Vol. 19 No. 2, June 2004
Tanzania Medical Journal
1
PERINATAL RISK FACTORS FOR NEONATAL BLEEDING AT THE MUHIMBILI NATIONAL HOSPITAL
DAR-ES-SALAAM, TANZANIA
ZK Ibrahim Maduhu, Karim P Manji, Roger L Mbise,
Summary
This incident case-control study of bleeding neonates in a Baby
Friendly Hospital was done to obtain the prevalence and risk factors
associated with bleeding disorders in the neonatal unit.
During a 4-month period from August to November 1998, 175
out of 1628 admitted infants were found to have some sort of bleeding.
These were compared with 414 control infants. Prematurity, Low
Birth Weight, Caesarian Section and anesthesia, and presence of
asphyxia were significantly associated with bleeding. The Prothrombin
and Activated Partial thromboplastin Test were not significantly
altered in bleeding infants and had a poor correlation with clinical
presence of a bleeding disorder.
The low prevalence of bleeding disorder and coagulation defects
is discussed and suggested that Breast Feeding may not be a risk factor
for bleeding disorder in this unit. Further studies are needed in this
regard.
Keyword: Neonatal bleeding, risk factors.
The total annual admissions range between 5000-6000
neonates. Neonates are admitted from outside the hospital
and those delivered within the hospital.
This study was done for 4 months from August to
November 1998. At recruitment maternal, antenatal,
intrapartum and postpartum details were recorded. These
were obtained from the history, admission records,
partograms, referral letters and the nurse accompanying the
baby. This was followed by the routine physical
examination and gestational age assessment by Dubowitz
method.(1) The weight was recorded daily using a standard
scale (Seca) to the nearest 10 grams.
On discharge, the diagnosis, date of discharged and
treatment given was all recorded. In case of death, the
causes of death were classified according to the World
Health Organization Manual of International Statistics
Classification of disease.(2)
Introduction
Inclusion Criteria
Bleeding disorder is a common cause of morbidity and
mortality during neonatal period (3,5-14).
The commonest cause is considered to be Vitamin K
deficiency bleeding. However, there is no consensus for
Vitamin K prophylaxis in the newborns.(22,23,24) At the
neonatal unit of Muhimbili National Hospital (MNH);
Vitamin K prophylaxis at birth is given only to those infants
who have a “high risk” of bleeding. Literature sites that
Exclusive Breast fed infants are more prone to Hemorrhagic
disease of newborn(15,16,18-21). Tanzania strongly advocates
exclusive breast-feeding, in line with the WHO Global
Breast Feeding Program. Exclusive breast-feeding may
therefore expose the newborn to risk of heamorrhagic
diseases if vitamin K is not given at birth. Anecdotal
reports are indicating that bleeding disorders may be
common in this unit.
However, we do not have any audits indicating the
magnitude of bleeding disorder in the centre and therefore a
need to have baseline study for the same. Information on the
magnitude of Bleeding disorder and its related factors
particularly Vitamin K deficiency and Breast feeding would
help to guide the policy on supplementation of Vitamin K in
the newborn.
Newborn infants with clinical evidence of bleeding
diathesis and had not received Vitamin K or blood
transfusion were recruited as cases. Infants with no clinical
evidence of bleeding were recruited as controls. The
controls were matched for the age with cases. The sample
size estimation and analysis of data was done using the EPIInfo version 6 software.
Specimen collection
Three milliliters of blood were drawn from each
newborn infant in the study on admission to the unit, using
disposable syringes and needles and after thorough cleaning
of the site with cotton swab soaked in 70% alcohol. The first
1.8mls of blood were collected in a glass tube containing
0.2mls of 3.13% sodium citrate for coagulation indices,
while the remaining 1.2 milliliters were collected in
Ethylene Diamino Tetra Acetic Acid glass containers for
full blood picture and platelet counts. The collected samples
were also protected from strong sunlight and heat by storing
them in an ordinary refrigerator at temperature of 4 0 C. The
specimens were analyzed on the same day.
Methodology
Estimation of PT and APTT
This incident case-control study was conducted at the
Neonatal Care Unit of Muhimbili National Hospital (MNH),
Dar-Es-Salaam, Tanzania. MNH is a tertiary referral centre
and teaching hospital. The unit has a capacity of 70 beds.
This was done to establish whether the bleeding
disorder was related indirectly to Vitamin K deficiency. A
senior laboratory technician who was blinded about the
clinical features performed the Prothrombin Time (PT) and
Activated Partial Thrombin Test. This was done at the
Department of Hematology and Blood Transfusions using
standard methods described by Quick and Proctor
respectively.(3,4) The normal range for PT was taken to be
Corresponding Author: Karim P. Manji, P.O.Box 65001, Muhimbili University College
of Health Sciences, Dar-es-Salaam, Tanzania
1
Dept. of Paediatric, Mbeya Refferal Hospital, 2 Dept. of Paediatric Muhimbili
University College of Health Sciences, 3Dept. of Paediatric Hindu Mandal Hospital
Vol. 19 No. 2, June 2004
13-18 seconds and for APTT it was taken to be 35-45
seconds.
Breast feeding Status
Although this centre is a Baby Friendly Hospital and it
is known to practice Exclusive breast feeding, data was
obtained for identifying it as a risk factor. This was taken
into account, because some studies have suggested that
Exclusive Breast feeding may be a risk factor. The reason is
that breast milk is sterile, has low content of Vitamin K and
therefore establishing the gut flora is delayed.(15,16,18-21) This
information was obtained from the history and clinical
notes.
Result
During the study period of 4 months a total of 1628
newborn infants were admitted to the Neonatal Unit. There
were 175 infants who presented with some form of bleeding
diathesis; therefore the prevalence of bleeding disorder was
10.7%. Four hundred and fourteen infants who did not have
bleeding and who had not received blood transfusion were
recruited consecutively as controls.
The mean gestational age was found to be 36.3 weeks
(+5.1) while that of the controls was 37.5 (+4.4). This was
statistically significant (X2+7.3, p=0.006). The birth weight
ranged from 500-4800 grams and was not different between
the two groups. The age of the infants ranged from birth to 7
days. Only 4 infants from the controls group were aged 14
days or more.
The associated risk factors with bleeding in the infant
are presented in Table 1. The different clinical manifestation
of bleeding is shown in Table 2. Suspected bleeding was
considered in 17 infants (9.9%). These include
intraventricular hemorrhage in 13, thoracic and abdominal
bleeding in 2 each. Some infants had bleeding at more than
one site.
The PT ranged from 7.6 to 53.9 seconds with a mean of
13.8(+3.3 seconds) and the APTT ranged from 30-69
seconds with a mean of 37.3 seconds (+6.0 seconds).
Prolonged PT was found in 18 (3.3%) and prolonged APTT
in 47 (8.5%) among the study population, including the
cases and controls. However, only 5/18 (2.9% of the total
cases) among those with prolonged PT and 14/47 (8%of the
total cases) among those with a prolonged APTT had
obvious bleeding disorder, as seen in Table 3.
In a separate analysis, the platelet count was not
different in both the groups of infants. The lowest platelet
count was 90,000/cmm with a range of 90,000486,000/cmm. The mean hemoglobin was 14.8 gms/dl and
ranged from 10-18gms/dl, in both the group of infants. The
rate of blood transfusions in the unit was 4%. The
commonest cause of blood transfusion was sepsis related
(78%), while blood transfusion due to bleeding diathesis
was indicated in only 8%, the other 14% were related to
anemia of prematurity.
Tanzania Medical Journal
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Table 1. Bleeding disorders and risk factors.
X2
Risk factor
Cases
Controls
Total
p-value
Pregnancy (n=589):
Singleton
Multiple
157
18
368
46
525
64
0.09 0.76
Gestational age (n=589):
Term
Preterm
121
54
319
95
440
149
4.07 0.04
Birth Weight (n=589):
>2500gms
<2500gms(LBW)
96
79
266
148
362
227
4.58
0.03
Exclusive Breast Feeding
(n=589)
Yes
No
168
7
396
18
564
25
0.08
0.96
Anesthesia (n=307):
Nil
Yes
59
27
100
121
159
148
13.53 0.0002
Apgar score at 5 min
(n=589)
>7 (normal)
5-7
< 4 (asphyxia)
89
78
8
290
116
8
379
194
16 20.4 <0.00003
Mode of delivery ((n=589)
SVD
ABD
LCVE
LSCS
119
12
14
30
248
22
5
139
367
34
19
169 4.58 <0.00001
LBW =Low birth weight, SVD =Spontaneous vertex delivery, ABD=
assisted breech delivery, LCVE =Low cavity vacuum extraction,
LSCS=Lower Segment Caesarian Section.
Table 2. Various sites and types of bleeding.
Type of bleeding*
Cord bleeding
Bruises and ecchymosed
Injection site bleeding
Cephalhematoma
Pulmonary heamorrhage
Vaginal bleeding
Hematemesis
Rectal Bleeding
Unexplained pallor
Suspected internal bleeding
Distribution (n=175)
Frequency
%
81
46.3
77
44.0
14
8.0
11
6.3
7
4.0
2
1.1
1
0.6
1
0.6
1
0.6
17
9.9
*Some patients had more than one type/site of bleeding.
Table 3. PT, APTT and bleeding status
Cases
Total(%)
X2 P-value
PT: (Range 7.6-53.9 seconds, mean 13.8, SD 3.3)
Normal
109
224
Low
60
140
High
5
13
333(60.4)
200(36.3)
18(3.3)
0.56
APTT: (Range 30.0-69.0 sec, Mean 37.3, SD 6.0)
Normal
96
188
Low
63
156
High
14
33
284(51.6)
219(39.8)
Discussion
Controls
1.52
Vol. 19 No. 2, June 2004
The prevalence of bleeding disorders in this study was
found to be 10.7% among the admissions. When taking into
account that this is a referral hospital with an average of
4500 deliveries during the study period then the prevalence
would be much lower, in the order of around 4% or less.
The risk factors significantly associated with bleeding
was found to be prematurity, low birth weight, general
anesthesia during delivery, mode of delivery, and low
APGAR score at 5 minutes as seen in Table 1.These are also
recognized risk factors for intraventricular hemorrhage. (5,6,7)
General anesthesia was found to be significantly
associated with risk for bleeding and maybe related to the
need for Caesarian section, such as prolonged labor or fetal
distress, and therefore risks of perinatal asphyxia. The
General anesthesia may have an additive effect in
propounding perinatal asphyxia. The mode of delivery has
similar implication as for general anesthesia.
Cord bleeding was the commonest manifestation
(46.3%). Although this may be a manifestation of bleeding
diathesis, the possibility of accidental bleeding due to
improper cord ligature may also be responsible. Deliveries
that were associated with birth trauma such as breech were
found to have ecchymosis and bruises as seen in Table 2.
The proportion of infants with an abnormal PT and APTT in
the study population was 3.3% and 8.5% respectively. Only
5 out of 174 (2.9%) with bleeding disorders had a prolonged
PT and 14 out of 174 (8%) cases had prolonged APTT.
There were a significant number of infants, who did not
have bleeding diathesis, yet had prolonged PT and APTT as
seen in Table 3. The association of bleeding and abnormal
PT or APTT was not significant. Studies done in the USA
indicate that indeed bleeding diathesis may not be
necessarily associated with abnormal coagulation index.(8)
The small proportion of infants with abnormal
coagulation indices in comparison with those who had
obvious bleeding is not surprising and could be due to
several reasons. First, MNH is a referral hospital and cater
for high-risk deliveries such as obstructed labor, low birth
weight, antepartum hemorrhage and so on. Furthermore,
these deliveries may be done by caesarian section and
general anesthesia. These findings are supported by a study,
which proposed that stressful pregnancy and delivery were
responsible for bleeding disorder rather than deficiency of
clotting factors or Vitamin K.(9) Secondly, PT and APTT are
non-specific methods and indirect methods for assay of
coagulation factors as well as for Vitamin K. Thirdly; some
of the specimen may have been already activated before
being tested. Specific methods for assay of coagulation
factors ad Vitamin K include assays of prothrombin, the
non-carboxylated prothrombin (Protein Induced By Vitamin
K Absence-II) or vitamin K levels by high performance
liquid chromatography.(10) Lastly, the selection of patients
with bleeding diathesis included those with birth trauma
such as bruises in a preterm baby and those with possibly
accidental umbilical cord bleeding as indicated in table 2.
This would reduce the actual prevalence of bleeding due to
coagulation factor deficiency even further.
Vitamin K prophylaxis is given routinely to all newborn
infants in many industrialized as well as in some developing
countries.(11-13) However, in Tanzania, vitamin K
Tanzania Medical Journal
3
prophylaxis is given only to newborn infants with “high risk
“ of Heamrrhagic Disease of Newborn (HDN) and this too
is done in only a few hospitals in the country.
Studies have reported a significant decrease in
incidence of HDN with the introduction of Vitamin K
prophylaxis.(11) This epidemiological evidence and the
dramatic response observed(12,13) have been assumed to be
proof of Vitamin K deficiency. However, findings noted by
different authors are extremely diverse, and consensus in
this regard is still not reached. The diversity may be
attributed to the lack of standardized method of Vitamin K
assay.(9,14,15,16)
Although Vitamin K deficiency may not be directly
related, these factors may be regarded as indications for
administration of Vitamin K owing to its potential to reverse
HDN. For this reason, the technical working group for
management of sick children in resource poor setting has
recommended Vitamin K prophylaxis for the “high risk”
group of infants.(17)
The age of onset of bleeding was within 7 days of life
and despite the limitations mentioned above can be regarded
to be due to Hemorrhagic Disease of Newborn, as this the
usual time of presentation of classical HDN.
Many authors implicate exclusive breast-feeding as a
significant risk factor in HDN. (15,16,18-21) The finding of a
relatively low prevalence of bleeding disorder and
furthermore, lower prevalence of abnormal coagulation
indices in this study may indicate that breast-feeding is not a
high risk factor. Singh in his review of Vitamin K during
fancy has indicated that despite non-adherence to the
recommendations of Vitamin K supplementation for 15
years, they have observed only 0.1% incidence of classical
HDN, although high-risk infants were given routinely (23).
This is similar to what is practiced and is observed in this
unit. Similarly, the small risk of HDN among exclusively
Breast fed infants does not affect Breast-feeding promotion.,
but strategies for supplementing should be sought.(24) There
is need for further studies in this regard.
Conclusion
The prevalence of neonatal bleeding disorders was
10.7% at the Neonatal Unit in Dar-Es-Salaam. Low Birth
weight; prematurity, Caesarian delivery and low APGAR at
5 minutes were significantly associated with bleeding. There
was no significant association between bleeding and
Vitamin K deficiency and Breast feeding.
Recommendation
Further large-scale studies are needed for identifying
specific diagnosis of cause of bleeding.
Ackowledgements
To all the mothers and their infants who participated in this study.
The neonatal nurses and staff. The MNH for the source of participants, and
MUCHS for funding.
References
1.
Dubowitz LMS, Dubowitz V, Goldberg C. Clinical assessment of gestational age
in the newborn infant. J Pediatr 1970; 77:1-10
Vol. 19 No. 2, June 2004
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
WHO: Manual of International Statistics and Classification of Diseases, Injuries
and Cause of Death Vol. 1, WHO: Geneva, 1975
Quick AJ. The heamorrhagic disease and the physiology of hemostasis. In: JV
Dacie and SM Lewis (Ed): Practical hematology. J & A Churchill, London. 2nd
Edition. 1970; 269-73
Proctor RR, Rappaport SI. Partial Thromboplastin time with kaolin. A simple
test for first stage clotting factors deficiencies: In: JV Dacie and SM Lewis (Ed):
Practical hematology. J & A Churchill, London. 2nd Edition. 1970; 277-8
Lane PA, Hathaway WE, Githans JH et al. Fatal intracranial heamorrhage in a
normal infant secondary to vitamin K deficiency. Pediatrics 1983;72:562-4
Hutchinson JH, Cockburn F. Asphyxia neonatorum. Pathogenesis and Pathology
in bleeding. Practical Pediatric Problems 6th Edition. Lloyd-Luke, Sevenoaks,
Kent, 1992:3-4
Matoth Y. Plasma prothrombin in infantile diarrhoea. Am J Dis Child 1950;
80:944-954
Zipursky A, deSA D. Clinical and Laboratory diagnosis of haemostatic
disorders in the newborn infants. Am J Pediatr Haem Onc. 1979; 217-226
Corrigan FF, Krye JJ. Factor II (prothrombin) levels in cord blood: correlation
of coagulant activity with immuno-reactive protein. J Pediatr 1980; 79:979-83
Shearer MJ, Rahim S, Barkhan P. Plasma vitamin K1 in mothers and their
newborn babies. Lancet. 1982; 2:460-3
Mountain KR, Hirsh J, Gallus AS. Neonatal coagulation defect due to
anticonvulsant drug treatment in pregnancy. Lancet 1970; 1:265-8
Tanzania Medical Journal
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
4
Aballi AJ. Vitamin K and the newborn (letter). Lancet 1977; 2:559
Aballi AJ. Vitamin K and the newborn (letter). Lancet 1978; 1:1358
Van Doorm JM, Muller AD, Hamker HC. Heparin-like inhibitor, not vitamin-K
deficiency, in the newborn. Lancet 1977; 1:852-3
Sann L, Leclercq M, Bourgeois J et al. Pharmacokinetics of vitamin-K in
newborn infants (abstract). Pediatric Research. 1983;17:155A(408)
Gobel U, Sonnenschein-Kosenow S, Petrich C et al. Vitamin K-deficiency in the
newborn (letter). Lancet 1977;2:187
Management of the sick newborn. Report of a technical working group-Ankara.
1995. WHO/FRH/MSM96.12. WHO, Geneva.
Corrigan JJ Vitamin K-dependent proteins. In: Lane PA, Hathaway WE:
Vitamin K in Infancy (Review). J Pediatr 1985; 106:351-7.
Leonard S, Anthony B. Giant cephalhaematoma of newborn with heamorrhagic
disease and hyperbilirubineamia. Am J Dis Child 1961; 101:170-3
Sutherland JM, Glueck I, Gleser G. Hemorrhagic disease of the newborn:
breast-feeding as a necessary factor in the pathogenesis. Am J Dis Child. 1967;
113:524-33
Jimenez R, Navarrete M, Jimenez E et al Vitamin K dependant clotting factors
in normal breast-fed infants. J Pediatr 1982;100:424-6
. Current policy in the neonatal prophylaxis of Vitamin K. Lack of consensus.
http://www.blackwellpublishing.com/medicine/bmj/nnf4/pdfs/vitkcomment.pdf
Singh M. Vitamin K during infancy: current status and recommendations.
Indian Pediatr 1997; 34(8):708-12
Victora CG, Van Haccke P. Vitamin K prophylaxis in less developed countries:
policy issues relevance to breastfeeding promotion.