In Reply

(1)

week of life. Given the potential dangers of antibiotic treatment to the smallest of these infants, I would suggest that these infants present an opportunity to study the overall risks and beneﬁts of a policy of treating only culture-positive infection.

Figure 3 advocates EOS evaluation of asymptomatic infants born at term, on the basis of inadequate GBS prophylaxis or with rupture of mem-branes$18 hours, in the absence of any indication of chorioamnionitis. These recommendations contradict those contained in the Centers for Disease Control and Prevention 2010 GBS guidelines, and thus present neonatal clinicians with conﬂicting expert opinions, making local care decisions even more difﬁcult.

Overall, the algorithms contained in this statement continue the practice of giving consideration to EOS risk fac-tors in isolation, without consideration of the relative contribution of each risk factor, or the effect of combinations of these factors. Recently, Gabriel Escobar, myself, and colleagues published a large case-control study revisiting in-trapartum risk factors for EOS in the era of GBS prophylaxis.7_{We used}

ob-jective data only to develop a multi-variate model for prediction of EOS among term and late-preterm infants. We validated this model and demon-strated that it can perform better than algorithms based on cutoff values. The model only uses objective data; per-haps most important, we used“highest maternal intrapartum temperature” rather than the clinical diagnosis of chorioamnionitis. The model also accounts for use of all types and time frames of intrapartum antibiotics. This model can be incorporated with an electronic medical record, but a publi-cally accessible risk calculator is now available at http://www.dor.kaiser. org/external/DORExternal/research/ InfectionProbabilityCalculator.aspx.

This model is not meant to be used in isolation, infant clinical status and laboratory values must also be considered, but we hope that it can form the basis of a more effective means of identifying term and late-preterm infants who should be subject to EOS evaluations.

Neonatal EOS evaluation remains a subject of signiﬁcant controversy, and a dangerous one at that, among term infants it is a fairly low incidence, but a very high consequence condition. The COFN statement has given atten-tion to important issues and hopefully will motivate neonatal clinicians to continue to seek safe and effective approaches to EOS risk.

Karen M. Puopolo, MD, PhD

Assistant Professor of Pediatrics, Harvard Medical School, Brigham and Women’s Hospital

REFERENCES

1. Polin RA; Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis.Pediatrics. 2012;129(5):1006–1015

2. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Im-munization and Respiratory Diseases, Cen-ters for Disease Control and Prevention (CDC). Prevention of perinatal group B strep-tococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10): 1–36

3. Escobar GJ, Li DK, Armstrong MA, et al. Neo-natal sepsis workups in infants ./52000 grams at birth: A population-based study.

Pediatrics. 2000;106(2 pt 1):256–263

4. Cotten CM, Taylor S, Stoll B, et al; NICHD Neonatal Research Network. Prolonged du-ration of initial empirical antibiotic treat-ment is associated with increased rates of necrotizing enterocolitis and death for ex-tremely low birth weight infants.Pediatrics. 2009;123(1):58–66

5. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing en-terocolitis.J Pediatr. 2011;159(3):392–397

6. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical anti-biotic treatment is associated with adverse outcomes in premature infants. J Pediatr. 2011;159(5):720–725

7. Puopolo KM, Draper D, Wi S, et al. Estimating the probability of neonatal early-onset in-fection on the basis of maternal risk factors.

Pediatrics. 2011;128(5). Available at: www. pediatrics.org/cgi/content/full/128/5/e1155

doi:10.1542/peds.2012-2302C

Need Clari

ﬁ

cation on

“

Abnormal Labs

”

The clinical report on this topic was fascinating to read. However I have the following observations/concerns. (A) The committee recommends treating with a prolonged course of broad-spectrum antibiotics in well infants who have “abnormal labs.” It is un-clear what is considered as abnormal laboratory result. Is it just 1 abnormal immature-to-total neutrophil ratio or it is abnormal complete blood cell count 1 elevated C-reactive protein? The poor positive predictive value of either of these tests is well documented in published studies. (B) The committee acknowledges the fact prolonged antibiotic course in the neonates can be harmful. Hence, it is important to know how long the antibiotics (7 or 10 days) should be continued in culture-negative infants with initial abnormal and/or C-reactive protein.

Mike Sukumar, MD

Director, Special Care Nursery, West Maryland Memorial Health System

doi:10.1542/peds.2012-2302D

In Reply

We have received 4 letters to the editor1–4 _regarding _the _recently

published clinical report from the Committee on Fetus and Newborn (COFN) titled “Management of Neo-nates With Suspected or Proven Early-Onset Sepsis,”5_{which raise a number}

of important issues. Like the authors of these letters, we are concerned about unnecessary evaluations for

LETTERS TO THE EDITOR

PEDIATRICS Volume 130, Number 4, October 2012 e1055

at Viet Nam:AAP Sponsored on August 28, 2020 www.aappublications.org/news

(2)

sepsis and treatment of asymptomatic infants for an inappropriate length of time. The dangers of prolonged anti-biotic therapy in the preterm pop-ulation are well described.6–8 _Neither

the Centers for Disease Control and Prevention (CDC) guideline on group B streptococcal disease (GBS)9 _{nor the}

COFN clinical report on early-onset sepsis addresses the duration of antibiotic therapy. Furthermore, al-though there are data to support which groups of high-risk infants should receive empirical antibiotics, there are only observational data re-garding the duration of antibiotic therapy in late-preterm and term infants10,11_{and no data in the very low}

birth weight population.

The risk of sepsis in asymptomatic infants with risk factors for sepsis is low but signiﬁcant (0.5%–1.0%).10,12

The major area of uncertainty is the number of days an asymptomatic in-fant born to a woman treated for chorioamnionitis (or other risk fac-tors) should receive antibiotics when the results of the infant’s laboratory studies are abnormal. We would not treat a well-appearing, asymptomatic term infant with a negative blood culture longer than 48 to 72 hours, whose mother was treated for cho-rioamnionitis, even when the infant’s laboratory data are abnormal. Our rationale is as follows. The postnatal blood culture is difﬁcult to interpret when antibiotics have been adminis-tered before delivery. Adjunct tests for neonatal sepsis generally have a high negative predictive value (predicting absence of sepsis) and mediocre positive predictive value for identify-ing infected infants (40% or less).13

Experts might debate if a 40% risk of sepsis is high; however, by 48 to 72 hours of life, a physical examination with normal results in an otherwise well infant should exclude the possi-bility of early-onset sepsis.9 _When

laboratory studies in the infant are normal, we would stop antibiotics by 48 hours. It is worth noting that, in the study by Jackson et al,10_{only 13% of}

asymptomatic infants ($35 weeks’ gestation) had an elevated immature-to-total neutrophil ratio at age 12 hours (with the use of the reference ranges of Manroe). This is the neu-trophil index with the highest sensi-tivity for early-onset neonatal sepsis. In a preterm infant born to a woman with chorioamnionitis, prolonged rupture of membranes (PROM) .18 hours, or inadequately treated ma-ternal colonization with GBS, we sug-gest treatment of 72 hours (and not 48–72 hours) given the higher risk of sepsis in the preterm population and the greater difﬁculty with clinical assessments. The guidance of the COFN to treat preterm infants born to women with PROM .18 hours or women colonized with GBS who re-ceived inadequate (or no) intrapartum antibiotic prophylaxis differs from the CDC GBS guidelines, which recom-mended a limited evaluation but no treatment. COFN made that recom-mendation because of the signiﬁcantly higher risk of infection in the preterm population when those risk factors for sepsis are also present.12

We agree with the Cotten et al that treatment of 48 hours might be an acceptable alternative in the late-preterm infant or term infant. How-ever, that needs to be determined by the treating physician. As stated in the CDC GBS guideline, “This revised al-gorithm is not an exclusive approach to management; variation that incor-porates individual circumstances or institutional preferences may be ap-propriate.” The COFN agrees with that philosophy.

It is also worth emphasizing that the algorithms apply to only a small segment of the neonatal population. In the CDC Active Bacterial Core

surveillance system, the incidence of chorioamnionitis was 3.1% and the incidence of PROM .18 hours was 7.2%.14 _{Furthermore, as noted above,}

only a minority of infants will have an elevated immature-to-total neutrophil ratio by age 12 hours. Therefore, our guidance to treat those infants 48 to 72 hours will only apply to a small subset of the term neonatal pop-ulation. There are also some preterm infants (mostly late preterm infants) who are completely asymptomatic at birth and who remain asymptomatic. Our algorithm applies to those infants. With increasing degrees of pre-maturity, most preterm infants will be symptomatic. In the study by Cordero and Ayers, the average duration of antimicrobial therapy in extremely low birth weight infants with negative blood cultures was 5 6 3 days.15 _We

hope this guidance will reduce the duration of antimicrobial therapy in that population.

Dr Puopolo raises a few other issues we would like to address. The lack of speciﬁcity in the diagnosis of chorioamnionitis is a concern for all practitioners. Until the American Col-lege of Obstetrics and Gynecology arrives at a new deﬁnition, we would follow the recommendation in the 2010 CDC GBS guidelines,“Consultation with obstetric providers to assess whether chorioamnionitis was suspected is im-portant to determine neonatal man-agement.” As noted by Dr Puopolo, the COFN suggests a white blood cell count and differential count at 6 to 12 hours of life in term infants with risk factors for sepsis other than chorioamnionitis (ie, infants born to women who are GBS positive who received inadequate intrapartum antibiotic prophylaxis and infants born after PROM .18 hours). The CDC GBS guideline recommends a limited evaluation (blood culture and white blood cell count and differential count) and observation if there has

e1056 LETTERS TO THE EDITOR

(3)

been inadequate intrapartum antibiotic prophylaxis and PROM.18 hours. In an ideal world where every infant can be observed closely for changes in clinical activity or vital signs, no additional testing should be needed. If close ob-servation of an“at-risk”term infant can be guaranteed with frequent vital signs (every 2–4 hours) for 24 hours, that remains an acceptable alternative to testing. However, in many nurseries, observations occur less frequently and may not identify abnormal clinical signs at the earliest possible time point. A single white blood cell count and dif-ferential count (without a blood cul-ture) is not an unreasonable way to be reassured that the infant is very un-likely to be infected. An abnormal result would prompt a blood culture in the COFN algorithm (and perhaps closer observation), but no treatment. Dr Puopolo notes her recently published article, which provides a formula to estimate the probability of sepsis in infants$34 weeks’gestation.16_{We like}

this approach, and, if validated in other studies, it is likely to decrease the number of sepsis evaluations in that population. Last, Size and colleagues17

suggest an additional biomarker for the diagnosis of sepsis (urinary neutrophil gelatinase associated lipocalin). However, it needs further evaluation in infants with early-onset sepsis. Finally, we have chosen to publish this report as guidance for all practi-tioners who care for ill infants. The COFN wanted to make sure the guid-ance applies to practitioners with varying levels of expertise who care for infants in a wide variety of settings. Revised algorithms are being sub-mitted toPediatricsas an erratum to the clinical report.

Richard A. Polin, MD

Director Neonatology, Columbia University ON BEHALF OF THE COMMITTEE ON FETUS AND NEWBORN, 2011–2012

Lu-Ann Papille, MD, Chairperson Jill E. Baley, MD William Benitz, MD Waldemar Carlo, MD James Cummings, MD Eric C. Eichenwald, MD Praveen Kumar, MD Richard A. Polin, MD Kristy Watterberg, MD Rose Tan, MD Kasper S. Wang, MD Vinod K. Bhutani, MD

doi:10.1542/peds.2012-2302E

REFERENCES

1. Cotten M, Benjamin DK, Clark R, et al. Em-pirical antibiotic therapy for suspected early-onset bacterial sepsis [letter]. Pediatrics. 2012:130(4):xxxx

2. Puopolo K. Response to the American Academy of Pediatrics, Committee on the Fetus and Newborn statement,“Management of neonates with suspected or proven early-onset bacterial sepsis” [letter]. Pediatrics. 2012:130(4):xxxx

3. Sise ME, Parravicini E, Barasch J. Urinary neutrophil gelatinase associated lipocalin identiﬁes neonates with high probability of sepsis [letter].Pediatrics. 2012:130(4): xxxx

4. Sukumar M. Need clariﬁcation on“abnormal labs”[letter].Pediatrics. 2012:130(4):xxxx

5. Polin RA; Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis.Pediatrics. 2012;129(5):1006–1015

6. Cotten CM, Taylor S, Stoll B, et al; NICHD Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants.

Pediatrics. 2009;123(1):58–66

7. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing en-terocolitis.J Pediatr. 2011;159(3):392–397

8. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants.

J Pediatr. 2011;159(5):720–725

9. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010.MMWR Recomm Rep. 2010; 59(RR-10):1–36

10. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis workups in infants

./52000 grams at birth: a population-based study. Pediatrics. 2000;106(2 pt 1): 256–263

11. Jackson GL, Engle WD, Sendelbach DM, et al. Are complete blood cell counts useful in the evaluation of asymptomatic neonates exposed to suspected chorioamnionitis?

Pediatrics. 2004;113(5):1173–1180

12. Ottolini MC, Lundgren K, Mirkinson LJ, Cason S, Ottolini MG. Utility of complete blood count and blood culture screening to diagnose neonatal sepsis in the asymp-tomatic at risk newborn.Pediatr Infect Dis J. 2003;22(5):430–434

13. Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol. 1991;18(2):361–381

14. Van Dyke MK, Phares CR, Lynﬁeld R, et al. Evaluation of universal antenatal screening for group B streptococcus.N Engl J Med. 2009;360(25):2626–2636

15. Cordero L, Ayers LW. Duration of empiric antibiotics for suspected early-onset sep-sis in extremely low birth weight infants.

Infect Control Hosp Epidemiol. 2003;24(9): 662–666

16. Puopolo KM, Draper D, Wi S, et al. Esti-mating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics. 2011;128(5). Avail-able at: www.pediatrics.org/cgi/content/full/ 128/5/e1155

17. Parravicini E, Nemerofsky SL, Michelson KA, et al. Urinary neutrophil gelatinase-associated lipocalin is a promising bio-marker for late onset culture-positive sepsis in very low birth weight infants.Pediatr Res. 2010;67(6):636–640

LETTERS TO THE EDITOR

PEDIATRICS Volume 130, Number 4, October 2012 e1057

(4)

DOI: 10.1542/peds.2012-2302E

2012;130;e1055

Pediatrics

Watterberg, Rose Tan, Kasper S. Wang and Vinod K. Bhutani

James Cummings, Eric C. Eichenwald, Praveen Kumar, Richard A. Polin, Kristy

Richard A. Polin, Lu-Ann Papille, Jill E. Baley, William Benitz, Waldemar Carlo,

In Reply

Services

Updated Information &

http://pediatrics.aappublications.org/content/130/4/e1055.2

including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/130/4/e1055.2#BIBL

This article cites 12 articles, 4 of which you can access for free at:

Subspecialty Collections

b

http://www.aappublications.org/cgi/collection/infectious_diseases_su Infectious Disease

sub

http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ Fetus/Newborn Infant

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

(5)

DOI: 10.1542/peds.2012-2302E

2012;130;e1055

Pediatrics

Watterberg, Rose Tan, Kasper S. Wang and Vinod K. Bhutani

James Cummings, Eric C. Eichenwald, Praveen Kumar, Richard A. Polin, Kristy

Richard A. Polin, Lu-Ann Papille, Jill E. Baley, William Benitz, Waldemar Carlo,

In Reply

http://pediatrics.aappublications.org/content/130/4/e1055.2

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2012 has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it