Cai and colleagues5 use this last strategy to evaluate the association between birth by cesarean delivery and risk of childhood overweight at 12 months of age. The authors describe elective cesarean deliveries as those performed on maternal request but provide little additional information regarding indications or timing of the procedure in relation to the onset of labor. In the primary analysis of 727 Asian participants with a 13% rate of exclusive breastfeeding, after adjustment for maternal demographic characteristics, maternal overweight, pregnancy complications, and infant antibiotics and feeding, elective cesarean delivery was associated with an almost 2-fold increased odds for childhood overweight or risk for overweight at 12 months. Emergency cesarean delivery was not associated with an increased risk of childhood obesity. This is in direct contrast to a study from a primarily white Canadian cohort (CHILD [Canadian Healthy Infant Longitudinal Development] study)6 with a 53% rate of exclusive breastfeeding, which found postlabor cesarean delivery to be more associated with childhood overweight than prelabor cesarean delivery after adjustment for similar factors.6 The contrasting results may be due to differences in classifying either exposure or outcome. The outcome reported by Cai et al was body mass index–for–age z scores more than 1 SD above the mean using World Health Organization definitions, while Tun et al defined overweight as a z score greater than the 97th percentile. It is unclear whether the definitions for exposure were the same—ie, whether elective cesarean delivery would include the same type of participants as prelabor cesarean delivery. However, these differences may indicate an unmeasured confounder that mediates the relationship between delivery mode and weight.
The neonatal gut microbiome has been proposed as one potential mechanism for the association between cesarean delivery and infant weight. Several studies have demonstrated a lower microbial community diversity over the first 6 to 12 months in infants born via cesarean delivery, due in part to a consistently lower detection and/or abundance of Bacteroides species.7,8 Few studies have compared the gut microbiome of infants born via cesarean delivery before or during labor, but in the CHILD study, the composition of the gut microbiome was more similar between 3-month-old children born via cesarean delivery, whether before or during labor, than infants born vaginally.9 This was true whether or not mothers received intrapartum antibiotics, suggesting that mode of delivery was more important than timing of the delivery or receipt of antibiotics in determining the composition of the infant gut microbiome. Studies demonstrating a clear mechanistic link between early alterations in the infant gut microbiome and subsequent obesity are limited, but this link is supported by data from animal models.
The study by Cai and colleagues is undoubtedly an important piece for solving the cesarean delivery–childhood obesity puzzle. However, it highlights one of the key methodological issues that make it difficult to solve the puzzle: the lack of consistent definitions of exposures. What exactly does it mean to be exposed to a cesarean delivery? While it is fairly straightforward to differentiate vaginal from cesarean deliveries, there is a wide spectrum between clearly elective cesarean procedures and unmistakably emergency interventions. Cai and colleagues are not the first to struggle with making clear and consistent classifications for cesarean deliveries. While developed for a different purpose, one classification that may prove useful for addressing this issue is the Robson classification,10 promoted by the World Health Organization for monitoring cesarean birth rates worldwide. Correctly defining exposure is necessary for interpreting the clinical impact of study results; repeated surgical procedures are one of the primary drivers of high cesarean delivery rates, and if cesarean birth after labor is protective for obesity, this could encourage more physicians to offer women attempted vaginal delivery after a cesarean delivery. However, if any cesarean birth (prelabor or postlabor) is associated with obesity, then avoiding the first cesarean birth should be the priority. Better definitions of both exposure and outcome are necessary to be sure that results can be compared across studies. Only then will we be able to decipher whether this consistent association is causal, and also how we should address it.
Published: November 21, 2018. doi:10.1001/jamanetworkopen.2018.5008
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Mitchell C et al. JAMA Network Open.
Corresponding Author: Jorge E. Chavarro, MD, ScD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Chavarro reported grants from National Institutes of Health. No other disclosures were reported.
Funding/Support: Dr Chavarro was supported by grant R01HD093761 from the National Institutes of Health.
Role of the Funder/Sponsor: The National Institutes of Health had no role in the preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
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