Clinical trial NCT03948620: Macrolide in Pregnancy and Adverse Child Outcomes
Official title: Associations Between Macrolide Antibiotics Prescribed During Pregnancy and Adverse Child Outcomes
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Infection
Lead sponsor: Institute of Child Health
Sponsor class: OTHER
First posted: 2019-05-14
Enrollment: 726274
Sex: ALL
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population will consist of all eligible children from the source population where the mother was prescribed an only monotherapy of macrolides or penicillins during pregnancy. The source population will be all mother-baby pairs identified from CPRD Mother-baby linkage where the children were born from Jan 1st 1990 to June 30th 2016.

Brief summary: Over the last 20 years, concerns have been raised about rare but serious adverse outcomes associated with macrolide use during pregnancy. The strongest evidence comes from a large randomised controlled trial (RCT, ORACLE Child Study II) of women with spontaneous preterm labour (SPL), which reported an increased risk of cerebral palsy in children whose mothers received erythromycin compared with no erythromycin. A recent systematic review on macrolides prescription during pregnancy showed consistent associations with miscarriage, and less consistent associations with adverse child outcomes such as congenital malformations, cerebral palsy and epilepsy. In this study, the investigators will evaluate associations between macrolide antibiotics prescription during pregnancy and a range of adverse child outcomes.

The investigators compare children whose mothers were prescribed an only monotherapy of macrolides or penicillins during pregnancy (from 5 gestational week (GW) to delivery and by trimesters). The investigators estimate the risk ratios of major malformation (overall and five system-specific) and hazard ratios of four neurodevelopmental disorders (cerebral palsy, epilepsy, attention-deficit/hyperactivity disorder, and autism spectrum disorder) with control for potential confounders. The associations will also be examined by subtype of macrolides and treatment duration.

Mother-child pairs will be analysed in a cohort selected from the UK Clinical Practice Research Database (CPRD) between 1990 and 2016.


Eligibility criteria: Inclusion Criteria:

* Children whose mother was prescribed an only monotherapy of macrolides or penicillins during pregnancy (between 5 GW and delivery).
* Children born from Jan 1st 1990 to June 30th 2016 in the CPRD Mother Baby Link.
* Children who registered with the GP within 6 months of birth
* Children whose mother was aged 14 to 50 years and had been registered with GP at least 50 weeks before estimated conception date until after delivery

Exclusion Criteria:

* Children with known chromosomal abnormalities and pregnancies with exposure to known teratogenic medications (warfarin, angiotensin-converting enzyme (ACE) inhibitors, antineoplastic agents, isotretinoin, misoprostol, and thalidomide)

Primary outcomes:
measure: Number of major malformation overall
timeFrame: From birth up to 4 years after birth.
measure: Number of cardiovascular malformation
timeFrame: From birth up to 4 years after birth.
measure: Number of nervous system malformation
timeFrame: From birth up to 4 years after birth.
measure: Number of gastrointestinal system malformation
timeFrame: From birth up to 4 years after birth.
measure: Number of genital malformation
timeFrame: From birth up to 4 years after birth.
measure: Number of urinary malformation
timeFrame: From birth up to 4 years after birth.
measure: Rate of cerebral palsy
timeFrame: From birth up to 15 years after birth.
measure: Rate of epilepsy
timeFrame: From birth up to 15 years after birth.
measure: Rate of attention-deficit/hyperactivity disorder (ADHD)
timeFrame: From birth up to 15 years after birth.
measure: Rate of autism spectrum disorder (ASD)
timeFrame: From birth up to 15 years after birth.
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Institute of Child Health, University College London
name: Ruth Gilbert, MD
role: STUDY_DIRECTOR
affiliation: Institute of Child Health, University College London
name: Leah Li, PhD
role: STUDY_DIRECTOR
References:
citation: Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, Taylor DJ. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet. 2008 Oct 11;372(9646):1319-27. doi: 10.1016/S0140-6736(08)61203-9. Epub 2008 Sep 17.
citation: Fan H, Li L, Wijlaars L, Gilbert RE. Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis. PLoS One. 2019 Feb 19;14(2):e0212212. doi: 10.1371/journal.pone.0212212. eCollection 2019.
citation: Fan H, Gilbert R, O'Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ. 2020 Feb 19;368:m331. doi: 10.1136/bmj.m331.