April 27, 2023

expert reaction to study looking at birth by Caesarean section and development of early-onset colorectal cancer

A study published in JAMA Network Open looks at birth by C-section and development of early-onset colorectal cancer.

Prof Sir Mel Greaves, Professor of Cell Biology, The Institute of Cancer Research, London, said:

“Overall this study is interesting and merits follow up, possibly in countries such as Brazil where C-section rates are very high, but its conclusions should be regarded as very tentative and not a new cause of concern for individuals who were delivered by C-section or mothers who have given birth by C-section.

“Cao and colleagues report a large case/control study from Sweden that recorded a small but significant increased risk of early onset (18-49 years of age) colorectal cancer (CRC) in females but not males who had been born by C-section.  They cautiously interpret this as a possible causal link operating through the recognised impact that C-section birth has on the gut microbiome of infants.

“The idea is plausible as early life microbiome dysbiosis can have long lasting impacts on both immune function and metabolism.  A previous Danish study (ref 37 in Cao et al) reported an increased risk of inflammatory bowel disease as well as coeliac disease in adults – both male and female – who had been born by C-section.

“The main issue with the data of Cao et al is the selective effect on females.  This implies a hormonal influence for which there is little evidence.  The authors draw attention to the increasing prevalence of early onset CRC and C-section birth.  But in the light of their findings in females wouldn’t they expect or predict a more pronounced increase over recent time periods in early onset CRC in females compared to males?  These data are presumably available but the authors offer no comment on this.

“A rather odd feature of the study design is the exclusion of patients and controls who had inflammatory bowel disease (IBD).  This is a recognised precursor lesion for CRC and is associated with gut microbiome dysbiosis and C-section birth.

“A final point is that although C-section birth does impact, at least in the short term, on gut microbiome composition and diversity, the longer-term status of the microbiome will be influenced by multiple factors that might confound studies such that of Cao and colleagues.  These include breast feeding and social contacts in infancy, antibiotic exposure and diet throughout adult life.”

Reference 37 in Cao et al: https://www.dovepress.com/caesarean-delivery-and-risk-of-chronic-inflammatory-diseases-inflammat-peer-reviewed-fulltext-article-CLEP

Prof Kim Barrett, Vice Dean for Research and Distinguished Professor of Physiology and Membrane Biology, UC Davis (University of California, Davis), said:

“This is a carefully conducted study that takes advantage of closely integrated national health information databases.  It is intriguing that birth by C-section was associated with a later diagnosis of early onset colon cancer in women but not men.  The authors have been thorough in considering potential confounding factors.  They speculate that their findings may reflect an impact of mode of delivery on the gut microbiome, but this is not proven, and why it would impact subsequent outcomes in women only is not yet known.  However, this provocative work is certain to spur additional work to explore underlying mechanisms.”

Prof Neena Modi FMedSci, Professor of Neonatal Medicine, Imperial College London; and President-Elect, European Association of Perinatal Medicine, said:

“This paper represents a further addition to a growing list of adverse long-term conditions associated with birth by Caesarean section.  However, association should never be conflated with causation because of the all too possible likelihood of the association being due to an unrecognised factor.  Put simply there is a strong association between ice cream consumption and sunny weather, but eating ice cream doesn’t cause the sun to shine.  It is important in any epidemiological study, even if well conducted as this one is, to stress this important point.  To fail to do so would risk raising enormous public concern.

“Biological plausibility is another important consideration when discussing the likelihood of an association representing a true causal relationship.  The authors discuss only a single candidate mechanism, namely an altered microbiome consequent on Caesarean birth and lack of exposure to maternal vaginal flora.  There are other powerful differences between Caesarean and vaginal birth.  Exposure to the hormonal milieu of labour is another potential mechanism that might plausibly lead to differences in immune and metabolic development.  The authors do not appear to have been able to differentiate between pre-labour (elective) and in-labour Caesareans, nor do they discuss this point.

“It is also relevant to discuss how the uncertainties around the longterm risks of Caesarean section can be resolved reliably.  Caesarean section can be life saving for mothers and babies when needed.  However Caesarean section rates in the absence of medical indication are rising and are well over 50% in several countries; in other words are more common than vaginal births.  Whether Caesarean section is truly causally related to adverse long term health consequences is therefore an important global issue.  The most rigorous approach to identifying causality is the randomised controlled trial.  For this reason, we and others have argued that where there is no medical indication for a Caesarean and a mother is contemplating this, she should be told honestly about the uncertainties and offered allocation to Caesarean or vaginal birth by randomisation as part of a clinical trial.  However, given reasons of personal choice and preference, coupled with complexity and cost, a randomised trial would be an enormous challenge.  The consequence sadly, is continuing uncertainty regarding the longterm health implications of birth by Caesarean section.”

Prof Louise Kenny, Professor of Maternal and Fetal Health; Principal Investigator of the C-GULL (Children Growing Up in Liverpool) Study; and Executive Pro-Vice-Chancellor, University of Liverpool, said:

“This is an interesting study conducted in a large Swedish population of adults with early onset bowel cancer and matched controls.  The researchers found that there is an increased risk of early onset bowel cancer in female, but not male, adults who were born by Caesarean section.  The investigators speculate that this may be due to the presence of altered bacteria in the gut of female babies who are born by Caesarean section.

“Firstly, the overall risk of developing early onset bowel cancer is very low regardless of your sex and the mode of your birth.  The slight increase observed in this study is not easily explained by altered bacteria as there is no obvious reason why this would differ according to sex, and further mechanistic work is required.

“However, this study does support what we have always known and that is that the early life influences on later disease are poorly understood and need more attention.

“Finally, it is worth remembering that Caesarean section can be a lifesaving procedure and parents and prospective parents should remember that the absolute risk of early onset bowel cancer is extremely low regardless of the mode of birth.”

‘Evaluation of Birth by Cesarean Delivery and Development of Early-Onset Colorectal Cancer’ by Yin Cao et al. was published in JAMA Network Open at 16:00 UK time on Thursday 27 April 2023.

DOI: 10.1001/jamanetworkopen.2023.10316

Declared interests

Prof Sir Mel Greaves: “No conflicts of interest to declare.”

Prof Kim Barrett: “I have no conflicts with respect to this work.”

Prof Neena Modi: “Immediate past-president: British Medical Association; Medical Women’s Federation.  Past-president: Royal College of Paediatrics and Child Health.”

Prof Louise Kenny: “No COI that I am aware of.”