Some maternal infections during pregnancy can cause adverse outcomes in children (e.g. miscarriage, congenital malformations). Previous research has raised the possibility that some antibiotics used to treat infection might also cause adverse child outcomes. For example, results from some clinical studies show maternal use of macrolides antibiotics (including erythromycin, clarithromycin and azithromycin) during pregnancy, may be associated with increased risks of some rare but serious adverse outcomes in children, such as congenital malformations, and neurodevelopmental outcomes, including cerebral palsy and epilepsy. Cerebral palsy (CP) refers to a group of permanent movement disorders that appear in early childhood. We want to disentangle whether the higher risks of adverse outcomes in some children are associated with the underlying maternal infections or with the macrolide antibiotics used to treat the infection. There is inconsistency in findings from previous research about whether macrolides are associated with adverse child outcomes and a lack of consensus across guidelines and authorities regarding the safety of prescribing macrolide antibiotics during pregnancy.
We propose to study the links between macrolide antibiotics, maternal infections, and potential adverse outcomes such as CP or epilepsy in children whose mothers were prescribed antibiotics in pregnancy. Our study also aims to scope key factors with the potential to influence the impact of macrolides such timing and type of macrolide antibiotics.
To analyse the safety of antibiotics use during pregnancy, a key challenge for an observational design is to disentangle associations between specific types of antibiotics and adverse outcomes from the association between the indications for using antibiotics, i.e. infections.
Some maternal infections are known to be fetal-damaging, including genital tract infection, TORCH (Toxoplasmosis, Other agents such as HIV, Rubella, Cytomegalovirus and Herpes simplex) and sexually transmitted infections (STIs)). However, associations are less clear between other common types of maternal infection (e.g. urinary tract infections (UTI), respiratory tract infection (RTI), skin infections and ear infections) and adverse children outcomes, including major congenital malformations, neurodevelopmental disorders and chronic conditions. Therefore, we aim to first determine 1) whether different types of maternal infections (e.g. respiratory tract infection and urinary tract infection) during pregnancy are associated with adverse child outcomes.
We then aim to evaluate 2) whether maternal macrolide antibiotic exposure (versus penicillins) is associated with adverse child outcomes (while adjusting for fetal damaging infections identified in 1)); and whether the association changes according to antibiotics subtypes, exposure timing, and number of recorded prescriptions. The head to head design between macrolides and penicillins minimise the risk of indication bias due to infection, considering macrolides are often prescribed as the alternative for women with suspected allergy to penicillin.
We will use a large UK representative birth cohort of mothers and children, born between 1990 and 2018. Our cohort will be based on the mother-baby link in CPRD, linked to Index of Multiple Deprivation data (IMD).
We will first describe the distribution of antibiotics prescriptions during pregnancy, maternal infections and their correlations. We also derive covariates and adverse outcomes in the dataset. For complex conditions for which diagnoses were unreliably recorded in primary care (e.g. CP), we integrate sources from literatures, clinical expertise and machine learning methods to ascertain the cases.
For the main analysis, we will compute propensity-score adjusted logistic model and Cox proportional hazard models to study the associations with prenatal infection, macrolides versus penicillins, co-variates and a range of adverse outcomes.
Primary outcomes:
Our primary outcomes include neurodevelopmental disorders and major congenital malformations including:
cerebral palsy, epilepsy, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD)
major malformation as a whole and individual malformations
psychiatric disorders as per the ICD-10 and DSM-5.1,2
chronic conditions in children as defined by Hardelid et al.3
The final list of primary outcomes will reflect a refined set of indicators with public health importance of diseases based on machine learning outcomes, prevalence, homogeneity with previous research and input from an expert steering group.
Ruth Gilbert - Chief Investigator - University College London ( UCL )
Heng Fan - Corresponding Applicant - University College London ( UCL )
Arturo Gonzalez-Izquierdo - Collaborator - University College London ( UCL )
Harry Hemingway - Collaborator - University College London ( UCL )
Janice Allister - Collaborator - Not from an Organisation
Leah Li - Collaborator - University College London ( UCL )
Linda Wijlaars - Collaborator - University College London ( UCL )
Shabeer Syed - Collaborator - University College London ( UCL )
Spiros Denaxas - Collaborator - University College London ( UCL )
CPRD Mother-Baby Link;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation