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blood levels of cytokines with later CP has been reproduced in another cohort of term infants.4

In this issue, Shalak et al7 _{refine this further by}

measuring at various times the association of cyto-kines with proximal neurologic outcomes in critically ill term newborns born to infected mothers. Two chemokines, interleukin-8 and RANTES, were ele-vated and then cleared after clamping of the cord, suggesting origin from the placenta. Interleukin-6 peaked after birth, suggesting endogenous produc-tion by the neonate. The prevalence of neonatal de-pression and tone abnormalities showed a similar decay from time of birth. Hypotonia correlated with postnatally produced interleukin-6 levels. All 3 cyto-kines were most elevated in those infants with hy-poxic-ischemic encephalopathy, consistent with de-tection of multiply elevated cytokine concentrations in term infants who later progressed to CP.

Given these findings, should we be intervening to block the proinflammatory cytokine cascade associ-ated with infection and NE? No. Although this article posits that inflammatory cytokines may directly damage cellular constituents of the brain, the func-tion of cytokines in the CNS is highly complex, de-pends on developmental stage, and differs from that elsewhere in the body.7 _{Inflammatory cytokines,}

such as TNF␣, can be neuroprotective as well as neurotoxic and serve a physiologic role in brain plas-ticity. Meddling with imperfectly understood pro-cesses risks causing harm—“brain-sparing” cyto-kines interleukin-10 and TGF-␤ are associated with neurologic disease when given exogenously.8

The key point here is that we need to recalibrate as clinicians. Maternal or placental infection increases the risk of moderate to severe NE, not just sepsis. Our clinical evaluations of NE should include con-sideration of maternal infection, examination of the placenta, and use of neonatal markers of infection/ inflammation.

Rodney E. Willoughby, Jr, MD Department of Pediatrics

Johns Hopkins School of Medicine Baltimore, MD 21287-4933

REFERENCES

1. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy: multivariate analysis of risk.N Engl J Med.1986;315:81– 86

2. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral palsy.

J Pediatr.2000;112:515–519

3. Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and coagulation factors in children with cerebral palsy.Ann Neurol.

1998;44:665– 675

4. Foster-Barber A, Ferriero DM. Neonatal encephalopathy in the term infant: neuroimaging and inflammatory cytokines.Ment Retard Dev Disabil Res Rev.2002;8:20 –24

5. Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy.JAMA.2000;284:1417–1424

6. Willoughby RE Jr, Nelson KB. Chorioamnionitis and brain injury.Clin Perinatol. 2002. In press

7. Shalak LF, Laptook AR, Jafri HS, Ramilio O, Perlman JM. Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants.

Pediatrics. 2002;110:673– 680

8. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration.Nat Rev Neuroscience.2001;2:734 –744

Infant Formula Safety

ABBREVIATIONS. CDC, Centers for Disease Control and Preven-tion; NICU, neonatal intensive care unit; FDA, Food and Drug Administration; ADA, American Dietetic Association.

I

n the April 12th issue ofMorbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention (CDC) reported on a fatal case of meningitis in an intensive care nursery in Tennes-see.1_{The infecting organism was}_Enterobacter

sakaza-kii, an unusual but often fatal, invasive pathogen. In the fatal Tennessee case, the infection was traced to contaminated powdered infant formula. Other in-fants in the same nursery were screened for E saka-zakii. Of 49 screened infants, 10 events were discov-ered (1 proven infection, 2 assumed infections, and 7 colonizations).E sakazakiihas been reported to cause or be associated with bacteremia,2,3 _necrotizing

en-terocolitis,4 _meningitis,5,6 _{and colonization.}7 _There

are also reports of E sakazakii contaminating infant formula8 –10_{; however, this report detailed for the}

first time a direct link to an unopened product. The manufacturer voluntarily recalled the contaminated batch of powdered formula identified as the source. The editorial comment after the report, pointed out that powdered infant formula is not sterile. The CDC concluded its report with the following recommen-dations for the use of powdered infant formula in the neonatal intensive care unit (NICU): 1) use alterna-tives to powdered formula whenever possible, 2) use aseptic technique in the preparation of infant for-mula, 3) refrigerate prepared formula and discard any reconstituted formula stored for longer than 24 hours, 4) limit ambient temperature “hang time” to no⬎4 hours, and 5) have written guidelines on how to deal with a manufacturer’s recall.

In a letter addressed to “Health Care Profession-als” and dated April 11, 2002, the Food and Drug Administration (FDA) outlined the problems withE sakazakii and other organisms with respect to pow-dered infant formula11_{(www.cfsan.fda.gov/}_⬃_dms/

inf-ltr3.html). The FDA published its own set of rec-ommendations similar to the CDC’s, but added that small quantities of formula should be made up at a time and that boiling water should be used to recon-stitute powdered formulas.

Infant formula, like no other food, is regulated by its own law, the Infant Formula Act of 1980 as amended in 1986. The act sets lower limits on 29 nutrients (so called “table nutrients” because they appear in table form. US Code of Federal Regulations 21 CFR 107.100). It requires that the formula supports normal growth and that contents are clearly labeled. Manufacturers are required to follow “good manu-facturing practice,” but no requirement for sterility is specified. In fact, the FDA performs bacterial counts

Received for publication Aug 15, 2002; accepted Aug 15, 2002.

Reprint requests to (R.D.B.) Digestive Disease and Nutrition Center, Chil-dren’s Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222. E-mail: rbaker@upa.chob.edu

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on infant formula, and up to 10 000 colony forming units per gram powder are acceptable. Powdered formula is not guaranteed nor required to be free of pathogenic organisms.

Powdered formula is made from pasteurized (ie, sterile) liquid that is then freeze-spray dried into a powder. It is possible for organisms to be introduced in the final stages of production. The preparation of infant formula for special care nurseries within insti-tutions is not regulated by law. The most widely followed guidelines are those of the American Die-tetic Association (ADA) issued in 1991 and amended since the E sakazakii warning12 _{(www.eatright.org/}

formulaguide.html). These guidelines are presently being reviewed and updated. The amended guide-lines suggest using ready-to-feed or concentrated formulas rather than powdered formulas in neonatal intensive care nurseries. As they stand, the guide-lines call for the use of aseptic technique in a desig-nated formula preparation room. The guidelines call for the refrigeration of prepared formula so that a temperature of 2° to 3°C is reached by 4 hours after reconstitution.

The recommendation to use boiling water (recom-mended by the FDA but not the CDC) is controver-sial. First, adding boiling water may not accomplish the job of killing E sakazakii13 _{or other organisms.}

Second, boiling water certainly alters the ingredients of the formula, destroying an unknown amount of vitamins, and possibly also altering other substances such as proteins. It is not clear to what extent boiling water will alter the formulas or if formula mixed in boiling water will meet the requirements of the In-fant Formula Act. Third, boiling water changes the dissolution characteristics of the formula causing it to clump. Fourth, these recommendations cannot be applied to Human Milk Fortifier, because it is gen-erally added as a powder directly to mother’s milk. Finally, adding boiling water directly to powdered formula may endanger those preparing the formula. Most formula labs are not equipped to perform this maneuver, risking spills and burns. The risks of us-ing boilus-ing water to reconstitute powered formula outweigh the benefits. This recommendation is not supported.

There is an urgent need to minimize the dangers and insure the safety of formulas given to infants. Improvement should start with the manufacturing process. Manufacturers should explore new methods or change present practices that could assure sterility at the end of production (eg, irradiation). The clean-liness and practices of formula labs need to be exam-ined, improved when necessary, and undergo con-tinuing monitoring by an established process. As a consequence of the additional scrutiny given formula labs, it is clear that a greater level of oversight is necessary. When Joint Commission reviews hospitals for accreditation, formula labs should be an element included for inspection. For the present, institutions should assure that formula labs are adhering to the ADA guidelines. Premature infants in the intensive care setting do not exist in a sterile environment. Yet the risk of introducing an infecting organism in for-mula at the time of administration can be reduced.

Nursing units should review and update policies and procedures regarding the administration of en-teral feeds. Hygienic handling of delivery systems at the bedside, limiting “hang-time” to 4 hours and avoiding open delivery systems will decrease the risk of contamination.

The recommendations by the CDC and the FDA pertain to intensive care nurseries only, suggesting that these vulnerable infants are at most risk. Present practice leads to early discharge from the NICU, so a significant number of premature infants are being cared for at home. Should the precautions be ex-tended to this group? A few term infants will be immune compromised. Are they at risk and can they be identified? Perhaps newborns could be protected from enterically introduced pathogens in other ways—for example, probiotics or prebiotics.

A number of problems and questions have been brought to the forefront by theE sakazakiiissue that require urgent answers: 1) No universally followed standards exist for formula labs. Physicians should take the lead in examining their institutions’ formula lab policies and should work with clinical nutrition departments and pharmacies to develop standard-ized policies and procedures for formula preparation and handling. Surveillance policies should also be developed to monitor quality and safety of formulas prepared and used in hospitals. The present ADA guidelines should be updated, but for now, offer practical guidance. 2) Infant formula needs to be handled in a way to reduce the chance of infection. This starts with the manufacture and finishes with the way the formula is administered. 3) The CDC and FDA recommendations, if implemented, will im-prove the safety of formula feeding in the NICU. The preponderance of evidence does not support using boiling water as recommended by the FDA. 4) It is presently unknown whether powdered formula con-tamination effects groups other than premature in-fants in NICUs. Other populations need to be studied and new ways of protecting all infants from food-borne diseases sought.

Robert D. Baker, MD, PhD

Digestive Disease and Nutrition Center Children’s Hospital of Buffalo

Buffalo, NY 14222

REFERENCES

1. Enterobacter sakazakii infections associated with the use of powdered infant formula—Tennessee, 2001.MMWR Morb Mort Wkly Rep.2002;51: 297–299

2. Monroe PW, Tift WL. Bacteremia associated withEnterobacter sakazakii

(yellow-pigmented Enterobacter cloacae). J Clin Microbiol. 1979;10: 850 – 851

3. Gallagher P. Enterobacter bacteremia in pediatric patients.Rev Infect Dis.1990;12:808 – 812

4. Van Acker J, De Smet F, Muyldermans G, Bougatef A, Naessens A, Lauwers S. Outbreak of necrotizing enterocolitis associated with Enter-obacter sakazakiiin powdered milk formula.J Clin Microbiol.2001;39: 293–297

5. Wolf MA, Young CL. Antibiotic therapy for Enterobacter meningitis: a retrospective review of 13 episodes and review of the literature.Clin Infect Dis.1993;16:772–777

6. Willis J, Robinson JE. Enterobacter sakazakii meningitis in neonates.

Pediatr Infect Dis J.1998;7:196 –199

7. Arseni A, Malamou-Ladas E, Koutsia C, Xanthou M, Trikka E. Outbreak

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of colonization of neonates with Enterbacter sakazakii. J Hosp Infect.

1987;9:143–150

8. Muytjens HL, Roelofs-Willemse H, Jaspar GHJ. Quality of powdered substitutes for breast milk with regard to members of the family Enter-obacteriaceae.J Clin Microbiol.1988;26:743–746

9. Nazarowec-White M, Farber JM. Incidence, survival and growth of

Enterobacter sakazakiiin infant formula.J Food Protect.1997;60:226 –230 10. Simmons BP, Gelfand MS, Haas M, Metts L, Ferguson J.Enterbacter

sakazakiiinfections in neonates associated with intrinsic contamination of a powdered infant formula.Infect Control Hosp Epidemiol.1989;10: 398 – 401

11. Taylor CJ. Health professionals:Enterobacter sakazakiiinfections

associ-ated with the use of powdered (dry) infant formulas in neonatal inten-sive care units [letter]. April 11, 2002. US Food and Drug Administra-tion, Center for Food Safety and Applied NutriAdministra-tion, Office of Nutritional Products, Labeling and Dietary Supplements. Available at: www.cfsan.fda.gov/⬃dms/inf-ltr3.html

12. American Dietetic Association. Preparation of formula for infants: guidelines for health-care facilities. Chicago, IL: American Dietetic Association; 1991. Abbreviated version, updated April 2002. Available at: http://www.eatright.org/formulaguide.html

13. Nazarowec-White M, Farber JM. Thermal resistance of Enterobacter sakazakiiin reconstituted dried-infant formula.Letters Appl Microbiol.

1997;24:9 –13

SUPERFECUNDITY IS BASIC FOR EVOLUTION

“The basic formulation of natural selection is a disarmingly simple argument based on three undeniable facts (overproduction of offspring [superfecundity is Darwin’s lovely term], variation, and heritability) and one inference (natural selection, or the claim that organisms enjoying differential reproductive success will, on average, be those variants that are fortuitously better adapted to changing local environments, and that these variants will then pass their favored traits to offspring by inheritance.”

Gould SJ.The Structure of Evolutionary Theory. Harvard University Press; 2002

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DOI: 10.1542/peds.110.4.833

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