Subependymal and Intraventricular Hemorrhages in the Newborn

Subependymal and Intraventricular Hemorrhages
in the Newborn
Richard W. Leech, MD and Paul Kohnen, MD
The pathogenesis of intraventricular hemorrhage in the newborn includes that of
subependymal hemorrhage (SEH), the single most common pathologic alteration
seen in the brains of 417 consecutively autopsied infants. A clearly recognizable
relationship of SEH to gestational age and clinical status exists in that all SEH
occur in premature infants under 2500 g birthweight (although only 56% of all
premature infants have SEH) and 95% of SEH occur in infants with the respiratory distress syndrome (although only 60% of infants with the respiratory distress
syndrome have SEHl). The pathogenesis appears to involve a combination of
hypoxia, metabolic acidosis, venous stasis and rupture of the thin-walled veins
so prominent in the germinal matrix (Am J Pathol 77:465-476, 1974).
INTRAVENTRICULAR HEMORRHAGE (IVH) is often cited as a
major cause of death in the newborn 13 and is generally recognized as
a disease of the small premature. Valdes-Dapena and Arey 1 found that
IVH played a role in the death of 26% of 501 infants studied, two-thirds
of IVH occurring in infants weighing under 1000 g and most of these
occurring before 36 hours of age. Many factors have been associated
with IVH, including hypoxia and pulmonary disease, growth retardation, social status and abnormal clotting status.2- Most investigators
state that IVH results from rupture of the large veins lying in the
germinal matrix6-8 or from venous infarcts of the germinal matrix,9
implving a relationship to subependymal hemorrhage (SEH), but there
are few adequate anatomic or statistical studies actually relating IVH
to SEH.
In addition, there is verv little uniformity of reporting in the literature, so that it is difficult to estimate the true incidence of the different
types of intracranial hemorrhages. Because etiologic considerations
have been intermixed with pathoanatomic classifications, one must
conclude that the simple recording of intraventricular or intracranial
hemorrhage is all too often inadequate and even misleading, so that
the several statistical analyses based on such results and relating cerFrom the Laboratorv of Neuropathology, Department of Pathology, Universitv of
WVashington School of Medicine, Seattle, Wash.
Suprted in part bv Neuropathology Training Grant 5TO1 NS05231-15 from the
National Institutes of Health, US Public Health Service.
Accepted for publication Julv 29, 1974.
Address reprint requests to Dr. R. W. Leech, Department of Pathology, Neuropathology
RJ-05. Universitv of Washington School of 'Medicine, Seattle, WVA 98105.
465
LEECH AND KOHNEN
466
American Joumal
of Pathology
tain clinical situations to the occurrence of such hemorrhages are inadequate and correspondingly misleading.
In an attempt to resolve these difficulties in the interpretation of
the pathogenesis of IVH, and with the hypothesis that SEH may have
other complications which may be incompatible with further survival
of the infant, with or without neurologic deficit, the present study was
undertaken to evaluate the frequency and relationship of SEH to IVH.
Furthermore, if SEH and IVH are to be prevented or treated, it is
necessary to establish the exact metabolic and clinical status of the
infant at the precise time of occurrence of SEH, a situation which at
the moment cannot be recognized clinically.10
Materials and Methods
We reviewed material from 417 consecutive autopsies of stillborn and newborn infants seen at the University Hospital from January 1967 through December
1970. All cases had been examined grossly and described bv members of the
Neuropathology Laboratory. Routinely recorded were the presence or absence of
IVH and SEH and whether the latter was ruptured or not. In most cases, the site
of rupture was usually determined by careful gross dissection after the first routine
transverse (coronal) section through the brain at the level of the mammillary
bodies revealed evidence of hemorrhage. After making radial cuts through the
dorsolateral angle of the lateral ventricle, one could gently elevate the intraventricular clot and see its continuity through a small rupture of the ependyma with
a subependymal hemorrhage, which most commonly extended over the bead of
the caudate nucleus near the foramen of Monro. Hemorrhage into the falx cerebri
and tentorium cerebelli was also recorded; but, unfortunately, the dura was not
always present with the brain at the time of brain-cutting, and the recording at
the time of autopsy was found to be generaly inadequate for evaluation of the
true degree of intradural hemorrhage. Subarachnoid hemorrhage was also commonly present, and an estimate was generaDy made as to whether or not the
subarachnoid hemorrhage was primary or secondary to IVH with extension into
the subarachnoid space.
Adequate histologic material was available on 109 cases, generally consisting of
sections of an individual SEH stained routinely with hematoxvlin and eosin and,
in selected cases, for iron.
Results
There were 184 cases of intraventricular hemorrhage, representing
44% of the total 417 cases (Table 1). Of the 184 cases of IVH, rupture
of subependymal hemorrhages accounted for 165 (90%), hemorrhage
into the choroid plexus accounted for 8 more cases, and no source was
detectable in 11 cases (usually because of the massive amounts of intraventricular blood clot present and subsequent destruction of the
very fragile brain on cutting). There were 36 additional cases of unruptured SEH; thus, one could conclude that at least 82¶ of SEH had
ruptured to produce IVH.
Vol. 77, No. 3
December 1974
Table 1-Prevalence of
Diagnosis
Total
IVH
NoIVH
Total SEH
Ruptured SEH
Unruptured SEH
No SEH
IVH from other sites
Choroid plexus
U nidentified
Sex (M/F)
Sex ratio
HEMORRHAGE IN NEWBORNS
Intraventricular
467
and Subependymal Hemorrhages by Clinical
IRDS
Other*
Stillborn
Total
311
175
136
190
158
32
106
17
7
10
65
8
57
9
6
3
54
2
1
1
41
1
40
2
1
1
39
0
0
0
417
184
233
201
165
36
199
19
8
11
199/112
37/28
21/29
257/160
1.8:1
1.3:1
1:1
1.6:1
* Pneumonia, sepsis, meningitis, enterocolitis, congenital heart disease, etc.
IRDS = Idiopathic respiratory distress syndrome, IVH = intraventricular hemorrhage,
SEH = subependymal hemorrhage
There was an absolute and relative preponderance of SEH and IVH
in infants with the idiopathic respiratory distress syndrome (IRDS)
with a total prevalence of about 60%. There was only 1 case of IVH and
1 additional case of unruptured SEH in stillborns for a total prevalence
of only 5% (Table 1).
SEH had its greatest frequency in the small premature (Table 2)
under about 33 weeks gestation (1900 g birthweight). SEH could occur
within 5 hours after birth, but the peak incidence did not occur until
11 or more hours after birth (Table 3, Text-figure 1). Only 46% of
small premature infants surviving less than 10 hours had SEH, whereas
71% of those surviving more than 10 hours had SEH.
Ninety percent of SEH occurred in the germinal matrix overlying
the caudate nucleus adjacent to the foramen of Monro, and the rest
were about equally distributed in the germinal matrix overlying the
body of the caudate nucleus (lateral to the bulk of the thalamus) and
in the germinal matrix in the lateral aspect of the occipital horn in the
region of the trigone. SEH has occurred wherever germinal matrix is
Table 2-Prevalence of Cases with Subependymal Hemorrhage to Total Number of Cases
by Birthweight and Clinical Diagnosis
Birth weight (g)
500-1899
1900-2499
2500
Total
IRDS
181/273
9/23
0/15
190/311
Other
8/28
1/8
0/29
9/65
Stillborn
Total
1/20
190/321
11/39
0/57
201/417
1/8
0/13
2/41
468
LEECH AND KOHNEN
American Joumal
of Pathology
Table 3-Ratio of Number of Cases with IRDS and SEH to Total Number of Cases with
IRDS as Functions of Birthweight and and Postnatal Survival Time
Postnatal survival time (hrs)
Birthweight (g)
500-1899
1900-2499
2500
Total
5
6-10
11-24
25-36
37-48
48
Total
11/23
0/0
0/0
11/23
5/13
2/4
0/0
7/17
45/61
3/6
0/7
48/74
23/36
1/2
0/2
24/40
20/25
1/4
0/2
21/31
77/111
2/7
0/3
79/121
181/269
9/23
0/14
190/306
found, including occasional examples in the temporal horn and roof
of the fourth ventricle. There was no predilection for one side over the
other (54 right, 47 left side, 7 not specified).
Rupture into the ventricle to produce IVH occurred in 82% of the
cases with SEH, slightly more often when the SEH was bilateral (85
cases) than unilateral (74 cases). Intracerebral hemorrhage of more
severe degree than simply subependymal occurred in only 12 cases.
Intradural hemorrhages occurred in about 31% of the population,
but there was no relationship to birthweight (Table 4). Unfortunately
these data are only approximate since the dura was not always described in detail by the general pathologist at the time of autopsy or
always retained with the brain and described in detail by the neuropathologist. Unless one examines the falx and tentorium by transillumination, one can easily miss small intradural hemorrhages.
:
I',
-E
xt
0
1
2
4
3
Days Survival
5
6
>6
TET-FIG 1-Prevalence of subependymal hemorrhages (±+ 1 SD with number of cases
studied at each interval) in 278 premature infants weighing 500 to 1899 g at birth and
dying with IRDS and in 19 stillborn infants of similar weight.
Vol. 77, No. 3
December 1974
HEMORRHAGE IN NEWBORNS
469
Table 4-Prevalence of Intradural Hemorrhage by Birthweight
Intradural hemorrhage
Birthweight (g)
500-1899
1900-2499
2500
Total
Present
Absent
97
14
15
126
219
28
33
280
Total
described
316
42
48
406
There were no examples of grossly obvious old SEH with residual
lesions during the 4-year period studied, but examples of such lesions
have been found both before and after this period. Considering the
109 cases in which adequate material for histologic exaiination was
available, we sought microscopic evidence for increasing duration of
the SEH, such as red blood cell ghosts, erythrophagocytosis, macrophages without and then with hemosiderin. Independent evidence for
increasing duration of necrosis of the germinal matrix included karyorrhexis of the germinal cell nuclei and then karyolysis. There were 8
cases with hemosiderin-containing macrophages and 3 cases with the
only other evidence of less prolonged SEH. These 11 cases occurred
in infants dying 0 to 10 or more days after birth (Table 5). Although
the rare case under 42 hours of survival showed evidence of old hemorrhage (ghost red blood cells, etc), it was only after 43 hours of survival
that hemosiderin could be detected.
Although venous congestion was uniformly present, venous thrombi
were not found, and infarcts of the germinal matrix were not found
except in those 11 cases in which there was evidence for longer duration of the hemorrhage. In such cases there were zones of pallor and
karyorrhexis of the germinal cell nuclei. Because of the random nonserial nature of the sections, only 4 cases were found to contain veins
which had ruptured. In each case a fibrin clot was found adherent to
the site of rupture.
Table 5-Histologic Examination of SEH
Survival
time (hr)
Total
No.
0-42
43-96
97-168
169+
182
72
26
20
Ghost RBC,
Percent
No. with No. sampled
erythroHemosiderin hemosiderin
SEH histologically phagocytosis
present
present
110
63
2
0
0
53
32
3
2
6
19
10
2
2
20
4
4
4
4
100
470
LEECH AND KOHNEN
American Joumal
of Pathology
Discussion
Although most previous studies 1` have considered only IVH, it
seems more appropriate to include the milder cases with unruptured
SEH since it seems most likely that the pathogenesis of IVH is essentially the same as that of SEH. That is, at least 90% of IVH could be
demonstrated grossly to have come from SEH, while over 80% of the
cases of SEH had ruptured to produce IVH. Although the statistical
error related to the omission of SEH is relatively small (about 20%),
the study of SEH is of considerable importance in its own right since
it is the most common gross lesion seen in the brain of autopsied infants.
Furthermore, cases with unruptured SEH may have fewer or milder
other complications which the infant may survive, possibly with varying degrees of neurologic deficit (eg, intracerebral hemorrhage or
simple unruptured SEH with destruction of germinal cells which provide the glial cells, or building blocks, for the future cerebral white
matter especially).
Previous hypotheses to explain the occurrence of IVH or SEH have
included trauma, hypoxia-acidosis, physical factors (such as thin-walled
veins susceptible to distension and rupture) and venous thrombosis
with infarction. Trauma has been generally discounted by most authors,89 and we would further discount it since the frequency of intradural hemorrhage (presumably secondary to molding of the head
at birth and probably a lesion preceding dural tears and subdural
hemorrhage) remains constant for all age ranges and in all diagnostic
categories (Table 4 and Text-figure 2) in contrast to the clear association of SEH with prematurity and IRDS (Tables 1 and 3).
Previous studies have varied so greatly, both in the manner of reporting and in the type of population studied, that it is very difficult to
compare our results with those of others, but Table 6 attempts to sum-
Tm-nc 2-Prevalence of subependymal
(open columns) and intradural (hatched columnrs)
hemorrhages related to birthweight.
ZI
Birthweight (g)
HEMORRHAGE IN NEWBORNS
Vol. 77, No. 3
December 1974
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LEECH AND KOHNEN
American Journal
of Pathology
marize the situation as clearly as possible. A large part of the diculty
can be attributed simply to differences in the populations coming to
autopsy as the result of changes in obstetrical practices. In earlier reports, traumatic subdural hemorrhages were a common 4'11,12 16 or even
the most common713'14 cause of intracranial hemorrhages, whereas we
have found not a single such example. Indeed, the high frequency and
mixture of traumatic lesions (dural tears and rupture of the vein of
Galen with subdural hemorrhages) with other lesions (SEH, IVH and
intracerebral hemorrhages) led Schwartz 11 to conclude that it was not
possible to distinguish whether a lesion was traumatic or anoxic in
origin. Only within the past several decades were Gruenwald and
Ross and Dimette 8 able to show that the gestational age and manner of
presentation and delivery were quite different, subdural hemorrhages
occurrng in mature infants with difficult deliveries,'1 and SEH occung in prematures without such difficult deliveries. Even so, arguments persist concerning the cause of IVH, whether mostly from
choroid plexus 14 or from SEH."3 It seems quite clear that confusion
will continue to result from misiterpretation of most of these early
reports, where postulated etiologies, such as anoxia vs trauma4'7'16
are more or less mixed with imprecise statements of the sites of hemorrhage, such as intracranial vs subdural, intracerebral vs intraventricular
or subependymal, and subarachnoid in continuity with IVH or separate
from IVH.4'5'7 Considerations only of IVH without regard to possible
sources2'3 or presentations of detailed case reports without adequate
summaries of the entire population"11 lead to further statistical difficulties when one attempts comparisons with our results or those reported by others.
Briefly then, there is no unanimity of opinion as to what constitutes
a traumatic or anoxic intracranial hemorrhage. Some reports have been
presented from a purely pathoanatomic view, some from a presumed
etiologic basis, and others from the simple presence or absence of
hemorrhage without consideration of sources or site. From the early
pathoanatomic studies we have come full circle to the present presentation in which the role of trauma, although less apparent, cannot be entirely excluded, and in which the role of hypoxia and its companion
acidosis, although more readily apparent, cannot be positively fixed.
According to our results (Tables 1 and 2) there are clearly recognizable relationships to gestational age and clinical status: 100% of
SEH occur in premature infants under 2500 g birthweight, although
only 56% of all premature infants have a SEH. Furthermore, 95% of
SEH occur in infants with the respiratory distress syndrome, although
Vol. 77, No. 3
December 1974
HEMORRHAGE IN NEWBORNS
473
only 60% of infants with IRDS have SEH. Many observers 4' '9 have
commented on the role of hypoxia and pulmonary disease in premature
infants with IVH, although the most recent investigators, Fedrick and
Butler2 and Harke et al 3 believe that these relationships are artifactual.
In our material (Tables 1 and 2) the presence of IRDS is the single
most striking feature. The two most consistent concomitants have been
hypoxia and metabolic acidosis, most infants having lived long enough
to develop respiratory distress and its metabolic complications, even
though not all have lived long enough to develop hyaline membranes.
We cannot refine the clinical correlates better at this time since we
have little or no information pertaining to the precise time of rupture
of the SEH, which is after all the "moment of truth" for these infants.
What is apparent, however, is that SEH can occur at any tim even
prenatally, but only rarely (5% in stillborn)-and that evidence of old
SEH can be found irregularly in those infants living over 43 hours, so
that one can conclude that SEH does not occur particularly at birth
but at some time, even many days, after birth.
In our experience and in that of others,,8" SEH occurs wherever
there is a germinal matrix. Thus, it seems likely that some aspect of
this highly cellular and fragile growth zone of the developing brain
must account for the inverse relationship of SEH to birthweight and
gestational age. That the germinal matrx occurs predominantly in the
distribution of the terminal vein and its tributaries complicates the
interpretation somewhat, since venous stasis-thrombosis may precede
or follow infarct-necrosis. Ross and Dimette 8 found that all but 2
of their 30 cases of SEH occurred in the lateral one-half of the matrix,
suggesting origin of the hemorrhage from the tributaries of the terminal
vein and not from the vein itself. We have noted that the ruptured
veins are quite variable in size, but this is based on only 4 proven
cases. However, more than 80% of the hemorrhages are of recent duration and not associated with necrosis of the surrounding matrix elements by histologic criteria. Hence, although we found no evidence for
venous infarction, we would otherwise agree with Towbin,9 who formulated an interaction between systemic hypoxia with venous congestion
and resultant SEH.
Finally, although there is a consistent relationship of SEH to the
clinical presence of hypoxia and metabolic acidosis, it is necessary to
determine what underlying abnormality is present that could have a
more direct bearing on the occurrence of hemorrhage in the newborn.
Hathaway et all7 have emphasized the common occurrence of disseminated intravascular coagulopathy (DIC) in severely ill newborn
474
LEECH AND KOHNEN
American Joumal
of Pathology
infants, and Jensen et aid8 found significantly decreased levels of fibrinogen and factor V in sick premature infants, mainly with IRDS, as
compared to thriving premature infants. Thus, of the two major complications of DIC as outlined by Simpson and Stalker,"9 it is the hemorrhagic diathesis rather than the microvascular obstruction which is
possibly most important in the production of SEH. There are no experimental or clinical data directly bearing on this possibility and our own
material does not answer the question. It would seem, however, in
view of the strong relationship of SEH to IRDS and the high frequency
of abnormal coagulation in such sick infants, that it is the latter point
to which we must ultimately direct our attention if this problem is
to be solved.
In summary, then, SEH is the result of several interacting but related factors including: a) hypoxia and metabolic acidosis, usually as
the result of respiratory distress and b) venous stasis with distension
of fragile thin-walled veins in a milieu of c) a fragile, poorly supporting, germinal matrix, characteristically present in the younger premature infant and d) abnormal coagulation. Rupture of the distended
veins results in SEH, and further expansion of the SEH leads to rupture of the ependyma with IVH and further extension of the blood
via the path of least resistance through the ventricles into the subarachnoid space about the medula.
References
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Vol. 77, No. 3
December 1974
HEMORRHAGE IN NEWBORNS
475
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Dr. Kohnen's present address is Department of Pathology, Arizona Medical Center,
University of Arizona, Tucson, AZ &5724.
476
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