Title: In-utero antibiotic exposure in babies born by caesarean section and subsequent risk of allergic disease and asthma in the Born in Bradford birth cohort
Funder: Department of Health and Social Care

Abstract: Design: Quasi-experimental study within a prospective birth cohort. Setting: Population-based birth cohort based at Bradford Royal Infirmary (BRI) from 2007-2011. Target population: Children born by caesarean section (CS). Inclusion/exclusion criteria: Only the first-born of multiple births will be included to ensure independence of observations Health technologies being assessed: Prophylactic antibiotics to reduce the risk of post-operative infections are administered during CS. In 2011 NICE recommended giving antibiotics prior to incision. Some hospitals, including BRI, began administering pre-incision antibiotics prior to NICE guidelines, responding to evidence of reductions in post-operative infections. Measurement of exposure: We will collect time of birth, time antibiotics given, type of antibiotic (broad or narrow-spectrum) and length of post-partum hospital stay from maternity notes for each CS birth (n=2443). Measurement of outcomes: The following outcomes in children born by CS and exposed to antibiotics in utero will be compared to those born by CS but not exposed to antibiotics in utero: Primary outcome: GP diagnosis or prescriptions for eczema, hay fever, wheeze and asthma at age 7 years and earlier. Secondary outcomes: 1) Atopy (positive skin prick test) at age 4 years 2) Parental report of eczema and hay fever at age 2 years and eczema, hay fever, wheeze and asthma at age 4 years. The prevalence of these outcomes among children born by vaginal delivery will also be compared to those born by CS. To investigate potential beneficial effects of pre-incision antibiotics, we will compare length of stay after CS for the two groups (exposed and unexposed to antibiotics). BMI and obesity will be investigated as potential outcomes. Sample size: For all sample size calculations we have assumed 22% were born by CS as per the overall study cohort, with 7% exposed [Ex] and 15% unexposed [UE] to antibiotics in utero. The following examples are for the smallest (asthma at age 7, primary care data) and largest (atopic status at age 4, MeDALL sub-study) effect sizes likely to be detectable: Of those with primary care data, comparing the 1664 UE with 779 Ex children assuming 10% (166) of UE have an asthma diagnosis by age 7 years (BiB data, unpublished) there will be 80% power to detect a 1.4-fold increase in prevalence in the Ex group (14%). Of those with SPT data at 4 years, comparing the 340 UE children with 159 Ex children, assuming 18% (61) of UE are atopic (ALL IN data, unpublished), there will be 80% power to detect a 1.6-fold increase in the Ex group (29%). Project timetable: May-Oct 2018: notes review to determine antibiotics timing for 2374 CS deliveries; extraction of relevant primary care data Nov 2018–Oct 2019: data management and analysis Nov 2019–Apr2020: preparation of publications Expertise in team: Lucy Pembrey is an epidemiologist and the BiB Allergy and Infection Study PI. John Wright is a clinical epidemiologist and PI for the BiB study. Sam Oddie is a Consultant Neonatologist at BRI working closely with BiB. Emily Petherick is an epidemiologist and biostatistician with expertise in longitudinal analyses. Pippa Bird is a Principal Research Fellow with BiB with expertise in social epidemiology and quasi-experimental approaches to evaluation. Neil Pearce is Professor of Epidemiology and Biostatistics with expertise in asthma and allergy.

Lay abstract: Women who have their babies by caesarean section (CS) are given antibiotics to prevent infection of the wound. In the past, these antibiotics were given to the mother after the cord was clamped so none of the antibiotics passed to the baby. Since 2011, national guidelines have recommended that antibiotics are given to the mother before the skin is cut for the CS, as there is good evidence that this reduces the risk of wound infection. A possible disadvantage of giving the antibiotics earlier is that babies born by CS will get a dose of antibiotics just before birth. Having antibiotics early in life may affect the balance of ‘good bacteria’ and other organisms in the gut (the gut microbiome). This, in turn, might increase the chance that the babies will develop allergic diseases such as eczema, hay fever and asthma when they are older. There are likely to be many different causes of asthma and allergic disease; antibiotics are just one possible part of the puzzle. We do not yet know if antibiotics in early life will increase or decrease the risk of developing allergic diseases (although current knowledge suggests that if there is any effect, it will involve an increased risk). The Born in Bradford (BiB) birth cohort study, which includes over 10,000 children in total, provides the opportunity of a natural experiment to compare the risk of allergic disease in children born by CS and exposed to antibiotics with those born by CS but not exposed to antibiotics. The cohort includes babies born between 2007 and 2011 and a review of maternity notes indicates a change in the timing of giving antibiotics around 2009/2010 in Bradford. This means that pre-incision antibiotics were given ‘routinely’ in some CS births but not others, rather than for any reason linked to the risk of infection in the mother or baby. The findings of previous studies on the association between antibiotics and asthma have been difficult to interpret because the symptoms or infections for which the antibiotics are given to children might be related to asthma or risk factors for asthma. Information on timing of birth and antibiotics will be collected from the maternity notes for each BiB child born by CS (n=2443) to determine whether or not they were exposed to antibiotics just before birth. We have already collected data on atopic status (a positive reaction to at least one allergen on skin prick testing indicating an increased risk of allergic disease) at age 4 years (for a total of 2269 children) and questionnaire data on parental report of eczema or hay fever at age 2 years (n=2052) and eczema, hay fever, wheeze or asthma at age 4 years (n=2594). In addition, we have linked data on GP diagnoses and prescriptions for allergic disease for all BiB children (n=10,915). Detailed information on other factors which might affect the relationship between antibiotic exposure and allergic disease, such as breastfeeding and pet ownership, has been collected from BiB children. We will also be able to account for antibiotic exposure at other times (earlier in utero if mother treated with antibiotics during pregnancy; during infancy/childhood) using linked primary care data. The findings of this study will show whether having antibiotics at birth increases the risk of children subsequently developing hay fever, eczema or asthma. The findings will help us decide the best time to give antibiotics to women during CS, by balancing the benefits and risks to the mother and her child.

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