RE: Overall PostneonatalMortality and Rates ofSIDSGoldstein et al discuss sudden infantdeath syndrome (SIDS) in the contextof overall postneonatal mortality(PNNM). However, their definition ofSIDS is incorrect, and they makequestionable choices in constructingcomposite groupings of unknowncauses and circumstantial respiratorycauses, which they combine with SIDSfor a cumulative unexplained infantdeath composite. If they rereadWillinger et al1 more closely theywould see that “There wasconsiderable discussion of whethertwo definitions should be drafted, onefor administrative purposes to be usedby medical examiners or coroners, andone for research [page 678].” To avoidconfusion, Willinger et al agreed that asimple definition of SIDS would bedrafted with accompanying statementsto guide research scientists, which ledto the upper cutoff of exactly 1 year ofage; this cutoff was chosen because ofthe higher likelihood of false-positiveSIDS cases occurring at age .1 yearcontaminating the actual SIDS cases.1 year of age. Indeed, they cited aEunice Kennedy Shriver NationalInstitute of Child Health and HumanDevelopment Collaborative SIDS Studyin which 2% of the cases occurred at.1 year of age.

In their Table 1, Goldstein et al failedto include the International Classificationof Diseases, 10th Revision, causes ofPNNM from severe birth asphyxia(P21.0) and birth asphyxia, unspecified(P21.9), perhaps because theyassumed birth asphyxia did not lead toPNNM. In addition, a new InternationalClassification of Diseases, 10th Revision,code was introduced in 2006 forhypoxic-ischemic encephalopathy(P91.6) for cases that previously werecoded as P21.9. These PNNM cases arehighly relevant because they may berelated to the intrinsic vulnerability ofthe neural abnormalities of the triplerisk model (TRM) that the authors citeas a possible cause of SIDS. The TRM

posits interactions between anunderlying intrinsic vulnerability, acritical development period, andextrinsic factors in the infant’senvironment. There is no criticaldevelopment period (the “legal fiction”of a 12-month cutoff notwithstanding),as the full age distribution of SIDSextends from birth up to 3.5 years asmodeled by a single equation.2 Also,SIDS cases do occur without anyextrinsic risk factors, as reported for asudden unexpected death of anapparently healthy child put to sleepsupine and found dead in the identicalsupine position with face completelyuncovered.3 If a lung culture had notbeen taken by Dr Sidney Farber(eponymous of Dr Goldstein’sinstitution), the cause of death wouldhave been given as “suffocation,ʺ4 andif the culture results were sepsisnegative, it also would have beencalled “SIDS” today without anyextrinsic factor present.5

David T. MageHealth Scientist World Health Organization

(retired)

Eva M. DonnerGenetic Toxicologist

E-mail: magedonner@aol.com

Conflict of Interest: None declared

REFERENCES

1. Willinger M, James LS, Catz C. Defining thesudden infant death syndrome (SIDS):deliberations of an expert panel convenedby the National Institute of Child Healthand Human Development. Pediatr Pathol.1991;11(5):677–684

2. Mage DT. A probability model for the agedistribution of SIDS. J Sudden InfantDeath Syndrome and Infant Mortality.1996;1(1):13–31

3. Farber S. Fulminating streptococcusinfections in infancy as a cause of suddendeath. N Engl J Med. 1934;211:154–158

4. Brooks EG, Gill JR; National Association ofMedical Examiners NAME Ad HocCommittee for Bioterrorism andInfectious Disease. Testing for infectiousdiseases in sudden unexpected infantdeath: a survey of medical examiner andcoroner offices in the United States. JPediatr. 2015;167(1):178–182.e1

5. Phua J, Ngerng W, See K, et al.Characteristics and outcomes of culture-negative versus culture-positive severesepsis. Crit Care. 2013;17(5):R202

doi:10.1542/peds.2016-1592A

RE: Overall PostneonatalMortality and Rates ofSIDSWe read with interest the recentpaper by Goldstein et al1 in whichthe authors compared the overallpostneonatal mortality rates withthose of sudden infant deathsyndrome (SIDS), and thecommentary on this article by Moonand Hauck,2 which appeared in thisjournal. We were surprised at thepaucity of reference to the role ofinfection. We draw attention to thefact that while a study of riskfactors, although important, doesnot necessarily provide a cause, inour opinion, linking risk factorswith potential causes of a givencondition deserves seriousconsideration.

In a comment we made recently3

discussing bed-sharing (anestablished risk factor for SIDS), wenote how the “The parental bed orsofa represents a dangerous sleepingsurface, as both of these are heavilycontaminated with bacteria such asEscherichia coli and Staphylococcusaureus which are equipped with avariety of lethal toxins” that areknown to be shed by adults. Weestablished a mouse model for SIDS,4

in which we found that 4 apparentlyhealthy pups of 37 pups of thechallenged mice died unobservedovernight aged between 17 and 21days but no pups of the 54 controlmice died suddenly (P 5 .0247,Fisher’s exact test). These weconsidered to represent suddenunexpected death. We combinedthese microbiologic studies with theepidemiologic investigations on SIDS5

and from these studies were able toconclude “that the risk factors of bed-sharing, and smoke exposure, prone

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sleep position and alcohol can beexplained by the theories of amicrobiological infection model ofSIDS pathogenesis.” Most recently6 asa further confirmation, we found that:“Gut microbiome in sudden infantdeath syndrome (SIDS) differs fromthat in healthy comparison babiesand offers an explanation for the riskfactor of prone position.” Wetherefore consider that a role ofinfection in SIDS should have beentaken far more seriously than it wasin the studies under question. Theseviews have been presented recently.7

Few researchers have taken intoaccount features of SIDS (bothanatomic pathologic and laboratoryfindings) such as organ weightabnormalities, vasculopathy, andraised fibrin degradation productsthat adhere congruently to aninfection model of SIDS.

Karl A. Bettelheim, PhD, FRCPathMicrobiologist, University of Melbourne

(retired)

Paul N. Goldwater, FRACP, FRCPAE-mail: bettelheim@talktalk.net

Conflict of Interest: None declared

REFERENCES

1. Goldstein RD, Trachtenberg FL, Sens MA,Harty BJ, Kinney HC. Overall postneonatalmortality and rates of SIDS. Pediatrics.2016;137(1):1–10

2. Moon RY, Hauck FR. SIDS risk: it’s morethan just the sleep environment.Pediatrics. 2016;137(1):e20153665

3. Goldwater PN, Bettelheim KA. Re: Bedsharing when parents do not smoke: isthere a risk of SIDS? An individual levelanalysis of five major case-control studies.BMJ Open Access Research. Available at:http://bmjopen.bmj.com/content/3/5/e002299/reply#bmjopen_el_7003

4. Bettelheim KA, Luke RK, Johnston N, PearceJL, Goldwater PN. A possible murine modelfor investigation of pathogenesis of suddeninfant death syndrome. Curr Microbiol.2012;64(3):276–282

5. GoldwaterPN, Bettelheim KA. SIDS riskfactors: time for new interpretations. Therole of bacteria. Pediatr Res Int J. 2013;(2013). Article ID 867520

6. Highet AR, Berry AM, Bettelheim KA,Goldwater PN. Gut microbiome in suddeninfant death syndrome (SIDS) differs fromthat in healthy comparison babies andoffers an explanation for the risk factor ofprone position. Int J Med Microbiol. 2014;304(5–6):735–741

7. Bettelheim KA, Goldwater PN. Escherichiacoli and sudden infant death syndrome.Front Immunol. 2015;6:343

doi:10.1542/peds.2016-1592B

Author’s Response

RE: Overall PostneonatalMortality and Rates ofSIDSIn reply to Mage and Donner, thereare indeed limitations to theoperational 1-year cutoff for suddeninfant death syndrome (SIDS) and, infact, our group has brought forthresearch challenging age conventions.However, the general Pediatricsreadership understands definitions asthey are conventionally used, and wedid not believe our analysis wascompromised by using terms as theyare generally understood. Regardingthe diagnoses included in the analyticcomposites, there is room for debateabout what might be best included.We do not agree with the point aboutintrapartum asphyxia codes, however.We understood intrapartum asphyxiacodes as being applied with the intentof capturing a specific mechanism ofdeath observed during delivery,which would make the cause ofmortality explained and thus outsideof the analytic composite. As for the“fiction” of the developmental period,our interest was to faithfully presentthe theory as proposed by Filiano andKinney.2 Finally, we recognize thatsudden unexpected death can occurwithout an extrinsic stressor, anobservation made by the estimableDr Farber but by others as well.3 Ourgroup, Robert’s Program on SuddenUnexpected Death in Pediatrics, isdedicated to approaching SIDS as anundiagnosed disease, and we believe

that many unexplained deaths remainso because they are not fullyexplored. We believe our perspectiveis also shared by many coroners andmedical examiners responsible formaking the diagnosis.

In reply to Goldwater and Bettelheim,we do not disagree that infectiousand/or immunologic etiologies are animportant part of the puzzle of SIDS.Furthermore, we strongly agree thatlinking risk factors with potentialcauses of a given condition deservesserious consideration. Our groupdevotes considerable energy towardreconciling the pathologic andlaboratory findings with the outcomeof SIDS. Insofar as our list ofpotentially contributing causes wasincomplete, it was due to the fact thatit was not the focus of our research.As such, only a few such causes werementioned as plausible exampleswhen bringing forth our conclusion ofbiological underpinnings reflected inepidemiologic trends. Goldwater andBettelheim make a fair point,although the same could be saidabout the use of routine paralysis ofventilated newborns, for example. Wethank them for making this aspect ofour article clearer.

Richard D. GoldsteinPalliative Care Pediatrician, Boston Children’s

Hospital, Dana-Farber Cancer InstituteE-mail: richard_goldstein@dfci.harvard.edu

Conflict of Interest: None declared

REFERENCES

1. Goldstein RD, Trachtenberg FL, Sens MA,Harty BJ, Kinney HC. Overall postneonatalmortality and rates of SIDS. Pediatrics.2016;137(1):1–10

2. Filiano JJ, Kinney HC. A perspective onneuropathologic findings in victims of thesudden infant death syndrome: the triple-risk model. Biol Neonate. 1994;65(3–4):194–197

3. Kinney HC, McDonald AG, Minter ME, BerryGT, Poduri A, Goldstein RD. Witnessed sleep-related seizure and sudden unexpecteddeath in infancy: a case report. ForensicSci Med Pathol. 2013;9(3):418–421

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