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出境医 / 临床实验 / Macrolide in Pregnancy and Adverse Child Outcomes

Macrolide in Pregnancy and Adverse Child Outcomes

Study Description
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.


Condition or disease Intervention/treatment
Infection Drug: Macrolides Drug: Penicillins

Study Design
Layout table for study information
Study Type : Observational
Actual Enrollment : 726274 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Associations Between Macrolide Antibiotics Prescribed During Pregnancy and Adverse Child Outcomes
Actual Study Start Date : January 1, 1990
Actual Primary Completion Date : June 30, 2016
Actual Study Completion Date : June 30, 2016
Arms and Interventions
Group/Cohort Intervention/treatment
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.

 Drug: Macrolides
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.

Drug: Penicillins
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.
Outcome Measures
Primary Outcome Measures :
  1. 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.

  2. 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).

  3. 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).

  4. 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).

  5. 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).

  6. 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).

  7. 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).

  8. 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.

  9. 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.

  10. 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.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   up to 14 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
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)
Contacts and Locations

Sponsors and Collaborators
Institute of Child Health
Investigators
Layout table for investigator information
Study Director: Ruth Gilbert, MD Institute of Child Health, University College London
Study Director: Leah Li, PhD Institute of Child Health, University College London
Tracking Information
First Submitted Date May 10, 2019
First Posted Date May 14, 2019
Last Update Posted Date May 15, 2019
Actual Study Start Date January 1, 1990
Actual Primary Completion Date June 30, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 13, 2019)
  • 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.
Original Primary Outcome Measures
 (submitted: May 10, 2019)
  • 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). We exclude musculoskeletal malformations which are not reliably recorded in 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.
  • 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 GA <37 weeks, Q2541, Q256 if GA<37 weeks, and Q261).
  • 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).
  • 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).
  • 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).
  • 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).
  • Cerebral palsy [ Time Frame: From birth up to 15 years after birth. ]
    We 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).
  • Epilepsy [ Time Frame: From birth up to 15 years after birth. ]
    We 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.
  • Attention-deficit/hyperactivity disorder (ADHD) [ Time Frame: From birth up to 15 years after birth. ]
    We 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.
  • Autism spectrum disorder (ASD) [ Time Frame: From birth up to 15 years after birth. ]
    We 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.
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Macrolide in Pregnancy and Adverse Child Outcomes
Official Title Associations Between Macrolide Antibiotics Prescribed During Pregnancy and Adverse Child Outcomes
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.
Detailed Description Not Provided
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Retrospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
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.
Condition Infection
Intervention
  • Drug: Macrolides
    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.
  • Drug: Penicillins
    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 Groups/Cohorts 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.

Interventions:
  • Drug: Macrolides
  • Drug: Penicillins
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.
  • 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.
  • 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. Erratum in: BMJ. 2020 Mar 4;368:m766.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: May 10, 2019) 		726274
Original Actual Enrollment Same as current
Actual Study Completion Date June 30, 2016
Actual Primary Completion Date June 30, 2016   (Final data collection date for primary outcome measure)
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)
Sex/Gender
Sexes Eligible for Study: All
Ages up to 14 Years   (Child)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number NCT03948620
Other Study ID Numbers Heng1
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Institute of Child Health
Study Sponsor Institute of Child Health
Collaborators Not Provided
Investigators
Study Director: Ruth Gilbert, MD Institute of Child Health, University College London
Study Director: Leah Li, PhD Institute of Child Health, University College London
PRS Account Institute of Child Health
Verification Date May 2019

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