We read with interest review of the association between cesarean delivery and immune function in the offspring by Cho and Norman. Although the authors are to be commended for attempting to synthesize what is known about the long-term effects of cesarean delivery on the offspring’s immune system, we fear that their limited review of a very complex literature leads the reader to a naïve conclusion: that the cesarean procedure itself might be bad for infants and children. Although the high rates of cesarean birth are concerning (representing 32.8% of U.S. births in 2010), this review might cause unfounded alarm among patients and providers alike.
See related article, page 249
First, with regard to the review itself, it concerns us that the literature search did not appear to be conducted in a systematic fashion. That is, the authors did not identify the number of potential articles that were identified in their search nor did they provide the criteria that were used for inclusion in the review. Indeed, when we sought to replicate their search, we found hundreds of articles that potentially were related to the topic at hand. The authors reviewed only a small fraction.
Second, the authors suggest that the validity of the fetal or early origins of adult disease hypothesis is well-established, when in fact that is not the case. Epidemiologists and others have been critical of the hypothesis, arguing that one must ensure that all potential confounders that might influence the eventual health outcomes are measured and appropriately controlled for in the analysis. For example, to establish a clear and valid association between gestational diabetes mellitus and subsequent obesity in the offspring, one would need to measure all of the factors that might be related to both gestational diabetes mellitus (eg, family dietary habits, exercise habits, and income) and childhood obesity. Further, others have argued that many of the fetal origins–type associations in fact could be statistical artifacts.
Consider the causal diagram in the Figure . Cho and Norman argue that the relation between cesarean birth and child and adult disease could be a direct effect; we suggest that there is another important pathway to consider. Specifically, that is that cesarean delivery is a contributor to preterm delivery, which can result in altered immune function and eventual disease. The literature supports this alternative pathway. Investigators from the Centers for Disease Control and March of Dimes conducted an analysis that suggested that the increased rate of preterm births that has been recently noted occurred among those women who delivered by cesarean section, particularly in the late preterm period. Moreover, there is an abundance of literature that suggests an association between preterm birth and altered immune function. In examining this diagram, one might assume that then adjusting for gestational age at delivery would allow the estimation of the direct effect of cesarean delivery on child and adult disease. However, as pointed out by Wilcox et al, a direct effect can be estimated in that instance only if there are no unknown and/or unmeasured confounders acting on preterm delivery and child and adult disease, which is highly unlikely. In fact, if we assume that these unknown and/or unmeasured confounders play a role (including the gray-shaded item in the causal diagram in the Figure ), adjustment for preterm delivery (or gestational age), which is now a collider, would lead to a biased estimate of the effect of cesarean delivery on child and adult health. Failure to adjust, however, would result in an invalid estimate because of residual confounding.
