Associations Between Macrolide Antibiotics Prescribed During Pregnancy and Adverse Child Outcomes
Conditions: Infection
Sponsor: Institute of Child Health

Macrolides and adverse child outcomes  
  
V3 
1 
 
 
 
 
Associations between macrolide antibiotics prescribed 
during pregnancy and adverse child outcomes 
 
 
Study Protocol 
 
Heng Fan Mphil, Ruth Gilbert MD, Leah Li PhD 
Version 3 22.4.2019 
 
 
 
 
 
 
 
 
 

Macrolides and adverse child outcomes  
  
V3 
2 
 
 
 
Contents 
1. Background ......................................................................................................................................... 3 
2. Objectives ............................................................................................................................................ 3 
3. Data source ......................................................................................................................................... 4 
4. Methods .............................................................................................................................................. 4 
4.1 Study design .................................................................................................................................. 4 
4.2 Study Population ........................................................................................................................... 4 
4.3 Study Variables ............................................................................................................................. 5 
4.3.1 Exposure ................................................................................................................................. 5 
4.3.2 Outcome ................................................................................................................................ 5 
4.3.3 Covariates .............................................................................................................................. 7 
4.4 Analyses ...................................................................................................................................... 10 
4.4.1 Statistical methods ............................................................................................................... 10 
4.4.2 Primary, subgroup and sensitivity analyses ......................................................................... 10 
4.5 Power analysis............................................................................................................................. 11 
Appendix ............................................................................................................................................... 13 
Reference .............................................................................................................................................. 13 
 
 
 
 

Macrolides and adverse child outcomes  
  
V3 
3 
 
1. Background 
Macrolide antibiotics are the third most frequently prescribed antibacterial class during pregnancy in 
western countries and are generally considered safe.(1-4) Over the last 20 years, concerns have been 
raised about some rare but serious adverse outcomes associated with macrolide use during 
pregnancy.(5-8) The strongest evidence comes from a large factorial randomised controlled trial (RCT, 
OCSII) of women with spontaneous preterm labour (SPL). The investigators reported an increased risk 
of cerebral palsy in children whose mothers received any erythromycin (i.e. erythromycin only or 
erythromycin and co-amoxiclav, 3.3%) compared with those who received no erythromycin (i.e. co-
amoxiclav or placebo, 1.7%) (odds ratio (OR) 1·93, 95% Confidence Interval (CI): 1·21-3·09).(8) The 
increased risk of cerebral palsy (CP) or epilepsy was also observed in a large cohort study of 195,909 
unselected pregnant women, where erythromycin was compared with penicillins.(7) Additionally, 
increased risks of stillbirth, miscarriage, major malformations, cardiovascular malformation and 
pyloric stenosis have been reported by some observational studies,(5, 9-12) but not in others.(13-15) 
Currently, there is no consensus about how to respond to this evidence. In Sweden in 2005, national 
policy advised against the use of erythromycin during early pregnancy.(11) In April 2015, the UK 
Medicines and Healthcare products Regulatory Agency (MHRA) reviewed the evidence reported by 
Meeraus et al. and decided there was insufficient evidence to warn against the use of macrolides in 
pregnancy.(7, 16)  
 
Prompt and adequate treatment for infection during pregnancy is vital given the well-established 
association between maternal infection during pregnancy and adverse birth outcomes, including 
miscarriage and stillbirth.(17) More evidence is needed on whether there is a causal association 
between maternal macrolide antibiotics treatment during pregnancy and adverse child outcomes.   
 
2. Objectives 
We will conduct a population-based cohort study to evaluate the association between the macrolide 
antibiotics prescription in pregnancy and adverse child outcomes (neurodevelopmental disorders and 
major malformation (overall and system-specific)) (primary analysis), and to examine this association 
by macrolides subtypes and length of prescriptions (subgroup analysis). 

Macrolides and adverse child outcomes  
  
V3 
4 
 
3. Data source 
We will use the Clinical Practice Research Datalink (CPRD), a UK-representative database which 
captures prospective, anonymised data on prescriptions, diagnoses, and symptoms records in primary 
care.(18)  A Mother-baby link was built within CPRD using family ID, practice ID, and date of 
birth/delivery, with details reported elsewhere.(19, 20) For each mother-baby pair, a delivery date 
was estimated (Appendix). 
4. Methods 
4.1 Study design 
Retrospective cohort study with prospectively collected data. 
4.2 Study Population 
The Mother-baby link includes 1,071,379 children born from Jan 1st 1990 to June 30th 2016.   
 
 
Inclusion Criteria: 
- 
Children whose mother was prescribed an only monotherapy of macrolide or penicillin 
during pregnancy (between 5 Gestational Week [GW] and delivery) 
- 
Children who registered with the general practice (GP) within 6 months of birth 
- 
Children whose mother was aged 14 to 50 years at delivery and had been registered with GP 
from at least 50 weeks before estimated conception date to delivery 
 
Exclusion Criteria: 
Children with known chromosomal abnormalities or with fetal exposure to known teratogenic 
medications (warfarin, angiotensin-converting enzyme (ACE) inhibitors, antineoplastic agents, 
isotretinoin, misoprostol, and thalidomide). 
 
Children will be followed from birth to death, end of follow-up (June 30th, 2016), or age 14, whichever 
came first. 

Macrolides and adverse child outcomes  
  
V3 
5 
 
4.3 Study Variables 
4.3.1 Exposure 
The exposure group will include children whose mother were prescribed an only monotherapy of 
macrolide antibiotics from 5 GW to delivery (hereafter, “during pregnancy”). 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 macrolides prescription is identified using a drug code list based on chapter 5.1.5 of 
the British National Formulary. The date of first prescription is used as the index date.  The reference 
group includes children whose mothers were exposed to an only monotherapy of penicillins during 
pregnancy. Preliminary analysis shows that 81% of all antibiotic prescriptions were monotherapies. 
We further divide the time window into 1) 5GW to 13GW (29 Gestational Day [GD] to 91GD, hereafter, 
“1st trimester”), the critical period for most major malformation, and 2) 14GW to delivery (hereafter, 
“2nd–3rd trimester”).(21) The negative control cohort (see “4.4.2 Sensitivity analyses [1]) includes 
children of mothers prescribed an only monotherapy of macrolides or penicillins during 10-50 weeks 
prior to conception and are not included in the study cohort. 
 
4.3.2 Outcome 
Based on previous evidence from experimental and epidemiological studies, we hypothesized that 
short-term fetal hypoxia induced by fetal arrhythmia could possibly be the underlying mechanism of 
observed adverse effects of macrolides.(22) We therefore include outcomes which could potentially 
result from short-term fetal hypoxia, i.e. neurodevelopmental disorders (CP, epilepsy, attention-
deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) and major congenital 
malformation (malformation overall and system-specific malformations).  
 
Neurodevelopmental disorders (CP, epilepsy, ADHD and ASD) are defined as the time to the first Read 
code or prescription indicating the outcomes by 14 years old. We have identified CP cases from 
informative prescription or Read codes using the Random Forest approach and were validated by a 
paediatric-neurologist blinded to the prenatal antibiotics exposure.(23) Other neurodevelopmental 
disorders (epilepsy, ADHD and ASD) will be identified with previously validated criteria using 
diagnostic codes and/or prescriptions (table 1). (24-26) 
 

Macrolides and adverse child outcomes  
  
V3 
6 
 
Major malformations will be identified from the European Surveillance of Congenital Anomalies 
(EUROCAT).(27) We will exclude musculoskeletal malformations (e.g. Club foot, knock-knee and hip 
dislocation) because they are not reliably recorded in GP records.(28) We also exclude children with 
known chromosomal abnormalities and children whose mother were exposed to known teratogenic 
medications (warfarin, angiotensin converting enzyme (ACE) inhibitors, antineoplastic agents, 
isotretinoin, misoprostol, and thalidomide).  Any of the remaining 11 system-specific malformations 
are defined as major malformation overall, identified from child GP records up to 3 years old using 
Read codes which are mapped to the tenth edition of the International Classification of Diseases (ICD–
10) code lists in EUROCAT (Table 1).(27)  Five system-specific malformations (nervous, cardiovascular, 
digestive, genital tract, and urinary tract) were included which met the power criterion using the 
EUROCAT prevalence table.(29) (see “4.5 Power analysis”) 
 
 
Table 1. Outcome identification. 
Outcome 
Case identification criteria 
Cerebral palsy 
Method based on predictor selection and prediction (23) 
Epilepsy 
2 prescriptions of antiepileptic drug (AED, identified 
based on British National Formula Chapter 4.8) within 4 
months or >= 1 diagnosis 
Attention deficit hyperactivity disorder (ADHD) 
>= 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) 
Autism spectrum disorder (ASD) 
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) 
Major congenital malformation 
Any  major system specific malformation according to the 
EUROCAT classification. We use Read code list mapped to 
ICD 10 codes Chapter Q.  Exclude: 1) minor anomalies 
post-2005; 
2) 
musculoskeletal 
malformations; 
3) 
malformations 
caused 
by 
known 
chromosomal 
abnormalities 
and 
teratogens 
(i.e. 
Teratogenic 
syndromes with malformations, Fetal alcohol syndrome, 
Valproate syndrome, Maternal infections resulting in 
malformations, Genetic syndromes + microdeletions, 
Chromosomal malformations) 
Cardiovascular malformation 
1 Read code mapped from ICD 10 (Q20-Q26, exclude 
Q2111, Q250 if GA <37 weeks, Q2541, Q256 if GA<37 
weeks, Q261)  

Macrolides and adverse child outcomes  
  
V3 
7 
 
 
4.3.3 Covariates 
We will control the covariates which are potential risk factors for adverse child outcomes. These 
include: 1) maternal characteristics at baseline (i.e. age at child birth, problematic alcohol use, illicit 
drug use, recent tobacco use, and obesity); 2) pregnancy related variables (i.e. birth year, parity, 
multiple birth, hypertension, diabetes, epilepsy, depression, anxiety, maternal chronic medical 
conditions during pregnancy, potentially fetal-damaging maternal infection during pregnancy, and 
baby gender) (details given below). Gestational age at delivery and Apgar score after birth are 
considered mediators on the pathway for the association between prenatal antibiotics exposure and 
adverse child outcomes and therefore not adjusted.  
 
1. Maternal variables 
1) Maternal age (at birth) 
By 5 year categories. 
2) Maternal life style: 
a. Problematic alcohol use:  
Most recent record between 10 years prior to and during pregnancy: 
- a Read code indicating alcohol misuse; or 
- a prescription for disulfarim or acamprosate; or 
- self-reported average weekly alcohol intakes of between 14-500 units of alcohol a 
week. 
b. Illicit drug use:  
Most recent record between 10 years prior to and during pregnancy: 
- a read code for drug use, addiction, and overdose; or 
- a prescription for methadone treatment 
c. Recent smoking/tobacco use:  
Most recent record between 3 years prior to and during pregnancy: 
Gastrointestinal malformation 
Read code mapped from ICD 10 (Q38-Q45, Q790, exclude 
Q381, Q382, Q3850, Q400, Q401, Q4021, Q430, Q4320, 
Q4381, Q4382)  
Nervous system malformation 
Read code mapped from ICD 10 (Q00-Q07, exclude 
Q0461, Q0782) 
Genital tract malformation 
Read code mapped from ICD 10 (Q50-Q52, Q54-Q56, 
exclude Q523, Q525, Q527, Q5520, Q5521) 
Urinary tract malformation 
Read code mapped from ICD 10 (Q60-Q64, Q794, exclude 
Q610, Q627, Q633) 

Macrolides and adverse child outcomes  
  
V3 
8 
 
- 
self-reported daily cigarette consumption of 1-100 cigarettes per day unless 
there was evidence of smoking cessation; or 
- 
a read code indicating tobacco consumption; or 
- 
a prescription to assist smoking cessation 
d. Obesity 
Most recent record from 3 years prior to the end of 1st trimester: 
A read code for obesity (or a BMI of ≥30 kg/m2 - either directly entered or calculated 
from the most recent height measurement and median pre-pregnancy weight after 
outliers, i.e. height outside the range 1-2m and weight outside the range 35-300kg, 
were removed).  
 
2. Pregnancy related variables 
3) Baby birth year 
Grouped into categories of 5 calendar years. 
4) Parity 
Categorised as “0”, and “>= 1”. 
5) Multiple births 
Categorize the baby as “singleton”, or “(one of the) twin, triplets, or quadruplets”. 
6) Hypertension 
Measurement from 50 weeks prior to delivery: 
- 
systolic and diastolic blood pressure was above 140mmHg and 90mmHg, 
respectively, or 
- 
a Read codes for hypertension and associated diagnoses (including pre-
eclampsia, eclampsia and HELLP syndrome), or  
- 
a prescription for hypertension drugs from sections 2.2 and 2.5 of the BNF. This 
variable identified mothers with both treated and untreated hypertension in 
pregnancy.    
7) Diabetes 
Measurement from 50 weeks prior to delivery: 
- 
a Read code for type I, type II, or gestational diabetes; 
- 
two or more prescriptions for anti-diabetic medication; or 
- 
laboratory tests indicative of diabetes (defined as ≥2 abnormal glucose tests, 
fasting glucose >7.0 millimoles per litre [mmol/L] or >126 milligrams per decilitre 

Macrolides and adverse child outcomes  
  
V3 
9 
 
[mg/dL], plasma glucose after glucose tolerance test >11.1 mmol/L or 200mg/dL, 
glycated haemoglobin >=6.5%, or with diabetes annual review). 
8) Epilepsy 
Measurement from 50 weeks prior to delivery: 2 prescriptions of antiepileptic drugs (AEDs) 
within 4 months or >= 1 diagnosis 
9) Depression 
Measurement from 50 weeks prior to delivery: >= 2 occurrences of diagnostic code, treatment 
code or symptom 
10) Anxiety 
Measurement from 50 weeks prior to delivery: >= 2 occurrences of diagnostic code, treatment 
code or symptom 
11) Treatment of chronic medical conditions during pregnancy 
Measurement during pregnancy: two or more prescriptions (on separate days during 
pregnancy and not more than four months apart) for drugs from the same BNF section or 
paragraph. Drugs used to treat common conditions in pregnancy such as reflux (BNF section 
1.2), nausea and vomiting (BNF section 4.6), and constipation (BNF section 1.3) were not 
included. 
12) Potentially fetal-damaging infections during pregnancy.  
Mothers are classified as having a potentially fetal-damaging infection in pregnancy if they 
had recorded at any time during their pregnancy, a Read code for a diagnosis or a laboratory 
test confirming any of the following infection: genitourinary infection, “TORCH” 
(Toxoplasmosis, Other agents such as HIV, Rubella, Cytomegalovirus and Herpes simplex) and 
sexually transmitted infections (STIs). “TORCH” and STIs have long been known as important 
risk factors to adverse pregnancy outcomes and teratogenic pathogens. (22, 23)  Intrauterine 
infection has been recognised as an important mechanism of disease in preterm labor. (24) 
Hyelonephritis and bacteriuria have also been linked with preterm labor and low birthweight. 
(25)  
 
3. Neonatal variables 
13) Baby gender 
 

Macrolides and adverse child outcomes  
  
V3 
10 
 
4.4 Analyses 
4.4.1 Statistical methods 
Standardized differences will be used to assess covariate balance between the macrolides group and 
the penicillins group; meaningful imbalances are defined by an absolute standardized difference of 
more than 0.1.(30) For neurodevelopmental disorders, absolute rates of outcomes and unadjusted 
hazard ratios with 95% confidence intervals will be calculated.  For malformations, absolute risks of 
outcomes and unadjusted risk ratios with 95% confidence intervals, will be calculated. Exposure 
propensity scores will be estimated as the predicted probability of receiving the macrolides 
prescription (vs. penicillins), conditional on the covariates described above, with the use of logistic-
regression models. For each estimated propensity score, the population in the nonoverlapping areas 
of the propensity-score distributions will be trimmed, and 50 strata will be created on the basis of the 
distribution of the treated women.(31) Weights for the reference group will be calculated according 
to the distribution of the treated women among propensity-score strata. We then use the weight to 
estimate adjusted baseline characteristics, and adjusted hazard ratios (in Cox proportional hazard 
models with weight statement for neurodevelopmental disorders) or risk ratios (in log-binomial model 
with weight statement for malformations) as well as their 95% confidence intervals. To account for 
the clustering of siblings and multiple births within mother, robust standard errors will be estimated. 
The analyses will be conducted using RStudio version 3.5.1.. No adjustment will be made for multiple 
comparisons, and results for comparisons of exposure timing and subgroup analysis should be 
interpreted as exploratory. 
   
4.4.2 Primary, subgroup and sensitivity analyses 
Primary analysis 
1. Association between adverse child outcomes and macrolide (versus penicillins) prescription 
during pregnancy (from 5 GW to delivery). 
2. Association between adverse child outcomes and macrolide (versus penicillins) prescription 
during 1st trimester (from 5 to 13 GW). 
3. Association between adverse child outcomes and macrolide (versus penicillins) prescription 
during 2st to 3rd trimester (from 14 GW to delivery). 
Subgroup analyses  
1. Association between adverse child outcomes and macrolide (versus penicillins) prescription 
during pregnancy, by macrolide subtype (erythromycin, clarithromycin and azithromycin). 

Macrolides and adverse child outcomes  
  
V3 
11 
 
2. Association between adverse child outcomes and macrolide (versus penicillins) prescription 
during pregnancy, by duration of antibiotics prescription (<7days and >=7days). 
Sensitivity analyses 
1. To evaluate the effect of potential confounding due to maternal baseline characteristics: 
association between adverse child outcomes and macrolide (versus penicillins) prescription 
10-50 weeks prior to pregnancy (negative control analysis). 
2. To evaluate the effect of potential bias due to infection: association between adverse child 
outcomes and macrolides (versus penicillins) prescription during pregnancy, restricted to 
children of mother whose antibiotics were prescribed for respiratory tract infection (RTI). 
3. To evaluate the potential effect of outcome misclassification for CP and malformations: define 
CP cases with diagnostic codes only, and identify malformation cases as only those with 
repeated (>=2) child diagnoses, or with diagnoses in both the maternal (18GW to 6 months 
postpartum) and child records (before age 3).  
4. To evaluate the potential effect of live-birth bias: Evaluate the direction and quantity of the 
potential live-birth bias by simulating proportions of fetal deaths among women exposed to 
macrolides versus those exposed to penicillins. 
4.5 Power analysis 
Initially interested outcomes include: cerebral palsy, epilepsy, ADHD, ASD, major malformation 
overall, and system-specific malformations according to the classification of EUROCAT.  
 
To avoid spurious associations by chance we will restrict our analyses to outcomes which have >= 80% 
statistical power to detect a 2-fold relative risk increase at a 5% level of significance. Baseline risks of 
CP, epilepsy, ADHD, and ASD were calculated based on literature review and preliminary analyses, 
while the prevalence of major malformations (overall and system-specific) were based on the 
EUROCAT estimates.(29) The needed sample size of macrolides group was calculated for each 
outcome, based on a cohort of about 100,000 pregnancies exposed to penicillins (data from 
preliminary analyses). Preliminary analysis shows there are about 10,000 pregnancies in the 
macrolides group, therefore outcomes which requires more than 10,000 samples in macrolides group 
were excluded and will not be evaluated in this study (i.e. eye malformation, ear and face 
malformation, orofacial cleft, respiratory malformation, abdominal wall malformation and other 
malformation). Power calculations were performed using R package “pwr”. (Figure 1 and Table 2) 
 

Macrolides and adverse child outcomes  
  
V3 
12 
 
Figure 1. Sample size estimation for macrolides group, n (penicillins) =100000, Sig=0.05, power=80%, 
risk ratio=2. 
 
Table 2. Baseline risks and inclusion result for each outcome. 
Outcome 
Baseline Risk 
Included 
Cerebral palsy 
0.002 
Yes 
Epilepsy 
0.006 
Yes 
ADHD 
0.006 
Yes 
ASD 
0.008 
Yes 
Any major malformation 
0.02 
Yes 
Cardiac malformation 
0.007 
Yes 
Genital tract malformation  
0.002 
Yes 
Urinary tract malformation 
0.003 
Yes 
Gastrointestinal malformation 
0.002 
Yes 
Nervous system malformation 
0.002 
Yes 
Eye malformation 
0.0003 
No 
Ear and face malformation 
0.0001 
No 
Orofacial cleft 
0.001 
No 
Respiratory system malformation 
0.0004 
No 
Abdominal wall malformation 
0.0005 
No 
Other malformation 
<0.001 
No 
 
 

Macrolides and adverse child outcomes  
  
V3 
13 
 
Appendix 
A hierarchy of available pregnancy markers was chosen that reflects their potential accuracy to 
estimate start of the pregnancy episode.  Pregnancy markers that directly provide gestational age such 
as gestational age in weeks, prenatal examination, and fertility procedures (IVF) were on the top of 
the hierarchy. Next hierarchy of markers include ranges of gestational week indicators (e.g. premature 
24-26 weeks) and outcome-specific estimates (e.g. premature labour, imputed as 36 weeks, because 
around 60% live premature births born at 36 gestational weeks).  Gestational weeks imputed from 
birthweight was on the 3rd hierarchy, based on the intrauterine growth curves published by Irene E. 
Olsen et al.(32) For pregnancies with no information available for the above three hierarchies of 
markers, full term births were assumed and gestational week 40 were used to calculate pregnancy 
start dates.  Codes used in each hierarchy is referenced from Matcho, A. et al. (33) 
 
For babies in the Mother-baby link, gestational age were measured from each hierarchy with the 
following proportion: 27.8% from the first hierarchy (from codes for gestational age), 14.3% from the 
second hierarchy (from codes for gestational week range), 8.2% from the third hierarchy (imputed 
based on birthweight), 49.6% (imputed as full term, 40 gestational weeks).  The proportion of preterm 
birth was 6.2% preterm births in general populations, which is marginally lower than reported by the 
Office for National Statistics (7.1%).(34) The potentially underestimated proportion of preterm births 
would over-record antibiotic exposure during the early pregnancy, which would bias the association 
towards null.  
 
 
Reference 
1. 
Agency MHPR. Package leaflet: Information for the user: Clarithromycin 250 mg Film-Coated 
Tablets 
2016 
[Available 
from: 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1507872162573.pdf. 
2. 
Britain; JFCG. British National Formulary. Pharmaceutical Press; 2016. p. 307. 
3. 
Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use 
during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Archives of 
pediatrics & adolescent medicine. 2009;163(11):978-85. 
4. 
Petersen I, Gilbert R, Evans S, Ridolfi A, Nazareth I. Oral antibiotic prescribing during pregnancy 
in primary care: UK population-based study. The Journal of antimicrobial chemotherapy. 
2010;65(10):2238-46. 
5. 
Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A, et al. A prospective controlled 
multicentre study of clarithromycin in pregnancy. Am J Perinatol. 1998;15(9):523-5. 
6. 
Kallen BA, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in 
humans? Reproductive toxicology (Elmsford, NY). 2005;20(2):209-14. 

Macrolides and adverse child outcomes  
  
V3 
14 
 
7. 
Meeraus WH, Petersen I, Gilbert R. Association between antibiotic prescribing in pregnancy 
and cerebral palsy or epilepsy in children born at term: a cohort study using the health improvement 
network. PLoS One. 2015;10(3):e0122034. 
8. 
Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, et al. Childhood outcomes after 
prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of 
the ORACLE II trial. Lancet. 2008;372(9646):1319-27. 
9. 
Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C, et 
al. Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register based 
nationwide cohort study. PLoS One. 2013;8(1):e53327. 
10. 
Muanda FT, Sheehy O, Berard A. Use of antibiotics during pregnancy and risk of spontaneous 
abortion. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 
2017;189(17):E625-e33. 
11. 
Kallen B, Danielsson BR. Fetal safety of erythromycin. An update of Swedish data. European 
journal of clinical pharmacology. 2014;70(3):355-60. 
12. 
Le Nguyen T, Araujo M, Hurault-Delarue C, Lacroix I, Damase-Michel C, Sommet A. Teratogenic 
risk of macrolides during the first trimester of pregnancy: A study with two complementary 
approaches within the EFEMERIS database. Fundamental and Clinical Pharmacology. 2017;31:25. 
13. 
Lin KJ, Mitchell AA, Yau WP, Louik C, Hernandez-Diaz S. Safety of macrolides during pregnancy. 
American Journal of Obstetrics and Gynecology. 2013;208(3):221e1-e8. 
14. 
Sarkar M, Woodland C, Koren G, Einarson AR. Pregnancy outcome following gestational 
exposure to azithromycin. BMC Pregnancy Childbirth. 2006;6:18. 
15. 
Romoren M, Lindbaek M, Nordeng H. Pregnancy outcome after gestational exposure to 
erythromycin - a population-based register study from Norway. British journal of clinical 
pharmacology. 2012;74(6):1053-62. 
16. 
Guardian T. Antibiotic used in pregnancy linked to risk of epilepsy and cerebral palsy 2015 
[Available from: https://www.theguardian.com/science/2015/mar/25/antibiotic-used-in-pregnancy-
linked-to-risk-of-epilepsy-and-cerebral-palsy. 
17. 
Causes of death among stillbirths. JAMA. 2011;306(22):2459-68. 
18. 
Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, et al. Data Resource 
Profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol. 2015;44(3):827-36. 
19. 
Margulis AV, Abou-Ali A Fau - Strazzeri MM, Strazzeri Mm Fau - Ding Y, Ding Y Fau - Kuyateh 
F, Kuyateh F Fau - Frimpong EY, Frimpong Ey Fau - Levenson MS, et al. Use of selective serotonin 
reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in 
CPRD. (1099-1557 (Electronic)). 
20. 
Agency; MaHPR. CPRD Mother Baby Link Documentation. London: CPRD; 2017. 
21. 
Czeizel AE. Specified critical period of different congenital abnormalities: a new approach for 
human teratological studies. Congenital anomalies. 2008;48(3):103-9. 
22. 
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;14(2):e0212212. 
23. 
Fan H, Li L, Gilbert R, O'Callaghan F, Wijlaars L. A machine learning approach to identify cases 
of cerebral palsy using the UK primary care database. The Lancet. 2018;392:S33. 
24. 
SE H, S J-J, CD P, CL M, D C, CJ C. The prevalence and incidence, resource use and financial 
costs of treating people with attention deficit/hyperactivity disorder (ADHD) in the United Kingdom 
(1998 to 2010). Child Adolesc Psychiatry Ment Health. 2013;7(1):34. 
25. 
Hagberg KW, Jick SS. Validation of autism spectrum disorder diagnoses recorded in the Clinical 
Practice Research Datalink, 1990-2014. Clin Epidemiol. 2017;9:475-82. 
26. 
Meeraus WH. ADVERSE PAEDIATRIC OUTCOMES OF ANTIBIOTIC TREATMENT IN PREGNANCY: 
University College London; 2015. 
27. 
Anomalies; ESoC. THE EUROCAT GUIDE 2019 [Available from: http://www.eurocat-
network.eu/. 

Macrolides and adverse child outcomes  
  
V3 
15 
 
28. 
Sewell MD, Rosendahl K, Eastwood DM. Developmental dysplasia of the hip. BMJ. 
2009;339:b4454. 
29. 
EUROCAT. EUROCAT Prevalence Data Tables 2018 [Available from: http://www.eurocat-
network.eu/. 
30. 
Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between 
treatment groups in propensity-score matched samples. Stat Med. 2009;28(25):3083-107. 
31. 
Desai RJ, Rothman KJ, Bateman BT, Hernandez-Diaz S, Huybrechts KF. A Propensity-score-
based Fine Stratification Approach for Confounding Adjustment When Exposure Is Infrequent. 
Epidemiology. 2017;28(2):249-57. 
32. 
Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New Intrauterine Growth Curves 
Based on United States Data. Pediatrics. 2010;125(2):e214-e24. 
33. 
Matcho A, Ryan P, Fife D, Gifkins D, Knoll C, Friedman A. Inferring pregnancy episodes and 
outcomes within a network of observational databases. PLoS One. 2018;13(2):e0192033. 
34. 
Statistics OfN. Gestation-specific Infant Mortality in England and Wales, 2011. 2013.