AAP GRAND ROUNDS

Vol. 25 No. 4 | Pages 37-48 | April 2011

www.aapgrandrounds.org

Mission: To provide pediatricians with timely synopses and critiques of important new studies relevant to
pediatric practice, reviewing methodology, significance, and practical impact, as part of ongoing CME activity.

SENIORS

Antibiotic Rx of AOM in Children <2 Years: Redux

Source: Hoberman A, Paradise JL, Rockette HE, et al. Treatment
of acute otitis media in children under 2 years of age. N Engl J
Med. 2011;364(2):105-115; doi:10.1056/NEJMoa0912254

nvestigators from the University

PICO
of Pittsburgh studied the utility
Question: Does antimicrobial treatment
of antimicrobial treatment of
affect the symptoms and signs of acute otitis
acute otitis media (AOM) among
media in children aged 6 to 23 months?
Pittsburgh area children aged 6 to
Question type: Intervention
23 months from 2006 to 2009. ParStudy design: Randomized, double-blind
ticipating children had received two
trial
doses of the pneumococcal conjugate vaccine and had a diagnosis
of AOM based on: 1) onset of symptoms within the previous 48 hours as
determined by a score of 3 or greater on the Acute Otitis Media Severity of
Symptoms (AOM-SOS) Scale1,2; 2) the presence of middle ear effusion; and 3)
bulging tympanic membrane, accompanied by otalgia or marked erythema.
Exclusion criteria were presence of another acute or chronic illness, allergy
to amoxicillin, prior receipt of antibiotics within 96 hours, presence of otalgia
for more than 48 hours, or perforated tympanic membrane. Children were
stratified based upon previous frequent bouts of AOM and exposure or lack
of exposure to three or more children 10 hours per week or more.
After screening of 1,385 children, 291 were randomly assigned to receive
either amoxicillin-clavulanate (90 mg of amoxicillin and 6.4 mg of clavulanate per kg) or a placebo with similar appearance and taste. Drug and
placebo were administered twice a day for 10 days. Symptoms were assessed
by a daily structured telephone parent interview until the first follow-up visit,
and then in person at each visit. Otoscopic exams were performed on day
4-5 of therapy, at the end of therapy on day 10-12, and at a follow-up visit on
day 21-25. At each visit, children were designated as having met criteria for
either clinical success or failure. Clinical
failure at or before the 4-5 day visit was
defined as lack of substantial symptom
INSIDE
improvement, worsening otoscopic exam,
Defining Normal CSF Profiles in
or both. Failure at the 10-12 day visit was
Febrile Infants Aged 1-90 Days
characterized as lack of complete resoluFebrile UTI in Infants 0-3 Months:
tion of all symptoms and otoscopic abnorImportance of Normal Renal US
malities except for persistence of middle
Severe Acne, Suicide, & Isotretinoin
Rx: A Risk Assessment
ear effusion.
Evaluating the Risk of
The primary outcome measures were
Intussusception
the time to symptom resolution and the
E coli 0157 Outbreak Traced to
symptom burden over time. The children
Unpasteurized Milk
who received antibiotic had a 35% initial
Tethered Cord: How Low Can a
resolution of symptoms by day 2, 61%
Normal Conus Medullaris Go?
by day 4, and 80% by day 7 compared to
Corticosteroids in Cardiopulmonary
Bypass Surgery
28%, 54%, and 74% for the correspondUse of Home HEPA Filters Reduces
ing periods in the placebo group (P=.14).
Unscheduled Asthma Visits
The rate of clinical failure, defined as the
Anti-Mllerian Hormone, Ovarian
Function, & Turner Syndrome
Back Page: BPA Derivatives
in Dental Resins Safe If
Precautions Are Followed

persistence of otoscopic signs of acute infection, was lower in the treatment

group compared to placebo, 4% versus 23% on day 4-5 (P<.001), and 16%
versus 51% (P<.001) at the 10-12 day visit. One child in the placebo group
developed mastoiditis, and adverse drug effects were increased in the treatment group.
The authors conclude that in children 6 to 23 months of age with AOM,
treatment with amoxicillin-clavulanate for 10 days reduced the burden of
symptoms and the persistence of otoscopic signs of acute infection.

Commentary by

Donald Schiff, MD, FAAP, University of Colorado School of Medicine and

The Childrens Hospital, Denver, CO
Dr Schiff has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

Clinicians continue to face the challenge of accurately diagnosing and

determining the optimal treatment for the child under 2 years of age who
may have AOM. In addition to the study described above, a second paper in
the same issue3 by investigators from Turku, Finland remarkably duplicates
and supports the data and conclusions reached by the Pittsburgh study. The
controversy regarding the necessity of treating children with AOM with
antimicrobial agents originated in Europe4,5 and has gained major support
in the United States over the past decade.
Many pediatricians, driven by concerns about the development of resistant bacteria and questions about the efficacy of antibiotics, have opted
to prescribe fewer antibiotics and adopted a watch and wait approach, particularly if the child is not very ill or if the diagnosis of AOM is not certain.
The AAP Subcommittee on Management of Acute Otitis Media in 2004
concurred that in children 6 months to 2 years of age with nonsevere illness, and for whom follow-up can be ensured and antibiotics can be given
if symptoms become worse, observation constitutes an accepted level of
care.6 The new PCV 13 vaccine remains too new to enable us to evaluate
its effectiveness against the strains of pneumococcus most responsible
for bacterial otitis media. The studies from Pittsburgh and Turku provide
sufficient data to support a clinical guideline which would recommend the
use of an effective antibiotic for children who are 6 months to 2 years of age
with a certain diagnosis of AOM. However, changes in the susceptibility of
common causative organisms to current antibiotics will undoubtedly occur,
potentially requiring adjustments in future treatment guidelines.
See Editors Note on Back Page.
References

Shaikh N, et al. Pediatr Infect Dis J. 2009;28:5-8

Shaikh N, et al. Pediatr Infect Dis J. 2009;28:9-12
Tahtinen PA, et al. N Engl J Med. 2011;364:116-126
Rosenfeld RM, et al. J Pediatr. 1994;124:355-367
Appelman CL, et al. Huisarts Wet. 1999;42:362-366
American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media.
Pediatrics. 2004;113:1451-1465
7. Katz A, et al. Pediatr Infect Dis J. 2003;22:878-882
1.
2.
3.
4.
5.
6.

Key words: acute otitis media, antibiotic

The AAP Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for AAP CME Activities is designed to ensure quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying and resolving all potential conflicts of interest prior to the confirmation of
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All individuals in a position to influence and/or control the content of AAP CME activities, including editorial board members, authors, and staff, are required to disclose to the AAP and subsequently to learners that the individual either has no relevant financial relationship or any financial relationships with
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to resolve any potential conflicts of interest.
Lane Palmer, MD (Editorial Board Member) disclosed a Speakers Bureau with Laborie.
Joseph Geskey, DO (Editorial Board Member) disclosed a Speakers Bureau with GlaxoSmithKline.

EPIDEMIOLOGY

Defining Normal CSF Profiles in Febrile Infants Aged 1-90 Days

Source: Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr. 2011;158(1):130-134;
doi:10.1016/j.jpeds.2010.07.031

Commentary by

Dr Bordley has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

nvestigators at Primary
PICO
Childrens Medical Center
Question: Among febrile infants aged 1 to
in Salt Lake City, Utah ana90 days with negative results of bacterial
lyzed cerebrospinal fluid (CSF)
cultures and enteroviral PCR testing, what
are normal values of CSF WBC counts, RBC
profiles of febrile infants who
counts, glucose, and protein?
had uniform testing for seriQuestion type: Descriptive
ous bacterial illness (SBI) and
Study design: Retrospective cohort
enteroviral (EV) infection. Their
objective was to compare CSF
profiles of these infants to existing pediatric references, using data
from a previously published pediatric emergency department study
of SBI in febrile neonates with and without proven viral infections.1
The original study enrolled 1,779 infants aged 1 to 90 days over six
years who presented with rectal temperatures 38C. Infants were
excluded if they had received antibiotics in the previous 48 hours or
oral polio virus vaccine. All 1,186 infants from the original cohort
who had complete CSF profiles were eligible for this study. Of these,
823 met selection criteria of: 1) term birth; 2) negative bacterial
cultures of blood, urine, and CSF; 3) negative EV polymerase chain
reaction (PCR) test of CSF (and blood if performed); and 4) no clinical evidence of herpes simplex infection. Of these, 743 infants had
nontraumatic lumbar punctures (LP). Traumatic LP was defined as
a CSF RBC count greater than 1,000/mm3.
After removing infants whose CSF WBCs were statistical outliers,
the investigators derived normative values for CSF WBC and RBC
counts, glucose, and protein from the remaining 677 infants. The
mean, median, and range of CSF WBC counts, glucose, and protein
levels by age are below:
Age
(days)

Mean

1-28
29-60
61-90

6.1
3.1
3.0

CSF WBC/mm3
Median
Range
5
3.0
3.0

0-18
0-8.5
0-8.5

Mean
45.3
48.0
57.7

Glucose mg/dL
Median
Range
46.0
48.0
51.0

30.0-61.0
30.5-65.5
33.5-69.5

RBC/mm3 were examined in all 823 infants to determine the

impact of traumatic LPs on WBC counts. All infants had fewer than
10,000 RBC/mm3. The mean, median, and range of CSF WBC counts
in febrile children with traumatic LPs were 6.5/mm3, 5/mm3, and
0-16/mm3 respectively, only slightly higher than the values derived
from the nontraumatic LPs.
The authors compare their results to published pediatric references and conclude that normal WBC counts in febrile infants
without evidence of bacterial or EV infection are lower than those
currently accepted, even in the context of traumatic LPs with fewer
than 10,000 RBC/mm3.

38

Clay Bordley, MD, MPH, FAAP, Department of Pediatrics, Duke University,

Durham, NC

Where do normal values come from? These authors inform us

that the numbers in standard pediatric references were derived from
four studies with a total of 294 infants,2 all performed before PCR
testing for EV was widely available. EV is the most common cause of
aseptic meningitis in this age group. As such, these norms may have
been derived from cohorts that included infants who had central
nervous system infections we can now identify, possibly skewing the
results to higher values.
Studying CSF profiles from a cohort of infants more than twice
the size of the four previous studies combined, these investigators
found mean, median, and ranges for CSF WBC counts lower than in
commonly cited references. The strength of this study is its size and
the extent to which the investigators were able to exclude infants with
identifiable infections. The number of infants studied also allowed
them to report the added information of normative data by age and
the impact on WBC counts of up to 10,000 RBC/mm3 introduced in
a traumatic LP. The investigators report several limitations of their
study (eg, single center, low rates of traumatic LPs, lack of herpes
simplex virus testing on all infants), but these pose little threat to the
validity of their conclusions.
The normative values were determined by identifying and eliminating outliers. This was done by first determining the interquartile
range (IQR), which is the value of the 75th percentile (Q3) minus the
value of the 25th percentile (Q1). The upper bound of normal then
is Q3 + 1.5 x IQR, and the lower bound is Q1 - 1.5 x IQR (truncated
at 0).3 This method was needed because their data had a non-normal
(skewed) distribution, which precludes use of simple means and 95%
confidence intervals.
Protein mg/dL
Who cares? Any of us who perMean
Median
Range
form LPs on febrile infants are
faced with a dichotomous deci75.4
73.0
15.8-131.0
58.9
54.0
535-105.5
sion: treat or dont treat. Treatment
39.2
38.0
7.0-71.0
typically means IVs, antibiotics,
hospitalization, the risk of medical
errors, and disruptions to young
families. Given the stakes, we should care a lot about where normal
values come from and their validity. Will these data replace our currently accepted CSF reference values? For now, consider putting Table
II from this study into your pocket reference!
References

1. Byington CL, et al. Pediatrics. 2004;113:1662-1666

2. Ahmed A, et al. Pediatr Infect Dis J. 1996;15:293-303
3. Stapel E. Box-and-Whisker Plots: Interquartile Ranges and Outliers. Available at: http://
www.purplemath.com/modules/boxwhisk3.htm. Accessed January 12, 2011

Key words: cerebrospinal fluid, febrile infants, interquartile range

www.aapgrandrounds.org

HOSPITAL CARE

Febrile UTI in Infants 0-3 Months: Importance of Normal Renal US

Source: Ismaili K, Lolin K, Damry N, et al. Febrile urinary
tract infections in 0- to 3-month-old infants: a prospective
follow-up study. J Pediatr. 2011;158(1):91-94; doi:10.1016/j.
jpeds.2010.06.053

elgian investigators rePICO

viewed data collected proQuestion: Among infants 0 to 3 months of
spectively on infants 0 to 3
age with a first febrile urinary tract infection,
months of age with a first febrile
what are the clinical characteristics and yield
of renal imaging in diagnosing significant
urinary tract infection (UTI) in
anatomic abnormalities?
order to characterize pathogens,
Question type: Diagnosis
antimicrobial resistance, renal
Study design: Prospective cohort
abnormalities, gender predilection, and recurrences. Urine was
collected using suprapubic aspiration or bladder catheterization. UTI
was defined as growth of at least 100,000 colony-forming units/ml or
any growth from urine collected by aspiration. Patients with multiple
pathogens or nosocomial UTI were excluded. All infants were treated
according to a protocol that included initial parenteral antibiotics and
hospitalization. All infants underwent renal ultrasound (US) during
hospitalization and a voiding cystourethrogram (VCUG) at least one
month after the UTI. All patients were followed for at least one year.
Of 209 children treated for a first episode of proved febrile UTI,
43 (21%) were infants 0 to 3 months of age. All infants had antenatal
US of which 6 (14%) were known to be abnormal. Of the 43 infants,
32 (74%) were male. All boys were uncircumcised. Escherichia coli
comprised 88% of the pathogens, Klebsiella pneumoniae 7%, and
Enterobacter species and Staphylococcus aureus occurred once
each. E coli resistance to ampicillin and trimethoprim-sulfamethoxazole was 71% and 47% respectively. Bacteremia accompanied the
UTI in three infants (7%). Sixty-seven percent of the US results were
normal. Nine infants (21%; 6 boys) had vesicoureteral reflux (VUR);
six infants had low grade VUR (I-III) and all of these resolved spontaneously within two years. US was abnormal in three of the six infants
with low grade VUR. All three infants with high grade VUR (IV, V)
had US demonstrating hydronephrosis, signs of dysplasia, or both.
Six infants (four girls) had recurrent UTI during follow-up. Three of
those patients had urinary tract abnormalities.
The authors conclude that 21% of children with a first febrile UTI
are 0 to 3 months of age; there is a male preponderance in this age
group; E coli is the most common pathogen and shows high rates of
resistance to ampicillin and trimethoprim-sulfamethoxazole; and
when US is normal in this population the incidence of high grade
VUR is extremely low.

Commentary by

The 1999 AAP practice parameter2 recommends renal US and

VCUG on every patient 2 months to 2 years of age with a first febrile
UTI, and antibiotic prophylaxis for those with an abnormal urinary
tract. These recommendations were based on the theory that UTI plus
VUR causes renal scarring which leads to decreased renal function,
hypertension, and eventually renal failure. More recently prenatal US
demonstrating congenital dysplasia, epidemiologic studies showing
no decrease in chronic renal failure rates despite widespread use of
prophylactic antibiotics, and multiple clinical studies challenging
the relationship of mild VUR with renal scarring and the efficacy
of prophylactic antibiotics to prevent renal scars have called these
recommendations into question.3,4 The ongoing RIVUR (randomized
intervention for vesicoureteral reflux) study will help answer these
questions, but only enrolls patients from 2 months to 6 years of age.
The current study generally confirms what we already know about
young infants with a first febrile UTI: boys (especially uncircumcised
boys) outnumber girls, E coli is the most common organism, and antimicrobial resistance is increasing. Small numbers prevent this study
from being definitive, but the authors have added some credence to
the stratified imaging approach, using the noninvasive US as a screen
to rule out high grade VUR, thereby avoiding the pain and radiation
inherent in the VCUG. Unfortunately, despite excellent follow-up,
they do not report on the use of prophylactic antibiotics or the grade
of VUR in the children who experienced recurrences; nor do they
correlate prenatal and postnatal US findings.
Infants 0 to 3 months of age presenting with suspicion of a first
febrile UTI should be treated with an antibiotic with activity against
E coli, taking into account local resistance patterns. In the otherwise
healthy infant, a normal renal US obviates the need for more invasive
renal imaging.

Editors Note
While this study certainly contributes to skepticism about the
routine use of VCUG after a first UTI, because of methodologic flaws
it does not define the value of routine US in such cases.
References
1.
2.
3.
4.

Conway PH, et al. J Pediatr. 2009;154:784-785

AAP. Pediatrics. 1999;103:843-852
Montini G, et al. Pediatrics. 2008;122:1064-1071
Moorthy I, et al. Arch Dis Child. 2005;90:733-736

Key words: UTI, renal ultrasound, infants

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Matthew D. Garber, MD, FAAP, University Pediatrics/University of South

Carolina School of Medicine, Columbia, SC

ISSN Numbers
Print: 1099-6605
Online: 1556-362X

Dr Garber has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

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Controversy exists over the current management of UTI in infants

and children. AAP Grand Rounds has addressed the issues of imaging and antibiotic prophylaxis at least 13 times in the past decade.
Guidelines vary from country to country, and there is considerable
practice variation within the United States.1
AAP Grand Rounds April 2011

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Managing Editor: Alain Park
Production: Michael Hayes
Editorial Associates: Nancy Cochran, Seattle, WA; Carol Frost, Tucson, AZ

39

YOUNG PHYSICIANS

Severe Acne, Suicide, & Isotretinoin Rx: A Risk Assessment

Source: Sundstrm A, Alfredsson L, et al. Association of suicide
attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ. 2010;341:c5812; doi:10.1136/
bmj.c5812

wedish researchers assessed the risk of suicide PICO

in patients with severe Question: Among patients with severe
acne, what is the risk of attempted suicide
acne before, during, and after before, during, and after isotretinoin
isotretinoin therapy. They linked treatment?
a registry of 15- to 49-year-old Question type: Harm/Causation
participants prescribed isotreti- Study design: Retrospective cohort
noin between 1980 and 1990 to
two national registries: the inpatient hospital registry and the cause of
death registry. From these registries, investigators extracted hospital
admissions related to suicide attempts and all deaths between 1980
and 2001. Rates of attempted suicides and deaths were standardized
by sex, age, and calendar year. Suicide attempts were classified as
occurring before treatment (up to three years prior to starting treatment), during therapy (onset of therapy to six months after treatment
stopped), and after treatment (up to 15 years following completion of
treatment). Comparisons were made between study groups (before,
during, after treatment) and with the expected number of suicide
attempts in the general population.
The study population included 5,756 patients (63% males). At
the beginning of therapy, the mean age of males was 22 and of females 27. The study covered 17,197 person-years before treatment,
2,905 person-years during treatment, and 87,120 person-years after
therapy. Of patients taking isotretinoin, 2.2% (128) were admitted to
the hospital for attempted suicide and 24 (17 males) actually committed suicide. The standardized incidence ratio for suicide attempts
(comparing the study cohort with the general population) increased
before therapy: 1.36 for a first attempt and 1.57 for all attempts during the year prior to treatment, suggesting that severe acne carries
an increased risk for suicide attempts. The risk was highest during
therapy and up to six months after its termination: 1.93 for first attempts. Males showed no increase in risk after termination of therapy
but females had a significant increase for repeat events, returning to
the expected rate three years after therapy.
This study is based on an administrative database of prescriptions,
not actual use. For three to four of the years of the study, isotretinoin
could also be prescribed from dermatology clinics without a record of
the prescription appearing in the database, a potential lost patient
group. The data does not include details regarding the patients baseline mental health or socioeconomic confounders associated with
suicide attempts such as unemployment, separation, or divorce. Only
25% of study patients had a documented end date for isotretinoin
treatment; for others, researchers estimated the end date based on the
prescribed amount and daily dose. Only suicide attempts requiring
hospitalization were included in the analysis.
While the authors cannot exclude the possibility that the raised
risk of suicide attempts during treatment and after treatment is due
to exposure to isotretinoin, their finding of an increased risk of at-

40

tempted suicide prior to isotretinoin exposure led them to conclude

that a more probable interpretation is that the underlying severe
acne may best explain the raised risk.

Commentary

Emily C. Webber, MD, FAAP, Pediatric Hospital Medicine, Riley Hospital for
Children, Indianapolis, IN
Dr Webber has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

Acne, affecting up to of 95% of adolescents, is increasingly associated with psychiatric morbidity.1,2 This makes it challenging to
delineate which psychiatric morbidity is due to acne alone versus
medical interventions. Isotretinoin is an effective treatment for
severe recalcitrant nodular acne; however, it is teratogenic and has
numerous adverse effects. A Canadian case-crossover study linked
the drug to depression3 while an American retrospective analysis did
not show an association.4
This study attempts to differentiate how much of the suicide risk
with severe acne is due to the condition itself and how much to
isotretinoin, but unfortunately does not provide a definitive answer.
The authors document an increasing rate of suicide risk for three
years prior to treatment followed by an even greater rise during
treatment. However, they do not conclude that this represents a
causal relationship.
The authors, therefore, would not exclude patients with a history
of attempted suicide from isotretinoin therapy when such treatment
is warranted. They speculate that continued failed treatments for a
disfiguring condition such as nodular acne could be responsible for
the rise in suicide attempts, and successful treatment could explain
the decline in suicide attempts to expected levels following treatment.
But providers should not conclude that this study demonstrates that
treatment with isotretinoin is without risk.
The accompanying editorial5 emphasizes that patients with severe
acne have significant mental health comorbidities. When isotretinoin
is prescribed, patients must be closely monitored for suicidal intention and mental health status. Since patients may obtain medications
over the internet without their physicians knowledge, it may be wise
to discuss medication risks even when they are not prescribed. Many
providers currently screen patients prior to isotretinoin treatment
with iPledge (intended to reduce teratogenic risk of the drug through
screening and education). A screening program for mental health
concerns may also be prudent.
References
1.
2.
3.
4.
5.

Yentzer BA, et al. Cutis. 2010;86:94-99

Purvis D, et al. J Paediatr. 2006;42:793-796
Azoulay L, et al. J Clin Psychiatry. 2008;69:562-532
Hersom K, et al. J Am Acad Dermatol. 2003;49:424-432
Magin P, et al. BMJ. 2010;341:1060-1061

Key words: acne, suicide, isotretinoin

www.aapgrandrounds.org

EMERGENCY MEDICINE

Evaluating the Risk of Intussusception

Source: Weihmiller SN, Buonomo C, Bachur R. Risk stratification of children being evaluated for intussusception. Pediatrics.
2011;127(2):e296-e303; doi:10.1542/peds.2010-2432

o determine risk facPICO

tors for intussusception
Question: Among children being evaluated
and to develop a clinifor possible intussusception in the
cal decision tree, investigators
emergency department, what clinical factors
from Childrens Hospital, Boston
predict the likelihood of its presence or
absence?
performed a prospective cohort
Question type: Diagnosis
study. Children ages 1 month to
Study design: Prospective observational
6 years presenting to the emercohort
gency department (ED) with
suspected intussusception between December 2008 and January 2010 were eligible for study
enrollment. Treating physicians provided clinical evaluation and
management and completed a standardized questionnaire regarding
history and physical examination findings prior to the completion
of advanced imaging (ultrasound, CT scan, or air enema) on study
patients. Plain radiographs of the abdomen were categorized as positive, suspicious, or negative using predefined criteria. Intussusception was defined as visualization of the intussusception at air enema
or operative intervention. Parents of children were contacted by
telephone at least two weeks after the ED visit to confirm that no cases
of intussusception were missed, and medical records were reviewed
when telephone contact was not successful. Study data were entered
in a recursive partitioning model for clinical decision tree development. (For an explanation of recursive partitioning, see AAP Grand
Rounds, October 2009;22:39.) The goal of the analysis was to identify
children at low risk for intussusception based on clinical findings.
About 68% of eligible patients were enrolled during the study
period. Data were analyzed on 310 enrolled children, 38 (12.3%) of
whom had intussusception. Significant predictors of intussusception
were male gender (P=.007), age over 6 months (P=.04), bilious emesis (P=.002), lethargy by history (P=.001), and positive or possibly
positive abdominal radiographs (P<.001).
These and other clinical findings were used for the clinical decision
tree development. With this analysis, patients could be considered
low risk if they were in one of two low risk categories: a) negative
radiograph and age 5 months or younger (0/31 = 0%); or b) negative
radiograph, age over 5 months, no bilious vomiting but with diarrhea
(1/54 = 1.9%). This low risk rule had a sensitivity of 97% (95% CI,
86%-100%) and negative predictive value of 99% (95% CI, 93%-100%).
The authors conclude that abdominal radiographs should be
obtained for all children with possible intussusception, and that
patients with certain clinical characteristics may be at low risk of
intussusception.

Commentary by

Michelle Stevenson, MD, MS, FAAP, Pediatric Emergency Medicine,

University of Louisville, Louisville, KY
Dr Stevenson has disclosed no financial relationship relevant to this commentary. This commentary does not contain
a discussion of an unapproved/investigative use of a commercial product/device.

Intussusception can be a challenging diagnosis because of the

variable penetrance of clinical signs and symptoms.1 For pediatric
AAP Grand Rounds April 2011

providers, tools which aid in identification of children at low risk

of intussusception could greatly assist with appropriate utilization
of advanced imaging such as ultrasound, which is not available 24
hours per day at many facilities, or air contrast enema, which is
invasive and requires the presence of a radiologist and availability
of a pediatric surgeon.
Other investigators have attempted to develop low risk prediction
rules for intussusception using retrospective data, with limited success.2,3 Although clinicians in the current study may have had knowledge of the abdominal radiographs (but not advanced imaging) prior
to recording their clinical findings, the prospective design enhanced
the ability to develop a clinical prediction algorithm. It is notable that
the abdominal radiographs were interpreted by experienced pediatric radiologists who were not blinded to the patients clinical data.
The evolution of quality clinical decision rules involves both
development and validation.4 It is important to recognize that the
95% confidence intervals of the sensitivity and negative predictive
values in the current study are wide. Due to the potential morbidity
and mortality associated with intussusception, these decision rules
require prospective validation, preferably with a larger sample of
children in a variety of clinical settings, prior to clinical use. In the
meantime, abdominal radiographs remain the key first step in determining the risk of intussusception in young children.

Editors Note
While this report is thought-provoking, there are a few important
caveats. First, 23% of the children with intussusception had negative
radiographs, and 54% had only suspicious findings such as paucity
of bowel gas in a specific quadrant. Second, since none of the 35
patients younger than 6 months had intussusception, the utility of
the radiograph or other findings in this age group cannot adequately
be tested. Finally, of the 275 children 6 months or older in whom intussusception was suspected, only 54 (20%) met the classification of
low risk, and one of the items used to classify a patient as low risk,
diarrhea, can be a nebulous component of the history. Thus, in most
instances ruling out intussusception without advanced imaging in
a child at risk will continue to be difficult.
References
1.
2.
3.
4.

Waseem M, et al. Pediatr Emerg Care. 2008;24:793-800

Klein EJ, et al. Clin Pediatr. 2004;23:343-347
Kuppermann N, et al. Arch Pediatr Adolesc Med. 2000;154:250-255
McGinn TG, et al. JAMA. 2000;284:79-84

Key words: intussusception, abdominal pain, risk factor

AAP Journal CME

You can complete and claim credit for all of your quizzes
online. Visit the AAP Grand Rounds CME Center at
www.aapgrandrounds.org.

41

AT-LARGE

E coli 0157 Outbreak Traced to Unpasteurized Milk

Source: Guh A, Phan Q, Nelson R, et al. Outbreak of Escherichia
coli O157 associated with raw milk, Connecticut, 2008. Clin Infect Dis. 2010;51(12):1411-1417; doi:10.1086/657304

nvestigators from the

PICO
C enters for Disease
Question: Is consumption of unpasteurized
Control and Prevention
milk a risk factor for E coli 0157 infection?
(CDC) and the Connecticut
Departments of Public Health Question type: Harm/causation
Study design: Case-control
and Agriculture investigated
an outbreak of Escherichia
coli O157:NM infections associated with unpasteurized milk
consumption from a local farm (farm X) in 2008. Case-finding
through surveillance review and laboratory reports identified
confirmed cases and probable infected cases. Illness was also
assessed in household contacts of index cases and customers of
raw milk from farm X. Community and household case-control
studies as well as an environmental investigation of farm X were
conducted.
A clinical or laboratory diagnosis of an E coli O157 infection was made in 14 persons. Seven were confirmed cases; the
other seven were from households who had consumed milk
from farm X and met the probable case definition of a diarrheal illness at least two loose stools per day for at least two
days. The median age of the confirmed and probable cases was
5 years; 10 (71%) were less than 18 years of age. Five of the 14
were hospitalized, one adult with thrombotic thrombocytopenic purpura and four children, of whom three had hemolytic
uremic syndrome (HUS) and required dialysis. No deaths were
reported. Raw milk consumption was the only factor that was
significantly associated with illness; none of the control individuals had had this exposure (P=.008).
An environmental investigation of farm X revealed the
absence of consumer advisory labeling on the bottles of unpasteurized milk; however, advisories were posted in stores
where the products were sold. There were no noted regulatory
violations of milking or disinfection practices, although substandard hand hygiene practices and manual bottling from a
larger tank were observed. A product recall was not issued as
farm X voluntarily suspended sales of unpasteurized milk after
private laboratory testing revealed increased colony counts
in several samples of unpasteurized milk products. One farm
worker was ill with diarrhea but a stool specimen was negative
for the outbreak isolate; however, one of 170 bovine specimens
was positive for the outbreak isolate.
The authors conclude that farm Xs raw milk was the outbreak
source, there were no violations of extant regulations, and substantial
costs were incurred. This event led to proposed legislation to prevent
future similar outbreaks.

Commentary by

Andi L. Shane, MD, MPH, MSc, FAAP, Emory University School of Medicine,
Atlanta, GA
Dr Shane has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

Despite the lack of substantiated health benefits and the known

risks of unpasteurized dairy products, their consumption continues.
Although interstate distribution of unpasteurized milk is banned,
Connecticut is one of 29 states where unpasteurized milk sales are legal. Efforts to introduce state legislation to restrict such sales following this outbreak were thwarted due to the claims of a minority who
desired access to unpasteurized dairy products. Three alternative but
questionably effective control measures were offered: strengthening
advisory labels; increasing frequency of raw milk testing; and limiting sale of raw milk to the farm.1 Traditional educational efforts are
unlikely to be beneficial, as the authors of the current study noted
that the five hospitalized patients or their parents were aware that
raw milk contains disease-causing bacteria. Even weekly testing had
not prevented this outbreak.
Multiple instances of outbreaks of infections with a variety of
pathogens associated with unpasteurized dairy products have
been documented and all ages have been involved.1,2 However,
E coli O157 and young children predominate. In 2006 and
2008, four outbreaks were associated with E coli O157:H7 (in
California, Connecticut, Missouri, and Vermont) and one with
Campylobacter (California). Several clusters of infection have
been associated with field trips to farms where unpasteurized
dairy products are consumed.
The American Academy of Pediatrics strongly endorses the
use of pasteurized milk and recommends that parents and public health officials be made fully aware of the serious risks associated with consumption of unpasteurized milk.2 The optimal
means of preventing morbidity and mortality of milkborne infections is the consumption of only pasteurized milk products.

Editors Note

Food safety is a major health and economic issue. Each year

more than 50 million illnesses and over 3,000 deaths are attributed to foodborne pathogens in the United States.3 Although
this article describes raw milk as a vehicle for E coli 0157, this
organism has been responsible for outbreaks of HUS from
foods as diverse and widely consumed as iceberg lettuce and
ground beef. Prevention of foodborne illnesses will undoubtedly be enhanced by the increased powers given the Food and
Drug Administration (FDA) by the new $1.4 billion Food
Safety Law. 4
References

1. Jay-Russell MT. Clin Infect Dis. 2010;51:1418-1419

2. AAP Committee on Infectious Diseases. Red Book: 2009 Report of the Committee
on Infectious Diseases. Elk Grove Village, IL. American Academy of Pediatrics;
2009:857-859
3. Morris JG. Emerging Infect Dis. 2011;17:126-127
4. Stokstad E. Science. 2011;331:270

Key words: Raw milk, E coli 0157, hemolytic uremic syndrome

42

www.aapgrandrounds.org

RADIOLOGY

Tethered Cord: How Low Can a Normal Conus Medullaris Go?

Source: Thakur NH, Lowe LH. Borderline low conus medullaris
on infant lumbar sonography: what is the clinical outcome and
the role of neuroimaging follow-up? Pediatr Radiol. Epub 16 Nov
2010; doi:10.1007/s00247-010-1889-y

ypically, a conus medullaris that ends below

PICO
the L2-L3 level has been
Question: Among infants with borderline
conus medullaris on imaging, what is their
considered abnormal, raising
clinical outcome?
concerns about a potential asQuestion type: Descriptive
sociation with tethered cord
Study design: Retrospective review with
syndrome. Investigators from
prospective follow-up
Childrens Mercy Hospital and
Clinics, Kansas City, MO, analyzed spinal ultrasound (US) findings from 90 infants with a borderline low-lying conus medullaris (terminating between the L2-L3 disc
space and the middle of the third lumbar vertebral body) to ascertain
their clinical outcome and need for follow-up. These 90 patients were
discovered among 748 consecutive children (from February 2007
to February 2009) imaged between one day and eight months after
birth for a sacral dimple, hemangioma, or hairy tuft. Eight months
was used as a cutoff because ossification of the vertebral column begins to limit US analysis. Twenty patients were excluded because of
other findings associated with a tethered cord (ie, a filum terminale
thicker than 2 mm, focal spinal canal lipoma, eccentrically positioned
conus [dorsal, ventral, or lateral] within the canal, abnormal conus
or cauda equina motion, dysraphism, syringomyelia) or because they
had disease entities or conditions associated with developmental
delay or death.
Each US was reviewed by a radiologist with a Certificate of Added
Qualification in pediatric radiology. The primary care physician of
each child with a borderline low-lying conus medullaris was contacted for clinical history and information on developmental motor
milestones (rolling over, considered normal if occurring between 3-9
months; crawling on hands and knees at 6-11 months; and walking
at 9-17 months). If later milestones were achieved at a normal time,
an earlier milestone lag would be ignored, and the child considered
developmentally normal.
Of the 70 infants (37 girls) who remained in the study, the mean
age at initial sonogram was 31.3 34.6 days. One patient had a
follow-up sonogram and 10 had MRI exams, performed on average
6.1 2.2 months after the US. All but one of these follow-up studies
showed a more normal conus position (above L3). One MRI showed
a small thoracic area syrinx not detected by sonogram. Clinical
follow-up and milestone data were obtained in 50 of the 70 infants
including 11 who had follow-up examinations. All of the 50 had gross
developmental milestones within the normal age ranges.
The authors state that this normalcy of milestones suggests that
when there is no other abnormality suggestive of a tethered cord
there need be less concern about a borderline abnormal conus position. They caution that their study involved too few participants to
make a definitive statement regarding whether the cord may ascend
in neonatal life. They also note that their study was limited by its
retrospective nature and a follow-up period insufficient to elicit some
AAP Grand Rounds April 2011

of the findings of tethered cord, such as urinary incontinence, low

back pain, and leg weakness. The authors conclude that isolated borderline low-lying conus, found in 12% of their 748 patients, suggests
that positioning of the conus between the top and midpoint of L3 is
a normal variant, and that infants with borderline conus positioning and no other abnormality on sonogram are probably normal but
should receive follow-up examinations at least three months later,
but before the age of 8 months.

Commentary by

Harris L. Cohen, MD, FAAP, Memphis, TN

Dr Cohen has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device

US is a fast, simple tool for analyzing the distal cord and its filum
for morphology and positioning. Its ability to assess for a lipomatous
mass within the canal and free cord motion on real time examination
allows US to play an important role in ruling out a tethered cord. The
added benefits of US include its low cost, ability to be performed at
the bedside, and the absence of radiation exposure.1,2
Major improvements in US transducers, including high frequency
linear array transducers (eg, L12-14 MHz), allow the creation of
sharp, high resolution images over a relatively long surface of the
cord. This is aided by lesser amounts of obstructing bone in the early
months of life. Better imaging has helped in the counting of vertebral
bodies and the determination of conus levels with respect to the
lumbar vertebral bodies.
The authors suggest that perhaps the lowermost position accepted
as normal, ie, the top of the 3rd vertebral body, may be somewhat
high and that the midpoint of L3 may be acceptable, especially in
cases in which no other abnormality is seen. Longer follow-up may
aid in confirming this assertion. A point worth noting, however, is that
US appears reliable in the assessment of the distal cord at least in the
first months and perhaps extending to the eighth month after birth.

Editors Note
This study is a reminder of the conundrums posed by technological advances. Although it attempts to delineate the clinical significance of an isolated US finding, it fails to do so definitely because of
both inadequate sample size and follow-up. We are left to fall back
on careful follow-up with repeated physical examinations by primary
care providers in concert, when indicated, with their radiologic
colleagues.
There is opportunity for general and specialty primary care providers to help coordinate long-term clinical follow-up, to answer
questions posed by radiologists, obstetricians, or neonatologists who
see findings and concerns in one small period of time and must determine the normalcy or long-term consequences of those findings.
References

1. Kirpekar M. In: Timor-Trisch I, et al (eds). Ultrasonography of the Prenatal and Neonatal Brain. 2nd ed. NewYork, NY: McGraw Hill; 2001:453
2. DiPietro M. AJR. 1993;188:149-153

Key words: spinal sonography, low conus medullaris, tethered spinal cord

43

CRITICAL CARE

Corticosteroids in Cardiopulmonary Bypass Surgery

Source: Pasquali SK, Hall M, Li JS, et al. Corticosteroids and
outcome in children undergoing congenital heart surgery.
Analysis of the Pediatric Health Information Systems Database.
Circulation. 2010;122(21):2123-2130; doi:10.1161/CIRCULATIONAHA.110.948737

PICO
esearchers from multiple
Question: Among children 0 to 18 years
institutions reviewed data
of age undergoing cardiopulmonary
from the Pediatric Health
bypass surgery, is the use of
Information System (PHIS) Datacorticosteroids beneficial?
base to determine if administraQuestion type: Treatment
tion of perioperative corticosteStudy design: Retrospective cohort
roids (CS) improves outcomes in
children undergoing cardiopulmonary bypass (CPB) surgery, presumably by decreasing the postoperative inflammatory response. The PHIS
Database includes information on children hospitalized at 38 freestanding childrens hospitals.1 For this study, data on patients undergoing CPB
surgery between 2003 and 2008 were abstracted. Outcomes in study
patients who did, or did not, receive corticosteroids were compared
after controlling for potential confounders such as age, gender, race,
prematurity, genetic syndrome, type of surgery, risk associated with
the surgery as stratified by the Risk Adjustments in Congenital Heart
Surgery Version 1(RACHS-1),2 center, and center volume.
Of 46,730 patients studied, 54% received perioperative CS. Use of
CS was associated with younger age, white race, genetic abnormality, more complex surgical repair, and centers with a lower annual
case volume (150-250 vs >350). Methylprednisolone was the most
commonly used CS (70%) followed by dexamethasone (27%). CS was
received by 79% on the day of surgery and 12% on both the day prior
and the day of surgery.
Overall, there was no difference in mortality between those receiving and those not receiving CS (OR=1.13; 95% CI, 0.98-1.30). The risk
of perioperative infection was significantly greater (OR=1.27; 95%
CI, 1.10-1.46) and length of stay was significantly longer for those in
the CS group (mean difference 2.18 days; 95% CI, 1.62-2.74 days).
There was also greater use of insulin in the CS group. There was no
difference in duration of mechanical ventilation between groups.
The authors conclude that perioperative CS use was not associated
with a significant benefit, but was associated with increased morbidity in lower-risk patients.
Commentary by

Katsuhide Maeda, MD, PhD, Pediatric Cardiac Surgery and Chandra

Ramamoorthy, MBBS, Anesthesiology, Stanford University Medical Center,
Stanford, CA
Drs Maeda and Ramamoorthy have disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device

CPB has been an epoch-making development in the history of

cardiac surgery. However, the subsequent postoperative course has
been a saga of the battle against the systemic inflammatory response
syndrome (SIRS) induced by CPB. SIRS complicates the postoperative period by causing serious multi-organ dysfunction, and since CS
are well known anti-inflammatory agents, their perioperative use has
become the gold standard in many pediatric cardiac surgery centers
despite the lack of clear evidence.3

44

The present study did not demonstrate a single significant benefit

associated with CS use before or during CPB; instead, it showed
adverse effects such as longer length of stay, greater infection rates,
and greater use of insulin. Although we cannot draw definitive conclusions, the implications are not trivial.
Among these, the greater use of insulin is worth noting. Although
the authors did not have information regarding blood glucose levels,
the indication for insulin use is commonly hyperglycemia. The results
of a recent study in children undergoing complex congenital heart
surgery indicated that a longer duration of perioperative hyperglycemia was associated with prolonged hospitalization.4 However, aggressive therapy of hyperglycemia with insulin may result in episodes
of inadvertent hypoglycemia,5 which are particularly detrimental to
the neonatal myocardium and central nervous system.
Another issue this study has identified is the association of CS
with increased morbidity, most prominent in the RACHS-1 lower
risk categories 1 to 3. Surgeries for atrial or ventricular septal defect
repair can generally be performed with relatively low risk. Therapies
which could complicate postoperative care, such as routine use of CS
in all CPB cases, should be questioned.
These findings are in contrast to the results of a meta-analysis of
the adult cardiac surgery literature which concluded that CS prophylaxis provided protective effects including: 1) preventing postoperative atrial fibrillation; 2) reducing postoperative blood loss; and 3)
reducing intensive care unit and overall hospital stay. No relationship
between CS use and the risk of postoperative infections was found.6
The current study is subject to the limitations of retrospective observational investigation. The CS used, dosage, and their indications
were not considered. Moreover, the possibility of selection bias cannot be ruled out. Large double-blind prospective trials are urgently
needed to examine the potential benefits or harmful effect of CS, such
as those underway in adult cardiac surgery.7

Editors Note
This study has at least three important albeit not new takehome messages that have implications well beyond cardiothoracic
surgery:
1) Test what seems like common sense eg, reducing inflammation by administering corticosteroid to speed recovery of cardiac
surgery patients proved not to be sensible.
2) Children are not simply little adults what seemed to be beneficial in adult cardiac surgery patients proved harmful to pediatric
patients.
3) Multi-institutional collaboration though contributing information to a common database can greatly accelerate quality improvement and improve clinical outcomes.
References

1. Childrens Health Corporation of America: A business alliance of childrens hospitals.

http://chca.com/index_no_flash.html. Accessed March 3, 2011
2. Jenkins KJ, et al. J Thorac Cardiovasc Surg. 2002;123:110-118
3. Checchia PA, et al. Pediatr Crit Care Med. 2005;6:441-444
4. Polito A, et al. Circulation. 2008;118:2235-2242
5. Van den Berghe G, et al. Crit Care Med. 2003;31:359-366
6. Cappabianca G, et al. J Cardiothorac Vasc Anesth. 2010 May 25. Epub ahead of print
7. http://www.clinicaltrials.gov/ct2/show/NCT00427388)

Key words: cardiopulmonary bypass surgery, corticosteroids

www.aapgrandrounds.org

ENVIRONMENTAL HEALTH

Use of Home HEPA Filters Reduces Unscheduled Asthma Visits

Source: Lanphear BP, Hornung RW, Khoury J, et al. Effects of
HEPA air cleaners on unscheduled asthma visits and asthma
symptoms for children exposed to secondhand tobacco smoke.
Pediatrics. 2011;127(1):93-101; doi:10.1542/peds.2009-2312

nvestigators conducted a douPICO

ble-blind randomized controlled
Question: Among children with asthma
trial on the efficacy of high effiand cigarette smoke exposure, what is
ciency, particulate-arresting (HEPA)
the effect of implementing home HEPA air
air cleaners in reducing symptoms in
filters on unscheduled asthma visits and
tobacco smoke-exposed asthmatic
asthma symptoms?
children aged 6 to 12 years. Study
Question type: Intervention
patients were recruited from the
Study design: Randomized, double-blind
Cincinnati area and randomized to
have HEPA air cleaners, or inactive
placebo air filters, installed in their homes. Air cleaners were installed in
the study childs bedroom and the main activity room of her/his house. No
attempt was made to reduce tobacco use or asthma triggers. The main study
outcomes were unscheduled asthma visits and asthma symptoms over a
one-year period. Air nicotine levels were measured by a nicotine dosimeter
that was placed in the childs house; nicotine exposure in study children was
assessed by measuring hair and serum continine (a metabolite of nicotine)
levels. Exhaled nitric oxide was measured in study participants to assess
airway inflammation, and measurements of indoor particle concentrations
were performed to assess the efficiency of the HEPA air cleaners.
A total of 225 children were enrolled in the study, including 110 randomized to receive the HEPA air cleaners and 115 who had placebo air cleaners
installed. After adjustment for baseline differences, there was a reduction
of 42 unscheduled asthma visits in the intervention group compared to the
control group (P=.043). The mean number of unscheduled visits decreased
by 8.9% per month in the intervention group compared to a 0.9% decrease
in the control group. This is equivalent to an 18.5% decrease in unscheduled
visits over the one year of study. A secondary analysis of those using the
HEPA air cleaners over 70% of the time (ie, frequent users) found even
greater between-group differences, with unscheduled asthma visits decreasing by 12.7% per month among those in the intervention group, but increasing by 0.7% per month for those randomized to placebo air cleaners. The
intervention group experienced a 25% mean reduction in airborne particles
greater than 0.3 mm versus only a 5% reduction for the control group. No
significant differences were found in parental reports of their childs asthma
symptoms, air nicotine levels, childrens serum and hair cotinine levels, or
exhaled nitric oxide.
The authors conclude that HEPA air filters may play a role in reducing
asthma morbidity as part of a comprehensive strategy.

Commentary by

Helen J. Binns, MD, MPH, FAAP, Chicago, IL

Dr Binns has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

Approximately 20% of United States children are exposed to household

second-hand smoke (SHS).1 SHS exposure is associated with a wide array
of negative health consequences, from diminished pulmonary function and
asthma to otitis media.2 Children living in homes with smokers are exposed
to indoor air with higher levels of airborne particles (levels of particles <2.5
mm are two to three times higher than in homes without smokers) and
tobacco gasses (eg, nicotine).3
The investigators for this study found that using HEPA air cleaners in
homes with smokers can reduce the number of unscheduled asthma visits

AAP Grand Rounds April 2011

in grade-school-age children having previously diagnosed asthma. While

this is good news, the study also showed that use of these air cleaners alone
will likely not lead to parent perception of reduced asthma symptoms for
their child, nor does it reduce the childs exposure to tobacco gasses, ie, air
nicotine. Each home in this study received two HEPA air cleaners (Austin
Healthmate, Austin Air, Buffalo, NY). These air cleaners are certified to
remove over 99% of airborne particles of over 0.3 mm in a 1,500-ft2 room.
A check of the companys internet sales site found that each new unit costs
about $500, a not inconsequential outlay. How other types of HEPA air cleaners compare with this brand is unknown.
There are several important take-home messages from this study. First,
HEPA air filters used in homes with smokers can reduce airborne particles
over 0.3 mm and this use is associated with a reduction in unscheduled
asthma visits. However, neither asthma symptoms nor exposure to the
gaseous phase of tobacco smoke is decreased. Effective interventions that
lead to actual decreases of tobacco use in homes, including counseling and
pharmacotherapy, are clearly needed.2,4

Editors Note
We would suggest that the efficacy of President Obama kicking the habit
is far greater than installing a HEPA filter in the White House.
References

1. Marano C, et al. Pediatrics. 2009;124:1299-1305

2. Best D. American Academy of Pediatrics Committee on Environmental Health, Committee on Native American Child Health, and Committee on Adolescence. Pediatrics.
2009;124:e1017-e1044
3. Wallace L, et al. Environ Health Perspect. 2003;111:1265-1272
4. Fiore M, et al. Treating Tobacco Use and Dependence: 2008 UpdateClinical Practice
Guideline. Rockville, MD: US Department of Health and Human Services, Public Health
Service; 2008

Key words: tobacco, asthma, airborne particulates

EDITORIAL BOARD
Editors-in-Chief

CME Question Editor

Leslie L. Barton, Tucson, AZ

Edgar K. Marcuse, Seattle, WA

Robert Wittler, Wichita, KS

Consulting Editors
Douglas Diekema, Seattle, WA
Daniel R. Neuspiel, Charlotte, NC
Tom Newman, San Francisco, CA
James A. Taylor, Seattle, WA

Editorial Board
Burris R. Duncan, Tucson, AZ
Joseph Geskey, Hershey, PA
Ronald D. Holmes, Littleton, CO
Lane S. Palmer, New Hyde Park, NY
Vasundhara Tolia, Bloomfield Hills, MI
Patty Vitale, Camden, NJ
Marcia Wofford, Clemmons, NC
Charles Reece Woods, Jr.,
Louisville, KY

Evidence eMended Editor

Contributing Section Editors

- April issue
Critical Care:
Susan L. Bratton, Salt Lake City, UT
Emergency Medicine:
Michelle Stevenson, Louisville, KY
Endocrinology:
Howard Heinze, Midland, GA
Epidemiology:
Clay Bordley, Durham, NC
Hospital Care:
Matthew D. Garber, Columbia, SC
Radiology:
Harris L. Cohen, Memphis, TN
Seniors:
Donald W. Schiff, Littleton, CO
Young Physicians:
Emily Webber, Bloomington, IN
At-large:
Andi Shane, Atlanta. GA

Bernhard (Bud) Wiedermann,

Washington, DC

45

ENDOCRINOLOGY

Anti-Mllerian Hormone, Ovarian Function, & Turner Syndrome

Source: Hagen CP, Aksglaede L, Sorensen K, et al. Serum levels
of anti-Mllerian hormone as a marker of ovarian function in
926 healthy females from birth to adulthood and in 172 Turner
syndrome patients. J Clin Endocrinol Metab. 2010;95(11):50035010; doi:10.1210/jc.2010-0930

nvestigators at three cenPICO

ters in Denmark set out to
Question: Among females with and
evaluate the utility of antiwithout Turner syndrome, do measures of
Mllerian hormone (AMH)
anti-Mllerian hormone serve as a clinical
marker of ovarian function?
measurements in assessing
Question type: Prognosis
ovarian function. A total of 926
Study design: Cohort
healthy females, ages 4 to 69
years, were recruited from three
Danish longitudinal cohort studies and registries, while 172 girls
with Turner syndrome (TS), ages 0 to 25 years, were recruited from
three separate Danish cohorts. In addition to AMH, measures of inhibin B produced by the granulosa cells of the ovarian follicle and
highest following ovulation were also measured for comparison.
Girls with TS were placed in one of three groups based on karyotype (45,X; various mosaic karyotypes with and without Y chromosome material; 45,X/46,XX) and further categorized by the presence
or absence of pubertal development and whether or not puberty
progressed towards regular, spontaneous menses.
Among healthy females, AMH was either low or undetectable
(median <2 pmol/L) in cord blood samples and increased in all participants by 3 months of age (median 15 pmol/L). Thereafter, AMH
remained measurable with little variation in participants between
8 and 25 years of age (median 19.9 pmol/L). This was followed by
a steady decline beginning at age 25 years with undetectable values
reached by 46 years of age.
In TS participants, AMH levels were associated with karyotype
and ovarian function as determined by degree of pubertal development. Eighty-five percent of 45X participants had AMH levels that
were undetectable or less than -2 SD for age. Forty-three percent
of miscellaneous TS karyotypes had AMH levels in the reference
range; all participants with a history of gonadectomy had undetectable values. All 45X/46, XX participants had AMH levels within the
reference range for age. AMH values correlated significantly with
remaining ovarian function in TS from ages 12 to 25 years. Using
an AMH cutoff value of 8 pmol/L, sensitivity was 96% (probability
of AMH <8 with premature ovarian failure [POF]), specificity 86%
(probability of AMH 8 with clinical evidence of ovarian function),
and positive predictive value 96% (probability of POF with AMH <8).
Inhibin B values in TS participants did not add additional information to the determination of remaining ovarian function. While 100%
of participants with POF and AMH under 8 pmol/L had undetectable
inhibin B levels, just 33% with clinical evidence of ovarian function
and AMH 8 pmol/L or greater had detectable inhibin B.
The authors conclude that AMH correlates significantly with TS
karyotype and remaining ovarian function based on clinical examination and progress through puberty. AMH appears to be a better

46

measure of ovarian follicular health when compared with inhibin B

and may serve as an additional aid when counseling women with TS
regarding their reproductive potential.

Commentary by

Howard Heinze, MD, FAAP, Pediatric Endocrinology, Midland, GA

Dr Heinze has disclosed no financial relationship relevant to this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial product/device.

Most discussions regarding TS in children generally focus on the

association with growth retardation. Each of us is all too familiar
with delays in diagnosis of this common genetic variant, in large part
related to girls presenting with subtle rather than classic features.1
This study brought to mind a 15-year-old young lady referred
to me with growth failure and pubertal delay. Her examination
was notable only for scattered pigmented nevi, increased carrying
angle (cubitus valgus), and hyperconvexity of her fingernails as the
sole features that might suggest TS, a diagnosis later confirmed by
karyotype. She had a mosaic karyotype which included the presence
of Y chromosome material. She will require gonadectomy, but her
family had many questions about her diagnosis and her future health
potential including fertility.
TS and fertility are rarely used in the same sentence; however,
assisted reproductive technologies may one day change the opinion
that all girls with TS are infertile.
This paper reviews the utility of measuring AMH as a measure
of ovarian health. Clearly, a small percentage of TS girls with mosaic
karyotypes are capable of spontaneous puberty and menses. While
POF is common in most, we may ultimately identify those girls with
sufficient ovarian follicular reserve for consideration of future oocyte
preservation.2
References

1. Rivkees SA, et al. J Clin Endocrinol Metab. Epub 20 December 2010

2. Oktay K, et al. Fertil Steril. 2010;94:753

Key words: anti-Mllerian hormone, inhibin B, Turner syndrome

CME INFORMATION
AAP Grand Rounds is an educational publication. The American Academy of Pediatrics is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing
medical education for physicians.
The American Academy of Pediatrics designates this enduring material for a maximum of 18
AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the
extent of their participation in the activity.
This activity is acceptable for up to 18 AAP credits. These credits can be applied toward the
AAP CME/CPD Award available to Fellows and Candidate Members of the American Academy of
Pediatrics.
This program is approved for 18 NAPNAP contact hours; pharmacology (Rx) contact hours to
be determined per the National Association of Pediatric Nurse Practitioners Continuing Education
Guidelines.
A CME Quiz Sheet can be found in the new CME Activity Center at www.aapgrandrounds.org. The
deadline for submitting the 2011 quiz sheet for 2011 credit is January 31, 2012.
This is a scientific publication designed to present updates and opinion to health care professionals. It does not provide medical advice for any individual case, and is not intended for the layman.

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 Understand the value of renal ultrasound imaging for infants with a febrile urinary
tract infection
Describe the association of suicide with isotretinoin treatment for severe acne
1. A mother has brought her 6-month-old daughter to the office for fever
and fussiness for one day and rhinorrhea for two days. Her temperature is
102.6F and examination reveals a a bulging right tympanic membrane that
is immobile with marked erythema. The remainder of her exam is normal.
She has no known allergies. Which of the following is the most appropriate
treatment recommendation?

a. Acetaminophen and amoxicillin-clavulanate

b. Acetaminophen and cetirizine
c. Ibuprofen alternating with acetaminophen every two hours for the next
three days
d. Ibuprofen and cefaclor
e. Ibuprofen and pseudoephedrine

2. A 21-day-old, term infant is brought to the emergency department with a

rectal temperature of 38.6C. A lumbar puncture is performed and it was
traumatic. The CSF cell count shows 8,500 RBC/mm3 and 38 WBC/mm3. The
CSF glucose is 45 mg/dl and the protein is 72 mg/dl. Based on the study
from investigators in Utah, which of the following is the most appropriate
interpretation of the cerebrospinal fluid results for this patient?

a. The CSF glucose is low

b. The CSF protein is elevated
c. The CSF protein is low
d. The CSF WBC count is elevated
e. The CSF WBC count is normal

3. A 9-week-old uncircumcised male infant is being discharged from the

hospital after treatment for his first febrile urinary tract infection. The urine
culture grew E coli resistant to ampicillin but sensitive to cefotaxime. He
has been treated with intravenous cefotaxime for three days and has been
afebrile for 48 hours. A renal ultrasound shows pelvic and calyceal dilatation. Which of the following is the most appropriate subsequent imaging
strategy for this patient?

a. DMSA scan
b. Intravenous pyelogram
c. No further imaging
d. Repeat renal US in three months
e. Voiding cystourethrogram

4. A 17-year-old girl has tried topical clindamycin, topical benzoyl peroxide,

and topical retinoids for severe nodular acne with minimal improvement.
She is extremely frustrated and withdrawn during appointments. She
has a friend whose acne was improved with isotretinoin, but her parents
read information online that isotretinoin was associated with suicide. The
patient when interviewed alone states she is not sexually active. A urine
pregnancy test is negative. Which of the following is the most appropriate
recommendation to the patient and parents at this time?

a. Enrollment in the iPledge program prior to beginning isotretinoin

b. Mandatory psychiatric evaluation prior to prescribing isotretinoin
c. Reassurance that the acne is not a significant problem for her
d. Refuse to prescribe her isotretinoin due to the established increased
risk for suicide
e. Refuse to prescribe her isotretinoin due to the teratogenicity risk

6. Following an outbreak of E coli O157 diarrheal illness in Connecticut

associated with consumption of food products from a local farm, a case
control study is performed to investigate epidemiologic factors and costs
of the outbreak. Which of the following is the most likely conclusion of the
study?

a. Adults made up the majority of the confirmed and probable cases

b. Consumption of unpasteurized milk was the strongest risk factor
for infection
c. Controls were just as likely as cases to have consumed unpasteurized milk
d. Estimated costs of the outbreak were approximately $125,000
e. Twenty percent of affected persons experienced hemolytic
uremic syndrome

7. A 3-day-old girl is noted to have a sacral dimple. She has normal motor
tone of both lower extremities. Lumbar ultrasonography is performed and
shows the termination of the conus at the upper aspect of the L3 vertebral
body. The filum terminale is normal size. Which of the following is the most
likely complication for this girl over the next nine months?

a. Gross motor developmental delay

b. No complication
c. Spastic urinary bladder
d. Syringomelia
e. Tethered cord

8. A multicenter retrospective cohort study is performed to assess if perioperative administration of corticosteroids is associated with improved
outcomes for children undergoing cardiopulmonary bypass surgery for
congenital heart disease. Which of the following is the most likely conclusion of the study concerning the use of corticosteroids?

a. Decreased mortality
b. Decreased mortality but only in the RACHS-1 category
c. Decreased postoperative infections
d. Increased use of insulin
e. Reduced length of hospital stay

9. A 7-year-old boy with asthma is brought by his mother to the pediatrician for a follow-up visit. The boys dad smokes cigarettes and he has
repeatedly tried to quit smoking without success. The mother inquires if
purchasing HEPA air filters would be beneficial. Which of the following is
the most appropriate counseling for the mother?

a. Air nicotine concentration will be decreased

b. Cotinine (nicotine metabolite) levels measured from the boys hair
will be lower
c. HEPA air filters will significantly improve his asthma symptoms
d. The boys exhaled nitric oxide concentration will be reduced
e. There is evidence that use of HEPA air filters reduces unscheduled
visits for asthma

10. A 15-year-old girl with Turner syndrome (karyotype 45 X) comes to the

office for a health maintenance examination. She has had no breast development or menses. Which of the following is the best measure of ovarian
follicular health for this girl?

a. 17-hydroxy progesterone
b. Androstenedione
c. Anti-Mllerian hormone
d. IGF-1
e. Inhibin
9. e
10. c

AAP Grand Rounds April 2011

7. b
8. d

Understand the efficacy of antibiotic treatment for acute otitis media in children under
2 years of age

a. Administration of a phosphate enema rectally

b. Computed tomography of the abdomen
c. Intramuscular promethazine
d. Plain abdominal radiographs
e. Stool culture

5. d
6. b

CME OBJECTIVES

3. e
4. a

The following continuing medical education questions cover the content of

the April 2011 issue of AAP Grand Rounds. Please keep this issue. Each years
material is worth up to 18 AMA PRA Category 1 Credit(s)TM.
Complete and claim credit online at www.aapgrandrounds.org. Need
username and password? Contact customer service at 866-843-2271.

Answers:
1. a
2. d

CME QUESTIONS

5. A 17-month-old girl is brought to the emergency department by her parents

with a 12-hour history of recurrent abdominal pain and nonbilious vomiting. During the past three hours she has had two watery stools that were
not grossly bloody. She has been previously healthy and is not lethargic or
toxic-appearing. Which of the following is the most appropriate next step
in management?

47

Back Page
Objective:To promote dialogue among readers and between readers and editors, we offer here briefreports andobservationson topics of interest authored
by members of the AAP Grand Rounds editorial team.

BPA Derivatives in Dental Resins Safe

If Precautions Are Followed
by Joel H. Berg, DDS, MS, FAAP, and Sheela Sathyanarayana, MD,
MPH, University of Washington, Seattle, WA
Drs Berg and Sathyanarayana have disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/service.

Source: Fleisch A, Sheffield P, Chinn C, et al. Bisphenol

A and related compounds in dental materials. Pediatrics.
2010;126:760-768; doi:10.1542/peds.2009-2693

isphenol A (BPA), the resin used in the manufacture of

plastic products, is also increasingly used in derivative
form in dental sealants and composite filling materials in
childhood dentistry. Evidence is mounting that BPA and some
BPA derivatives can pose health risks because of endocrinedisrupting, estrogenic, and other hormone-like properties.1,2 In
animal studies, BPA exposures are associated with changes to
hormone-sensitive tissues such as breast, prostate, and brain, but
few studies examine acute, short-term exposures such as might
result from dental procedures.
The urgency to clarify the potential risk posed by BPA in dental
materials prompted a thorough review of scientific literature
by a team of multidisciplinary medical and dental specialists
from Childrens Hospital and Harvard Medical School, Boston,
and Mount Sinai School of Medicine and Columbia University
College of Dental Medicine, New York. The authors conducted
a systematic evaluation of literature describing BPA content
of dental materials in order to: 1) assess BPA exposures from
dental materials and the potential health risks; and 2) develop
evidence-based guidance for reducing BPA exposures while
promoting oral health.

Continued from front page

Antibiotic Rx of AOM in Children <2 Years: Redux

Editors Note
This paper is well worth reading in its entirety because there are
important nuances: the symptomatic response to antibiotic therapy
was greater among children with more severe illness, but there were
also substantial between-group differences observed among children
who had the least severe symptoms. Notably, even though the authors
used stringent diagnostic criteria, symptoms resolved by day 4 in

48

The evaluation showed that BPA is released from dental resins

through salivary enzymatic hydrolysis of BPA derivatives. Traces
of BPA can be detected in saliva for up to three hours following
resin installment, but the quantity and duration of systemic BPA
body absorption is not clear from currently available data. Dental
products containing the bisphenol A derivative glycidyl dimethacrylate (bis-GMA) are not as likely to be hydrolyzed to BPA
and possess less estrogenicity than those containing bisphenol
A dimethacrylate (bis-DMA). Most other BPA derivatives used
in dental materials have yet to be well studied for estrogenicity.
The health impacts from acute, short-term exposures
are difficult to know. Regardless, there are a number of voluntary actions that dentistry practices can use to decrease
exposures. Pediatric dental practitioners can remove 20%
to 45% of the monomer that remains (unpolymerized) after
curing before it leaches into the patients saliva by rubbing the area with pumice on a cotton ball or in a rotating
rubber dental prophylaxis cup.4 The authors conclude that
the benefits of resin-based materials and the brevity of BPA
exposure warrant the continued use of these materials in
pediatric dental practice provided there is strict adherence
to careful application techniques. The one exception to
these recommendations might be to avoid the use of these
materials in pregnant women because the developing fetus
may be especially vulnerable to exposure.
On a legal and public policy level, the United States
Congress is currently considering legislation titled The
Kids, Worker, and Consumer Safe Chemicals Act (HR 6100,
S 3040) to require industry to undertake and report more
rigorous toxicity testing of chemical products. As well, the
United States Food and Drug Administration (FDA) is
supervising BPA safety study research. It is imperative that
the dental materials industry explore alternative materials
for use in composites and sealants.
References

1. Factor-Litvak P, et al. Environ Health Perspect. 2003;111:719-723

2. Lauterbach M, et al. J Am Dent Assoc. 2008;139:138-145
3. Sasaki N, et al. J Mater Sci Mater Med. 2005;16:297-300
4. Rueggeberg F, et al. J Am Dent Assoc. 1999;130:1751-1757

over one third of placebo recipients. These findings, coupled with the
complications, costs of antibiotic therapy, and its impact on antibiotic
resistance, suggest that we need to exercise individualized clinical
judgment to determine the optimal treatment option for each child.
Importantly, trends in complications of AOM, such as acute mastoiditis,7 require continued monitoring. Accurate diagnosis of AOM can
be devilishly difficult and likely accounts for much overtreatment.
Where the diagnosis is uncertain or the child mildly ill, watchful
waiting may be the best option.

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