2025-26 Project (Carroll & Paixao Cruz)

The impact of Caesarean section on childhood health

SUPERVISORY TEAM

Supervisor

Dr Orlagh Carroll at LSHTM
Email: orlagh.carroll@lshtm.ac.uk

Co-Supervisor

Dr Enny Paixao Cruz at LSHTM
Email: enny.cruz@lshtm.ac.uk

PROJECT SUMMARY

Project Summary

Caesarean rates have increased worldwide. Evidence is emerging that it may lead to adverse outcomes in children such as leukaemia, potentially due to differences in child stress response or microbiome exposure during caesarean versus vaginal delivery. The majority of this evidence stems from studies which are cross-sectional, have a small sample size, lack long follow-up and are focused on inferring associations rather than causality. The Target trial (TT) framework aims to emulate a randomised trial using observational data and thus estimate causal effects. This project will implement a TT using Brazilian data and apply various analysis techniques.

The objectives are: 
1. Conduct a systematic review investigating the effect of caesarean versus vaginal delivery on childhood leukaemia 
2. Implement a TT to investigate the effect of caesarean versus vaginal delivery on leukaemia  
3. Investigate whether the impact of caesarean delivery is mediated by post-intervention characteristics and triangulate evidence from various techniques

Project Key Words

Caesarean, Brazil, causality, target-trial, triangulation, leukaemia

MRC LID Themes

  1. Health Data Science
  2. Global Health

Skills

MRC Core Skills

  1. Quantitative skills

Skills we expect a student to develop/acquire whilst pursuing this project

This project will use large observational data containing millions of records. The student will gain experience in using R or Stata, cleaning data and running analyses on large-scale electronic health records. It is expected that the student will have the opportunity to learn and apply statistical methods such as causal inference (including developing and implementing a target trial and drawing directed acyclic graphs), triangulation (with methods such as within sibling analysis or negative controls), missing data techniques and more general modelling methods (survival analysis, longitudinal modelling).

Training opportunities for the student will include attending relevant statistics modules at LSHTM, distance learning courses on data linkage from CIDACS/Fiocruz, and external training courses using their RTSG funding.

The student will be expected to develop their presentation skills by giving seminars and talks within LSHTM, with collaborating institutions (including University of Bristol) and at conferences. They will gain skills in ethics for research and will apply for institutional ethical approval for this project. Additional skills will include academic writing with the aim of publishing in peer-reviewing journals.

The student will join the SEEDS group at LSHTM which focuses on the study of early-life exposures for children. The group meets monthly to present ongoing or completed work and discuss relevant papers. The student will be expected to present at SEEDS during their PhD and participate in discussion on statistical methods and provide feedback to SEEDS colleagues.

Routes

Which route/s are available with this project?

  • 1+4 = Yes
  • +4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

  • LSHTM – MSc Medical Statistics

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? Yes

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution, meeting – at the minimum – the institutional research degree regulations and expectations. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training (for research degree study). Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Primary location for duration of this research degree: LSHTM, London

Travel requirements for this project: The student will be primarily based at LSHTM, London but may be expected to travel to Bristol and Brazil to collaborate with colleagues.

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

  • Minimum LSHTM institutional eligibility criteria for doctoral study.
  • The project will require the student to have a first class or upper second class undergraduate degree in a subject with either a quantitative component (e.g. Mathematics, Statistics) or with a clinical background (e.g. Medicine, nursing), and an MSc (or equivalent) in Statistics, Biostatistics, Medical Statistics, or Statistical Science. If the student does not have an MSc in Statistics, they will be expected to attend an MSc Medical Statistics on the 1+4 route.

Other useful information

  • Potential Industrial CASE (iCASE) conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

The rate of caesarean section (CS) in Brazil is high with 56% of births delivered using this method. While CS tends to be higher in low- and middle-income countries (LMIC), the rate of CS is increasing worldwide. CS can be lifesaving but previous studies have identified potential increased risk of childhood leukaemia compared to children born via vaginal delivery. This may be due to the different type of microbiome a child is exposed to during CS or the absence of a stress response caused by vaginal delivery. Conducting a randomised trial for CS may be viewed as unethical and thus the majority of this evidence comes from observational studies set in high-income countries with small sample sizes, short follow-up and which are focused on associations between CS and childhood outcomes. In 2016, Hernán published a target trial (TT) framework to emulate a randomised trial using observational data for comparative effectiveness studies. By emulating a trial, common observational study challenges can be avoided and TT results have been shown to be comparable to results from trials. This project will implement a TT in nationwide linked health and socioeconomic data from Brazil, apply causal inference methodology and triangulate results.    

Objectives:
1. Conduct a systematic review investigating the effect of caesarean versus vaginal delivery on childhood leukaemia, and investigate whether this effect differs by LMIC status
2. Implement a TT to investigate the effect of caesarean versus vaginal delivery on leukaemia using Brazilian data.
3.Investigate whether the impact of caesarean delivery is mediated by post-intervention characteristics and integrate evidence from various analytical techniques (triangulation)

Techniques: 
Objective 1 will involve applying literature searching methods, using PRISMA and other reporting guidelines, and possibly implementing a meta-analysis. For objectives 2-3,  the student will use the CIDACS birth cohort (N=28,631,394) linked to hospitalisation and mortality records. They will follow the TT framework and will construct directed acyclic graphs (DAGS) to understand the relationship between CS and leukaemia. The student may apply advanced statistical methods such as inverse probability weighting, mediation analysis, within sibling analysis, negative controls and multiple imputation. The student will use R or Stata for this project.

Data: 
Objective 1 does not have data availability concerns as this will use published literature. Objectives 2-3 will be completed using the CIDACS birth cohort linked to hospitalisation and mortality data. The data for the proposed analyse are held securely at CIDACS-Fiocruz in Salvador, Brazil and can be accessed at LSHTM via a VPN connection.

Potential risks: 
The data for this project is available on a server at CIDACS. The VPN is regularly accessed by researchers at LSHTM so no long-term access issues are expected. While VPN issues are incredibly unlikely, a final back-up plan could involve the PhD supervisors generating replicate data for the student to develop code and later implement the analysis during a planned visit to CIDACS.

Further reading

Relevant preprints and/or open access articles:
(DOI = Digital Object Identifier)

Additional information from the supervisory team

The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.

Carroll-Paixao Cruz recording

MRC LID LINKS

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