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ARTICLE

Intravenous Ceftriaxone and Calcium in the Neonate:


Assessing the Risk for Cardiopulmonary
Adverse Events
John S. Bradley, MDa, Ronald T. Wassel, PharmDb, Lucia Lee, MDc, Sumathi Nambiar, MD, MPHd

aRady Children’s Hospital San Diego, San Diego, California; bOffice of Surveillance and Epidemiology and dOffice of New Drugs, Office of Antimicrobial Products, Center
for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland; cOffice of Vaccines Research and Review, Center for Biologics Evaluation
and Research, US Food and Drug Administration, Rockville, Maryland

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

The package label for ceftriaxone was changed in August 2007 to contraindicate the The cases reported to the FDA and the FDA AERS database search are provided and
co-administration of ceftriaxone with calcium-containing intravenous solution. discussed to provide clinicians the basis for these new precautions.

ABSTRACT
OBJECTIVES. Unsolicited reports regarding potentially serious adverse drug reactions in
neonates and young infants were reported to the Food and Drug Administration,
leading to changes in the package label for ceftriaxone. This report describes and www.pediatrics.org/cgi/doi/10.1542/
peds.2008-3080
summarizes the reported cases that led to safety concerns regarding the concurrent
administration of intravenous ceftriaxone and calcium in this age group. doi:10.1542/peds.2008-3080
The findings and conclusions in this report
METHODS. Nine reported cases were assessed. The Food and Drug Administration are those of the authors and do not
Adverse Event Reporting System database was searched for potential drug interac- necessarily represent the views of the Food
and Drug Administration.
tions in patients who were receiving concomitant ceftriaxone and calcium therapy.
Key Words
RESULTS. Eight of the reported 9 cases (7 were ⱕ2 months of age) represented possible ceftriaxone, calcium, newborn, drug
or probable adverse drug events. There were 7 deaths. None of the cases were therapy/adverse event, cardiopulmonary
arrest
reported from the United States. The dosage of ceftriaxone that was administered to
Abbreviations
4 of 6 infants for whom this information was available was between 150 and 200 FDA—Food and Drug Administration
mg/kg per day. The rate of occurrence of these serious adverse drug reactions cannot AERS—Adverse Event Reporting System
be accurately determined from available data. Accepted for publication Dec 17, 2008
Address correspondence to John S. Bradley,
CONCLUSIONS. The concurrent use of intravenous ceftriaxone and calcium-containing MD, 3020 Children’s Way, Mail Code 5041, San
solutions in the newborn and young infant may result in a life-threatening adverse Diego, CA 92123. E-mail: jbradley@rchsd.org.
drug reaction. Contributing factors for infants in this report may include the use of PEDIATRICS (ISSN Numbers: Print, 0031-4005;
ceftriaxone at dosages higher than those approved by the Food and Drug Adminis- Online, 1098-4275). Copyright © 2009 by the
American Academy of Pediatrics
tration, intravenous “push” administration, and administration of the total daily
dosage as a single infusion. Pediatrics 2009;123:e609–e613

O N SEPTEMBER 11, 2007, the US Food and Drug Administration (FDA) issued an alert that highlighted important
revisions to the prescribing information for ceftriaxone (Rocephin; Roche Pharmaceuticals, Nutley, NJ) for
young infants. This Information for Healthcare Professionals addressed the interaction between ceftriaxone and
calcium-containing products on the basis of reports of fatal cases in neonates. The alert stated that this information
was based on postmarketing reports of 5 neonatal deaths related to the interaction between ceftriaxone and
calcium-containing products submitted to the FDA by Roche Pharmaceuticals, the manufacturer of Rocephin, and 4
additional postmarketing reports of interactions between ceftriaxone and calcium-containing products in patients up
to 1 year of age received by FDA since Rocephin was approved in 1984.1 As of August 2007, the Rocephin product
label contraindicates the co-administration of ceftriaxone with calcium-containing intravenous solutions, including
calcium-containing infusions such as parenteral nutrition, in neonates (⬍28 days of age) because of the risk for
precipitation of ceftriaxone-calcium salt.2
On November 30, 2006, the French Health Products Safety Agency issued a warning letter to French medical
practitioners regarding incompatibilities between ceftriaxone and calcium-containing solutions that led to a modi-
fication in the product label. The letter stated that a fatal report in 2002 had led to a national pharmacovigilance
investigation, and on the basis of the findings of this investigation, the product label had been modified.3
The purpose of this communication is to summarize these reports and to increase the awareness of clinicians
regarding this potentially lethal adverse effect. Unusual or uncommon adverse events after drug therapy are most

PEDIATRICS Volume 123, Number 4, April 2009 e609


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likely to be observed by clinicians in medical practice. being treated for a variety of infections. Seven neonates
Their observations and reports serve as a reminder of the died. Information about underlying diseases, doses of
critical role that health care professionals play in com- drugs administered, drug infusion times, and other con-
municating postmarketing safety events of concern to current drug therapies was often incomplete in these
regulatory agencies that are charged with monitoring adverse event reports. Limited information was available
and updating the safety of approved drugs. from the postmortem examinations that were conducted
MedWatch, the FDA Safety Information and Adverse of 5 infants. The cases are outlined in Table 1.
Event Reporting Program, serves both health care pro- All infants received intravenous ceftriaxone, with
fessionals and the medical product– using public and dosages of 200 mg/kg per day administered to 3 of 6
provides safety information involving medical products, infants for whom a dosage was reported. For 2 of the 3
including prescription and over-the-counter drugs, bio- infants who received this dosage, the total daily dosage
logics, medical and radiation-emitting devices, and spe- was given once daily. Five of the infants were reported
cial nutritional products (eg, medical foods, dietary sup- to be preterm, with the youngest born at 30 weeks’
plements, infant formulas). MedWatch allows health gestation. The chronological ages of the infants at the
care professionals and consumers to report serious reac- time they received ceftriaxone ranged from 1 day to 50
tions, product quality problems, therapeutic inequiva- days. At least 3 of the infants had received multiple doses
lence/failure, and product use errors that they suspect of ceftriaxone.
are associated with the drugs and medical devices that Seven of the 8 infants received intravenous calcium
they prescribe, dispense, or use.4 In addition, drug man- gluconate, and 1 infant received calcium intravenously
ufacturers are required to report to FDA adverse drug as part of hyperalimentation. For 1 infant who received
experience information that they receive from any calcium gluconate, a white precipitate was noted in the
source, foreign or domestic, including information de- distal end of the intravenous tubing 2 hours after ad-
rived from commercial marketing experience, postmar- ministration of intravenous ceftriaxone, 30 minutes af-
keting clinical investigations, postmarketing epidemio- ter administration of intravenous calcium gluconate, and
logic/surveillance studies, reports in the scientific during intravenous amikacin administration. The in-
literature, and unpublished scientific papers.5 The Ad- fant’s nurse cleared the tubing by “pushing” the precip-
verse Event Reporting System (AERS) is a computerized itate into the infant, which was immediately followed by
information database designed to support the FDA’s cardiopulmonary arrest, with a white precipitate noted
postmarketing safety surveillance program for all ap- in the pulmonary artery at autopsy. No analysis was
proved drugs and therapeutic biological products. performed of this precipitate.
The autopsy findings from 4 of the 5 infants for whom
METHODS information was available documented the presence of
The 8 cases described herein were unsolicited, voluntary “crystalline” material or white precipitate in vascular
reports from health care professionals that were submit- beds, most often in the lungs. No analysis of the crystal-
ted to the FDA by the manufacturers of ceftriaxone line material was performed in any of these cases.
under the mandatory reporting requirements. The ninth
case included in the FDA alert is not included in this DISCUSSION
report because a follow-up autopsy report suggested that Ceftriaxone was first approved in the United States in
the infant died of pneumonia and sepsis with dissemi- 1984 under the trade name Rocephin.2 The product label
nated intravascular coagulation. The reporter, however, states that safety and effectiveness of Rocephin in neo-
did not rule out the possibility of intravascular precipi- nates, infants, and pediatric patients have been estab-
tates as a result of ceftriaxone and calcium gluconate. lished. The current, updated product label specifically
Drug interaction searches in the AERS database were contraindicates the co-administration of Rocephin with
conducted to identify reports in which both calcium calcium-containing intravenous solutions, including
chloride and calcium gluconate were listed as either a continuous calcium-containing infusions such as paren-
suspect or a concomitant product associated with ceftri- teral nutrition, in neonates because of the risk for pre-
axone administration. These searches were conducted cipitation of ceftriaxone-calcium salt.2
across the entire database without qualifiers and, there- These cases were collected through a passive surveil-
fore, included patients of any age. Searches were also lance reporting system (eg, voluntary reporting). The
conducted of calcium-containing solutions, including number of ceftriaxone treatment courses that have been
Ringer’s injection, lactated Ringer’s, Plasma-Lyte R, administered to infants who were younger than 2
Isolyte-R, Plasma-Lyte M, Calphosan, and Hartmann’s months is not known; therefore, the number of young
solution. A separate search was conducted for all adverse infants who have received the combination of ceftriax-
event reports received with ceftriaxone in patients up to one and calcium cannot also be determined. In addition,
2 months of age to ensure that no reports were missed as the actual number of cardiopulmonary events in young
a result of variations in reporting and coding. infants that are related to ceftriaxone and calcium is
The reports described 8 neonates and young infants, unknown. Reporting rates (ie, number of cardiopulmo-
most younger than 2 months, who experienced appar- nary event reports in infants per total ceftriaxone pre-
ent cardiorespiratory arrest while receiving the combi- scriptions) can be used to assess the magnitude of the
nation of ceftriaxone and calcium. No cases have been problem; however, because of underreporting and pos-
reported from the United States. These infants were sibly selective reporting, reporting rates do not provide

e610 BRADLEY et al
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TABLE 1 Eight Reported Cases of Serious Cardiopulmonary Events in Young Infants Who Received Concurrent Therapy with Intravenous Ceftriaxone and Intravenous Calcium
Patient Gestational Underlying Disease Event; Age on Day Days of Dosage of CRO Duration of Co-administration of Temporal Concurrent Autopsy
Age of Event CRO at (mg/kg per d) CRO Infusion Calcium-Containing Association of Event Intravenous Drugs
Time of Fluids With CRO
Event Administration
1 Term NEC Death; 12 d 3 200 intravenously Unknown
10% calcium gluconate Unknown Metronidazole No
every 24 h using a Y set
2 35 wk Mother with amnionitis Death; 1 d 1 200 intravenously Unknown
10% calcium gluconate ⬃2 h after CRO given; Vitamin K1, amikacin, Pulmonary
every 24 h using a Y set; white event occurred albumin, amoxicillin embolism found;
precipitate noted at immediately after white precipitate
end of intravenous precipitate injected noted
tubing
3 Preterm, 1.7 kg Underlying hyaline Death; 2 d 1 200 intravenously 30 min Calcium gluconate by Unknown Midazolam, furosemide, Crystallinea thrombi
at time of membrane disease, divided every continuous infusion, amikacin, amoxicillin in renal,
event renal insufficiency, 12 hours intermittent CRO via pulmonary,
neonatal infection Y set coronary, and
hepatic
circulation
4 Term Bilateral lung infection Death; 3 wk 4 80 intravenously 2–4 min 10% calcium 45 min after CRO Flumazenil, josamycin Diffuse fibrous
with Escherichia coli; every 24 h gluconate; same infusion destruction of
cardiac arrest at infusion line used for heart; chronic
admission; CRO and calcium myocarditis,
ventricular gluconate lymphocytic
extrasystoles, endocarditis;
hypotonia during intra-arterial
4-d hospitalization emboli of
crystallinea
material in lungs
and kidneys
5 36 wk Fetal distress, Death; 1 d 1 150 intravenously Slow, direct Calcium gluconate; Few minutes after Unknown No macroscopic
respiratory distress divided every intravenous CRO and calcium CRO injection abnormalities or
12 h push given by different abnormalities
routes, not at the reported on
same time autopsy slides
6 Preterm Unknown Death; unknown Unknown Unknown Unknown Calcium gluconate; Unknown Unknown Unknown, but
details of report states

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administration infant died of
unknown pulmonary
embolism
7 Unknown Fever and Death; 2 mo 21 Unknown Unknown Calcium gluconate; Unknown Unknown Death from
cardiomyopathy details of cardiomyopathy,
administration but crystalsa seen
unknown in the lungs
8 30 wk Klebsiella UTI Bradycardia, apnea, 1 50 mg/kg 2 min Calcium-containing 10 min after injection Gentamicin No

PEDIATRICS Volume 123, Number 4, April 2009


shock; 50 d injection intravenous hyperalimentation
push
CRO indicates ceftriaxone; NEC, necrotizing enterocolitis; UTI, urinary tract infection.
a Composition of crystals unknown.

e611
an accurate estimate of incidence that would allow cli- the United States and Europe, differences in calcium
nicians to put risks and benefits of ceftriaxone therapy formulations and other concurrent drugs administered
into a clinically relevant perspective. Reporting rates, to neonates, or differences in the manner in which mul-
however, do provide some context (association) for the tiple drugs are infused (eg, sequentially versus simulta-
number of adverse events reported with the amount of neously through a “Y” connector). It is not known
drug use. It is expected that adverse event reports are which, if any of these possibilities, singly or in combina-
proportional to use, particularly in the first few years of tion, are relevant to the occurrence of the lethal cardio-
marketing. Because these events can be lethal and rela- respiratory event or whether other currently unidenti-
tively equivalent antimicrobial agents are available, it fied risk factors may also be responsible for this adverse
is prudent to approach the risk/benefit assessment event.
conservatively. Other intravenously administered third-generation
Several aspects of the reported cases deserve com- cephalosporin antimicrobial agents with a spectrum of
ment. To our knowledge, the dosage of ceftriaxone pro- activity similar to ceftriaxone are FDA approved for use
vided to some infants, 200 mg/kg once daily, is greater in neonates and should be considered preferred agents
than that evaluated for any age group by Roche Labo- for intravenous use in this age group. It is not known
ratories and pediatric investigators in the United whether the risk for precipitate formation occurs with
States. Current package labeling for all age groups other antibacterial agents, particularly when used in ex-
advises a dosage of 50 to 75 mg/kg per day, either tremely high dosages, infused rapidly, or administered
every 24 hours or divided every 12 hours for infec- with intravenous calcium.
tions other than meningitis. For meningitis, the ap- On the basis of these reports, children who are
proved dosage is 100 mg/kg per day.2 older than 2 to 3 months might be less likely to
Ceftriaxone is known to form precipitates when ad- experience these cardiorespiratory complications;
ministered with calcium-containing solutions such as however, reasonable caution should be exercised
Ringer’s Lactate.6,7 The current product label states that when using the combination of intravenously admin-
ceftriaxone should not be used with diluents that con- istered ceftriaxone and calcium in older age groups.
tain calcium, such as Ringer’s solution or Hartmann’s For any age group, crystalline material in the intrave-
solution, because particulate formation can result.2 It is nous tubing may present a risk and should not be
biologically plausible, however, to assume that ceftriax- pushed into the child.
one given to a young infant at higher than a routinely Risk for complications after the administration of oral
prescribed dose and administered intravenously together calcium and intramuscular ceftriaxone may exist, but it
with a calcium-containing solution could also cause pre- remains to be defined. No cases have been reported with
cipitate formation. These calcium precipitates might act oral calcium administration or after intramuscular ceftri-
as emboli, resulting in vascular spasm or infarction. It is axone injection, suggesting that the risk for calcium-
this precaution that is being shared with clinicians. ceftriaxone precipitation may be less under these condi-
In some of the reported cases, ceftriaxone was admin- tions. Neither milk nor oral calcium supplementation is
istered by intravenous “push” over 2 to 4 minutes, likely to create the same transient serum concentrations
rather than by a more prolonged intravenous infusion of in the young infant as intravenously administered cal-
30 minutes as recommended in the product label. Ceftri- cium. Similarly, the peak serum concentrations of ceftri-
axone administration by rapid intravenous infusion, axone after intramuscular injection are lower than those
particularly at the highest dosages reported in this case achieved after intravenous administration of an equiva-
series, will result in transiently high serum concentra- lent dosage; therefore, the risk for complications from
tions and might also contribute to formation of calcium- intravascular precipitation is likely to be less than the
ceftriaxone salts. Precipitate formation was noted to oc- risk after intravenous injection, particularly rapid intra-
cur when both ceftriaxone and intravenous calcium venous push administration. The use of intramuscular
were infused simultaneously, as well as when given at ceftriaxone in an FDA-approved dosage in situations in
different time intervals. These observations suggest that, which intravenous access may be difficult or for daily
in certain infants, the serum concentration of ceftriax- outpatient parenteral therapy should not be associated
one may be sufficiently high for hours after infusion to with risks that would outweigh the benefits of ceftriax-
interact with subsequently administered intravenous one, particularly when intravenous calcium gluconate is
calcium. It is also not known whether neonates are not being co-administered.
particularly susceptible to this cardiopulmonary event as When considering antibacterial treatment for any ne-
a result of the greater tone and reactivity noted in the onate or infant, the risks and benefits of therapy should
neonatal pulmonary circulation, compared with older be individually assessed, on the basis of the most likely
children.8 pathogen(s), site of infection, seriousness of infection,
It is noteworthy that no cases have been reported comorbidities, and available safety and efficacy data for
from the United States. Many explanations are possible, dosages considered for use. These 8 cases provide addi-
such as the preferential use of other third-generation tional information for those who treat neonates and
cephalosporins (eg, cefotaxime) for neonates in the young infants regarding a potentially lethal adverse
United States,9–11 the use of lower dosages of ceftriaxone event that may occur after the concurrent use of intra-
in the United States than those reported in these cases venous ceftriaxone and calcium. Ceftriaxone adminis-
from Europe, differences in passive reporting between tered in dosages ⱕ100 mg/kg per day, by the intramus-

e612 BRADLEY et al
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cular route, with oral calcium supplements, seem less infant. Therefore, our corrected report now describes 7
likely to create the conditions that are associated with infants total. Of the 6 infants who died, age-at-event
the serious events reported in these 8 infants. No con- data were reported in 5; all were 3 weeks of age or
traindication to the use of ceftriaxone exists in these younger. Our conclusions regarding potential risks re-
situations, but increased vigilance for possible adverse main unchanged.
events is prudent.
Reporting of suspected adverse events is a critical
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PEDIATRICS Volume 123, Number 4, April 2009 e613


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Intravenous Ceftriaxone and Calcium in the Neonate: Assessing the Risk for
Cardiopulmonary Adverse Events
John S. Bradley, Ronald T. Wassel, Lucia Lee and Sumathi Nambiar
Pediatrics 2009;123;e609
DOI: 10.1542/peds.2008-3080 originally published online March 16, 2009;

Updated Information & including high resolution figures, can be found at:
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References This article cites 3 articles, 1 of which you can access for free at:
http://pediatrics.aappublications.org/content/123/4/e609.full#ref-list-
1
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http://classic.pediatrics.aappublications.org/cgi/collection/pulmonolo
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Cardiology
http://classic.pediatrics.aappublications.org/cgi/collection/cardiology
_sub
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
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Intravenous Ceftriaxone and Calcium in the Neonate: Assessing the Risk for
Cardiopulmonary Adverse Events
John S. Bradley, Ronald T. Wassel, Lucia Lee and Sumathi Nambiar
Pediatrics 2009;123;e609
DOI: 10.1542/peds.2008-3080 originally published online March 16, 2009;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/123/4/e609

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.

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