British Journal of Haematology, 2001, 112, 264±274
Review
PERINATAL MANAGEMENT OF NEWBORNS WITH HAEMOPHILIA
The dawn of potentially curative strategies for haemophilia,
advances in gene diagnosis and the availability of safer
clotting factor concentrates for treatment and prophylaxis
make it imperative that newborns with haemophilia be
appropriately diagnosed and managed. They can then avoid
the crippling consequences of haemophilia and avail
themselves of a better quality of life. Additionally, once a
diagnosis has been made, the infant's parents should be
provided with information concerning haemophilia, what to
look for, when to seek medical advice and how to care for
the child.
Haemophilia A and B are X-linked bleeding disorders and
can present with haemorrhage in the neonatal period. The
genes for factor (F) VIII and F IX are located at the tip of the
long arm of chromosome X. Haemophilia occurs in 1:5000
male births, affects all racial groups and is worldwide in
distribution. Approximately 80±85% of cases are haemo-
philia A (F VIII deficiency) and 15±20% are haemophilia B
(F IX deficiency). Based on plasma levels of F VIII or IX
coagulant (F VIII:C or F IX:C), which usually correlate with
disease severity, haemophilia is classified as mild (. 5% to
, 40%), moderate (1±5%) or severe (, 1%). Roughly two-
thirds of newly diagnosed infants have a family history of
haemophilia, whereas one-third have no family history
of haemophilia and are referred to as sporadic cases.
Haemophilia in these infants is usually as a result of a
mutation that arose in the infant's mother or in one of the
maternal grandparents. The most common genetic altera-
tion is an inversion mutation (commonly referred to as the
`flip tip' mutation). This accounts for 45% of cases of severe
haemophilia A, and 90% of the mothers of such patients are
carriers (Antonarakis et al, 1995).
Female carriers of haemophilia have one affected X
chromosome and should theoretically have circulating F
VIII:C (or F IX:C) that are 50% normal. However, because of
random inactivation of the X chromosome in somatic
cells (lyonization), levels may vary from 10 to 120 IU/dl.
Although carriers with factor levels at or above 30 IU/dl
may not bleed, those with levels of 10±30 IU/dl may
experience excessive bleeding following surgery (such as
caesarean section) or delivery, invasive procedures or
significant trauma, necessitating appropriate therapy. Car-
riers can be obligate (father has haemophilia), presumed
(more than one son with haemophilia), potential (maternal
haemophilic relative) or sporadic (no family history and
identified through affected child) (Miller, 1999).
Correspondence: Roshni Kulkarni, Michigan State University, Pediatrics/
Human Development, B220 Clinical Center, 138 Service Road, East
Lansing, MI 48824-1313, USA. E-mail: kulkarnl@msu.edu
264
Prenatal diagnosis
Pre-conceptual education and counselling should precede
prenatal diagnosis in known haemophilia carriers in order
to provide adequate information concerning the genetics of
haemophilia, the disease and its treatment, and information
regarding parental options and management of future
pregnancies (Kadir, 1999). Although not universally avail-
able (and not all women choose to avail themselves of
them), a variety of diagnostic protocols are now technically
feasible (Table I). In the first trimester of pregnancy,
chorionic villus sampling is the method most widely used
not only to determine fetal sex, but also to determine
whether or not a male fetus is affected. It is performed at
11±13 weeks of gestation and yields results within 24±
48 h for restriction fragment length polymorphisms (RFLPs)
and polymerase chain reaction (PCR), and within 5±7 d for
sequencing of a known mutation in the F VIII (or F IX) gene
(Kadir, 1999; Ljung, 1999). In recent years, there has been
significant progress in preimplantation diagnosis using
PCR-amplified DNA analysis of blast cell(s) in an embryo
up to the eight-cell stage. Another area of recent develop-
ment has been the use of fetal cells in the maternal
circulation for DNA analysis (Kadir, 1999).
In the second trimester, genetic diagnosis can be made
around 16 weeks, using amniocentesis for DNA analysis,
and around 18±20 weeks using umbilical cord (cordocent-
esis) fetal blood sampling for analysis of F VIII:C and F IX:C.
In addition, fetal gender determination in the second
trimester by ultrasound or in the first trimester by
transvaginal scanning can help in the management of
pregnancy and delivery. Despite the availability of prenatal
diagnostic techniques, Kadir et al (1997) reported that only
35% of 32 carriers agreed to a prenatal diagnosis. Of five
affected males, two had subgaleal haemorrhage (SGH) at
birth and three had no neonatal problems.
Carriers in the prepregnant state may have an abnor-
mally low ratio of F VIII:C to F VIII antigen (normal ratio
equals one). However, the hormonal changes associated
with pregnancy induce a rise in F VIII:C levels. Thus, carrier
detection during pregnancy by this method carries a
substantial error rate. It should be noted that levels of F
VIII:C do not rise significantly until the second trimester
and, after delivery, drop precipitously. Consequently, preg-
nant carriers of haemophilia A are at risk of bleeding during
the first trimester and for 3±5 d following delivery.
Haemophilia B carriers, on the other hand, show no change
in F IX:C levels during pregnancy (Kadir et al, 1997). If a
potential carrier has not been tested in the pre-pregnant
state, the carrier status can still be determined by analysis of
the woman's F VIII (or F IX) gene if the precise mutation in
q 2001 Blackwell Science Ltd

Table I. Prenatal diagnosis of haemophilia.
Pre-conceptual counselling
Factor VIIIC to F VIII antigen ratio in carriers
First trimester
Preimplantation DNA diagnosis of embryonic blast cells
(eight-cell stage)
11±13 weeks: chorionic villus sampling (CVS)
DNA analysis of fetal cells in maternal circulation
Transvaginal scanning for fetal gender
Second trimester
Amniocentesis 16 weeks
Umbilical cord (cordocentesis) fetal blood sampling for clotting
factor assay
Fetal gender determination
Third trimester and at delivery
Fetal gender determination
Umbilical cord blood sampling
the family is known. (It should be noted that . 200
mutations in the F VIII and IX genes have been identified, all
of which result in haemophilia.)
Laboratory diagnosis of haemophilia in the newborn
Neither F VIII nor F IX cross the placenta and, thus, a
diagnosis of haemophilia can usually be made from a blood
sample obtained at birth. Appropriate clotting factor assays
from a cord blood sample (obtained by drawing a blood
sample from a vein on the fetal side of the placenta) should
be carried out on all newborn males of haemophilia
carriers, as well as in newborns with suspected bleeding
disorders. If cord blood is not available, then a peripheral
blood sample should be obtained. Physicians should be
aware that infants with mild haemophilia may have a
normal prothrombin time (PT) and activated partial
thromboplastin time (APTT) for their age and yet be at
risk of a bleed.
The majority of newborns have slightly prolonged PT
(mean 13´0 s; range 10´1±15´9 s) and APTT (mean 42´9 s;
range 31´3±54´5 s), secondary to physiologically low levels of
vitamin K-dependent clotting factors (F II, F VII, F IX and F X).
In neonates, plasma levels of F IX:C range between 15 and
8´1 IU/ml, with a mean of 51±53 IU/ml, and reach adult
values by d 90 (Andrew et al, 1987, 1988; Zipursky, 1999).
Thus, mild haemophilia B may be difficult to exclude in
newborns. On the other hand, all degrees of severity of
haemophilia A can be diagnosed at birth as F VIII does not
cross the placenta and levels of F VIII:C at birth are similar
to adult values (50±150 IU/dl).
Influence of labour and delivery on haemophilic newborns
Labour and delivery impose a risk of bleeding not only on
the haemophilia carrier, but also on the affected newborn.
Newborns (normal as well as those with haemophilia)
delivered by vacuum extraction (VE) probably sustain
injuries more than those delivered spontaneously. Caesarean
section (CS) does not appear to eliminate the risk of
bleeding. Towner et al (1999) reported the rate of
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274
Review 265
intracranial haemorrhage (ICH) in nearly 600 000 term
newborns delivered by VE to be 1 in 860 deliveries. This
compared with 1 in 664 ICH with forceps delivery, 1 in 907
with CS during labour, 1 in 2750 CS without labour and 1
in 1900 delivered spontaneously. The authors provided no
information regarding outcome and structural congenital
anomalies in the infants (Benedetti, 1999) or whether any
of the newborns had a bleeding disorder such as haemo-
philia. Ljung et al (1994) reported the mode of delivery in
117 cases of haemophilia (87 vaginal, 17 VE and 13 CS).
The risk of haemorrhage (all sites) was 10% (nine out of 87)
with vaginal delivery, 64% (11 out of 17) with VE and 23%
(three out of 13) with CS. Similarly, ICH after elective CS has
been reported (Michaud et al, 1991). Of five affected males
born to known carriers, Kadir et al (1997) reported significant
subgaleal haemorrhage (SGH)/cephalohaematoma (CepH)
in two newborns (one VE, one CS). In a recent retrospective
study, Klinge et al (1999) reported ICH in 100% (11 out of
11) newborns with haemophilia associated with birth
trauma. It appears, therefore, that vacuum deliveries carry
a significant risk of SGH/CepH and that CS (elective or
during labour) does not eliminate the risk of bleeding.
Neonatal manifestations of haemophilia
Despite the availability of prenatal diagnosis, the majority of
the newborns with haemophilia are still being diagnosed
following a bleeding episode. There are a variety of reasons
for this: one-third have no family history of haemophilia; the
mother or her obstetrician may not understand her risk of
having an affected infant, etc. Nevertheless, in recent years,
the diagnosis of severe haemophilia is being made at an
earlier age than in the past. Baehner & Strauss (1966)
diagnosed haemophilia in only 10% of cases in the newborn
period and in 70% by 18 months of age. In all cases, a
bleeding event eventually led to the diagnosis. Conway &
Hilgartner (1994) diagnosed 54% (35 out of 65) of
haemophiliacs in the first month of life. Of these, 51%
presented with bleeding symptoms. Yoffe & Buchanan
(1988) reported that, in six out of eight haemophilic infants
with ICH in the newborn period, the average age at
diagnosis of haemophilia was 8´4 months (range 6 weeks
to 18 months). More recently, Pollman et al (1999), in a 10-
year single centre study, diagnosed 38% (14 out of 37) of
patients with haemophilia in the first month of life, all of
whom had presented with bleeding events.
The types of bleeding episodes in 349 newborns reported
in 66 publications are summarized in Table II. A MedLine
search from 1966 (when MedLine began) to 1999 yielded
58 reports of bleeding in newborns with haemophilia. The
eight publications before 1966 were obtained from refer-
ences listed in the articles. However, these published cases
do not reflect the true incidence of bleeding episodes in
haemophilic newborns, as we (the authors) are aware of a
number of cases that have not been reported in the
literature. Out of the 366 bleeding episodes reported in
349 newborns with haemophilia, the most common site of
bleeding was in the cranium (Fig 1). ICH accounted for 27%
(98) of all reported bleeds, while 13% (49) were SGH/CepH.
Puncture site bleeds (venous, arterial, heel stick and
266 Review
intramuscular) were reported in 16% (56) cases and 30%
(107) were circumcision bleeds. The majority (82 out of
107) of circumcision bleeds occurred before 1970. Umbili-
cal stump bleeding accounted for 6% (23) of cases, whereas
less than 5% of the bleeds were as a result of gastro-
intestinal/mouth, parenchymal organ (spleen, liver, lungs,
kidneys), joint bleeds or ecchymoses. Many of the newborns
presented with bleeding at more than one site.
The type of haemophilia was reported in 46 publications;
haemophilia A accounted for 87% and haemophilia B for
13% of 76 cases. Of the 70 reported deliveries, spontaneous
vaginal accounted for 47% of the cases, VE/vaginal with
forceps for 40% and CS for 13%.
Intracranial haemorrhages and subgaleal haemorrhage/
cephalohaematoma (SGH)
One of the most devastating and often preventable bleeding
episodes in newborns with haemophilia is ICH. It is usually
related to birth trauma and occurs irrespective of the mode
of delivery. Although ICH has been reported in 1±4% of
haemophilic newborns (Baehner & Strauss, 1966), the
precise incidence is unknown, probably because of under-
reporting or misdiagnosis. Subgaleal haemorrhage (below
the galea aponeurotica) and cephalohaematoma (subper-
iosteal haemorrhage) occur outside the cranial cavity and,
in published cases, are not identified separately (they will be
referred to henceforth as SGH in this article). ICH may occur
concomitantly with SGH, and both can cause life-threatening
hypovolaemic shock, although ICH alone causes neurological
deficits. In addition to F VIII and IX deficiency, ICH has also
been reported in 30% of newborns with F XIII deficiency
(Anwar & Miloszewski, 1999), as well as in newborns
with deficiencies in F II, F V, F VII, F X, inherited fibrinogen
disorders and vitamin K deficiency (Smith, 1990). In a
retrospective review (Kulkarni & Lusher, 1999), the
cumulative incidence of ICH and SGH/cephalohaematoma
in newborns with haemophilia A and B was 3´58%, and the
mean age of diagnosis was 4´5 d (0±28 d). In 11 out of 27
patients with haemophilia and ICH, bleeding was diagnosed
at birth (Klinge et al, 1999).
The precise anatomical location of the ICH is often not
specified in publications. Of 109 episodes of cranial bleeds in
102 newborns, 65% were as a result of ICH and 35% as a
result of SGH/cephalohaematoma (Table II) (Kulkarni &
Lusher, 1999). There have been only two published reports
of IVH in premature newborns with haemophilia (Pegelow
et al, 1989; Gale et al, 1998).
Mode of delivery
Controversy exists in the literature regarding the safest
mode of delivery of newborns known to be at risk for
haemophilia. Ljung et al (1994) recommended vaginal
delivery for pregnant haemophilia carriers and, as noted
earlier, reported a significant risk of cranial haematomas
with vacuum extraction. Kletzel et al (1989) reported the
association of ICH with traumatic deliveries in three out
of four haemophilic infants with cranial haemorrhages.
Elective CS has not prevented ICH (Kletzel et al, 1989;
Michaud et al, 1991; Buchanan, 1999). Kadir et al (1997)
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274
reported cephalohaematoma in two out of five affected
newborns, one following CS and the other following
instrumental vaginal delivery. In a North American survey
of haemophilia treatment centres, Goldsmith & Kletzel
(1990) reported that CS was routinely recommended by
14´4% of the sites. A recent survey (Kulkarni et al, 1999)
revealed that 94% of obstetricians in the USA had no
written guidelines for the management of pregnant haemo-
philia carriers or their newborns. Approximately 57%
preferred vaginal delivery and 11% preferred CS for
pregnant haemophilia carriers. Availability of high-risk
obstetrical services, coupled with access to specialized
haematology and neonatology services influenced delivery
by the vaginal route (Kulkarni et al, 1999). The importance
of meaningful communications between all involved (obste-
tricians, haematologist and neonatologist) throughout a
known (or possible) carrier's pregnancy cannot be over-
emphasized.
Signs and symptoms
Neonatal ICH may be the first indication of haemophilia.
Symptoms of ICH may be dramatic and include seizures
(generalized and focal), paralysis, hypertonia, pupillary
changes and, rarely, stridor as a result of vocal cord
paralysis (Fah & Tan, 1994). ICH may mimic sepsis and/
or disseminated intravascular coagulopathy (DIC) or menin-
gitis (Schmidt & Zipursky, 1986). SGH/CepH, although an
extracranial haemorrhage, can be equally life threatening
because of massive haemorrhage. Plauche (1980) reported
a 22´8% mortality rate with subgaleal haemorrhages in all
newborns. More often, however, the symptoms of both ICH
and SGH/CepH are vague, leading to a delay in diagnosis in
many instances. Symptoms frequently include anaemia,
hypovolaemic shock, pallor, vomiting, hypotension and
jaundice. A high degree of suspicion is therefore warranted
so that invasive procedures can be avoided and appropriate
treatment instituted promptly. One of the long-term con-
sequences of ICH, despite treatment, is long-term neurolo-
gical deficits. Klinge et al (1999) reported such deficits in
100% of haemophilic newborns with ICH. A literature
review (Kulkarni & Lusher, 1999) revealed neurological
deficits in 38% of haemophilic neonates with a follow up of
1±36 months.
ICH and SGH/CepH can occur regardless of the severity of
haemophilia. To what extent other factors, such as DIC,
vitamin K deficiency, prematurity, etc., contribute to the
severity of these cranial haemorrhages remains unknown.
Thirty-five (87´5%) out of 40 newborns with ICH and SGH/
CepH had haemophilia A (22 severe, 10 moderate and three
mild), whereas five (12´5%) had haemophilia B (one severe,
two moderate, one mild and one whose severity was not
specified) (Kulkarni & Lusher, 1999).
Diagnosis
The diagnosis of ICH is often confirmed by computerized
tomography (CT) scans and ultrasound (US) techniques that
have replaced skull radiographs and the more invasive
lumbar puncture (LP), subdural taps and ventriculography
(Alverez-Garijo et al, 1981). Although a `bloody tap' can
 Table II. Summary of bleeds in 342 newborns with haemophilia.
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274

Newborns F VIII F IX SGH/ Puncture Organ

Number Year References with bleeds Vag VE/VF CS deficiency deficiency ICH CepH bleeds Circ Umb bleed GI Bruise Joint

1 1999 Pollmann et al 14 2 1 1 2 1
2 1999 Johnson-Robbins et al 1 1 1 1 1 1
3 1999 Klinge et al 11 11 11
4 1999 Alcover et al 1 1 1
5 1998 Ries et al 1 1 1
6 1998 Le Pommelet et al 2 2 2 2
7 1998 Haya et al 1 1 1 1
8 1998 Gale et al 1 1 1 1
9 1998 Edwards 1 1 1 1 1 1
10 1998 MeÂnart et al 1 1
11 1998 Baujard et al 1 1 1 1
12 1997 Balliu Badia et al 1 1 1
13 1997 Bray 4 4 4
14 1997 Kadir et al 3 3 2 5 2 1
15 1997 Fields et al 1 1 1
16 1996 Onwuzurike et al 8 1 6 1
17 1995 Hanigan et al 1 1 1
18 1994 Ljung et al 47 9 11 3 5 12 24 4 1 1
19 1994 Fah & Tan 1 1 1 1
20 1994 Chen et al 1 1 1 1 1
21 1994 Dietrich et al 1 1 1 1
22 1994 Conway & Hilgartner 18 1 3 2 10 2
23 1994 Reish et al 1 1 1
24 1993 Stowell et al 1 1 1
25 1992 Martinowitz et al 3 3
26 1992 de Tezanos et al 4 4
27 1991 Michaud et al 1 1 1 1
28 1990 Goldsmith & Kletzel 21 19 2
29 1990 Ljung et al 28 5 7 12 2 2
30 1990 Jedele et al 2 1 1 1 1
31 1989 Pegelow et al 1 1 1 1 1
32 1989 Kletzel et al 4 1 3 3 1 2 2 2
33 1988 Bisset et al 1 1 1
34 1988 Yoffe & Buchanan 6 5 1 5 1 6
35 1988 Longon et al 1 1 1 1
36 1988 Ohga et al 1 1 1 1
37 1988 Franze & Forrest 1 1 1 1

Review
38 1987 Bray & Luban 1 1 1 1 1
39 1986 Schmidt & Zipursky 5 1 5 5 1 1
40 1986 Schmid et al 1 1 1 1
41 1985 Olson et al 1 1 1 1

267
42 1985 Heldrich & Garg 1 1 1 1
 268
Table II. continued

Newborns F VIII F IX SGH/ Puncture Organ

Number Year References with bleeds Vag VE/VF CS deficiency deficiency ICH CepH bleeds Circ Umb bleed GI Bruise Joint

Review
43 1985 Yonker et al 1 1 1 1 1 1
44 1984 Pettersson et al 1 1 1
45 1983 Trotter & Hasegawa 1 1 1 1
46 1982 Rohyans et al 2 1 1 2 2
47 1981 Iannaccone & Pasquino 1 1 1 1 1 1
48 1981 Alverez-Garijo et al 1 1 1 1
49 1981 Mimiya et al 1 1 1
50 1980 Barbero et al 1 1 1
51 1978 Eyster et al 3 3
52 1978 Cohen 1 1 1 1 1
53 1978 Koch 1 1 1 1
54 1976 Volpe et al 1 1 1 1
55 1973 McCarthy & Coble 1 1 1
56 1966 Baehner & Strauss 62 1 2 2 53 2 1 2
57 1966 Britten 1 1 1 1 1
58 1965 Kozinn et al 2 2 2
59 1964 Kozinn et al 2 2 1 1 2
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274

60 1963 Croziat et al 12 6 4 1 1
61 1962 Ramgren 13 2 1 6 1 3
62 1960 Ikkala 2 1 1
63 1961 McMillan et al 1 1
64 1957 Hartmann & Diamond 29 2 26 1
65 1951 Mosely & Bruton 1 1
66 1949 Davidson et al 2 2
66 published 349 33 28 9 66 10 98 49 56 107 23 10 10 9 4
Percentage 87% 13% 27% 13% 16% 30% 6% 3% 3% 3% 1%
366 bleeds in 349 newborns

Vag, vaginal delivery; VE, vacuum extraction; VF, vacuum with forceps; CS, caesarean section; ICH, intracranial haemorrhage; SGH/CepH, subgaleal haemorrhage/cephalohaematoma; Circ,
circumcision bleeds; Umb, umbilical bleeds; GI, gastrointestinal bleeds.

Non specified bleeds
Joint bleed
2.5%
1%
GI
Organ bleed 3%
2.5%
Umbilical
6%
Puncture bleeds
16%
Circumcision*
30%
lead to a suspicion of haemophilia, LP can be dangerous,
especially in the presence of a posterior fossa subdural
haematoma, where it can provoke a herniation. An
improperly performed LP in a haemophilic infant can also
lead to bleeding, cord compression and paralysis. Although
the majority of the ICH can be diagnosed by ultrasound, the
detection of subdural haematomas by this method can be
difficult. CT and magnetic resonance imaging (MRI) can
give the precise location of the haemorrhage(s). MRI,
although more expensive, is superior to CT in evaluating
posterior fossa haemorrhages. Nonetheless, CT and US are
safe, non-invasive and definitive means of diagnosing ICH.
Heibel et al (1993) detected evidence of ICH in nearly 10% of
clinically normal full-term newborns on ultrasound per-
formed 3 d post partum in 1000 babies. None of these
newborns were evaluated for haemophilia. In 102 new-
borns with ICH and SGH/CepH, diagnostic studies were
performed in 27 cases, of which CT and US were carried out
in 81% (Kulkarni & Lusher, 1999).
Laboratory confirmation of haemophilia can be obtained
by F VIII:C (or F IX:C) assay. Co-existing coagulation
abnormalities, as may occur with DIC, hypofibrinogenaemia
and thrombocytopenia, can sometimes obscure the diag-
nosis. It is therefore imperative that specific coagulation
factor assays be performed in all bleeding newborns,
especially those with ICH and/or with prolonged APTT.
The devastating consequences of ICH because of a delay
in diagnosis (and in many cases despite early diagnosis) has
raised a lively debate concerning the pros and cons of early
prophylactic administration of clotting factor in newborns
diagnosed with or suspected to have haemophilia (Berry,
1999; Buchanan, 1999). Such a strategy would involve
administration of the smallest available vial (250 IU/vial in
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274
Review 269
ICH
27%
SCH / CepH Fig 1. Sites of bleeding in 349 neonates.
14% Number of bleeding episodes was 366. *82
out of 107 cases of circumcision bleeds were
reported in publications from 1966 to
1949. ICH, intracranial haemorrhages;
SGH/CepH, subgaleal/cephalohaemotoma.
the USA) of recombinant F VIII (rF VIII) or IX to all such
newborns. In a 3 kg neonate, such an administration will
raise F VIII or F IX levels to 150±200 IU/dl and 60±80 IU/
dl, respectively, enough to provide haemostasis for 24±72 h
(Buchanan, 1999). A survey of paediatric haematologists
indicated that approximately 40% of those responding
would favour administering clotting factor concentrate to
prenatally diagnosed haemophilic newborns (and newborns
born to suspected carriers) immediately after birth, to offset
the trauma of delivery (Kulkarni et al, 1999). Intrauterine
infusion of rF VIII during early labour resulted in correction
of the haemostatic defect in one fetus with proven
haemophilia (Gilchrist et al, 1998). Such enthusiasm for
early prophylaxis must be tempered with the awareness that
traumatic bleeding may result, and that inhibitor formation
has been reported in newborns with haemophilia following
treatment with rF VIII (Haya et al, 1998).
Circumcision bleeds and haemophilia
Circumcision is one of the most common operative pro-
cedures performed in newborn males. Bleeding, a common
complication of circumcision, has an incidence of 0´1±35%
in healthy boys (Kavakli & Aldedort, 1998). Prolonged
circumcision bleeding often leads to a suspicion of haemo-
philia. There are 101 published cases of bleeding associated
with circumcision in haemophilia newborns. Earlier pub-
lications (Hartmann & Diamond, 1957; Baehner & Strauss,
1966) reported a large number of newborns that bled with
circumcision. Since 1995, however, there has been only a
single published report of bleeding associated with cir-
cumcision in a newborn, which led to the diagnosis of
haemophilia (Edwards, 1998). With circumcision no longer
a routine and with better education and communication
270 Review
between obstetricians, haematologists and parents, fewer
babies are experiencing bleeds. Additionally, the advent of
fibrin glue (Kavakli, 1999) has not only reduced the
duration of hospitalization, but also the use of factor
concentrate and the high cost associated with circumcision
in newborns with haemophilia.
Puncture bleeds (venepuncture, arterial, intramuscular
injections)
Prolonged oozing and/or enlarging subcutaneous haemor-
rhages from puncture sites, such as a venepuncture, arterial
puncture, heel sticks or an intramuscular (IM) bleed
following vitamin K injection, may represent the first sign
of a congenital coagulation disorder in a newborn and often
prompts further investigation. If a neonate is known to have
haemophilia (or other coagulopathy), venepuncture should
be carried out with great care and application of local
pressure. Arterial punctures should be avoided. In addition
to excessive bleeding, aneurism of the radial artery has been
reported following arterial puncture in a newborn with
haemophilia (Fields et al, 1997). Bleeding after injections or
blood sampling in haemophilic newborns has ranged from
3% (Conway & Hilgartner, 1994) to 42% (Ljung et al,
1990). In one study (Ljung et al, 1994), 24 out of 117
haemophilic newborns (20%) manifested abnormal bleeding
tendencies following simple medical procedures such as
blood sampling or injection of vitamin K. Pollmann et al
(1999) observed muscle bleeding in 7% of 14 previously
untreated newborns with haemophilia. Such bleeding has
prompted many to recommend oral vitamin K instead of IM,
as it is less expensive and less invasive. However, one should
be aware that oral vitamin K prophylaxis at birth and
supplemented during the neonatal period has not prevented
late haemorrhagic disease of the newborn. Problems with
compliance coupled with erratic absorption have interfered
with the effectiveness of oral vitamin K (Zipursky, 1999).
Lumbar puncture should be avoided in neonates diag-
nosed with or suspected of having haemophilia. If deemed
absolutely necessary, the procedure should be done with
great care by an experienced person and only after
administration of clotting factor concentrates.
Umbilical bleeding
Umbilical bleeding is seen in over 90% of infants with
congenital F XIII deficiency and has also been reported in
infants with congenital afibrinogenaemia (Smith, 1990)
and vitamin K deficiency. However, bleeding from the
umbilical stump is rare in haemophilia and accounts for
only 6% of bleeds in haemophilic newborns (Table I).
Sometimes the bleeding may be severe enough to require
sutures (Bray & Luban, 1987). As newborns are now
discharged from the hospital earlier following birth, parents
should be made aware of the need to seek immediate
attention for any persistent bleeding from a circumcision
site or from the umbilical stump.
Joint, visceral organ and other haematomas
Joint bleeding, the hallmark of haemophilia in older
children, is rare in the newborn period. Bilateral elbow
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274
bleeding, conceivably because of vigorous restraint for
antecubital puncture, has been reported in a haemophilic
newborn (Chen et al, 1994). Visceral organ bleeds (spleen,
liver, adrenal lung, gastrointestinal and kidney), although
dramatic and sometimes life threatening, are also rare and
require prompt diagnosis and treatment. Splenic rupture/
laceration has been described in two cases (Baehner &
Strauss, 1966; Johnson-Robbins et al, 1999) and has been
seen in another by the authors immediately after vaginal
delivery. Splenic haematomas have been reported in two
cases (Iannaccone & Pasquino, 1981). Spontaneous hae-
matomas including skin bruising, although uncommon,
can occur in the haemophilic newborn and should alert one
to the diagnosis. In other words, any unexplained or
prolonged bleeding in a newborn should raise the suspicion
of haemophilia, and screening tests must be followed by
appropriate factor assays (this can usually be done from the
same citrated blood sample).
Management of newborn haemophilia
Antenatal diagnosis of haemophilia coupled with prenatal
US (and proper communication between all involved) in
known carriers may aid in the management and ensure safe
delivery of haemophilic newborns. It is imperative that all
male offspring of haemophilia carriers have factor assays
carried out on a cord blood sample (or, if this has not been
done, by venepuncture as early as possible). Although the
majority of the newborns with haemophilia do not bleed in
the newborn period, in many instances, haemorrhage may
be of such a profound nature that therapy must be
instituted before a precise diagnosis can be made (Oski &
Naiman, 1982). If necessary, fresh-frozen plasma (FFP) can
be used for treatment of serious bleeding pending the results
of diagnostic coagulation tests. Once the diagnosis is
made, recombinant clotting factor concentrates are pre-
ferred (over plasma or plasma-derived products) because of
their increased margin of viral safety. If recombinant
clotting factor concentrates are unavailable, highly purified
virally inactivated plasma-derived F VIII or F IX products
should be used. In babies strongly suspected or confirmed as
having haemophilia, one might even consider administering
a prophylactic dose of F VIII or IX shortly after birth to offset
the trauma of labour.
Treatment of suspected head bleeds consists of appro-
priate recombinant coagulation factor replacement to
increase plasma levels to 100%. If recombinant clotting
factor concentrates are unavailable, highly purified virally
inactivated plasma-derived F VIII or coagulation F IX
products can be used. FFP (donor-retested FFP or solvent
detergent treated) can be used for treatment of serious
bleeding pending the results of diagnostic tests. If ICH is
confirmed, clotting factor replacement should be continued
for at least 2 weeks. This should be followed by a period of
prophylaxis whenever feasible. Neurosurgical intervention
under proper clotting factor coverage may be required to
evacuate the bleed.
Activated recombinant F VII (rF VIIa) concentrates have
been used for the management of severe bleeding (including
ICH) in older patients with severe haemophilia A and B with

and without inhibitor antibodies to F VIII (or F IX), as well
as in patients with congenital F VII deficiency (Rice &
Savidge, 1996; Ingerslev & Kristensen, 1998; Lusher et al,
1998). Its role and safety record in the treatment of severe
and life-threatening bleeding episodes (such as ICH) in
newborn haemophiliacs is unknown and warrants further
investigation.
As intracranial haemorrhages in haemophilic newborns
are often preventable and appropriate diagnosis and
treatment is urgent, the Medical and Scientific Advisory
Council (MASAC) of the National Hemophilia Foundation,
USA, issued a set of recommendations in 1998 which
included the following: (1) all infants with intracranial
haemorrhages should be evaluated for a bleeding disorder;
(2) vacuum devices and fetal scalp monitors should not be
used during vaginal deliveries of infants of haemophilia
carriers; (3) women with post-partum haemorrhage should
have a bleeding work-up and appropriate treatment; (4) a
national registry should be established for neonates with
haemophilia and other bleeding disorders; and (5) national
guidelines and recommendations for the care of pregnant
women with bleeding disorders should be established
(National Hemophilia Foundation, 1998).
Recommendations
The following are recommendations followed at the authors'
institutions for male infants born to possible or known
carriers of haemophilia A or B, or in newborns with
suspected haemophilia.
1. Vaginal delivery should be considered for all infants
with haemophilia or suspected haemophilia unless CS is
indicated for obstetrical purposes. Infants with haemophilia
or suspected of having haemophilia should not be delivered
by VE of forceps.
2. Appropriate clotting factor assays from a cord blood
sample should be done on all newborn males of haemophilia
carriers, as well as in newborns with suspected bleeding
disorders. If cord blood is not available, a peripheral blood
sample should be obtained. If screening tests such as PT and
APTT are performed in a newborn, instruct the laboratory
to freeze any remaining sample as factor assays can be
performed on the same blood sample. Physicians should be
aware that mild haemophilia patients might present with a
normal PT and APTT and yet be at risk of a bleed. Signs of
ICH may not be apparent in the first few days of life.
3. A repeat blood sample, if deemed necessary to confirm
the diagnosis, is best collected when the infant is 6 months
old.
4. As one-third of all newborns with haemophilia have no
family history of haemophilia, any child born at term with
an ICH should have a PT and APTT and appropriate clotting
factor assays. A coagulation work-up should be considered if
the screening tests are prolonged or haemophilia suspected.
5. The signs of ICH are vague and may include anaemia
(pallor), lethargy, neurological deficits, hypotension, aniso-
coria (unequal pupils), tense fontanel, vomiting, etc. In
cases of suspected ICH, administer a dose of clotting factor
first and then obtain a CT of the head. Note that ultrasound
of the head may fail to detect subdural haematomas.
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 264±274
Review 271
6. In cases of haemorrhage, one can administer
intravenously the smallest available vial (250 IU is the
smallest size available in the USA) of rF VIII or IX to provide
immediate haemostasis for at least 24±7 h. Further dosing
and administration will depend on the levels of F VIII:C or F
IX:C and the clinical circumstances. If recombinant clotting
factors are unavailable, highly purified virally inactivated
plasma-derived F VIII or F IX products can be used. If
the diagnosis is not known, one should administer FFP,
15±20 ml/kg.
7. Circumcision should be discouraged in order to prevent
the possibility of prolonged bleeding. If the family insists on
a circumcision, call the Haemophilia Treatment Centre so
that appropriate dialogue and/or proper arrangements can
be made.
8. Heel sticks and venepuncture should be carried out
with great care and be followed by local application of
pressure applied for 5 min, with close observation of the site
for 24 h. Note: these procedures should be avoided unless
absolutely necessary.
9. If vitamin K is given IM, apply firm pressure to the site
for 5±10 min. Although oral vitamin K prophylaxis
prevents classic haemorrhagic disease of the newborn
[HDN; more appropriately termed vitamin K deficiency
bleeding (VKDB)], it is ineffective in preventing late HDN
(Zipursky, 1999). Increasing the dose or giving it weekly, or
for a longer period, increases the efficacy of oral prophylaxis
for HDN (Sutor et al, 1999).
10. Hepatitis B vaccine can be given subcutaneously
rather than IM in newborns with haemophilia or suspected
haemophilia.
11. Newborns with haemophilia and ICH should be
started on early prophylaxis with F VIII or F IX concentrates
to prevent recurrent or late ICH.
12. Discharge instructions for neonates with haemophilia
should include measurement head circumference and
education of parents about signs of intracranial haemor-
rhage, ie. excessive sleepiness, irritability, irregular breathing,
pallor, pupils of unequal size, seizures, excessive vomiting,
tense fontanelle and feeding difficulty. The patient and his
parents should be given an appointment with the haemo-
philia clinic 1 week after discharge.
1
Michigan State University, Roshni Kulkarni 1
Pediatrics/Human Development, B220 Jeanne Lusher 2
Clinical Center, 138 Service Road,
East Lansing, MI 48824-1313, and
2
Children's Hospital of Michigan,
Division of Hematology/Oncology,
Wayne State University, 3901
Beaubien Blvd., Detroit, MI 48201-
2196, USA
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Keywords: newborn/ neonate, haemophilia, haemorrhages,
delivery, intracranial.