1. Obladen M. Necrotizing enterocolitis -150 years of fruitless search for the cause. Neonatology.

Sources of Neonatal Medicine
Neonatology 2009;96:203–210
DOI: 10.1159/000215590
formerly Biology of the Neonate
Received: January 12, 2009
Accepted after revision: January 22, 2009
Published online: April 29, 2009
Necrotizing Enterocolitis – 150 Years of
Fruitless Search for the Cause
Michael Obladen
Department of Neonatology, Charité University Medicine, Berlin, Germany
Abstract
Necrotizing enterocolitis (NEC) is not a new disease but one
that has been reported since special care units began to
house preterm infants. It was observed in foundling hospitals in Paris [Billard, 1828] and Vienna [Bednar, 1850] and, as
it occurred in clusters, was regarded as a nosocomial infection in the infant hospitals of Zurich [Willi, 1944] and Berlin
[Ylppö, 1931]. Clinical and patho-anatomic characterization
was achieved by Schmidt and Quaiser in 1952. The unproven
hypothesis of mesenteric hypoperfusion as a major etiological factor arose from animal models and analogous perforating disorders in term infants. Despite similarities between
NEC and clostridial infections, few studies employed anaerobic culture techniques. The pathogenesis remains unclear
and its distinction from related disorders uncertain. It is unlikely that strategies to prevent NEC will be successful unless
the disease is better understood.
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Introduction/Epidemiology
Neonatal necrotizing enterocolitis (NEC) is an inflammatory disease of the gut with symptoms of abdominal distension, bilious vomiting, and bloody stools. It
may proceed to septic shock, disseminated intravascular
coagulation, peritonitis, and intestinal perforation. All
parts of the gastrointestinal tracts may be involved, manifesting as multifocal hemorrhages, ulceration, and necroses. Almost exclusively a disorder of preterm infants,
NEC was not recognized until special care units facilitated their survival. Presently, NEC has become the most
common gastrointestinal emergency in neonates. This
historic search focuses on the etiology and diagnosis of
NEC in preterm infants and omits discussion of animal
models as well as prevention and therapy.
Early Reports Based on Postmortem Anatomy
In 1823, the Paris Athénée de Médecine offered a scientific prize to ‘describe, following precise observations,
the anatomic characteristics specific for inflammation of
the gastrointestinal mucous membrane’ [1]. The prize
was won by the 24-year-old intern Charles Billard for his
book entitled ‘De la membrane muqueuse gastro-intestiProf. Dr. Michael Obladen
Department of Neonatology, Charité University Medicine
Augustenburger Platz 1
DE–13353 Berlin (Germany)
Tel. +49 30 450 566 122, Fax +49 30 450 566 922, E-Mail [email protected]
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Key Words
Necrotizing enterocolitis ⴢ Etiology, necrotizing
enterocolitis ⴢ History, necrotizing enterocolitis
nale dans l’état sain et dans l’état inflammatoire’. At the
Hôtel-Dieu of Angers he had not seen premature infants;
the 81 observations in his 565-page book did not include
neonatal NEC. But the prize, connected with membership to an academic society, allowed Billard to continue
his medical training in Paris. He chose the Hôpital des
Enfants Trouvés which, in 1826, admitted 5,392 foundlings [2], giving him ample opportunity for clinical and
postmortem observations in neonates. His next book [3]
described a neonatal disease which he termed ‘gangrenous enterocolitis’:
‘the mucosa of small and large intestines swollen, injected, in
the colon often a large number of millet-sized dirty-dark red
spots. ... In addition, the mucosa including the submucous tissue
frequently corroded ... in many areas of the small intestine yellowgrey infiltrates with a tendency towards gangrene.’
‘50th observation. Caroline Jossey, 9 days old, small and weak,
is admitted to the ward for sick neonates on the 7th of November
(1826). She shows generalized redness of the integuments and
edematous extremities. The temperature of her skin is normal,
her cry unaltered; her pulse irregular at a rate of 92/min. The infant has copious green-stained diarrhea. An intense perianal redness is noticed; the abdomen is swollen. On the 12th the green
stool is mixed with streaks of blood. ... On the 14th the infant
yields a large amount of blood with the stool; her face is thin,
livid and entirely distorted; she vomits the administered liquids;
her extremities are cold and livid, her belly is tense; the heartbeat
extremely slow; finally she dies in the evening yielding a large
quantity of black liquid blood through the anus. – When opening
the body on the next morning ... the duodenum is in healthy state,
the terminal ileum is intensely red and swollen, its mucosa friable
and the surface covered with blood. When these fluids are removed, the membrane looks rough and bloody; its surface furrowed by numerous wrinkles between which there are deep and
black lines with the aspect of being burned by nitric acid. In addition to these blackish furrows, there are a large number of spots
or ecchymoses with the same appearance in different regions of
the colon. On these spots the mucosa is so soft that it turns to
mash when scraped with the fingernail ...’
Arvo Ylppö [6], later director of the Helsinki University Children’s Hospital, organized Germany’s first special care unit for preterm infants at the Berlin Kaiserin
Auguste Victoria Haus from 1912 to 1920, and described
NEC in 1931:
‘... a stomach gangrenous at its small curvature with a perforation the size of a silver penny, containing a green liquid which, as
the large curvature was unharmed, had not leaked into the peritoneal cavity. Also the duodenum’s origin participated in the gangrenous metamorphosis. ... It deserves mention that both from
the mother’s calculation and from the infant’s aspect the birth had
occurred about 6 weeks too early.’
Among 597 neonates admitted to the Vienna hospital
for foundlings from 1846 to 1847, its director, Alois Bednar
[5], observed 25 infants with ‘entero-colitis’ of whom ‘8
were well nourished, 7 were premature and 10 were emaciated; 15 of them were between 3 and 10 days of age, 4 between 12 and 20 days, 5 between 22 and 30 days and 1 of 1
month and 22 days’. In 20 lethal cases, necropsy showed
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Neonatology 2009;96:203–210
Systematic Observation in the First NICUs
‘The mucosal hemorrhages and ulcers in some cases lead to
bean-shaped swellings in certain sections of the small intestine.
These swellings originate from extensive necrosis of the intestinal
wall which gives way to increased gas pressure within the gut. From
these necrotic parts of the gut peritonitis easily arises, and therefore
it is not at all rare that we find peritonitis with hemorrhagic or purulent exudation at postmortem examination of preterm infants.
This is rarely diagnosed in vivo: It is so rapidly lethal that the clinical symptoms are unspecific (vomiting, meteoristic swelling of the
abdomen without clear tension of the abdominal wall).’
In 1907, Switzerland’s first neonatal special care unit
was founded – the Zurich Cantonal Infant Hospice
Rosenberg. Heinrich Willi [7], its director since 1937, described 62 cases of ‘malignant’ enteritis occurring between 1941 and 1943:
‘The following case is characteristic: Sch., Anna Lilli (J.-Nr.
159/40), born June 10, 1940, birth weight 1,110 g, vital. On the 2nd
day of life severe edema, spasmophilia, increasing icterus. On the
5th day asphyctic spell, recurring during the next day (heart malformation). At the beginning of July progressive pallor; stools become frequent, but did not raise concern as the infant nearly exclusively received wet nurses’ milk. On the July 8, vomiting; on
the July 11, ballooned, tense abdomen, bilious vomiting, decay,
finally fecal vomiting. Death on the July 12. Autopsy: Ulcerous
and phlegmonous enteritis. Small intestine and coecum show numerous irregular round-oval defects with jagged and somewhat
prominent margins, up to 8 mm in diameter. Enlarged mesenteric lymph glands. Fibrinous peritonitis. The heart shows hypoplasia of the tricuspid valve.’
Among Willi’s cases, 37 had a birth weight below
2,500 g; 12 were below 1,500 g. The disease occurred in
clusters, as shown in figure 1c, and he assumed: ‘An indirect contact infection is most probable. ... Our prophylacObladen
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Adam Elias von Siebold [4], director of the Obstetric
Hospital of Berlin University since 1817, observed a preterm infant who had some but not all features of NEC:
The critical scientist Bednar admitted: ‘If we refrain
from pure speculation, we are without any knowledge of
a specific cause’.
Fig. 1. a Darmbrand in an adult and in an infant with jejunal perforation; from Hansen et al. [75]. b Localization of necrotic lesions in the cases of Schmidt and Quaiser [8, 9]. Black = Frequent; hatched = less frequent;
x = rare. c Relation of occupancy in Willi’s ward and occurrence of ‘malignant’ enteritis [7]. White squares =
Cases referred because of infection; hatched squares = in-house infection.
tic measures had failed, due to the frequent overcrowding
of our institution, which normally can provide for 44 infants.’
From 1948 to 1950, Kurt Schmidt [8] and Karl Quaiser [9] observed 85 mostly preterm infants in Graz, who
died from a disease which they termed ‘enterocolitis ulcerosa necroticans’. All had been breast-fed:
‘Pathoanatomically it is an exceptionally characteristic enterocolitis predominantly in the ileocecum and the physiologic
colon curvatures. It is frequently complicated by peritonitis due
to transmigration or perforation. A specific pathogen could not
be proven.’
The distribution of necrotic lesions is shown in figure 1b.
Before the advent of modern neonatal intensive care,
NEC remained rare, as did the survival of very immature
infants. Schaffer’s 1965 issue of ‘Diseases of the Newborn’
did not mention it, and Beryl Corner, who in 1946 set up
the preterm infants unit at Southmead Hospital in Bristol, emphasized [10]:
‘We never saw a case of NEC prior to 1967, and we know it did
not exist, because of our very high postmortem rate and our very
careful care of all babies. So we know it did not exist, and seemed
to occur when we started fairly extensive catheterization, venous
catheterization, for all sorts of different purposes.’
wide, affecting 7% of very-low-birth-weight infants in the
US [11] and Canada [12] and killing approximately 500
infants per year in the US [13].
Diagnostic Criteria
In 1899, Hahn [14] observed pneumatosis intestinalis
during a laparotomy. In 1938, Botsford and Krakower
[15] anatomically described it in 6 infants, among them a
4-week-old preterm infant. Ann Arbor radiologist Arthur Stiennon [16] saw pneumatosis on X-ray in 1951 and
proposed:
‘From the mesenteric root gas can dissect, extend to the mesenteric insertion of the intestine and from here either dissect
along the subserosal layers or, following the blood vessels ..., enter
the submucosa.’
Pneumatosis portalis was described by Wolfe and Evans [17]; the whole spectrum of X-ray signs in NEC was
characterized by Berdon et al. [18]. In 1978, Bell et al. [19]
combined historical, clinical and radiographic data to define three stages, which were further subdivided by Walsh
and Kliegman [20], whose classification gained widespread acceptance. Paracentesis and lavage were proposed by Kosloske and Lilly [21] to detect gangrene, peritonitis and perforation.
History of Necrotizing Enterocolitis
Neonatology 2009;96:203–210
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By the turn of the century, NEC had become the most
important gastrointestinal emergency in infants world-
Table 1. Clinical series on preterm infants since Willi, with major suggestions for the pathogenesis of NEC
Proposed pathogenesis
Year
First author
Site
Cases
n
AC
Ref.
Nosocomial infection
Air dissection at mesenteric root
Endemic infection, probably virus
1944
1951
1952
Zurich
Ann Arbor
Graz, infants born 1948–1950
1953
1955
62
2
(85)
73
9
?
no
no
no
Cluster within 53 days
House endemy, viral
Endemic, ischemia,
Shwartzman reaction
Noninfectious etiology, systemic hypoxemia
Pseudomonas infection
Reaction to endotoxin and deficient lysozyme;
intestinal ischemia; injury + bacteria + feeds
Willi
Stiennon
Schmidt,
Quaiser
Refinetti
Köttgen
no
no
[7]
[16]
[8]
[9]
[23]
[24]
1959
1961
1963
1964
1965
1967
1975
1969
1969
1969
1970
1971
1971
1972
1974
1975
1975
1976
1976
1977
1978
1978
1981
1982
Rossier
Singleton
Waldhausen
Berdon
Mizrahi
Touloukian
Santulli
Wilson
Lloyd
Stevenson
Hopkins
Stevenson
Bell
Stein
Virnig
Frantz
Book
Siassi
Volsted Pedersen
Book
Bell
Kosloske
Nagaraj
Lawrence
Paris Hérold
Houston
Indianapolis
New York Babies, four
reports, infants born
since 1955
15
10
6
(21)
(18)
(25)
64
16
87
(21)
(13)
(38)
43
11
21
54
16
1
13
74
48
17
21
2
no
t.n.s.
no
no
t.n.s.
no
t.n.s.
t.n.s.
no
no
t.n.s.
no
no
no
t.n.s.
no
no
no
yes
no
yes
yes
no
no
[25]
[26]
[27]
[18]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[19]
[44]
[45]
[46]
Mesenteric ischemia, DIC
Circulation like reflex in diving mammals
Decreased mesenteric flow, umbilical/aortic
catheters create spasm
Salmonella cluster
Endemic in summer, no agent found
Formula feeding, DIC, umbilical artery catheter
Hyperosmolar feeding
Patent ductus arteriosus
Gas-gangrene due to Clostridium perfringens
Clustering: enteric transmissible agent
Etiology, pathophysiology unclear: staging
Clostridia infection in most severe cases
Indomethacin
Intestinal flora changed by antibiotics
São Paulo
Mainz
Los Angeles Children’s
Detroit
Seattle, four reports, infants
born since 1962
Johannesburg
St. Paul
Minneapolis
Salt Lake City
Los Angeles USC
Copenhagen
Salt Lake City
St. Louis Children’s
Albuquerque
Louisville
Brisbane
AC = Anaerobic culture from blood or peritoneal fluid; no = no cultures reported; t.n.s. = technique not stated; DIC = disseminated intravascular coagulation.
A frustrating aspect of NEC is the continuing lack of
understanding of its etiology, despite thoughtful and
well-designed basic and clinical research for over a century. Clustering suggested nosocomial infection with a
remarkable variation in incidence between hospitals
[22]. An impressive list of etiologic proposals has been
published, some of which are shown chronologically in
table 1.
The disease became widely known when it attacked
New York Babies Hospital. A total of 64 neonates with
NEC were observed from 1954 to 1974, prompting 10
206
Neonatology 2009;96:203–210
clinical papers from this institution. In addition to animal studies, they generated the hypothesis of mesenteric
hypoperfusion as major pathogenetic factor [28]:
‘The noncontagious nature of the disease is evidenced by the
lack of epidemics. ... All premature infants at Babies Hospital are
fed cow’s milk formula.’
Santulli et al. [30] specified:
‘Indirect injury to the mucosa may result from selective circulatory ischemia. This is the most acceptable theory of pathogenesis. It is supported by our clinical and pathological data.’
Obladen
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Putative Causes and Pathogenesis
Asphyxial or hypoxic episode
Selective circulatory ischemia
of the gut wall
Resuscitation
Vascular
congestion
Increased capillary
permeability and
fragility
Focal hemorrhage
Focal necrosis,
primarily mucosal
Invasive bacterial proliferation
Transmural inflammation
Intestinal ileus and dilatation
Medical Rx
Recovery
Related Disorders and Differential Diagnosis
(1) NEC in term infants accounts for less than 10% of
cases. The onset is earlier and more rapid than in preterm
infants and predisposing disorders affecting the circulation are usually present. NEC in term infants has been
linked to congenital heart disease and/or heart operation
[48, 49], perinatal asphyxia, polycythemia [50], exchange
transfusion [51–54], protracted diarrhea with dehydration, maternal cocaine abuse, and exposure to HIV or
antiretroviral medication.
(2) Appendicitis has long been feared as a rare severe
disorder of preterm infants: Isaac Abt [55], pediatrician
at Chicago Northwestern University, found 20 cases under 3 months of age published before 1917. Additional
cases were reported by Wilson [56], Engstrom [57], Meyer [58], Walker [59], and Hardman and Bowerman [60].
It is likely that today this disease is perceived as NEC.
(3) Focal intestinal perforation was proposed to be different from NEC by Aschner et al. [61]. Also a disease of
immature infants, it does not present with pneumatosis
and the localized perforation is surrounded by normal
tissue. Its pathogenesis is unknown as is that of NEC [62].
In the peritoneal fluid at laparotomy, Coates et al. [63]
found enterobacteriaceae more frequently in NEC than
in focal intestinal perforation.
(4) Meconium plug/fetal peritonitis: Several commentators on this disease, which is not specific for preterm
infants, were falsely credited for the ‘first’ NEC description. Simpson [64] published 23 instances of fatal peritonitis which began in utero; 4 other cases were reported by
Zillner [65] in 1884, and 5 more by the Prague pathologist
History of Necrotizing Enterocolitis
Perforation
Transmural
necrosis
Operative Rx
Sepsis, peritonitis
Death
Fig. 2. Pathogenesis of NEC as proposed by Touloukian et al. [47]
in 1972.
Arnold Paltauf [66] in 1888. Also in Anton Genersich’s
[67] much cited case of 1891 the perforation of the terminal ileum had occurred long before birth, the intraperitoneal masses were calcified, organized and vascularized. In 1905, ileus due to thickened meconium was correctly related to exocrine pancreatic insufficiency by
former blood group discoverer and later Nobel prize winner Karl Landsteiner [68] in Vienna.
(5) Septicaemia with ileus: That neonatal sepsis may
originate from the intestine was shown by Bonn obstetrician H. Cramer [69]. A pioneer in neonatology at Yale,
Ethel Dunham showed that staphylococcal septicemia
may lead to gastric perforation [70].
(6) Neonatal pseudomembranous colitis is a complication of antibiotic treatment resulting from disrupted bacterial flora, overgrowth of Clostridium difficile in the colon, and release of toxins leading to mucosal damage and
inflammation [71]. The pathogen’s name alludes to painstaking culture techniques.
(7) Darmbrand (fire bowel): In 1918, Rudolf Jaffé [72]
described 7 cases of lethal necrotizing and ulcerizing inflammation of the small intestine he had seen in severely
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Most of the supposed pathogenetic factors featured in
table 1 act during the first days of life; NEC, however,
usually develops at 2 weeks of age and often catches by
surprise infants who were postnatally stable and have left
the intensive care unit when everyone believed the battle
to be won. Monocausal explanations did not provide an
accurate explanation of NEC’s pathogenesis, and most researchers took refuge in more or less complex multifactorial models, as shown in figure 2 [47]. Immaturity, formula feeding, bowel ischemia, diminished immune function, infection with enterotoxin-producing bacteria all
played a role, but their interaction and sequence remained
elusive. It is remarkable that despite NEC’s clinical similarity to clostridial infection, endemic occurrence, and
different frequency among hospitals, only a few studies
employed anaerobic culture techniques.
undernourished Russian prisoners of war. Expulsed from
his Berlin chair of pathology in 1933, the Jewish scientist
Jaffé escaped the Holocaust by emigrating to Venezuela
where he observed exactly the same necrotizing enteritis
in cachectic natives in 1947 [73]. An epidemic of the same
disease, termed ‘darmbrand’, was observed in northern
Germany from 1946 to 1948, with 364 cases in Lübeck
(among them 13 infants) and a high mortality [74–76]. It
occurred in starved persons who had eaten a large meal.
In 1948, Zeissler [77] found that darmbrand was due to
Clostridium perfringens infection.
(8) Pigbel (enteritis necroticans) is probably identical to
darmbrand. It was published by Murrell et al. [78] to be
the most frequent cause of death in children in the highlands of Papua New Guinea. Patchy enteral necrosis occurred after ritual pork feasts in protein-deprived persons who consumed sweet potatoes containing heat-stable trypsin inhibitors [79]. Given that the major source of
defense against this toxin is adequate proteolysis in the
gut, these children were specifically vulnerable to the ␤toxins of C. perfringens contaminating the pork. The disease disappeared from New Guinea with ␤-toxoid vaccination. Pigbel has been observed in many underdeveloped regions and rarely in developed countries among
diabetics [80, 81] and vegetarians [82]. Volsted Pedersen
[42] first called attention to the striking clinical, roentgenological, and morphological similarities between pigbel and NEC.
Perspectives/Conclusions
By 1978, most features of NEC had been described;
however, despite extensive research no substantial progress has been made since then in understanding its pathogenesis. Surprisingly little effort has been made to distinguish NEC from other diseases and to elaborate its definition. Several related diseases are linked to enterotoxic
clostridial infections, which were sometimes reported in
NEC, but require anaerobic detection. NEC may be a pool
of different disorders instead of a single entity. Although
these disorders may lead to the same outcome, the underlying mechanisms vary greatly. It is unlikely that effective
prevention will be established unless the disease is better
understood.
Acknowledgements
The author thanks Karl-Heinz Leven, MD, PhD, Institut für
Geschichte der Medizin, Freiburg, and Anneliese Rossak, Zentrum für Kinder- und Jugendmedizin, Freiburg, for giving him
generous and guided access to their libraries; Gabi Völker, Department of Neonatology, Charité Berlin, for help with the artwork, and Sarah Lieber, National Institutes of Health, Washington, D.C., for language editing.
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