InfectionNCT03948620
Macrolide in Pregnancy and Adverse Child Outcomes
An observational study of Infection, run by Institute of Child Health.
Trial 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… Read more about this study
- Who is it for?
- Ages Up to 14 years
- Conditions the study is for
- Infection
- What is being tested?
- Macrolides and Penicillins
- How many people
- 726,274 participants
- Where
- No sites listed yet
- Study dates
- 1 Jan 1990to 30 Jun 2016
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 14 years
- All sexes
- No healthy volunteers
- Child
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.
Who may be able to join
- 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
Who cannot join
- 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)
About this study
Official title: Associations Between Macrolide Antibiotics Prescribed During Pregnancy and Adverse Child Outcomes
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.
- Conditions
- Infection
- Being tested
- Macrolides, Penicillins
- Medical subject headings
- Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MacrolidesDrug
Macrolide antibiotics, including erythromycin, clarithromycin and azithromycin. Prescriptions of macrolides will be identified using a drug code list based on the British National Formulary (chapter 5.1.5) and the date of the first prescription was used as the index date of exposure.
PenicillinsDrug
The comparison group consists of children whose mother were prescribed penicillins during pregnancy. Prescriptions of penicillins will be identified using a drug code list based on the British National Formulary (chapter 5.1.1) and the date of the first prescription will be used as the index date of exposure.
| Study group | Role | What they receive |
|---|---|---|
| Children whose mother prescribed antibiotics during pregnancy | Children whose mother were prescribed an only monotherapy of macrolides or penicillins from 5 gestational weeks (GW) to delivery. A monotherapy is defined as one or more consecutive prescriptions for a single antibiotic (i.e. same drug substance) separated by no more than 30 days and uninterrupted by prescriptions for other antibiotic drug substances.
The investigators will also build a negative control cohort which includes children whose mother were prescribed an only monotherapy of macrolides or penicillins from 50 to 10 weeks before conception. Receives: Drug: Macrolides; Drug: Penicillins |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of major malformation overall
Major malformation overall will be defined as any of the 11 major system-specific malformations defined in the European Surveillance of Congenital Anomalies (EUROCAT)(Congenital heart defect, nervous system, eye, ear/face/neck, respiratory tract, oro-facial cleft, digestive system, abdominal wall defect, urinary tract, genital tract, and other malformations). The investigators exclude musculoskeletal malformations which are not reliably recorded in general practice (GP) records, and malformation with known cause such as malformation resulted from maternal infections, fetal alcohol syndrome and chromosomal malformations. The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT.
Measured: From birth up to 4 years after birth.
Number of cardiovascular malformation
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (ICD Q20-Q26; exclude Q2111, Q250 if gestational age (GA) <37 weeks, Q2541, Q256 if GA<37 weeks, and Q261).
Measured: From birth up to 4 years after birth.
Number of nervous system malformation
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q00-Q07, exclude Q0461, Q0782).
Measured: From birth up to 4 years after birth.
Number of gastrointestinal system malformation
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q38-Q45, Q790, exclude Q381, Q382, Q3850, Q400, Q401, Q4021, Q430, Q4320, Q4381, Q4382).
Measured: From birth up to 4 years after birth.
Number of genital malformation
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q50-Q52, Q54-Q56; exclude Q523, Q525, Q527, Q5520, Q5521).
Measured: From birth up to 4 years after birth.
Number of urinary malformation
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q60-Q64, Q794; exclude Q610, Q627, Q633).
Measured: From birth up to 4 years after birth.
Rate of cerebral palsy
The investigators identify children with cerebral palsy using informative Read codes or prescription codes (selected by the Random Forest approach) and validated by a paediatric neurologist (FC) and a clinical epidemiologist with paediatrics expertise (RG) blinded to their prenatal exposure (A machine learning approach to identify cases of cerebral palsy using the UK primary care database.Fan, Heng et al.The Lancet , Volume 392 , S33).
Measured: From birth up to 15 years after birth.
Rate of epilepsy
The investigators identify epilepsy by 2 prescriptions of antiepileptic drug (AED, identified based on British National Formula Chapter 4.8) within 4 months or >= 1 diagnosis in children's GP records.
Measured: From birth up to 15 years after birth.
Rate of attention-deficit/hyperactivity disorder (ADHD)
The investigators identify ADHD by >= 2 occurrence of prescriptions for ADHD ( identified based on British National Formula Chapter 4.4) or diagnoses (attention deficit hyperactivity disorder, hyperkinetic disorders, hyperkinetic syndrome, hyperkinetic reaction of childhood or adolescence, overactive child syndrome and disturbance of activity and attention) in children's GP records.
Measured: From birth up to 15 years after birth.
Rate of autism spectrum disorder (ASD)
The investigators identify ASD by at least 1 diagnostic code ((infantile or childhood) autism, Asperger's syndrome, Rett's syndrome, Heller's syndrome, Autistic spectrum disorder, disintegrative disorder, and other pervasive developmental disorders) in children's GP records.
Measured: From birth up to 15 years after birth.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2019
- Study start1 Jan 1990
- Primary completion30 Jun 2016
- Study completion30 Jun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 726,274 participants (actual)
Sponsor and investigators
- Lead sponsor
- Institute of Child Health
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ruth Gilbert, MD, Study director, Institute of Child Health, University College LondonLeah Li, PhD, Study director, Institute of Child Health, University College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03948620
- Sponsor's protocol ID
- Heng1
- Status last verified
- May 2019
- First submitted
- 10 May 2019
- Last updated
- 15 May 2019
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 18804276Fan 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.
PubMed 30779772Fan 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.
PubMed 32075790
Study at a glance
From the registry record, last updated by the sponsor on 15 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Associations Between Macrolide Antibiotics Prescribed During Pregnancy and Adverse Child Outcomes
- ClinicalTrials.gov ID
- NCT03948620
- Acronym / sponsor ID
- Heng1
- Conditions
- Infection
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 726,274 participants (actual)
- Lead sponsor
- Institute of Child HealthUniversity, hospital or other
- Study start
- 1 Jan 1990 (actual)
- Primary completion
- 30 Jun 2016 (actual)
- Study completion
- 30 Jun 2016 (actual)
- First posted
- 14 May 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Children whose mother prescribed antibiotics during pregnancy | – | Drug: Macrolides, Drug: PenicillinsChildren whose mother were prescribed an only monotherapy of macrolides or penicillins from 5 gestational weeks (GW) to delivery. A monotherapy is defined as one or more consecutive prescriptions for a single antibiotic (i.e. same drug substance) separated by no more than 30 days and uninterrupted by prescriptions for other antibiotic drug substances. The investigators will also build a negative control cohort which includes children whose mother were prescribed an only monotherapy of macrolides or penicillins from 50 to 10 weeks before conception. |
Who may qualify
- Ages
- Up to 14 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
- 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.
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (1 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MacrolidesMacrolide antibiotics, including erythromycin, clarithromycin and azithromycin. Prescriptions of macrolides will be identified using a drug code list based on the British National Formulary (chapter 5.1.5) and the date of the first prescription was used as the index date of exposure. | Drug | Children whose mother prescribed antibiotics during pregnancy |
| PenicillinsThe comparison group consists of children whose mother were prescribed penicillins during pregnancy. Prescriptions of penicillins will be identified using a drug code list based on the British National Formulary (chapter 5.1.1) and the date of the first prescription will be used as the index date of exposure. | Drug | Children whose mother prescribed antibiotics during pregnancy |
Primary outcome
Number of major malformation overall
Time frame: From birth up to 4 years after birth.
Major malformation overall will be defined as any of the 11 major system-specific malformations defined in the European Surveillance of Congenital Anomalies (EUROCAT)(Congenital heart defect, nervous system, eye, ear/face/neck, respiratory tract, oro-facial cleft, digestive system, abdominal wall defect, urinary tract, genital tract, and other malformations). The investigators exclude musculoskeletal malformations which are not reliably recorded in general practice (GP) records, and malformation with known cause such as malformation resulted from maternal infections, fetal alcohol syndrome and chromosomal malformations. The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT.
Number of cardiovascular malformation
Time frame: From birth up to 4 years after birth.
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (ICD Q20-Q26; exclude Q2111, Q250 if gestational age (GA) <37 weeks, Q2541, Q256 if GA<37 weeks, and Q261).
Number of nervous system malformation
Time frame: From birth up to 4 years after birth.
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q00-Q07, exclude Q0461, Q0782).
Number of gastrointestinal system malformation
Time frame: From birth up to 4 years after birth.
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q38-Q45, Q790, exclude Q381, Q382, Q3850, Q400, Q401, Q4021, Q430, Q4320, Q4381, Q4382).
Number of genital malformation
Time frame: From birth up to 4 years after birth.
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q50-Q52, Q54-Q56; exclude Q523, Q525, Q527, Q5520, Q5521).
Number of urinary malformation
Time frame: From birth up to 4 years after birth.
The malformations will be identified in the children's medical records using Read codes mapped from the tenth edition of the International Classification of Diseases (ICD-10) code lists provided by EUROCAT (Q60-Q64, Q794; exclude Q610, Q627, Q633).
Rate of cerebral palsy
Time frame: From birth up to 15 years after birth.
The investigators identify children with cerebral palsy using informative Read codes or prescription codes (selected by the Random Forest approach) and validated by a paediatric neurologist (FC) and a clinical epidemiologist with paediatrics expertise (RG) blinded to their prenatal exposure (A machine learning approach to identify cases of cerebral palsy using the UK primary care database.Fan, Heng et al.The Lancet , Volume 392 , S33).
Rate of epilepsy
Time frame: From birth up to 15 years after birth.
The investigators identify epilepsy by 2 prescriptions of antiepileptic drug (AED, identified based on British National Formula Chapter 4.8) within 4 months or >= 1 diagnosis in children's GP records.
Rate of attention-deficit/hyperactivity disorder (ADHD)
Time frame: From birth up to 15 years after birth.
The investigators identify ADHD by >= 2 occurrence of prescriptions for ADHD ( identified based on British National Formula Chapter 4.4) or diagnoses (attention deficit hyperactivity disorder, hyperkinetic disorders, hyperkinetic syndrome, hyperkinetic reaction of childhood or adolescence, overactive child syndrome and disturbance of activity and attention) in children's GP records.
Rate of autism spectrum disorder (ASD)
Time frame: From birth up to 15 years after birth.
The investigators identify ASD by at least 1 diagnostic code ((infantile or childhood) autism, Asperger's syndrome, Rett's syndrome, Heller's syndrome, Autistic spectrum disorder, disintegrative disorder, and other pervasive developmental disorders) in children's GP records.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 May 2019.
- Background: PubMed 18804276Kenyon 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.
- Background: PubMed 30779772Fan 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.
- Derived from this study: PubMed 32075790Fan 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ruth Gilbert, MD study director
Institute of Child Health, University College London
Leah Li, PhD study director
Institute of Child Health, University College London
Questions about this trial
What is this clinical trial studying?
An observational study of Infection, run by Institute of Child Health.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 May 2019. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of major malformation overall (time frame: From birth up to 4 years after birth.). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03948620, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 May 2019.