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Very Early Exposure to Erythromycin and Infantile Hypertrophic Pyloric Stenosis
William O. Cooper, MD, MPH;
Marie R. Griffin, MD, MPH;
Patrick Arbogast, PhD;
Gerald B. Hickson, MD;
Shiva Gautam, PhD;
Wayne A. Ray, PhD
Arch Pediatr Adolesc Med. 2002;156:647-650.
ABSTRACT
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Objective To assess the link between very early erythromycin exposure and pyloric
stenosis in young infants.
Design Retrospective cohort study.
Participants and Methods Medicaid or TennCare (Tennessee's program for Medicaid enrollees and
uninsured individuals) births in Tennessee from 1985 to 1997. Cases of infants
with a hospital discharge diagnosis of pyloric stenosis and an associated
surgical procedure code were used. Erythromycin exposure and other antibiotic
exposure between 3 and 90 days of life were identified from prescription files.
Main Outcome Measures Hospital discharge diagnosis of pyloric stenosis, and an associated
surgical procedure code.
Results Of 933 239 births in Tennessee during the study period, 314 029
were enrolled in Medicaid. Among these infants, 804 (2.6/1000 infants) met
the criteria for pyloric stenosis. Very early exposure to erythromycin (between
3 and 13 days of life) was associated with a nearly 8-fold increased risk
of pyloric stenosis (adjusted incident rate ratio, 7.88; 95% confidence interval,
1.97-31.57). No increased risk of pyloric stenosis was seen in infants exposed
to erythromycin after 13 days of life or in infants exposed to antibiotics
other than erythromycin.
Conclusions The significant increase in pyloric stenosis in children with very early
exposure to erythromycin is consistent with reports of other investigators.
The risks and benefits of erythromycin should be weighed carefully prior to
initiating such therapy in young infants.
INTRODUCTION
INFANTILE HYPERTROPHIC pyloric stenosis (IHPS) is a condition of infancy
in which hypertrophy of the pylorus results in gastric outlet obstruction.1-3 The onset of symptoms,
including projectile vomiting, usually occurs in the first 3 to 5 weeks of
life.2 Morbidity from IHPS includes dehydration,
weight loss, and electrolyte abnormalities, with death occurring rarely.2
While the etiology of IHPS is unknown, previous reports suggest a link
between early erythromycin exposure and IHPS.4-7
It has been hypothesized that erythromycin interacts with motilin receptors,
inducing strong gastric and pyloric bulb contractions and resulting in pylorus
hypertrophy.8-10
Recently, Honein et al4 reported a cluster
of 7 cases of pyloric stenosis attributable to very early erythromycin prophylaxis
of infants potentially exposed to pertussis in a single newborn nursery.4 This represented a nearly 7-fold increased risk of
pyloric stenosis. In the Honein et al study and in a recent study from a single
urban hospital where infant use of erythromycin was associated with increased
risk of IHPS,7 exposure to erythromycin occurred
in the first 2 weeks of life, which is much earlier than typical clinical
uses of erythromycin. We performed a large population-based study among infants
enrolled in the Tennessee Medicaid population to assess the link between very
early exposure to erythromycin and IHPS.
PARTICIPANTS AND METHODS
Children were included in the base population if they were born in Tennessee
between 1985 and 1997 and had complete information in the Tennessee birth
certificate files.11 Study years were selected
based on the earliest available data in the Tennessee Medicaid or TennCare
(Tennessee's program for Medicaid enrollees and uninsured individuals) database
and to avoid including the cases described in the Honein study,4
which was performed in a Tennessee community shortly after the end of the
study period. Children with prolonged neonatal intensive care unit stays would
be unable to have an outpatient prescription filled. Therefore, the base population
included only infants who were discharged from a birth hospital by 3 days
of life and who were enrolled in Medicaid by 3 days of life. To ensure complete
ascertainment of erythromycin exposure and study outcomes, infants who had
any lapses in Medicaid enrollment or who died in the first 3 months of life
were excluded from the base population.12
Cases were identified from infants in the base population as defined
above (N = 314 029). Medicaid encounter files were searched to identify
infants having IHPS hospitalizations between 3 and 90 days of life. Initial
screening included the specific International Classification
of Diseases, Ninth Revision (ICD-9) code for IHPS (750.5) and ICD-9 codes for other diagnoses that could be coded for
IHPS (ie, acquired pyloric stenosis [537.0] and pylorospasm [537.81]).13 Current Procedural Terminology (CPT) codes from physician
and hospital claims were searched to identify codes for pyloromyotomy, the
definitive surgical procedure for IHPS (CPT, 43520; ICD-9, 433). Cases were defined as infants with a discharge diagnosis code
for IHPS along with a procedure code for pyloromyotomy.
Outpatient prescription files for all children in the cohort were searched
to identify prescriptions occurring between 3 days of life and the date of
admission for pyloric stenosis (cases) or 90 days of life (controls). Antibiotics
included oral erythromycin and other oral antibiotics previously described
as being used in children during the first months of life.14
Other oral antibiotics included cephalosporins, penicillins, and sulfa medications.
In addition, the databases were searched for nonerythromycin macrolides (lincomycin
hydrochloride, clindamycin hydrochloride, clarithromycin, azithromycin, and
dirithyromycin). Restricting prescriptions to those occurring from 3 days
of life allowed for differences in length of hospitalization following births
that occurred during the study period. Age exposure categories were developed
a priori based on age of exposure to erythromycin in previous reports, with
particular interest in exposure during the first 2 weeks of life, as seen
in the Honein et al4 study.5-7
Antibiotic age exposure categories included 3 to 13 days of life, 14 to 27
days of life, 28 to 90 days of life, or no exposure during the study period.
Outpatient encounters and physician claims occurring within 14 days
of the erythromycin prescription were searched to identify a possible indication
for antibiotic use among infants with very early exposure to antibiotics.
The encounter occurring closest to the date of the prescription was considered
to represent the visit resulting in the prescription. Thus, the primary diagnosis
from that encounter was used to determine a possible indication. Encounters
were grouped into conjunctivitis, respiratory infections, otitis media, chlamydial
infections, skin infections, vomiting, and other diagnoses not typically treated
with erythromycin.
Comparisons were made between infants who had erythromycin prescriptions
filled and infants who did not, using  2 analysis. Age-adjusted
incidence rates for each category of antibiotic exposure (any, 3-13 days of
life, 14-27 days of life, and 28-90 days of life) were calculated. Poisson
regression models were constructed using factors shown in previous literature
to influence the development of pyloric stenosis.15
Variables contributing significantly were retained in final models (SAS statistical
software 8.2; SAS Institute Inc, Cary, NC).
The study protocol was approved by the institutional review boards of
Vanderbilt University (Nashville, Tenn) and the state of Tennessee.
RESULTS
There were a total of 933 239 births in Tennessee between 1985
and 1997. Of these infants, 918 526 had complete birth certificate information
(98.4%), and 408 667 (44.5% of infants with complete information) were
enrolled in Medicaid within 2 weeks of life. Of infants enrolled in Medicaid,
23 341 (5.7%) remained in the hospital past 3 days of life, and 1494
(0.4%) died, leaving a total of 383 832 children. Of these children,
314 029 (81.8%) had continuous Medicaid enrollment during the follow-up
period, accounting for 74 739 child-years of follow-up.
Among the 314 029 cohort members, 7138 had a prescription filled
for erythromycin during the study (2.3%). Children with erythromycin prescription
filling were more likely to weigh 2500 g or more at birth, were more likely
to have older sibling(s), and were more likely to be male (Table 1). Mothers of infants having erythromycin prescriptions filled
were less likely to be black and were more likely to have less than 12 years
of education and live in rural counties.
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Table 1. Characteristics of Children With Filled Erythromycin Prescriptions:
Medicaid/TennCare Infants Born in Tennessee, 1985-1997*
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There were 804 infants (2.6/1000) who met the criteria for IHPS, a rate
consistent with the incidence of IHPS in other populations.1-4
The mean ± SD age at hospital admission for case infants was 39.1 ±
15.9 days. The incidence of IHPS was higher in males (4.1/1000 infants) than
in females (1.0/1000 infants), and higher in white children and children of
other races (3.5/1000 infants) than black children (1.0/1000 infants).
After adjusting for the child's age, sex, and race, exposure to erythromycin
before 90 days of life was associated with a 2-fold increased risk of pyloric
stenosis (adjusted rate ratio, 2.05; 95% confidence interval, 1.06-3.97) (Table 2). Very early exposure to erythromycin
between 3 and 13 days of life was associated with a nearly 8-fold increased
risk of IHPS (adjusted rate ratio, 7.88; 95% confidence interval, 1.97-31.57).
The risk of IHPS was not increased in children receiving erythromycin after
14 days of life. The use of other antibiotics was more common in early infancy,
accounting for 4140 child years of follow-up, but such use was not associated
with an increased risk of IHPS. There were only 12 children with nonerythromycin
macrolide prescriptions in the cohort. None had prescriptions filled before
14 days of life, and none developed pyloric stenosis.
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Table 2. Antibiotic Use in the First 3 Months of Life and the Development
of Infantile Hypertrophic Pyloric Stenosis Among Infants With Medicaid or
TennCare Born in Tennessee Between 1985 and 1997*
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Encounter claims for children having erythromycin prescriptions filled
were reviewed to identify a possible indication for the prescription. Of the
2 cases with early erythromycin exposure and IHPS, 1 filled an erythromycin
prescription on the sixth day of life, with a temporally associated encounter
for conjunctivitis; the IHPS admission occurred 3 days later. The other patient
with very early exposure had no temporally associated claim, received erythromycin
beginning on the 10th day of life, and then was admitted 3 days later. Among
the 70 children with very early exposure to erythromycin and no pyloric stenosis,
the most common possible indications included conjunctivitis (n = 23, 32.9%),
respiratory infections (including upper respiratory infections [n = 10, 14.9%],
nonspecific respiratory infections [n = 3, 4.3%], and pneumonia [n = 1, 1.4%]),
otitis media (n = 4, 5.7%), chlamydia infection (n = 2, 2.9%), impetigo or
cellulitis (n = 3, 4.3%), vomiting (n = 2, 2.9%), and other diagnoses typically
not treated with erythromycin (n = 12, 17.1%); 9 infants (12.9%) did not have
a temporally linked diagnosis.
COMMENT
The data from this retrospective cohort study representing exposure
in more than 74 000 child-years of follow-up are consistent with the
hypothesis that early erythromycin exposure can cause IHPS. Exposure to oral
erythromycin prior to 14 days of life was rare in this population, but such
use increased the risk of IHPS nearly 8-fold. These findings must be viewed
in the context of prior studies.4-7
In 1976, SanFilippo5 reported 6 cases of pyloric
stenosis among 963 infants born at a single military hospital during 1 year.
Five of these 6 infants received erythromycin between 8 and 17 days of life,
had onset of symptoms of pyloric stenosis shortly thereafter, and had surgery
between 17 and 27 days of life. In 1986, Stang6
reported that 6 of 122 children (5%) with pyloric stenosis who were operated
on at a single children's hospital throughout 5 years had received erythromycin
prior to symptom onset. An investigation of a 6-fold increase in pyloric stenosis
(7 cases) at a single community hospital in February 1999 revealed that all
7 infants had received erythromycin prophylaxis between day 2 and day 17 of
life because of a nursery outbreak of pertussis.4
This cluster was remarkably similar to that of SanFilippo in that children
received erythromycin very early in life, had symptoms shortly thereafter,
and also had relatively early onset of pyloric stenosis. In a more recent
study7 of 14 876 infants born in a single
urban hospital, erythromycin exposure in the first 2 weeks of life was found
to represent the highest risk for IHPS as compared with exposure at later
ages.7 The temporal relationship between erythromycin
exposure and hospitalization for pyloric stenosis seen in the current study
parallels the temporal relationship described in previous reports.6-7
Automated pharmacy records have been shown to be an excellent, unbiased
source of prescription drug information.16-22
However, there are some limitations of these data that could cause misclassification
of exposure. The Medicaid pharmacy files only contain claims for outpatient
prescriptions.23-24 Therefore,
the study was unable to detect inpatient prescribing of erythromycin. To partially
address misclassification of antibiotic exposure, the current study included
infants who were discharged from a birth hospital before 3 days of life, as
it would not be possible for infants with prolonged hospital stays to have
outpatient prescriptions filled. It is possible that some children in the
study received erythromycin while still in the hospital. In addition, measuring
filled prescriptions is an indirect measure of antibiotic exposure, since
infants may not actually receive a medication, even though a prescription
is filled. In addition, the study methodology is unable to account for variable
dosage or length of antibiotic use.
The data from the current study and previous reports4-7
provide support for the hypothesis that the increased risk of IHPS among infants
with very early exposure to erythromycin is high. Alternatives to erythromycin
include other macrolide antibiotics,25 although
there are no data on any association between other macrolide antibiotics and
IHPS. Another alternative is sulfamethoxazole-trimethoprim, but it does not
have proven efficacy for pertussis prophylaxis, and it is relatively contraindicated
in this age range because of concern of bilirubin displacement and kernicterus.25 Thus, there is no clear best alternative for young
infants at risk for pertussis. However, the risk of pyloric stenosis is sufficiently
high (approximately 1%), suggesting that the risks and benefits of erythromycin
in very young infants should be carefully weighed and discussed with parents
prior to the initiation of therapy.
| What This Study Adds
Previous reports have described an association between early erythromycin
exposure in infants and the development of infantile hypertrophic pyloric
stenosis. No large population-based studies have been performed to confirm
the findings of these earlier reports. Drawing from 314 029 births (representing
74 739 child-years of follow-up) to mothers in Tennessee who were enrolled
in Medicaid or TennCare, this study identified 804 cases of pyloric stenosis.
Compared with infants not exposed to erythromycin, children with filled prescriptions
for erythromycin in the first 2 weeks of life were at an 8-fold increased
risk for pyloric stenosis. Taken in context with previous reports, this study
suggests that erythromycin should be avoided in young (younger than 2 weeks)
infants when possible.
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AUTHOR INFORMATION
Accepted for publication March 20, 2002.
Dr Cooper received the support of grant 03816 from the Generalist Physician
Faculty Scholars Program of the Robert Wood Johnson Foundation, Princeton,
NJ. Drs Ray, Griffin, and Gautam received the support of grant 1U18HS10384-01
from the Centers for Education and Research in Therapeutics (CERTs) program
of the Agency for Healthcare Research and Quality, Nashville, Tenn.
Presented at the Pediatric Academic Societies Meeting, Baltimore, Md,
May 1, 2001.
Corresponding author and reprints: William O. Cooper, MD, MPH, Division
of General Pediatrics, Department of Pediatrics, Vanderbilt University School
of Medicine, Suite 5028 MCE, Nashville, TN 37232-8555 (e-mail: william.cooper{at}mcmail.vanderbilt.edu).
From the Department of Pediatrics, Division of General Pediatrics (Drs
Cooper and Hickson), and the Department of Preventive Medicine, Divisions
of Pharmacoepidemiology (Drs Griffin and Ray) and Biostatistics (Drs Arbogast
and Gautam), Vanderbilt University, Nashville, Tenn.
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