Title: Long term impact of giving antibiotics before skin incision versus after cord clamping on children born by caesarean section: longitudinal study based on UK electronic health records
Funder: Department of Health and Social Care

Abstract: Aim: To investigate whether the change in the NICE guidance in 2011 from recommending prophylactic antibiotics after cord clamping to pre-incision antibiotics has had any effect on the incidence of allergic and other related health conditions in children born by Caesarean Section (CS). Design: A controlled interrupted time series study using mother-baby linked routine health record data from UK primary (THIN, CPRD) and secondary care (HES) databases. Target population: Children born in the UK during 2006-2018 delivered by CS, compared to a control cohort delivered vaginally. Intervention and comparator: In utero exposure to prophylactic antibiotics immediately prior to CS will be compared to no exposure when given after cord clamping at CS. The exposure to intra-partum antibiotics is not routinely recorded in any available healthcare databases in the UK, but nearly all women undergoing CS receive prophylactic antibiotics. We will use the findings from the national survey of hospitals regarding the change in the timing of antibiotic administration as an indicator of the probability of exposure. We will account for the cumulative increase of hospitals giving pre-incision antibiotics in our analysis. For the analysis of outcomes recorded in secondary care, we will be able to link the survey data regarding the timing of policy change at hospital level for each birth. Primary outcomes: asthma and eczema, the most common allergy related childhood diseases. Secondary outcomes: other allergic and allergy related diseases, autoimmune diseases, infections and inflammation, other immune system related conditions, healthcare utilisation. Maternal postpartum infectious morbidity will allow us to investigate if the effects of pre-incision antibiotics demonstrated in randomised trials can be replicated using routine data. Planned sample size: We will use all available data from THIN, CPRD and HES. We have identified the likely number of deliveries, asthma diagnosis (for primary care) and asthma admissions (for secondary care) across the study time period. For primary care we will compare outcomes in 95,000 CS deliveries receiving pre-incisional antibiotics with 112,000 receiving post-clamping antibiotics, with outcomes from 571,000 vaginal births being used to control for time effects. This will provide 80% and 90% power to detect relative increases in risk of asthma of 16% and 18%, respectively at the 5% significance level. For secondary care we will compare outcomes in 955,000 CS deliveries receiving pre-incisional antibiotics with 1,116,000 receiving post-clamping antibiotics, with outcomes from 5,973,000 vaginal births. This will provide 80% and 90% power to detect relative increases in risk of asthma hospital admission of 10% and 12%, respectively at the 5% significance level. Timetable: Year 1 - Development of the analysis model; exploration of case-mix co-variates; finalisation of the outcome variables including findings from the PPI workshop; HES & CPRD data acquisition; dataset merging and data linkage, dataset cleaning and preparation for the analysis. Year 2 - Analysis and data interpretation; co-production of messages with PPI for dissemination, dissemination of findings.

Lay abstract: Aim: This study will look to see if there is any long term impact of antibiotics given at the time of Caesarean Section (CS) on the health of children. The study findings will help women and their families to make informed decisions before CS with regards to whether or not, and how, they wish to receive antibiotics before their baby is born. Background: In the UK, about a quarter of women give birth by CS. Before 2011, national guidance recommended offering antibiotics to women undergoing CS after the umbilical cord was cut, to reduce the risk of the mother developing an infection, particularly wound infection. However, it became clear that the earlier antibiotics were given the less likely mothers were to develop an infection. So, the guidance changed in 2011 to recommend giving antibiotics before the operation to reduce the risk of infection in mothers even further. Antibiotics given to the mother before CS also reach the baby via the placenta. This does not appear to affect their health in the short term following the birth. We do not know, however, whether these antibiotics have a long term impact on children’s health. The newborn gut during and after birth is colonised by bacteria which are vital for health and believed to be important in the development of the child’s immune system. The bacteria differ between babies who receive and who do not receive antibiotics during a CS which may affect their chances of developing health conditions such as asthma, eczema and food allergies. Design and methods: To assess the longer term effects of antibiotic use in CS, we will use routine NHS information already collected by hospitals and GPs from women who gave birth in the UK (before and after the change in the national policy) and their children. We will look at a range of health conditions in children, particularly asthma, eczema and allergies, as well as infections and immune system related disorders. We will compare rates of asthma and other diseases in children born by CS before and after the change in the national guidance. We will also compare their health to children whose mothers had a vaginal birth over the study period. This will ensure that any changes in the health of the children are not due to changes in other factors over time such as, for example, changes in the diagnosis and recording of asthma in GP medical records. Patient and public involvement: We have actively involved parents of young children and members of the wider public in the development of this proposal. They were reassured that the researchers have access only to fully anonymised data that does not allow identification of individual mothers and children. We will work in partnership with two PPI advisors (one of them is a co-applicant), throughout the project. In response to the PPI feedback, we will organise two workshops with a larger group of parents to help select outcomes important for children and their families, and co-produce messages based on the project findings to ensure that they are helpful when making decisions about when to receive antibiotics at the time of CS. Dissemination: Findings will be disseminated via professional organisations such as the Royal College of Obstetricians and Gynaecologists, third sector organisations, such as the National Childbirth Trust (NCT) and policy makers in the Department of Health. We will also publicise our findings at conferences, in peer-reviewed publications and press releases.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH;RESPIRATORY