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Title: Adverse paediatric outcomes of macrolide antibiotics treatment in pregnancy
Author: Fan, Heng
ISNI:       0000 0004 9352 8305
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Background: Over the last 20 years, concerns have been raised about rare but serious adverse outcomes associated with macrolide use during pregnancy. Currently there was no consensus about whether macrolides are considered safe in pregnancy or not. This PhD study aims to examine the association between maternal exposure of macrolide antibiotics during pregnancy and adverse paediatric outcomes where short-term fetal hypoxia could be aetiologically involved. Methods: I first conducted a systematic review and meta-analysis of both random controlled trials and observational studies to investigate the association. I prioritized comparisons of macrolides with alternative antibiotics (mainly penicillins) for comparability of indication and effect. I then performed a large cohort study using a mother-baby linkage derived from the Clinical Practice Research Datalink (CPRD), a UK-representative primary care database. The cohort study assessed the association between macrolide (versus penicillin) prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) in children. Results: The systematic review and meta-analysis found consistent evidence for an association between macrolide antibiotics use during early pregnancy and an increased risk of miscarriage, inconsistent evidence for cerebral palsy and epilepsy, and insufficient evidence for malformations, stillbirth and neonatal death. The cohort study demonstrated that prescribing macrolides compared with penicillins during the first trimester of pregnancy (4 to 13 Gestational Week) was associated with increased risks of any major malformation and specifically cardiovascular malformations. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (mostly hypospadias). Erythromycin in the first trimester was found to be associated with an increased risk of any major malformation. Indication bias, unmeasured confounding, live-birth bias and outcome misclassification were unlikely to explain the findings. Conclusions: Considering the widespread use of macrolides during pregnancy, international collaboration is in urgent need to bring together existing datasets for large-scale analyses of high quality trial and observational cohorts that have accurate measurements of macrolides treatment and specific child outcomes. Analyses should pre-specify treatment exposure periods based on the critical period of specific outcomes. The findings of this study warrant cautious use of macrolides in pregnancy and recommendation of alternative antibiotics where feasible.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available