ductos

1. in response to treatment as weight classification increases. J Pediatr
2011;158:624-7.
18. Danielsson P, Kowalski J, Ekblom O, Marcus C. Response of severely
obese children and adolescents to behavioral treatment. Arch Pediatr
Adolesc Med, in press.
19. Glaser Pediatric Research Network Obesity Study Group. Metformin
extended-release treatment of adolescent obesity: a 48-week random-
ized, double-blind, placebo-controlled trial with 48-week follow-up.
Arch Pediatr Adolesc Med 2010;164:116-23.
20. Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orli-
stat on weight and body composition in obese adolescents: a randomized
controlled trial. JAMA 2005;293:2873-83.
21. Yanovski JA, Krakoff J, Salaita CG, McDuffie JR, Kozlosky M,
Sebring NG, et al. Effects of metformin on body weight and body com-
position in obese insulin-resistant children: a randomized clinical trial.
Diabetes 2011;60:477-85.
22. Kelly AS, Rudser KD, Nathan BM, Fox CK, Metzig AM, Coombes BJ,
et al. The effect of glucagon-like peptide-1 receptor agonist therapy on
body mass index in adolescents with severe obesity: a randomized,
placebo-controlled, clinical trial. JAMA Pediatr 2013. In press.
23. Alqahtani AR, Antonisamy B, Alamri H, Elahmedi M, Zimmerman VA.
Laparoscopic sleeve gastrectomy in 108 obese children and adolescents
aged 5 to 21 years. Ann Surg 2012;256:266-73.
24. Inge TH, Jenkins TM, Zeller M, Dolan L, Daniels SR, Garcia VF, et al.
Baseline BMI is a strong predictor of Nadir BMI after adolescent gastric
bypass. J Pediatr 2010;156:103-8.
25. O’Brien PE, Sawyer SM, Laurie C, Brown WA, Skinner S, Veit F, et al.
Laparoscopic adjustable gastric banding in severely obese adolescents:
a randomized trial. JAMA 2010;303:519-26.
26. Pallati P, Buettner S, Simorov A, Meyer A, Shaligram A, Oleynikov D.
Trends in adolescent bariatric surgery evaluated by UHC database col-
lection. Surg Endosc 2012;26:3077-81.
Patent Ductus Arteriosus and Intraventricular Hemorrhage:
A Complex Association
P
ersistent patency of the ductus arteriosus is a common
occurrence in very low birth weight neonates. Closure
of a patent ductus arteriosus (PDA) with indometha-
cin, a nonspecific cyclooxygenase (COX) inhibitor, was first
reported in 1976.1
Despite the availability of an effective
therapy for >3 decades, neonatologists
continue to struggle with the optimal man-
agement of a persistently PDA in the early neonatal period.
Although numerous studies have examined the association
of various neonatal morbidities in the presence of a PDA
and their occurrence after treatment, the cause-and-effect re-
lationships remain unclear.2,3
In this issue of The Journal,
Brunner et al4
address whether treatment of a PDA with
either indomethacin or ibuprofen, both potent COX
inhibitors, in the presence of varying degrees of thrombocy-
topenia increases the risk of intraventricular hemorrhage
(IVH) in very low birth weight neonates.
The association of IVH with PDA is unique and complex.
Presence of a PDA has been implicated in the occurrence of
IVH due to fluctuation in cerebral blood flow.5
However,
indomethacin may protect against severe IVH by various
mechanisms, including enhancement of cerebral autoregula-
tory responses.6
Prophylactically administered in low doses
within the first 24 hours after birth, indomethacin lowers
the incidence and severity of IVH.7
However, in the large
multicenter Trial of Indomethacin Prophylaxis in Preterms,
this decrease in IVH did not translate into an improvement
in survival without neurosensory impairment at 18 months
corrected age.8
Notably, ibuprofen, the other nonspecific
COX inhibitor used in the management of PDA, has no
preventive effect on the occurrence of severe IVH.9
This is
possibly because ibuprofen, unlike indomethacin, does not
cause initial vasoconstriction in the cerebral circulation and
rapid reduction in cerebral blood flow.10
Thrombocytopenia
and platelet dysfunction may contribute to the patency of the
ductus arteriosus and occurrence of IVH.
Ductal closure is achieved by a 2-step pro-
cess: an initial phase of smooth muscle constriction causing
functional closure and hypoxic changes followed by extensive
remodeling of the intima and loss of smooth muscle cells
from the inner muscle media causing anatomic closure.11,12
Echtler et al13
suggested that the interaction of platelets and
ductal endothelial cells contributes to ductal closure in
a mouse model. Thrombocytopenia in the first day of life
in neonates of <30 weeks of gestational age was also associ-
ated with failure of ductal closure.13
However, this was not
observed in subsequent larger retrospective studies.14,15
Thrombocytopenia has also been implicated as an indepen-
dent risk factor for IVH in very low birth weight neonates;
however, its role is unclear.16
COX inhibitors can cause plate-
let dysfunction, but their significance in contributing to hem-
orrhagic complications like IVH is not well studied.
Indomethacin used antenatally as a tocolytic agent has been
associated with an increased incidence of IVH infants born
at #30 weeks of gestational age in one study, but this was
contested in subsequent studies.17,18
In the study published in this issue, Brunner et al report
a retrospective analysis of PDA, use of a COX inhibitor,
and IVH in very low birth weight neonates included in
their neonatal intensive care unit database.4
Neonates
COX Cyclooxygenase
IVH Intraventricular hemorrhage
PDA Patent ductus arteriosus
The authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.01.043
See related article, p 23
THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 163, No. 1
8

2. with a persistently open ductus arteriosus diagnosed with
early echocardiography were treated with COX inhibitors.
Presymptomatic treatment of PDA is an accepted
management strategy that reduces the incidence of later
development of a symptomatic PDA in neonates of 32
weeks of gestational age.19
However, it does not decrease
mortality or the incidence of IVH or change respiratory
outcome.20
The incidence of IVH did not differ between
neonates with or without treatment with COX inhibitors.
However, the combination of moderate thrombocytopenia
(ie, a platelet count of 50-99 Â 109
/L) and a COX inhibitor
on postnatal days 2-7 amplified the risk for IVH. The in-
teractions between the occurrence of IVH, the presence
and treatment of PDA, thrombocytopenia, and the occur-
rence of platelet dysfunction with COX inhibition are com-
plex. There are limitations to a retrospective analysis in
clearly defining and identifying the morbidities and in
the timing of collection of these data in a sequential man-
ner. In other words, it is necessary to have evidence of no
IVH before use of the COX inhibitor and then to have a fol-
low-up demonstrating its occurrence and relationship to
thrombocytopenia. Larger, prospective studies are needed
to determine if this predisposition to IVH during treat-
ment with COX inhibitors in neonates with thrombocyto-
penia is not just another association in premature infants
with PDA. Until such studies are available, it might be
prudent to exercise caution during treatment with COX
inhibitors in premature infants with moderate thrombocy-
topenia.
Caution also needs to be exercised in treatment of an
asymptomatic PDA. Nearly 40% of extremely low birth
weight (and a larger proportion of very low birth weight)
neonates experience spontaneous closure of the ductus
arteriosus at 1 week postnatal age.21,22
Prophylactic or early
presymptomatic treatment may unnecessarily expose these
infants, in whom the ductus might close spontaneously, to
pharmacologic agents and their adverse effects.3
On the other
hand, with advancing postnatal age, delaying treatment could
potentially decrease successful medical closure,23
thereby
increasing the rate of surgical ligation and the complications
associated with surgery.24
The essential question remains to be answered whether
the various morbidities associated with PDA, including
IVH, are in fact caused by the presence of a PDA or if
they are comorbidities manifesting in a sick premature
neonate. n
Mambarambath A. Jaleel, MD
Charles R. Rosenfeld, MD
Division of Neonatal-Perinatal Medicine
Department of Pediatrics
University of Texas Southwestern Medical Center
Dallas, Texas
Reprint requests: Charles R. Rosenfeld, MD, Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, UT Southwestern Medical Center,
5323 Harry Hines Blvd, Dallas, TX 75390-9063. E-mail: charles.rosenfeld@
utsouthwestern.edu
References
1. Friedman WF, Hirschklau MJ, Printz MP, Pitlick PT, Kirkpatrick SE.
Pharmacologic closure of patent ductus arteriosus in the premature in-
fant. N Engl J Med 1976;295:526-9.
2. Chiruvolu A, Jaleel MA. Therapeutic management of patent ductus arte-
riosus. Early Hum Dev 2009;85:151-5.
3. Benitz WE. Treatment of persistent patent ductus arteriosus in pre-
term infants: time to accept the null hypothesis? J Perinatol 2010;
30:241-52.
4. Brunner B, Hoeck M, Schermer E, Strief W, Kiechl-Kohlendorfer U.
Patent ductus arteriosus, low platelets, cyclooxygenase inhibitors,
and intracerebral hemorrhage in very low birth weight preterm infants.
J Pediatr 2013;163:23-8.
5. Mullaart RA, Hopman JC, Rotteveel JJ, Stoelinga GB, De Haan AF,
Daniels O. Cerebral blood flow velocity and pulsation in neonatal respi-
ratory distress syndrome and periventricular hemorrhage. Pediatr Neu-
rol 1997;16:118-25.
6. Bandstra ES, Montalvo BM, Goldberg RN, Pacheco I, Ferrer PL, Flynn J,
et al. Prophylactic indomethacin for prevention of intraventricular hem-
orrhage in premature infants. Pediatrics 1988;82:533-42.
7. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indometh-
acin for preventing mortality and morbidity in preterm infants. Co-
chrane Database Syst Rev 2010;CD000174.
8. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S,
et al. Long-term effects of indomethacin prophylaxis in extremely-
low-birth-weight infants. N Engl J Med 2001;344:1966-72.
9. Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwe W,
Jespers A, et al. Prophylactic ibuprofen in premature infants: a multi-
centre, randomised, double-blind, placebo-controlled trial. Lancet
2004;364:1945-9.
10. Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative
evaluation of the effects of indomethacin and ibuprofen on cerebral per-
fusion and oxygenation in preterm infants with patent ductus arteriosus.
J Pediatr 1997;131:549-54.
11. Slomp J, van Munsteren JC, Poelmann RE, de Reeder EG, Bogers AJ,
Gittenberger-de Groot AC. Formation of intimal cushions in the
ductus arteriosus as a model for vascular intimal thickening. An
immunohistochemical study of changes in extracellular matrix compo-
nents. Atherosclerosis 1992;93:25-39.
12. Chiruvolu A, Jaleel MA. Pathophysiology of patent ductus arteriosus in
premature neonates. Early Hum Dev 2009;85:143-6.
13. Echtler K, Stark K, Lorenz M, Kerstan S, Walch A, Jennen L, et al. Plate-
lets contribute to postnatal occlusion of the ductus arteriosus. Nat Med
2010;16:75-82.
14. Shah NA, Hills NK, Waleh N, McCurnin D, Seidner S, Chemtob S, et al.
Relationship between circulating platelet counts and ductus arteriosus
patency after indomethacin treatment. J Pediatr 2011;158:919-23. e1-2.
15. Sallmon H, Weber SC, Huning B, Stein A, Horn PA, Metze BC, et al.
Thrombocytopenia in the first 24 hours after birth and incidence of pat-
ent ductus arteriosus. Pediatrics 2012;130:e623-30.
16. Lupton BA, Hill A, Whitfield MF, Carter CJ, Wadsworth LD, Roland EH.
Reduced platelet count as a risk factor for intraventricular hemorrhage.
Am J Dis Child 1988;142:1222-4.
17. Norton ME, Merrill J, Cooper BA, Kuller JA, Clyman RI. Neonatal com-
plications after the administration of indomethacin for preterm labor. N
Engl J Med 1993;329:1602-7.
18. Abbasi S, Gerdes JS, Sehdev HM, Samimi SS, Ludmir J. Neonatal out-
come after exposure to indomethacin in utero: a retrospective case co-
hort study. Am J Obstet Gynecol 2003;189:782-5.
19. Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent
ductus arteriosus in preterm infants. Cochrane Database Syst Rev
2003;CD003745.
20. Van Overmeire B, Van de Broek H, Van Laer P, Weyler J,
Vanhaesebrouck P. Early versus late indomethacin treatment for patent
ductus arteriosus in premature infants with respiratory distress
syndrome. J Pediatr 2001;138:205-11.
July 2013 EDITORIALS
9

3. 21. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prev-
alence of spontaneous closure of the ductus arteriosus in neonates at
a birth weight of 1000 grams or less. Pediatrics 2006;117:1113-21.
22. Thankavel PP, Rosenfeld CR, Christie L, Ramaciotti C. Early echocardio-
graphic prediction of ductal closure in neonates /=30 weeks gestation. J
Perinatol 2013;33:45-51.
23. Hermes-DeSantis ER, Clyman RI. Patent ductus arteriosus: pathophysiol-
ogy and management. J Perinatol2006;26(Suppl1):S14-8. discussionS22-3.
24. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neu-
rosensory impairment after surgical closure of patent ductus arteriosus
in extremely low birth weight infants: results from the Trial of Indo-
methacin Prophylaxis in Preterms. J Pediatr 2007;150:229-34. 34 e1.
Optimizing Newborn Screening for Congenital Adrenal Hyperplasia
C
lassic congenital adrenal hyperplasia (CAH), caused
by steroid 21-hydroxylase (CYP21) deficiency, occurs
in 1 in 16 000-20 000 births. Approximately 75% of
these infants have the severe salt-wasting form of the disease
that, if not promptly diagnosed and treated, can cause death
in early infancy from shock, hyponatremia,
and hyperkalemia. The remaining infants
have a somewhat-milder form, without significant electrolyte
abnormalities, called simple virilizing CAH. Whereas affected
female infants usually have ambiguous genitalia, male infants
appear normal and are thus more difficult to diagnose.
Therefore, in the US, newborn screening has been adopted
in all 50 states and in many other countries since it was first
proposed in 19771
(reviewed in White2
). By identifying
infants with salt-wasting CAH before they develop adrenal
crises, screening reduces morbidity and mortality, particu-
larly among male infants. Screening is performed on the
same dried blood spots as are obtained for screening
metabolic defects. The initial testing usually is performed
with a commercially available dissociation-enhanced
lanthanide fluoroimmunoassay (DELFIA; PerkinElmer,
Waltham, Massachusetts) to detected increased levels of
17-hydroxyprogesterone (17-OHP), the most abundant sub-
strate for the CYP21 enzyme.
The challenges for any screening program are to maximize
both sensitivity (the proportion of positive tests among all
individuals who actually have the condition) and positive pre-
dictive value (the proportion of true positive tests among all
positive tests). To obtain sensitivity close to 100%, most
screening laboratories use cut-off levels for 17-OHP that are
so low that $1% of all tests are reported as positive. Because
CAH is a rare disease, the positive predictive value is obviously
verylow—also $1%—eventhoughthespecificity(thepropor-
tion of negative tests among all unaffected individuals) is high
(Table).2
Thus, pediatricians and pediatric endocrinologists
are confronted by infants with positive screens at a rate far
exceeding the actual frequency of the disease.
Several factors limit accuracy of these tests. First, levels of
17-OHP are normally high at birth and decrease rapidly dur-
ing the first few postnatal days. In contrast, 17-OHP levels
increase with time in infants affected with CAH. Thus, diag-
nostic accuracy is relatively poor during the first 2 days,
which is when newborns usually are discharged from the hos-
pital. Moreover, premature, sick, or stressed infants tend to
have greater levels of 17-OHP than healthy term infants
and generate many false-positive results un-
less greater threshold values are used.
Several strategies have been used to address these prob-
lems. First, diagnostic accuracy might be improved by screen-
ing a second sample obtained when the infant is a few days
older. This is performed in 9 states, including Texas, which
published its experience in 1998.3
In the article by Chan
et al4
in this issue of The Journal, the authors reported the
last 10 years of their experience in Colorado, supporting
the idea that both sensitivity and positive predictive value
are improved by this approach.
Second, specificity for screening premature infants can be
improved by the use of actual gestational age rather than
birth weight to stratify subjects because 17-OHP levels are
much better correlated with gestational age.5
However, gesta-
tional age generally is not used in the US.
Finally, the specificity of the screening assay itself might be
improved. The DELFIA assay, which is almost universally
used, was reformulated in late 2009 to make it less sensitive
to cross-reacting compounds that tend to circulate at partic-
ularly high levels in premature infants.6
In their report, Chan
et al present useful comparative experience with this assay,
demonstrating that the positive predictive value has indeed
been dramatically improved (from 0.4% to 3.7% for the first
screen alone).
All this notwithstanding, the data provided by Chan et al
do not convincingly demonstrate that a second screen for
CAH should be universally adopted. Colorado has an unusu-
ally low detection rate for its first screen ($1/25 000 for pa-
tients with classic CAH), although this difference from the
usual incidence rate for 1/16 000 is not statistically signifi-
cant. Thus, the high detection rate on the second screen
may simply be attributable to chance. Moreover, if the
main goal of CAH screening is to detect neonates with
the salt-wasting form before they develop potentially
CAH Congenital adrenal hyperplasia
CYP21 Steroid 21-hydroxylase
17-OHP 17-Hydroxyprogesterone
The author declares no conflicts of interest.
0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.02.008
See related article, p 109
THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 163, No. 1
10