J Clin Pathol 1984;37:283-287

Small intestinal mucosal abnormalities inpost-perinatal deathsS VARIEND, R SUNDERLAND

From the Department of Pathology, Children's Hospital, Western Bank, Sheffield SIO 2TH

SUMMARY Examination of small intestinal mucosa from cases of post-perinatal death in Sheffieldbetween September 1980 and September 1981 showed mucosal changes before death in 18 of 78cases (20%). There was no significant difference in prevalence between explained and unex-plained deaths, nor was there any positive association with viral isolation from the small intestine.The lesion was much more common in males than females and showed a strong association withbottle feeding-no infant wholly breast fed showed an enteropathy. There was a low incidence ofsymptoms referrable to the gastrointestinal tract among affected infants, and no appreciableevidence of failure to thrive, as reflected by the postmortem body weight, was present.

Mucosal changes of the small intestine in cases of sudden infant death syndrome have previ-ously been reported and attributed to heatstroke. Although the finding of similar lesions ininfants who died explicably does not appear to support this view, overheating is difficult toexclude as most of the explained deaths with a mucosal lesion occurred at home.

Small intestinal mucosal abnormalities in childrenare fairly well documented and their pathogenesesare complex. Although the basis of considerablemorbidity, they are rarely, if ever, directly related tothe cause of death. Small bowel changes are infre-quently reported in postmortem material, and thismay be largely due to difficulty with histologicalevaluation in the presence of autolytic change.Postmortem mucosal abnormalities of the smallintestine have been reported in cases of suddeninfant death syndrome,' where they have been attri-buted to heatstroke.

Standardised sampling from the small intestinewas used in this investigation, and an attempt wasmade to determine the frequency, extent, and poss-ible aetiology of enteropathic changes in infantdeaths. The study was prospective and tissues wererapidly fixed in formalin to minimise autolysis.

Material and methods

All infants between the ages of one week and oneyear dying between September 1980 and September1981 and examined in the department of pathologyat the Sheffield Children's Hospital were included inthis study. The time interval between death and nec-ropsy varied from 2-0 to 96 h with a mean of 39-9 h.

Accepted for publication 3 November 1983

Postmortem body weights were plotted on Tannerand Whitehouse percentile charts.The Sheffield paediatric necropsy includes three

standard blocks of small intestine: proximaljejunum, mid-jejunum, and terminal ileum. Ilealcontent was removed aseptically for bacterial cul-ture and was also examined for viruses by electronmicroscopy using negative staining. Paraffin embed-ded tissue was sectioned and stained withhaematoxylin and eosin.

Enteropathic lesions were classified into threegrades based on the degree of villous blunting: (+)mild villous blunting (Fig. la); (+ +) moderate vill-ous blunting (Fig. Ib); (+ + +) severe or total villousblunting (Fig. 1c). Cases were included only ifmucosal changes could be clearly distinguished fromautolytic change, and areas showing oblique section-ing or containing mucosal lymphoid tissue wereavoided. Clinical details were abstracted from hospi-tal records or coroners' statements.

Eighty seven infants were studied, including 24 inwhom death could be explained; this comprised 11severe congenital malformations, eight infections,four trauma/asphyxia, and one tumour. The birthweight was available in 61 (70%) of the cases, and inseven ( 11%) of these the weight was less than 2500g. The reason for the proportionately large numberof inexplicable deaths in this series is that thepathology service at the Sheffield Children's Hospi-tal covers all home deaths in the whole of south

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284 Variend, Sunderland

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\Fig. 1 (a) Grade I mucosa with a mild* degree ofshortening of villi. Surface

epithelium is cuboidal. There is no obviousincrease in lamina propria cellularity.(Haematoxylin and eosin. Original

i4 ' magnification x 128). (b) Grade 11 mucosa witi

covered by flattened epithelium.(Haematoxylin and eosin. Original

.~~~~~~~~~ ~,Amagnification x 128). (c) Flat mucosa (gradei111) with surface epithelium still intact inFj1|-tw ic.<iplaces. (Haematoxylin and eosin. Original>,,, 4omagnification x 128).

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Small intestinal mucosal abnormalities in post-perinatal deaths

Yorkshire whereas explicable deaths largely occur-red at this hospital.

Results

Mucosal changes were present in 18 infants (fourexplicable, 14 inexplicable deaths). Details of ter-minal symptoms and severity of small intestinalmucosal changes are given in the Table. Only four ofthe 18 had symptoms directly referrable to the gas-trointestinal tract. Three infants with enteropathywho died suddenly and inexplicably had no preced-ing symptoms. In the remainder, symptoms werediverse and non-specific and the degree ofenteropathy bore no relation to the type of symp-toms. Variable villous blunting and flattening of thesurface epithelium characterised the mucosal lesion.These changes were found in 14 of 49 males (28%)and four of 38 females (10%), a significant differ-ence (X2 = 4-25, df = 1, p < 0.05). Lamina propriacellularity was variable and ranged from being mod-erately increased to slightly depressed. Cryptepithelial degeneration with cellular debris in cryptlumina was an associated feature in 12 of theabnormal mucosae. Although mucosal changes weremore or less uniformly distributed along the lengthof the small intestine, they occasionally tended todominate distally (Fig. 2).No bacterial pathogen was isolated from any

child, but viruses were found in 12 (adenovirus infive, rotavirus in three, calcivirus in two, small virus

Symptoms related to degree of villous abnormality

Case no Symptoms Grade ofenteropathy

1 Found pale, limp and grey +2t Vomiting for 3 weeks +3 None ++4 Cough and "cold' for few days +5 Sleeping poorly/crying a lot for 3 days ++ +6 Found bleeding and rothing at mouth + + +7* Moaning for"few" hours +++

(gastroenteritis)8* grying, reluctant to feed (congenital +

heart disease)9 Slight cold for 5 days + +10t (Previously found ashen) abdominal +

pain for 1 da11 Apnoeic spe s since birth (premature) +12 None +13*t Diarrhoea and vomiting for 3 weeks,

then "cold"' for 1 week (pneumonia) + +14 (Previous meningitis) Crying a lot + +

night before15t Anorexia and vomiting for 24 h +++16 None ++17* Irritable, pyrexia, poor feeding 1 + +

day (meningitis)18 Found"unwelir +++

*Explicable deaths with a mucosal lesion.tSymptoms related to gastrointestinal tract.

Case No

234

56789101112131415161718

Prox Mid Distal

N + *+ *

++ *++ ++N +

N +++

++N

+N

++N

++++

++ ++++ ++

++++ *+ *

++ *+++++ *++ *++ *++ *

Fig. 2 Distribution ofthe degree ofvillous abnormality bygrade is shown at the three levels examined. Prox =proximal jejunum; Mid = mid-jejunum; Distal = terminalileum. Cases with crypt epithelial degeneration are indicatedby an asterisk.

in one, and one child had both rotavirus andadenovirus); adenovirus and rotavirus were eachfound in two unexplained cdeaths with enteropathy,while rotavirus, calcivirus, and adenovirus werefound in six unexplained deaths withoutenteropathy. Rotavirus, adenovirus, a small virus,and a calcivirus were each found in four explicabledeaths with enteropathy. The mean interval fromdeath to necropsy of those with a virus was 35.9 h(range 7 h 15 min-96 h) and those without a viruswas 32-1 h (range 2 h-82 h 30 min). The intervalsare not significantly different (t = 0-519, p > 0.5).

Feeding histories were available in 66 cases. Tenwere wholly breast fed (no enteropathy), eight werebreast fed and bottle fed (one with enteropathy),and 48 were wholly bottle fed (17 withenteropathy); these differences are statisticallysignificant (X2 = 6-235, df = 2, p < 0.05). Postmor-tem body weights plotted on percentile charts areshown in Fig. 3. One female with enteropathy had abody weight just below the third percentile for ageand, while four males with enteropathy had bodyweights below the third percentile, two had birthweights less than 2500 g.The four cases in which death was explicable and

which were associated with enteropathy includedpneumonia, congenital heart disease, (Ivemark'ssyndrome with an ostium primum defect), gastro-enteritis with severe dehydration, and one case

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Fig. 3 Postmortem weights on Tanner and Whitehousepercentile charts for females and males: solid circle refers tothose without a mucosal lesion; a cross refers to those with a

mucosal lesion. Age range I week to 1 year.

of Down's syndrome complicated by short seg-ment Hirschsprung's disease and meningitis. Theinfant with Down's syndrome died in hospital, whilethe remainder were home deaths. No bacterialpathogen or virus was isolated after death from theinfant with gastroenteritis and there was no evi-dence of necrotising enterocolitis in the child withHirschsprung's disease.

Discussion

We are unaware of other studies which haveexamined necropsy material from infants eitherprospectively or blind. The increased incidence ofthe enteropathy among males was significant, andalthough the male is the weaker gender,2 we do notknow of any mechanism that lowers the protectionof the gut which is mediated by gender. Enteropathyof the small bowel was significantly associated withartificial feeding. Small bowel mucosal changes arefound in infants with cows' milk protein sensitivity,3and fatal anaphylactic reactions have been associ-ated with that condition.4 Mucosal damage in coeliacdisease predominates in the proximal small bowel,5

Variend, Sunderland

and, although a similar situation is likely to apply inother forms of dietary protein intolerance, theextent of the mucosal lesion in cows' milk proteinsensitivity has not, unfortunately, been adequatelystudied. Lack of any important gastrointestinalsymptoms preceding the deaths of these infants,however, and the absence of any appreciable weightloss, as reflected by postmortem body weight, tendto rule against a dietary protein intolerance ofappreciable duration. Only one female infant withan enteropathy showed a postmortem body weightbelow the third percentile and, although there werefour such male infants, two had low birth weightsand their postmortem body weights may reflect adelay in catch up growth.

This investigation and one by Stanton et allemphasise the feature of crypt epithelial change withaccumulation of cellular debris in the crypt lumina,which is dissimilar to the pattern usually describedwith cows' milk protein sensitivity as assessed onbiopsy material in life. Stanton et al found cryptepithelial degeneration of the small bowel mucosa ineight of the 33 cases of otherwise unexplaineddeaths, five of which had overwhelming clinical evi-dence of overheating from excessive clothing or overwrapping. They also referred to a previous report6 inwhich five infants were thought to have succumbedto heatstroke for similar reasons and in whom themucosal changes were more advanced and includedvillous flattening and blunting.As far as we know, viruses identified by electron

microscopy in postmortem bowel content have notbeen previously reported; with this technique, vir-uses were identified in 15% of the entire group.There was no significant difference in the time fromdeath to necropsy between the group with and thegroup without viruses and postmortem autolysis istherefore unlikely to have underrated the actualnumber of viruses present in life. Of the 12 caseswith viruses, only two had a mucosal lesion and in nocase with virus were enteric symptoms present. Thusmucosal change appears to be unrelated to the pres-ence of any of the commonly recognised enteric vir-uses.A postmortem study in which the small bowel was

studied stereologically showed villous malformationmainly distributed in the proximal part7 and a biopsyinvestigation among live infants with clinical gas-troenteritis did not describe crypt epithelial changesof the type seen here,8 presenting further evidencethat the mucosal lesion referred to is unlikely tohave an infective basis.The causes of the four explicable deaths with

mucosal changes were diverse, and it is, of course,quite possible that the lesion is of heterogeneousaetiology. On the other hand, the significant associa-

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Small intestinal mucosal abnormalities in post-perinatal deaths

tion with bottle feeding and the preponderance ofmales does suggest a specific mode of injury. Theslightly increased incidence of the mucosal lesionamong the unexplained deaths was not significantand is therefore probably not causally related to thesudden infant death syndrome. Since three of theexplained deaths with the mucosal lesion occurred athome, however, it would be difficult totally toexclude overheating as having had a role inpathogenesis.

We are grateful to Mr SR Penny for carrying outvirological studies and to Mrs BP Wilson for typingthe manuscript.

References

Stanton AN, Scott DJ, Downham MAPS. Is overheating a factorin some unexpected infant deaths? Lancet 1980;i: 1054-7.

2 Taylor DC. The influence of sexual differentiation in growthdevelopment and disease. In: Davies J, Dobbing J, eds. Sci-entific foundations of paediatrics. London: Heinemann,1974:19-44.

3 Fontaine JL, Navaro J. Smail intestinal biopsy in cows' milk pro-tein allergy in infancy. Arch Dis Childh 1975;50:357-62.

4 Coombs RRA, McLaughlan P. The enigma of cot deaths: is themodified anaphylaxis hypothesis an explanation for somecases? Lancet 1982;i: 1388-9.

Creamer B, Leppard P. Post mortem examination of a smallintestine in coeliac syndrome. Gut 1965;6:466-71.

6 Bacon C, Scott D, Jones P. Heatstroke in well wrapped infants.Lancet 1979;i:422-5.

Walker-Smith JA. Small intestinal morphology in childhood.Arquives de Gastro-enterologia 1972;9: 119-30.

8 Barnes GL, Townley RRW. Duodenal mucosal damage in 31infants with gastroenteritis. Arch Dis Childh 1973;48:343-9.

Requests for reprints to: Dr S Variend, Department ofPathology, Children's Hospital, Western Bank, SheffieldSlO 2TH, England.

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