Updated Australian consensus statement on management of inherited bleeding disorders in pregnancy

Abstract

Introduction
There have been significant advances in the understanding of the management of inherited bleeding disorders in pregnancy since the last Australian Haemophilia Centre Directors’ Organisation (AHCDO) consensus statement was published in 2009. This updated consensus statement provides practical information for clinicians managing pregnant women who have, or carry a gene for, inherited bleeding disorders, and their potentially affected infants. It represents the consensus opinion of all AHCDO members; where evidence was lacking, recommendations have been based on clinical experience and consensus opinion.

Main recommendations
During pregnancy and delivery, women with inherited bleeding disorders may be exposed to haemostatic challenges. Women with inherited bleeding disorders, and their potentially affected infants, need specialised care during pregnancy, delivery, and postpartum, and should be managed by a multidisciplinary team that includes at a minimum an obstetrician, anaesthetist, paediatrician or neonatologist, and haematologist. Recommendations on management of pregnancy, labour, delivery, obstetric anaesthesia and postpartum care, including reducing and treating postpartum haemorrhage, are included. The management of infants known to have or be at risk of an inherited bleeding disorder is also covered.

Changes in management as a result of this statement
Key changes in this update include the addition of a summary of the expected physiological changes in coagulation factors and phenotypic severity of bleeding disorders in pregnancy; a flow chart for the recommended clinical management during pregnancy and delivery; guidance for the use of regional anaesthetic; and prophylactic treatment recommendations including concomitant tranexamic acid.

Full text

Consensus statement
MJA 210 (7) ▪ 15 April 2019
Updated Australian consensus statement on
management of inherited bleeding disorders in
pregnancy
Scott Dunkley1, Julie A Curtin2,3, Anthony J Marren4, Robert P Heavener4, Simon McRae5, Jennifer L Curnow6
Inherited bleeding disorders pose a unique challenge during
pregnancy and childbirth. Women who are affected with, or
are carriers of, inherited bleeding disorders, and their infants,
are at risk of bleeding complications from haemostatic chal-
lenges during pregnancy and childbirth. Therefore, pregnancy
and delivery need to be managed appropriately.1–6
This statement is an update of the 2009 Australian Haemophilia
Centre Directors’ Organisation (AHCDO) consensus statement
on pregnancy and delivery management in women with inher-
ited bleeding disorders.7 Over the past 9 years there have been
key advances in the understanding and management of inher-
ited bleeding disorders in pregnancy. The aim of this updated
consensus statement is to improve the care of women who have,
or are carriers of, inherited bleeding disorders, and their poten-
tially affected infants, by providing practical recommendations
for the management of pregnancy and delivery.
Despite inclusion of pregnancy and delivery management in a
number of published evidence- based guidelines on the man-
agement of inherited bleeding disorders, many guidelines are
lengthy and not user- friendly.1,2,6 ,8 –10
AHCDO includes all directors of haemophilia centres (adult and
paediatric) throughout Australia, as well as additional haema-
tologists registered through AHCDO who care for patients with
haemophilia either at these sites or at satellite centres. The con-
sensus statement was developed by an AHCDO working party
following extensive consultation, face- to- face meetings and revi-
sions. The final document represents the consensus opinion of
all AHCDO members.
As pregnancy and delivery management for women with inher-
ited bleeding disorders involves a multidisciplinary team that
includes an obstetrician, anaesthetist, paediatrician or neonatol-
ogist, and haematologist, we anticipate that this consensus state-
ment will serve as a useful reference document for the broader
medical community.
Methods
We reviewed current international clinical practice guidelines
on the management of inherited bleeding disorders in preg-
nancy. We also conducted broad literature searches and manu-
ally searched reference lists. Inclusion criteria were restricted
to high quality meta- analyses, systematic reviews, randomised
controlled trials and clinical practice guidelines. Studies pub-
lished in English and conducted in humans, and with an abstract
available, were included for review. In several areas, evidence
was lacking and, in such cases, recommendations were based on
the clinical experience and consensus opinion of the AHCDO
directors.
Inherited bleeding disorders in women
The most common inherited bleeding disorders and their phe-
notypes in women are outlined in Box 1.1,2 ,4, 8,11
Haemophilia A and B are X chromosome- linked conditions that
are often mistakenly thought to affect males with females being
carriers; however, a range of phenotypes are observed in females
who have one copy of an abnormal gene for coagulation factor
VIII (haemophilia A) or factor IX (haemophilia B). This pheno-
type range extends from a carrier with normal factor levels (the
majority of patients), to those with mildly reduced factor levels
(mild haemophilia) through to (very rarely) those with extremely
low factor levels consistent with severe haemophilia. This range
is due to genetic factors including skewed X chromosome inac-
tivation (lyonisation), Turner syndrome or other chromosomal
translocations and deletions.
Although there are differences in the reference ranges cited
by coagulation laboratories, the normal plasma range for both
1 Insti tute of Haema tology,Royal Pr ince Alfre d Hospital, Sy dney, NSW. 2 The Childre n’s Hospit al at Westme ad, Sydney, NSW. 3 Aus tralian Haem ophilia Cent res Direct ors’ Organis ation,
Melbou rne, VIC . 4 Royal Prin ce Alfred Ho spital, Sydn ey, NSW. 5 Royal Adelai de Hospital , Adelaide, SA . 6 Haemophilia Treatm ent Centre,Westmead Hos pital, Sydney, NSW.
scottmdunkley@gmail.com ▪ do i: 10.5694/mja2.50123
Abstract
Introduction: There have been significant advances in the
understanding of the management of inherited bleeding disorders
in pregnancy since the last Australian Haemophilia Centre Directors’
Organisation (AHCDO) consensus statement was published in 2009.
This updated consensus statement provides practical information
for clinicians managing pregnant women who have, or carry a gene
for, inherited bleeding disorders, and their potentially affected
infants. It represents the consensus opinion of all AHCDO members;
where evidence was lacking, recommendations have been based on
clinical experience and consensus opinion.
Main recommendations: During pregnancy and delivery, women
with inherited bleeding disorders may be exposed to haemostatic
challenges. Women with inherited bleeding disorders, and their
potentially af fec ted infants, need specialised care during
pregnancy, delivery, and postpar tum, and should be managed by a
multidisciplinary team that includes at a minimum an obstetrician,
anaesthetist, paediatrician or neonatologist, and haematologist.
Recommendations on management of pregnancy, labour, delivery,
obstetric anaesthesia and postpartum care, including reducing and
treating postpartum haemorrhage, are included. The management
of infants known to have or be at risk of an inherited bleeding
disorder is also covered.
Changes in management as a result of this statement: Key
changes in this update include the addition of a summary of the
expected physiological changes in coagulation factors and
phenotypic severit y of bleeding disorders in pregnancy; a flow
chart for the recommended clinical management during pregnancy
and delivery; guidance for the use of regional anaesthetic; and
prophylactic treatment recommendations including concomitant
tranexamic acid.
326

MJA 210 (7) ▪ 15 April 2019
327
Consensus statement
MJA 210 (7) ▪ 15 April 2019
327
factor VIII and factor IX is 50–200 IU/dL.6 In practical terms,
normal equates to levels of factor VIII, factor IX and von
Willebrand factor antigen > 50 IU/dL for haemophilia A, hae-
mophilia B and type 1 von Willebrand disease. Bleeding risk is
dependent on factor levels and the lower the factor level below
40 IU/dL the greater the bleeding risk.5 Together, haemophilia
A and B, von Willebrand disease, and factor VII and factor XI
deficiency account for around 90% of all women with inher-
ited bleeding disorders.12
Physiological response expected in pregnancy
As part of the normal physiological response, factor VIII and von
Willebrand factor antigen levels rise during pregnancy, usually
reaching a plateau at around 29–35 weeks’ gestation (Box 1).13,14
For many but not all women with low factor VIII levels due to
a mutation in one of their factor VIII genes, this physiological
rise in factor VIII will result in levels rising to within the nor-
mal range and thus there is no increased risk of bleeding. For
some women, however, factor VIII levels may remain low at
term.6,8,13 –15 Factor IX and factor XI do not change significantly
in preg n a ncy.6,8,10,15 –18
For women with von Willebrand disease, the type influences
their ability to mount this physiological response. Women with
type 1 von Willebrand disease — the common, mild form —
will achieve normal levels of von Willebrand factor antigen and
factor VIII. Those with type 2, in which the function of the von
Willebrand factor molecule is impaired, will show a rise in their
von Willebrand factor antigen level, but the functional activity
will remain low. Patients with type 2B may show worsening
thrombocytopenia due to increased levels of the abnormal von
Willebrand factor molecule. Patients with type 3 will not ex-
hibit a rise in levels. Therefore, patients with type 2 and 3 von
Willebrand disease typically remain at risk of bleeding.16
1 Bleeding disorders, coagulation factor affected and expected range of bleeding phenotypes in women1,2 ,4, 8,11 ,15
Disorder
Coagulation factor
affected
Bleeding phenotype
in women*
Expected factor
level changes dur ing
pregnancy
Treatment options
(if required)
Haemophilia A Factor VIII levels
decreased†
Mild to moderate when levels
< 40 IU/dL‡
Typically, increase
throughout
pregnancy
Factor VIII or DDAVP antenatally; f actor
VIII replacement therapy before delivery,
if required
Haemophilia B Factor IX levels decreased Mild to moderate when levels
< 40 IU/dL‡
No Factor IX replacement therapy before
delivery, if required
Factor XI deficienc y Factor XI levels decreased Highly variable; r isk increased
with levels < 15 IU/dL
No Factor XI replacement or fresh f rozen
plasma before deliver y, if required
von Willebrand disease
Typ e 1 VWF levels decreased†Mild to moderate Yes, tends to increas e
throughout
pregnancy
VWF containing concentrates or DDAVP
antenatally; VWF- containing concen-
trates before delivery, if required
Typ e 2§Dysfunc tional VWF Variable, usually moderate No, small increases
only§
VWF- containing concentrates
antenatally and before delivery, if
required
Typ e 3 VWF absent Severe ( VWF antigen
undetectable; factor VIII
levels < 10 IU/dL)
No, does not improve VWF- containing concentrates
antenatally and before delivery, if
required
Rare coagulation
deficiencies
Afibrinogenaemia; factor
II, fac tor V, combined
factor V and VIII, fac tor VII,
factor X and factor X III
deficiencies
Highly variable, mild to
severe, not alway s
predictable based on factor
levels
Recurrent fet al loss
associated with fac tor I
(fibrinogen), factor II and
factor XIII deficiencies
No Specific factor replacement or fresh
frozen plasma for f actor V deficienc y, if
required
Congenital platelet disorders
Glanzmann
thrombasthenia
Disorder of platelet
function
Often associated with severe
bleeding phenotype
No Avoid blood or platelet transfusion
during pregnancy; HLA- matched
platelets transfused at delivery
Bernard–Soulier
disease
Glycoprotein Ib- IX- V
receptor abnormality
Often associated with severe
bleeding phenotype
No Avoid blood or platelet transfusion
during pregnancy; HLA- matched
platelets transfused at delivery
Other Usually mild No
DDAVP = D- amino D- argini ne vasopres sin (desmopres sin); HLA = human l eukocyte a ntigen; VW F = von Willebra nd factor. * Blee ding risk fac tor levels: s evere, < 1 IU/dL; mo derately se vere,
3–10 IU/dL; mild, 1 0–40 IU/dL ; low, > 40 IU/dL. Women with le vels < 1 IU/dL (seve re) should be mo nitored mo re closely. † Le vels may normalise during pr egnancy.6 ‡ Women with f actor VII I
or IX l evels > 40 IU/dL b ut below the lower limit of the refere nce inter val (50–20 0 IU/dL, but no te that labo ratory re ference in tervals v ary based on methodol ogy) may also have increas ed
bleeding tendencies.5 § Thromboc ytopenia as sociated wit h type 2B von Wi llebrand disea se may worsen during pr egnancy. Note reg arding units: 1 in ternationa l unit (IU) of fac tor VIII acti vity
is equiv alent to that quan tity of fact or VIII in 1 mL of normal hum an plasma. Levels ar e cited in % or IU/dL as the two uni ts are equival ent and can be used int erchangeab ly. Some laborat ories
give uni ts as IU/mL; no te, 50 IU/dL = 50% = 0. 5 IU/mL. ◆

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MJA 210 (7) ▪ 15 April 2019
328
The rise in factor levels is unpredictable during pregnancy and
ideally levels should be checked before pregnancy, at the first an-
tenatal visit (Box 2),19 before any invasive procedure, and during
the third trimester to facilitate planning of delivery.1,2, 6,8,14,17
After delivery, factor levels usually return to baseline after 7–21
days but may drop earlier.5,6,8,13–16,20
Management of pregnancy and delivery
Before pregnancy
Pre- conception genetic counselling should be considered for any
mother at risk of having a child with haemophilia (eg, known
family history, known low factor levels) to allow for appropriate
planning with a multidisciplinary team (Box 2). If factor levels
are not known, they should be measured and, if levels are low,
the pregnancy should be managed appropriately. Historical di-
agnosis and response to desmopressin (D- amino D- arginine vas-
opressin; DDAVP) should also be established. Pre- implantation
genetic diagnosis as well as antenatal genetic diagnosis (via cho-
rionic villus sampling) for haemophilia genotypes are available
in Australia and can be considered in families where the genetic
mutation responsible for the haemophilia has been identified.
Special considerations may need to be made for women with
inherited bleeding disorders when undergoing invasive in vitro
fertilisation procedures, such as oocyte retrieval, that carry a risk
of bleeding. Management is multidisciplinary and includes the
fertility specialist, haematologist and anaesthetist. Factor replace-
ment and/or tranexamic acid around the time of procedure may
be indicated. Consideration should be given to the most appro-
priate location in which such procedures should occur.21,22
Women with rarer bleeding disorders, such as fibrinogen or factor
XIII deficiency, may be at increased risk of recurrent fetal loss (Box
1). Such women may benefit from prophylactic therapy (Box 3).23
During pregnancy
While it is important to recognise that women with mild haemo-
philia and other inherited bleeding disorders may have an in-
creased risk of bleeding depending on factor levels, they usually
require no specific therapy or factor replacement antenatally.
Women with factor VIII or factor IX levels < 40 IU/dL, or type
2 or type 3 von Willebrand disease may be at risk of bleeding
and may require factor replacement for procedures and delivery.
The lower their factor level or von Willebrand factor activity, the
more likely they will be to require replacement.10,25
Bleeding in women with factor XI deficiency is highly variable,
and provision of replacement therapy should be individualised;
however, it may be required if factor XI levels are < 15 IU/dL.6,17,18
Treatment of women with rare bleeding disorders during preg-
nancy should be individualised and guided by a haemophilia
clinician as early as possible (Box 1).
Fetal sex determination
For women who carry the mutation for haemophilia and are
pregnant with a male fetus, there is a 50% chance the fetus will
be affected by haemophilia; for a female fetus there is a 50%
chance she will inherit the mutation for haemophilia. While
most female fetuses will have normal or only mildly reduced
factor levels, very rarely a female fetus may have moderately
or severely reduced factor levels. Fetal sex determination using
ultrasound and free fetal DNA in maternal circulation aids la-
bour and delivery planning, and may also preclude the need
for more invasive prenatal diagnostic testing such as chorionic
villus sampling and amniocentesis if the fetus is female. In the
case of unknown fetal haemophilia status, it should be assumed
that the fetus has haemophilia, and the pregnancy and delivery
should be managed accordingly.
Preparation for labour and delivery
Factor replacement should be organised before delivery if levels
remain below normal (Box 2). Risk factors for postpartum haem-
orrhage should also be reviewed at this time and a clear intra- and
postpartum multidisciplinary care plan for both mother and neo-
nate should be documented.19
Treatment options
In women with factor levels < 50 IU/dL, or if clinically indicated,
tranexamic acid should be considered to cover surgical or inva-
sive procedures.6 Following miscarriage, it should be continued
until bleeding settles.6
DDAVP is a synthetic analogue of vasopressin that increases the
plasma levels of von Willebrand factor and factor VIII by endothe-
lial release. DDAVP can be used antenatally to raise factor V III and
von Willebrand factor plasma levels two- to sixfold during preg-
nancy in women with haemophilia A and type 1 von Willebrand
disease;6,10,19,26–2 8 it has a category B2 safety warning for use in
pregnancy in Australia29 but does not cross the placenta at detect-
able levels.28,3 0 with peak levels at 30–90 minutes after infusion,
although there is considerable inter- individual variation.2 7, 2 8 , 3 0
Importantly, in most patients with type 1 von Willebrand disease
who would respond to DDAVP, factor levels will have increased
during pregnancy, but in patients with type 2 and type 3 von
Willebrand disease, who have the greatest need for elevation of
von Willebrand factor levels, the response to DDAVP is gener-
ally poor.27 As such, if treatment is needed, administration of
von Willebrand factor- containing concentrates is recommended
in the antenatal treatment of von Willebrand disease, although
DDAVP may be a suitable alternative in women who are carriers
of haemophilia A.
It is important to note that DDAVP can stimulate uterine con-
traction and cause premature labour, as well as hyponatrae-
mia.28 –30 It has an antidiuretic effect, and fluids should be
restricted to 1 L for 24 hours after use and electrolytes should
be monitored.6
In women with Glanzmann thrombasthenia or Bernard–Soulier
syndrome, blood and platelet transfusion should be avoided
wherever possible because of the risk of sensitisation to antigens
not present on their own platelets6–8 (Box 1). No treatment is re-
quired antenatally, but the presence of anti- human leukocyte
antigen and anti- platelet antibodies should be assessed before
delivery. If antibodies to fetal antigens are present, the delivery
should be managed appropriately.
Labour and delivery
Women with inherited bleeding disorders should be referred to
a specialist haemophilia clinician, as individualised and specific
treatment protocols must be followed. Ideally, women with se-
vere bleeding disorders, or who are at risk of delivering a boy
with haemophilia, should be managed jointly by an obstetric
unit with facilities for caring for high risk infants and a haemo-
philia treatment centre.
The mode of delivery should be determined by obstetric indica-
tions. Spontaneous vaginal delivery, without instrumentation,
is a suitable option for many women with inherited bleeding

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Consensus statement
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2 Key points in the care of women with inherited bleeding disorders and their potentially af fected infants
Adapte d from Lavee a nd Kidson- Gerbe r.19 CS = caesarean section; IM = intramusc ular; IU = intern ational units; IV = intr avenous; PPH = postpar tum haemo rrhag e; PO = per oral. ◆

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MJA 210 (7) ▪ 15 April 2019
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disorders, based on obstetric advice.31 It is important to note that
an inherited bleeding disorder in the mother or fetus, by itself, is
not an indication for delivery by lower segment caesarean sec-
tion. Although lower segment caesarean section is an alternative
option for delivery, it does not eliminate the risk of intracranial
haemorrhage in the neonate, and elevates the risk of bleeding and
factor replacement requirements of the mother.6,10 Instrumental
deliveries should be avoided because of the increased risk of intra-
cranial haemorrhage. However, where an instrumental delivery
is deemed unavoidable, a forceps delivery by an experienced ac-
coucheur is preferred over vacuum extraction.6,10, 31–33 Use of fetal
scalp blood sampling, mid- cavity manipulation, scalp electrodes
and a prolonged labour should also be avoided if possible.6,10,33
Tranexamic acid 1000 mg, orally or intravenously, should be given
to all women with an inherited bleeding disorder as close to the
time of delivery as possible.34,35 The dose should be repeated at
4 hours if there is postpartum haemorrhage.34,35 If needed, fac-
tor replacement should be given to the mother as close to the
time of delivery as possible, but it should be noted that this does
not normalise the baby’s factor levels. In haemophilia A and B
and von Willebrand disease, factor replacement therapy, if re-
quired, should be administered so that levels are maintained
above 50 IU/dL (ie, in the normal range) for labour and delivery.
DDAVP has poor efficacy in type 2 and type 3 von Willebrand
disease but may be used in carriers of haemophilia A.
In patients with severe platelet disorders, platelets (human leu-
kocyte antigen matched if available) should be transfused at
the time of delivery. Lower segment caesarean section should
be offered to women with severe platelet function disorders.6,36
Obstetric anaesthesia
There are few studies reporting outcomes following the use of
epidural or spinal anaesthesia in patients with inherited bleeding
disorders and no gu idelines t hat cover this topic comprehensively.
Patients with inherited bleeding disorders are at an increased
risk of spinal haematoma.6,37,38 However, if coagulation factor
levels are in the normal range, or supported and maintained
in the normal range, then regional anaesthesia is not absolutely
contraindicated.1,2 ,6, 37– 41
It is recommended that factor VIII, factor IX and von Willebrand
factor levels be maintained in the normal range (> 50 IU/dL) for
epidural catheter insertion, the duration of catheter placement,
catheter removal and for 12 hours (mild bleeding disorder) to
24 hours (moderate to severe bleeding disorder) after catheter
removal (Box 3). If levels are < 50 IU/dL, epidural or spinal an-
aesthetic modalities should only be considered for use in close
consultation with a senior anaesthetist and haematology team.
Alternative forms of analgesia and anaesthesia are available and
may be more appropriate, depending on the context. In partic-
ular, patients with severe hereditary platelet functions, such as
Glanzmann thrombasthenia and Bernard–Soulier syndrome, in
general should not receive neuraxial anaesthesia.6,36
Postpartum care
To reduce the risk of postpartum haemorrhage and surgical bleed-
ing, factor levels should be maintained in the normal range for
≥ 3 days after vaginal delivery and for ≥ 5 days after caesarean
delivery.1,2,6,14,17 Factor levels should be monitored closely in the
postpartum period, even in women whose levels normalised dur-
ing preg n a n c y.13,16 ,24 Women who have low factor VIII, factor IX
or von Willebrand factor levels after delivery are at continued
risk of postpartum haemorrhage and should be advised to re-
port symptoms. In the event of caesarean delivery, insertion of an
intra- abdominal drain in order to detect bleeding should be con-
sidered. Tranexamic acid is encouraged postpartum until lochia
is minimal.
To minimise the risk of thrombosis, excessively high levels of fac-
tor VIII and IX should be avoided. Thromboprophylaxis should
be considered in women with thrombotic risk factors whose fac-
tor levels have been normalised physiologically or therapeuti-
cally, especially in patients with von Willebrand disease.
Postpartum haemorrhage
Postpartum haemorrhage is defined as blood loss > 500 mL; pri-
mary postpartum haemorrhage occurs within the first 24 hours
and secondary postpartum haemorrhage occurs after 24 hours
and before 6 weeks.
3 Pre- procedural administration of clotting factor products in women with factor levels below reference interval* 1, 2, 6,13 ,14,16 ,17,2 4
Disorder Product
Timing of
treatment before
procedure†
Duration of factor
treatment after delivery
Further dose required for
epidural/spinal catheter
removal?
Haemophilia A Recombinant factor VIII 0–2 hours ≥ 3 days or ≥ 5 days‡ (daily
or twice daily)
Yes, if prior dose > 8 hours ago
Haemophilia B Recombinant factor IX 0–2 hours ≥ 3 days or ≥ 5 days ‡ (dai ly) Yes, if prior dose > 8 hours ago
Factor XI deficienc y Factor XI concentrate (plasma derived);
fresh f rozen plasma in an emergenc y if
factor XI concentrate unavailable
0–8 hours 1–3 days (every 1 –2 days) No, if prior dose < 36 hours ago
von Willebrand disease
Typ e 1 VWF containing fac tor VIII concentrate 0–4 hours 1–3 days (daily) Yes, if prior dose > 12 hours ago
Typ e 2§VWF containing factor V III concentrate 0–4 hours 1–3 days (daily) Yes, if prior dose > 12 hours ago
Typ e 3 VWF containing fac tor VIII concentrate 0 –2 hours ≥ 3 days or ≥ 5 days‡ (daily
or twice daily)
Yes, if prior dose > 8 hours ago
VWF = vo n Willebrand f actor. * Women wit h factor VI II or IX levels be low 50 IU/dL or the low er limit of the re ference int erval (note t hat laborato ry referen ce interva ls vary base d on meth-
odolo gy), or VWF levels < 30–5 0 IU/dL, at physicia n’s discre tion. † Includin g deliver y, insertion of epidural or spinal cathe ter, chorion ic villus sampli ng or amniocent esis proce dures . ‡ Conti nue
treat ment for ≥ 3 da ys following vaginal deli very and ≥ 5 d ays followin g caesarea n delivery, u nless othe rwise sta ted. § Thro mbocyto penia assoc iated with t ype 2B von W illebrand d isease
can wor sen during pr egnancy. ◆

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Obstetric causes are the most common reason for postpartum
haemorrhage, and causes other than haemophilia should also
be considered. Causes of primary postpartum haemorrhage
include uterine atony, retained placental tissue,42 trauma to the
female reproductive tract, and coagulopathy. Causes of second-
ary postpartum haemorrhage include retained placental tissue
and infection. Women with low factor levels and von Willebrand
disease have a significantly higher risk of both primary and sec-
ondary postpartum haemorrhage.1,2,6,17–20,24,43,44
The risk of postpartum haemorrhage can be reduced by the
active management of the third stage of labour.45 This in-
cludes administration of a prophylactic oxytocic agent within
2 minutes of the baby’s birth to induce uterine contraction,
immediate clamping and cutting of the cord to enhance pla-
cental separation, and placental delivery by controlled cord
traction.46
Additionally, women with low factor levels should be identified
as being at risk of postpartum haemorrhage and at least one
large bore (16G) intravenous cannula should be inserted; up- to-
date coagulation factor studies, full blood count and group and
hold testing should be conducted.
Intrapartum management should be aimed at reducing the risk
of postpartum haemorrhage (eg, labour should not be allowed
to become prolonged). In addition to active management of
third stage, there should be a low threshold for 40 IU oxytocin
infusion (or use of other agents that facilitate uterine tone). Any
trauma should also be promptly identified and repaired.
Management of postpartum haemorrhage should follow local
guidelines;47 however, in women with early postpartum hae-
morrhage associated with low factor levels, factor replacement
therapy or, in some instances, DDAVP (in carriers of haemo-
philia A or women with type 1 von Willebrand disease) may be
required.1,2,6,19,20 DDAVP is not recommended for use in breast
feeding mothers as it is transferred to breast milk (MIMS Online;
www.mims.com.au).
Should late or secondary postpartum haemorrhage occur, first
line management includes tranexamic acid,6,1 9,3 5 which is safe in
breastfeeding mothers and is classed as category B1 for use in
pregnancy in Australia.29 The oral contraceptive pill and, in the
longer term, a levonorgestrel- releasing intrauterine device are
alternative therapies.48 Retained placental tissue and endometri-
tis need to be excluded.
Infants at risk of a severe bleeding disorder
Testing of cord blood for inherited bleeding disorders is recom-
mended by AHCDO and is useful for excluding severe disease.6
However, its value in milder disease (particularly mild haemo-
philia B) is less certain, and results should be confirmed by pe-
ripheral blood testing. Factor IX is physiologically lower at birth
and increases over the first 6–12 months of life; infants at risk
of haemophilia B will therefore need retesting at a later stage to
define baseline factor IX levels.49,50 Other vitamin K- dependent
clotting factors and factor II, VII, IX, X and XI levels may be physi-
ologically low in neonates.
All neonates at risk should be carefully observed for signs of
intracranial haemorrhage, and transfontanelle ultrasonogra-
phy should be considered soon after birth. Any neonate with
bleeding should be managed in consultation with a haemo-
philia physician. Because intracranial haemorrhage may be de-
layed (median time after delivery is 4.5 days), mothers should
be made aware of potential symptoms, such as vomiting,
seizures and poor feeding, and be advised how to seek help if
concerned.51
All neonates with an identified inherited bleeding disorder
should be examined by a paediatrician and referred to the ap-
propriate haemophilia treatment centre. It is important to note
that even in neonates known to have a severe bleeding disorder,
prophylactic factor replacement therapy should not be routinely
given and may be associated with an increased risk of inhibitor
development in children with haemophilia.
Inhibitor development is a serious complication for patients with
haemophilia. It results from an immune- mediated response
that inhibits factor replacement, thus preventing control of a
bleeding episode.3,6,52 Patients with inhibitors require the use
of bypassing agents to achieve haemostasis.53 While inhibitors
remit spontaneously in some patients, many require an inten-
sive regimen of immune tolerance, which has an average suc-
cess rate of 70%. Moreover, the use of prophylactic recombinant
factor VIIa has not been shown to improve clinical outcomes.3
The risk of cranial haemorrhage is also increased in neonates
with severe forms of von Willebrand disease1,2 but is very rare in
infants with factor XI deficiency.18 The risk of intracranial hae-
morrhage is about 2.5% in newborns with severe haemophilia,
and the risk of extracranial haemorrhage is about 3.7%.6,10,33 In
haemophilia, pre- delivery ultrasound determination of fetal sex
is useful, because female infants do not ordinarily have an ele-
vated risk of cranial haemorrhage.
In general, intramuscular injections should be avoided until
after the results of cord blood factor levels are available. Neonatal
heel- prick screening (Guthrie test) should still be carried out
with firm pressure applied afterwards, to allow early identifi-
cation of phenylketonuria, congenital hypothyroidism and cys-
tic fibrosis. Vitamin K should be routinely administered, orally
(or subcutaneously if required),6 and all three doses should be
given, to avoid the risk of intramuscular haematoma. All infants,
including those already known to have bleeding disorders,
should be immunised for hepatitis B (administered subcutane-
ously or intradermally).3,6
Management of bleeding in neonates
Urgent liaison with a paediatric haemophilia treatment centre
should be sought. Neonates known (or suspected) to have hae-
mophilia A or B, and who have evidence of either intracranial
bleeding or severe bleeding elsewhere, should receive immedi-
ate factor replacement with recombinant factor VIII or IX, respec-
tively, to obtain plasma factor levels of 100 IU/dL in accordance
with AHCDO guidelines and the product information.54
Acknowledgements: We are grateful to Steph P’ng, J ohn Rowell, Tim Br ighton,
Huyen Tran and Ian Douglas for th eir helpful feedback and comments. We
acknowledge Ru th Hadfield f or medical writing and editing assistanc e.
Competing interests: No relev ant disclosures.
Provenance: Not commissioned; ext ernally peer r eviewed. ■
© 2019 The Aut hors.
Medic al Journal of A ustralia
pub lishe d by Joh n Wile y & Sons Au stra lia, L td
on behal f of AMPCo Pt y Ltd
This is an o pen acc ess ar ticle u nder the terms of t he Creative Commons Attribution License,
which pe rmit s use, dis tribution and reproduction in any medium , provi ded the o rigina l work
is prope rly cited.
The copyr ight l ine for th is art icle wa s chan ged on 26 Jun e 2019 a fter ori gina l onlin e publi cati on.

332
Consensus statement
MJA 210 (7) ▪ 15 April 2019
332
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