Reduced Platelet Count as a Risk Factor

for Intraventricular Hemorrhage

Brian A. Lupton, MB; Alan Hill, MD, PhD; Michael F. Whitfield, MD;
Cedric J. Carter, MB; Louis D. Wadsworth, MB; Elke H. Roland, MD

\s=b\ The role of thrombocytopenia as a
risk factor for intraventricular hemor-
rhage in infants of very low birth weight
is unclear. This study investigates the
relationship between the lowest platelet
count and the occurrence of intraven-
tricular hemorrhage in 302 consecu-
tively admitted infants with birth weights
under 1500 g. Intraventricular hemor-
rhage, which occurred in 90 infants
(29.8%), was correlated with the lowest
platelet count obtained during the first
4 days of life. In 27 infants with intraven-
tricular hemorrhage, the lowest platelet
count was less than 100\m=x\109/L. Statis-
tical analysis of the data demonstrated
that reduced platelet count was not as-
sociated significantly with intraventric-
ular hemorrhage. Similarly, the severity
of intraventricular hemorrhage did not
correlate with the lowest platelet count.
These data suggest that a reduced plate-
let count does not play a major role in
the pathogenesis of intraventricular
hemorrhage in infants of very low birth
weight.
(AJDC 1988;142:1222-1224)
TVTany factors have been implicated
in the pathogenesis of intraven¬
tricular hemorrhage (IVH) in the pre¬
term infant.1·2However, the role of
reduced platelet count in this context
remains unclear. Thus, several studies
have suggested a direct relationship
between low platelet count and the
occurrence of IVH,3-6 whereas others
have failed to demonstrate this asso¬
ciation.7·8 In the light of this contro¬
versy, the purpose of this study is to
determine the role of reduced platelet
counts in the genesis of IVH in a large
population of infants of very low birth
weight (VLBW).
METHODS
Patient Population
The patient population comprised 302
infants with birth weights less than 1500 g
who were admitted consecutively to the
Neonatal Intensive Care Unit at British
Columbia's Children's Hospital, Vancouver,
during a period of 18 months. The mean
gestational age was 27.5 weeks (range,
23 to 35 weeks) and the mean (±SD)
birth weight was 1076 ±246 g. Infants
were admitted during the first day of
life and received standard treatment in
terms of ventilation, circulatory support,
and parenteral nutrition. The following
variables, which have been implicated in
the pathogenesis of IVH, were recorded:
birth weight, mode and location of delivery,
condition at delivery, respiratory distress,
perinatal asphyxia, presence or absence of
pneumothorax, and outcome. Perinatal as¬
phyxia was defined as a fetal scalp or an
umbilical cord pH of less than 7.2, or Apgar
scores under 3 at one minute or under 6 at
five minutes, or all of these. Four patients
with platelet counts less than 20 x ÎO'/L
received platelet transfusions. Indometha-
cin sodium trihydrate was administered to
two patients only during the first 4 days of
life for the treatment of symptomatic pat¬
ent ductus arteriosus and was not used
prophylactically.
Diagnosis of IVH
Intraventricular hemorrhage was diag¬
nosed by routine ultrasound scanning on
days 4 and 14 of life with a mechanical
sector scanner (Diasonics ADA 400)
equipped with a 7.5-MHz transducer. Scans
were performed by a radiologist who was
unaware of the infant's platelet count. The
IVH was graded as I to IV according to
the system of Papile et al,9 adapted for use
with ultrasound scanning. Grades III and
IV were considered to represent severe
IVH.

Accepted for publication June 12, 1988.

From the Divisions of Neurology (Drs Lupton,
Hill, and Roland) and Neonatology (Dr Whit-
field), Department of Pediatrics, and the Division
of Hematopathology, Department of Pathology
(Drs Carter and Wadsworth), University of Brit-
ish Columbia, and the British Columbia's
Children's Hospital, Vancouver.
Presented in part at the meeting of the Amer-
ican Pediatric Society/Society for Pediatric Re-
search, Anaheim, Calif, May 1, 1987.
Reprint requests to Division of Neurology, Platelet Count 109/L
British Columbia's Children's Hospital, 4480 Oak
St, Vancouver, British Columbia, Canada Distribution of lowest platelet count and intraventricular hemorrhage. Solid bars indicate
V6H3V4 (Dr Hill). presence of, and striped bars, absence of, intraventricular hemorrhage.

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 Table 1.—Correlation of Intraventricular Hemorrhage (IVH) With Lowest
the first day of life in all infants and
Platelet Count* were repeated between age 2 and 4
days in 215 infants (71%) who had
Lowest Platelet Count x 10VL medical complications. In 27 infants
No. of
Patients <100 100-150 151-200 >200 (9%), the LPC was less than
IVH (n 302)
=
(n 27)
=
(n 26)
=
(n 72)
=
(n 177)
= 100 109/L; in 26 infants (9%), the LPC
Present 90 7 9 27 47 was between 100 and 150 x 10VL; and
Absent 212 20 17 45 130 in 72 infants (24%), the LPC was
*X2 3.41,df=3;P
= =
.33. between 151 and 200xl09/L. In the
remaining 177 infants (59%), all
platelet counts were greater than
Table 2.—Correlation Between Grade of Intraventricular Hemorrhage (IVH) and 200 x 10VL.
Lowest Platelet Count* The distribution of the LPC in the
Lowest Platelet Count 10"/L
entire study population and in the
No. of infants who developed IVH is dis¬
IVH
Patients
(n 302)
=
<100
(n 27)
=
100-150
(n 26)
=
151-200
(n 72)
=
>200
(n 177)
=
played in the Figure. There was no
16 46
apparent difference between the inci¬
Absent 212 20 130
dence of IVH in infants with platelet
Present counts less than 100, 100 to 150, and
Grades I and II 40 2 11 23
150 to 200 x 109/L as compared with
Grades III and IV 50 5 15 24
the incidence in the remaining infants
0.47, df=1;P .5.
=

(Table 1). To avoid assumptions con¬

=

cerning a minimum "safe" platelet

count, variances of the LPC in infants
Table 3.—Correlation Between Birth Weight and Lowest Platelet Count* both with and without IVH were ex¬
Lowest Platelet Count 10»/L amined by the Student t test. There
No. of was a similarity of LPC in infants in
Patients <100 100-150 151-200 >200 each group (F' 1.23, P>f" .278),
= =
Birth Weight, g (n 302)
=
(n 27)
=
(n 26) =
(n=72) (n 177)
=

<750 32 6 5 4 17 indicating the absence of a direct re¬

750-999 84 7 7 23 47 lationship between the LPC and the
occurrence of IVH. A stepwise logistic
1000-1499 186 14 14 45 113
regression procedure was performed
V 8-57, df=6;P
= =
.199. to allow for interactions between de¬
pendent variables that might mask a
possible effect of thrombocytopenia on
Table 4.—Correlation Between Perinatal Asphyxia and Lowest Platelet Count* the risk of IVH due to other variables.
Lowest Platelet Count 10"/L Three variables (severity of respira¬
Perinatal
No. of
Patients <100 100-150 151-200 >200
tory distress, pneumothorax, and
birth weight) were found to have a
Asphyxia (n 302)
=
(n 27)
=
(n 27)
=
(n 69)
=
(n 179)
=

Present 88 12 9 21 46 significant influence on the incidence

Absent 214 15 18 48 133 of IVH. After allowing for the effect
of these factors, other variables, eg,
* * 4.15, df= 3; =.246.
=

LPC, perinatal asphyxia, serum so¬

dium level, and location of delivery,
Platelet Counts Statistical Analysis were not significant (P =
.05).
Blood samples were obtained by punc¬ Results analyzed statistically in
were
The relationship between the LPC
ture of the prewarmed heel or from an terms of absolute platelet count and by and severity of IVH was examined
indwelling arterial catheter. Platelet counts stratification, using the 2 test, the Student (Table 2). Severe IVH, ie, grades III
were performed on all infants at the time t test, and progessive logistic regression. and IV was not associated with a
of admission and repeated daily on all sick higher incidence of reduced platelet
infants in whom the lowest platelet count RESULTS counts than mild IVH, ie, grades I
(LPC) had been noted between 2 and 4 Intraventricular hemorrhage oc¬ and II (x* 0.47, d/=l;
=
.5). Fur¬
=

days of age.6 Platelet counts were per¬ curred in 90 (29.8%) of the 302 infants. thermore, there was no significant
formed on an electronic cell counter (Coul¬
In 40 infants, the IVH was grade I or association between reduced platelet
ter S Plus IV). Platelet counts less than
30 x 109/L were confirmed by manual cham¬ II, and in 50 infants, it was grade III count and birth weight (Table 3). The
or IV As has been reported previously, relationship between the LPC and
ber counts using phase-contrast micros¬
copy. The LPC measured during the first 4 IVH occurred before age 4 days in perinatal asphyxia is demonstrated in
days of life was used in subsequent analy¬ most instances.2·10-12 Table 4. Although there was a trend
sis. Platelet counts were measured on toward lower platelet counts in infants

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 who sustained perinatal asphyxia, this
did not reach statistical significance.
Assessment of the power of the
study demonstrated that a 14% de¬
crease of low platelet counts in infants
with IVH would have been detected
with a ß error of 0.1 (a 0.05), indi¬
= within the first 2 weeks of life.6 How¬
cating that the study population was
sufficiently large to detect any clini¬
cally significant decrease in reduced
platelet counts in infants with IVH.
COMMENT
These data do not demonstrate a
clear association between reduced
platelet count and IVH, an observa¬
tion that is in contrast to several re¬
cent reports.3"6 Thus, Beverley et al,3
in a study of coagulation status in 106
infants of less than 34 weeks' gesta¬
tion, observed significantly lower
platelet counts at 48 hours of age in
infants with IVH. However, these data
do not permit conclusions as to
whether the low platelet counts were
a cause or consequence of IVH. Simi¬
larly, McDonald et al" reported a sig¬
nificantly higher incidence of IVH in
50 infants of gestational ages less than
33 weeks in whom platelet counts were
less than 150 x 109/L within the first 8
hours of life. In a study of 58 VLBW
infants, Setzer et al5 observed a rela¬
tionship between mean platelet counts
in the first day of life and IVH in 71%.
However, when adjusted for the effect
of perinatal asphyxia, this relationship
was no longer statistically significant.
1. Volpe JJ: Neurology of the Newborn, ed 2.
Philadelphia, WB Saunders Co, 1987, pp 316\x=req-\
325.
2. Ment LR, Duncan CC, Ehrenkranz RA:
Intraventricular hemorrhage of the preterm ne-
onate. Semin Perinatol 1987;11:132-141.
3. Beverley DW, Chance GW, Inwood MJ, et al:
Intraventricular hemorrhage and hemostasis de-
fects. Arch Dis Child 1984;59:444-448.
4. McDonald MM, Johnson ML, Rumack CM,
et al: Role of coagulopathy in newborn intracra-
nial hemorrhage. Pediatrics 1984;74:24-31.
5. Setzer ES, Webb IB, Wassenaar JW, et al:
Platelet dysfunction and coagulopathy in intra-
ventricular hemorrhage in the premature infant.
J Pediatr 1982;100:599-605.
6. Andrew M, Castle V, Saigal S, et al: Clinical
impact of neonatal thrombocytopenia. J Pediatr
1987;110:457-464.
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Finally, in a study of VLBW infants
born in one year in whom the incidence
of IVH was 56%, an increased inci¬
dence and severity of IVH was ob¬
served in infants in whom platelet
counts were less than 100 109/L
ever, in this study, thrombocytopenic
infants were compared with "sick con¬
trols." Thus, although two studies3·6
have identified major differences be¬
tween infants with and without IVH
in terms of factors such as birth as¬
phyxia and severity of respiratory dis¬
ease, multivariate analysis was not
performed to determine whether
these variables could explain the ap¬
parent association between platelet
count and IVH. Our study, as well as
others that use multivariate analysis,
have failed to demonstrate a signifi¬
cant association between IVH and
platelet counts.7·8 The conclusions
from our data are similar whether or
not multivariate analysis is applied.
Additional factors may produce a
noncausal association between throm¬
bocytopenia and IVH in this context.
Thus, an increased risk of IVH with
perinatal asphyxia has been re¬
ported.5·1316 However, because perina¬
tal asphyxia may cause a consumptive
coagulopathy, it may result in both
IVH and thrombocytopenia, which
may create an apparent association
between the two variables. Second, in
this study, platelet counts were re¬
peated more often in the sicker infants
References
7. Szymonowicz W, Yu VYH, Wilson FE: An-
tecedents of periventricular hemorrhage in in-
fants weighing 1250 g or less at birth. Arch Dis
Child 1984;59:13-17.
8. Szymonowicz W, Yu VYH, Walker A, et al:
Reduction in periventricular hemorrhage in pre-
term infants. Arch Dis Child 1986;61:661-665.
9. Papile LA, Burstein J, Burstein R, et al:
Incidence and evolution of subependymal and
intraventricular hemorrhage: A study of infants
with birth weight less than 1500 gm. J Pediatr
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10. Rumack CM, Manco-Johnson ML, Manco\x=req-\
Johnson MJ, et al: Timing and course of neonatal
intracranial hemorrhage using real-time ultra-
sound. Radiology 1985;154:101-105.
11. Perlman JM, Volpe JJ: Cerebral blood flow
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after the first day of life. Thus, there
is a greater likelihood of detecting
thrombocytopenia in the sickest in¬
fants, ie, those who are at highest risk
for IVH from any cause. Third, it has
been demonstrated that hemorrhage
itself may result in consumption of
platelets.16 Consequently, infants who
have sustained IVH may have lower
platelet counts following the hemor¬
rhage.
The lack of association between IVH
and reduced platelet count in our
study population, despite various fac¬
tors that would tend to emphasize a
positive relationship, argues against a
role for reduced platelet count in the
pathogenesis of IVH. Because of the
small number of infants with an LPC
of less than 50 x 109/L, we were unable
to establish whether such very low
counts are related causally to IVH.
Other variables, eg, methods of blood
collection, location, and mode of deliv¬
ery, may explain the differences in
incidence of thrombocytopenia be¬
tween various studies.16
The lack of a causal relationship
between reduced platelet count and
IVH suggests that treatment of mod¬
erate thrombocytopenia (>50 109/L)
is unlikely to decrease the incidence
of IVH in infants of VLBW
We thank Sam Sheps, MD, and the Department
of Clinical Epidemiology, University of British
Columbia, Vancouver, for assistance with statis¬
tical analysis.
1982;100:956-959.
12. Ment LR, Duncan CC, Ehrenkranz RA,
et al: Intraventricular hemorrhage in the preterm
neonate: Timing and cerebral blood flow changes.
J Pediatr 1984;104:419-425.
13. Reynolds ML, Evans CAN, Reynolds
EOR, et al: Intracranial hemorrhage in the pre-
term sheep fetus. Early Hum Dev 1979;3:163\x=req-\
186.
14. Lou HC: Perinatal hypoxic-ischemic brain
damage and intraventricular hemorrhage. Arch
Neurol 1980;37:383-397.
15. Meidell R, Marinelli P, Pettett G: Perinatal
factors associated with early-onset intracranial
hemorrhage in premature infants. AJDC 1985;
139:160-163.
16. Preston FE: Disseminated intravascular
coagulation. J Hosp Med 1982;28:129-137.