Main Findings

We investigated the association between CS birth, particularly elective CS, and the risk of childhood obesity using a large, prospective, nationally representative, longitudinal cohort study. In the multinomial logistic regression analysis we found insufficient evidence to support a causal relationship between elective CS and childhood obesity. Indications for emergency CS likely explained the increased risk of obesity observed in infants delivered via this mode, but not elective CS, suggesting that there is no causal effect due to vaginal microflora.

Strengths and limitations

Firstly, the GUI study is a large and nationally representative sample due to the application of sampling weights. The major strength was that our main outcome, BMI, based on height and weight was collected prospectively by trained personnel using validated techniques thus minimising measurement error. In addition, BMI was classified using widely accepted international criteria which allows comparison with other populations. We did not assume that once an individual is classified as obese, they remain so at a future time point. This allowed us in addition to evaluate if the mode of delivery was associated with transition into or out of obesity between time points. The availability of an ample suite of variables to adjust for confounding also strengthened our study. For example, we included gestational diabetes which was not included by several previous studies20.

A limitation was the unavailability of maternal pre-pregnancy BMI which has been highlighted to attenuate effect estimates when included in models20. However this limitation was partially ameliorated because we had access to maternal gestational weight gain, an important variable in its own right, which has been suggested to be significantly correlated with maternal pre-pregnancy BMI47. Recall bias remains a concern because some key variables were collected sometimes a year after pregnancy. Our main predictor, mode of delivery, relied on maternal recall nine months post-partum. We can be confident however that this is likely to be accurate in the vast majority of cases given that a similarly designed and conducted population-based study from the United Kingdom, the Millennium Cohort Study reported that 94% of mothers recalled their mode of delivery nine months post-partum when compared to their hospital records35. Another aspect worth mentioning is that infants born during the months of July to November, inclusive, were omitted from the GUI cohort. This is a constraint because month of birth can serve as a proxy for specific seasonal environmental circumstances that can significantly influence future health48.

The classification of CS into elective and emergency, although addressing a limitation of previous studies, did not allow sufficient granularity of issues like whether the CS was purely on maternal request; these may differ from other elective CSs, or if membranes had ruptured prior to surgery (exposure of the fetus to vaginal microbiota). All the women classified in the elective CS group had pre-labour CS. Although it is likely that women in the emergency CS group mostly had in labour CS, we cannot rule out the possibility that some of them had pre-labour CS. This is unlikely to have influenced the elective CS result, especially in terms of our hypothesis which is based on pre-labour CS. Improving CS classification is an ongoing worldwide effort that is only gaining traction during this century49. There was lack of statistical power for some analyses, like the overweight analysis, however the RRRs were similar to previously reported associations. Given the consistency of our results we thus think there is merit in them.

Our proxy measure for parity, the number of individuals in the study household who were a son/daughter of the mother, assumed for instance that the mother had no biologic children outside the household. Despite the assumptions we made, the average number of children a mother had in the GUI cohort, infants born circa 2008, was 1.97 which is close to the 2008 reported total fertility rate for Ireland of 2.0650. Thus the proxy parity variable was likely to be accurate in most cases and capture birth order sufficiently in the models.

Interpretation

The CS rate in this cohort was 26.0%, and is consistent with published national estimates of 25.6%9. This corroborates the national representativeness of the GUI cohort and the likely external validity of our findings. The 13.9% prevalence of macrosomia (>4000 g) however, was almost twice the 7.6% prevalence for the United States, another high-income country, during a similar time period circa 200851. This suggests a highly obesogenic Irish milieu with high baseline levels of excess adiposity from birth.

We found high rates of childhood obesity and overweight, for comparison global obesity rates for girls and boys in 1975 were less than 1%52. The slightly lower prevalence of obesity at age five (5.0%) than at age three (5.3%) was in keeping with the natural obesity prevalence decline observed from approximately age two to 14 years53.

Approximately 80 studies of various designs (cohort, case control, cross sectional) and several systematic reviews have investigated the association between CS and offspring obesity20,21,54. Most of these studies found a positive association, however evaluation of this association was limited by publication bias, potential for residual confounding and moderate heterogeneity20. Studies which accounted for maternal pre-pregnancy weight and adjusted their analyses for a greater number of potential confounders reported effect sizes closer to the null20.

As reported by the previous systematic reviews and meta-analyses, we also found a small effect size (odds ratio/RRR < 1.50) before accounting for macrosomia in the association between CS birth and subsequent overweight and obesity20,22. We too found a greater association between CS birth and being obese than with being overweight22.

Few studies have been able to differentiate between emergency and elective CS20,22,23. However our finding that elective/planned CS is a risk factor for obesity at three years has been found previously in an American prospective cohort from Boston followed up largely during this century55. Nevertheless this study did not explore the potential confounding effect of macrosomia. Inability to account for elective and emergency CS calls into question the findings and conclusions of a sibling-control study23 which suggested a causal link between CS birth and future obesity. Another study with a sibling-control design, albeit also limited by inability to distinguish between elective and emergency CS, did not find an association between CS birth and higher BMI z score at age five years56. Unfortunately, the GUI cohort did not have data that allows sibling-cohort analysis.

The association between CS and obesity generally dissipates with increasing age, which can be attributed to attrition, greater interference by external factors such as antibiotic therapy or because of the natural decline in obesity prevalence from two to 14 years22,23,53. A study with follow-up to age twenty found higher overweight and obesity rates as well as higher concentrations of total and low-density lipoprotein cholesterol, leptin and apolipoprotein B in those born by CS29. It however remained unsettled if these unfavourable rates and markers of cardiometabolic disease could be attributed to CS birth itself or to the underlying reasons that necessitated CS birth.

Most studies have adjusted for birth weight22, however, a Canadian population-based survey is to the best of our knowledge the only study to specifically consider macrosomia, defined in that study as >4080 g30. Although a non-modifiable risk factor, it is important to highlight that emergency CS was associated with being overweight and obese at three years and being obese at five years. In addition, infants delivered by emergency CS were more likely to ‘transition’ between ages three and five, namely: remain obese, become non-obese (normal, overweight or thin), or have any other transition between the IOTF BMI categories.

As mentioned in the introduction, infants born by CS may have a microbiota that is more capable of harvesting dietary nutrients16,17,18. With emergency CS, membranes are more likely to have ruptured with consequent exposure of the infant to vaginal microbiota resulting in reduced odds of future obesity compared with elective CS infants. However finding a greater effect size for obesity following emergency CS, as previously reported55, suggests other mechanisms may be at play with emergency CS namely confounding by indication. Indeed a recent study suggested that the main mechanism driving the microbiota’s structure and function in infancy is body site and not mode of delivery57. Like we mentioned the natural history and drivers of being overweight or obese differ significantly by age. Although there is literature on adults21, some of which supports our findings, we focused our discussion on childhood at ages comparable to those in our study.