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

Authors:

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.
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.comdo 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 decreasedMild 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
MJA 210 (7) 15 April 2019
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Consensus statement
MJA 210 (7) 15 April 2019
329
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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Consensus statement
MJA 210 (7) 15 April 2019
330
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.
MJA 210 (7) 15 April 2019
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Consensus statement
MJA 210 (7) 15 April 2019
331
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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... If, after preconception counseling, a couple decides they want to avoid the risk of having an affected child, we inform them about the possibilities of preimplantation genetic screening or antenatal genetic screening by chorionic villus sampling (weeks 10-14 of gestation) or amniocentesis (from week 15 of gestation) followed by (early) termination of pregnancy in case of an affected male fetus. [16][17][18] The latter is only possible if the causative mutation is known and if the national laws governing such procedures make this possible. ...
... Because most female carrier newborns will have normal or only mild reduced FVIII/FIX levels and severe reduced factor levels are very rare, delivery of a (possible) carrier of hemophilia does not carry a risk of neonatal bleeding. 17,18 A male fetus has a 50% chance of being affected with hemophilia. When the causative mutation is known, it is possible to determine antenatally whether the boy is affected or not by analyzing fetal DNA obtained by chorionic villus sampling or amniocentesis. ...
... Instrumental vaginal deliveries should be avoided as much as possible, but if unavoidable, forceps delivery is preferred over ventouse delivery. 17 As mentioned earlier, we recommend an unassisted vaginal delivery with an early recourse to an emergency cesarean delivery if the second stage of labor is prolonged or there is suspected fetal distress. 17,18 The use of potentially harmful invasive techniques, like fetal scalp electrodes or fetal blood sampling, is avoided, as well as intramuscular injections in the neonate after birth: this is so-called atraumatic management ( Figure 1). ...
Article
Women with inherited bleeding disorders, including carriers of hemophilia A and B, or with von Willebrand disease, have an increased risk of bleeding during pregnancy and delivery. Also the unborn child may be affected by the bleeding disorder for which specific measures have to be considered. This requires a multi-disciplinary approach, including a hematologist, pediatric hematologist, clinical geneticist, obstetrician-perinatologist, and anesthesiologist. An optimal approach includes pre-pregnancy genetic counselling, prenatal diagnostic procedures, and making a treatment plan for delivery for both the mother and child. Recent retrospective studies show that even if strict guidelines are followed, these women are still at risk of postpartum bleeding. This occurs even in case of normalization of coagulation factor levels, either due to the pregnancy-induced rise of factor levels or by infusion of coagulation factor concentrates at the time of delivery. In this article we describe our current diagnostic and clinical management of pregnancy and delivery in women with inherited bleeding disorders. We also briefly discuss possible interventions to improve the outcome of current strategies by increasing target factor levels during and after delivery.
... 9,10 Current guidelines recommend maintaining factor levels above 50 U/dl for birth and 3-7 days postpartum depending on mode of birth. 10 Neuraxial analgesia is safe when levels are above this threshold. 10 Recombinant factor VIII or factor IX concentrates are the treatments of choice when factor levels are inadequate. ...
... 10 Neuraxial analgesia is safe when levels are above this threshold. 10 Recombinant factor VIII or factor IX concentrates are the treatments of choice when factor levels are inadequate. 11 von Willebrand disease (VWD) is the most common IBD and is divided into three types. ...
... This increase is generally adequate in women with Type 1, fails to overcome the functional impairment in Type 2 and is insufficient in Type 3. 10 VWF levels (or activity) greater than 50 U/dl are recommended for birth, neuraxial analgesia and 3-7 days postpartum. 10 Desmopressin, which releases endogenous VWF, or VWF-containing concentrates can be administered to increase VWF levels. 11 Rare bleeding disorders include disorders of prothrombin, fibrinogen, factors V, VII, X, XI and XIII and functional platelet disorders. ...
Article
Full-text available
Objective: To describe the characteristics and outcomes of women with inherited bleeding disorder during pregnancy and birth. Design: Retrospective cohort study. Setting: Tertiary care hospitals, NSW and Victoria Australia. Population: 100 women with inherited bleeding disorders, who birthed 134 live infants from 132 pregnancies. Methods: Data was retrospectively obtained from the patient and neonatal medical records. Descriptive analysis was used to report maternal and pregnancy characteristics, birth and neonatal outcomes. Main outcome measures: Factor replacement, neuraxial analgesia use and complications, post-partum haemorrhage and neonatal complications. Results: PPH occurred in 22% of deliveries with primary PPH occurring in 20% and secondary PPH in 2% of births. 48% of PPHs were classified as major. PPHs occurred across the spectrum of IBD and was evenly distributed between women who had "normalised" (46%) their factor levels in pregnancy compared to those requiring factor at the time of birth (50%). An obstetric cause was identified in almost half of PPHs (46%). Neuraxial analgesia was administered in 40% of births without complication and refused on 3% of births despite documented adequate haemostatic potential. Conclusions: Women with inherited bleeding disorders can deliver safely and receive neuraxial analgesia without complication when best practices are adhered to. PPH appears to occur at higher rates than the general population despite adequate factor levels or planned replacement. Whilst an obstetric cause was demonstrable in the many cases, these findings raise concern over the current definition of "adequate" factor levels at the time of birth.
... In contrast to FIX levels, FVIII levels increase significantly throughout pregnancy and exceed recommended thresholds for birth in the majority of women. (3,4) Maintaining factor levels >50U/dL are currently recommended for birth and 3-7 days post-partum depending on mode of birth (4). Neuraxial analgesia is deemed safe when levels are above this threshold.(4) ...
... In contrast to FIX levels, FVIII levels increase significantly throughout pregnancy and exceed recommended thresholds for birth in the majority of women. (3,4) Maintaining factor levels >50U/dL are currently recommended for birth and 3-7 days post-partum depending on mode of birth (4). Neuraxial analgesia is deemed safe when levels are above this threshold.(4) ...
Preprint
Objective To describe the characteristics and outcomes of women with inherited bleeding disorder during pregnancy and birth. Design Retrospective cohort study. Setting Tertiary care hospitals, NSW and Victoria Australia. Population 100 women with inherited bleeding disorders, who birthed 134 live infants from 132 pregnancies. Methods Data was retrospectively obtained from the patient and neonatal medical records. Descriptive analysis was used to report maternal and pregnancy characteristics, birth and neonatal outcomes. Main outcome measures Factor replacement, neuraxial analgesia use and complications, post-partum haemorrhage and neonatal complications. Results PPH occurred in 22% of deliveries with primary PPH occurring in 20% and secondary PPH in 4% of births. 48% of PPHs were classified as major. PPHs occurred across the spectrum of IBD and was evenly distributed between women who had “normalised” their factor levels in pregnancy compared to those requiring factor at the time of birth. An obstetric cause was identified in more than half of PPHs. Conclusions Women with inherited bleeding disorders can deliver safely and receive neuraxial analgesia without complication when best practices are adhered to. PPH appears to occur at higher rates than the general population despite adequate factor levels or planned replacement. Whilst an obstetric cause was demonstrable in the many cases, these findings raise concern over the current definition of “adequate” factor levels at the time of birth.
... Despite this, normal levels are considered to be 50% or above. Maintaining factor levels above 50% during the period of catheter insertion to 12-24 hours after catheter removal has been recommended in patients with hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), and type 1 von Willebrand disease [15]. For an additional measure of safety, an additional dose of FXIII (500-1000 U) should be administered on the day of a neuraxial procedure. ...
Article
Full-text available
Factor XIII (FXIII) deficiency is a rare coagulation defect that can be associated with significant bleeding. A 28-year-old pregnant woman, with a history of hemorrhagic stroke secondary to severe congenital FXIII deficiency, presented in active labor requesting an epidural. Factor XIII levels had been monitored throughout her pregnancy and treated with intermittent factor XIII infusions to maintain factor levels above 30% of normal. After careful multidisciplinary peripartum evaluation and FXIII replacement, neuraxial analgesia was performed without complication. Neuraxial analgesia can be performed without complication in patients with FXIII deficiency if FXIII levels are carefully managed and no other coagulopathy exists.
Article
Introduction Published guidelines are available to assist in the management of patients with inherited bleeding disorders in the elective surgical setting however good quality outcome data is lacking. Aim - Evaluate the outcomes of adult patients with inherited bleeding disorders, who received factor replacement for elective surgery in NSW/ACT, Australia. - Assess adherence to relevant guidelines including Haemophilia Treatment Centre (HTC) utilisation and appropriate factor replacement. Method A retrospective analysis was performed between 2000 and 2018 to describe patient characteristics, surgical details, factor provision and outcomes. Univariate analysis was used to determine variables associated with guideline adherence. Covariates with p < 0.1 were included in the multivariate analysis. Results A total of 1065 surgeries were performed on 571 patients. Diagnoses included Haemophilia A (43.5%), Haemophilia B (9.7%), von Willebrand disease (VWD) (45.3%) and rare bleeding disorders (RBDs) (1.6%). Bleeding complications were reported in 14 surgeries and 19 patients received factor replacement beyond standard duration of prophylaxis. Approximately 50% of all surgeries were performed in a HTC. Multivariate analysis demonstrated that diagnosis, surgical specialty, sex and year (p < 0.001) were associated with non-compliance with variable pattern within each category. Factor replacement was as expected except for plasma-derived Factor VIII/VWF usage in patients with VWD undergoing major bleeding risk surgery. VWD classification (p < 0.001) was associated with this deviation. Conclusion Low complication rates demonstrate that elective surgery in Australia is being safely performed in patients with inherited bleeding disorders however non-compliance with published guidelines exists highlighting areas of practice and policy discrepancies that warrant further exploration.
Article
Female carriers are more common than males with hemophilia and unrecognized factor VIII or IX deficiency is associated with intrauterine growth retardation, epidural hematomas, blood transfusion, and peripartum hemorrhage. A review was conducted to assess the evidence for professional society recommendations for > 50% factor levels during labor. Two searches of Pubmed, CINAHL, Cochrane, and Google Scholar were completed in October 2019. The first for case reports and series described neuraxial techniques in patients with hemophilia—regardless of sex, age, or pregnant status. The second for case reports and series described bleeding outcomes of parturients with hemophilia. Primary outcomes were diagnosis of neuraxial hematoma (first search) and postpartum bleeding complications (second search). Thirteen articles (n = 134) described neuraxial techniques in patients with hemophilia. Neuraxial hematoma with paraplegia occurred in 3/134 patients—all had a factor level of 1%. Nineteen articles (2712 deliveries in 2657 women) described bleeding outcomes. Postpartum hemorrhage occurred in 7.1% (193/2712) of deliveries, of which 60% necessitated blood transfusion. Postpartum bleeding complications were twice as likely (51.0% [25/49] vs. 25.6% [52/203], P < 0.001) with factor activity < 50%. Therefore, factor levels should be assessed and increased above 50% prior to neuraxial technique and delivery.Trial registration: PROSPERO 2018 CRD42018110215.
Article
Background von Willebrand disease (vWD) is a heterogeneous hereditary bleeding disorder and associated with risk of primary postpartum haemorrhage (PPH). Design and Methods An observational study at a tertiary referral centre in Australia of 16 women with 23 deliveries with a median age of 27.5 years (range, 21‐39; IQR=9). Median gestational age at delivery was 39 weeks (range, 35‐41; IQR=1.1). Results All cases had type 1 vWD apart from one case with type 2. Patients were managed in combined obstetrics and haematology clinics. PPH occurred in ten deliveries (44%). Intravenous desmopressin was administered in 6 cases and IV human vWF was administered in 4 cases. Two cases with mild vWD had received oral tranexamic acid. The median Apgar score at 1 and 5 min was 9 (IQR=1.0) while the median Apgar score at 10 min was 10.0 (IQR=0.0). One case required transfusion of blood products post‐delivery. There were no other significant complications observed. Conclusions vWD was associated with a high incidence of PPH. Individualised treatment to restore haemostasis, according to the severity of the disease could achieve as possible normal haemostasis with favourable outcomes for both mothers and their infants. Further studies to confirm our findings are warranted.
Article
The aim of this review is to provide practical guidance for the treatment of carriers of haemophilia and newborns presenting with haemophilia. Both mother and newborn have an increased risk for clinically relevant bleeding. An experienced team should manage genetic counselling, prenatal diagnosis, pregnancy, delivery and the newborn presenting with haemophilia. Published and regularly updated guidelines must guide this team. Vaginal and caesarean deliveries before labour entail a comparable bleeding risk. Haemophilia carriers should receive factor concentrate (FC) at the time of delivery if their factor level is below normal. Evidence remains insufficient to recommend systemic desmopressin and tranexamic acid for the prevention of peripartum haemorrhage. Primary prophylaxis with FC for all newborns with severe haemophilia is not justified. The pattern of bleeding seen in the affected newborns is essentially different from that seen in older children. Estimated frequency of intracranial haemorrhage (ICH) is 2 to 3%. Cranial ultrasound is a good screening method for ICH in newborns. Many neonatal bleeds are iatrogenic in origin. The most prominent concerns regarding neonatal factor replacement are the risk for inhibitor development, followed by local bleeding and issues related to poor vascular access. The preference for plasma-derived FC and recombinant FC differs widely between centres and countries. Replacement therapy should be monitored since newborns may require higher doses of FC. Emicizumab, licensed for all age groups since 2019, should not be used in newborns with severe haemophilia A and acute bleeding, although “non-factor” agents are expected to revolutionise haemophilia therapy.
Poster
Full-text available
Janus kinase 2 (JAK2) is a tyrosine kinase receptor that plays a central role in signal transduction from multiple growth factors and it can be mutated in myeloproliferative diseases, including cancers. The JAK2-V617F mutation establishes a hematopoietic progenitor cell disorder that results in overproduction of platelets, with an increase in thrombotic events. Patients are managed with anticoagulation therapy under which neuraxial anesthesia practice is controversial. We present a parturient G4P2022 with JAK2-V617F thrombocytosis, protein-C deficiency, and sickle cell trait on daily low-dose aspirin and twice-daily lovenox who, after multidisciplinary planning, received combined spinal-epidural labor analgesia. Labor progressed to an uneventful vaginal delivery and post-operative course.
Article
The area of women and inherited bleeding disorders has undergone quick expansion in recent years. More patients are being identified and expertise to diagnose and manage these patients is now essential for practising physicians. Programs to help educate and empower patients and caregivers are now in place. Common inherited bleeding disorders affecting women include von Willebrand disease (VWD), inherited platelet disorders, and rare inherited bleeding disorders such as factor VII (FVII) deficiency and factor XI (FXI) deficiency. Specific clinical tools have been developed to help clinicians and patients screen for the presence of these bleeding disorders in both adult and pediatric populations. Affected women can experience heavy menstrual bleeding and resulting iron deficiency anemia, postpartum hemorrhage, and hemorrhagic ovarian cysts which need to be properly managed. Excessive bleeding can adversely affect quality of life in these women. Front line therapy for bleeding in mild cases focuses on the use of non-specific hemostatic agents such as DDAVP ®, tranexamic acid and hormonal agents but specific factor replacement and/or blood products may be required in more severe cases, in severe bleeding or as second line treatment when bleeding is not responsive to first line agents. Iron status should be optimised in these women especially in pregnancy and use of an electronic app can now help clinicians achieve this. These patients should ideally be managed by a multidisciplinary team whenever possible even remotely. Although clinical research has closed some knowledge gaps regarding the diagnosis and management of these women, there remains significant variation in practise and lack of evidence-based guidelines still exists in many spheres of clinical care in which caregivers must rely on expert opinion. Ongoing efforts in education and research will continue to improve care for these women and restore quality of life for them.
Article
Full-text available
This study was designed to determine the postnatal development of the human coagulation system in the healthy premature infant. Consecutive mothers of healthy premature infants born at either St Joseph's Hospital or McMaster University Medical Centre in Hamilton were asked for consent. One hundred thirty-seven premature infants (30 to 36 weeks of gestational age) entered the study. The premature infants did not have any major health problems and did not require ventilation or supplemental oxygen. Demographic information and a 20-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 96 premature infants were studied on each day for each of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, plasminogen; 13 factor assays [fibrinogen, II, V, VII, VIII, IX, X, XI, XII, XIII, high-mol-wt kininogen (HMWK), prekallikrein (PK), von Willebrand factor (vWF)] and eight inhibitors [antithrombin III (AT-III), heparin cofactor II, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C (PC), and protein S (PS)]. A combination of biologic and immunologic assays were used. Between 30 to 36 weeks there was a minimal effect of gestational age for levels of AT-III, PC, and factors II and X only; therefore, the entire data set was used to generate reference ranges for these components of the coagulation system for premature infants. Next, the results for the premature infants were compared with those of a previously published study in 118 fullterm infants and with those for adults. An effect of gestational age was shown for plasminogen, fibrinogen, factors II, V, VIII, IX, XI, XII, HMWK, and all eight inhibitors. In general, the postnatal maturation towards adult levels was accelerated in premature infants as compared with the fullterm infants. By 6 months of age, most components of the coagulation system in premature infants had achieved near adult values.
Article
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Background: Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods: In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings: Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65-1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52-0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88-1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation: Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding: London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.
Article
Background: Congenital bleeding disorders can cause obstetric haemorrhage during pregnancy, labour and following delivery. Desmopressin acetate (DDAVP) is found to be an effective drug which can reduce the risk of haemorrhage and can also stop bleeding in certain congenital bleeding disorders. Its use in pregnancy has been controversial. Hence beneficial and adverse effects of DDAVP in these groups of pregnant women should be evaluated.This is an update of a Cochrane Review first published in 2013 and updated in 2015. Objectives: To evaluate the efficacy and safety of DDAVP in preventing and treating acute bleeding in pregnant women with bleeding disorders. Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant and abstract books of conferences proceedings. We also searched several clinical trial registries and grey literature (27 August 2017).Date of most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register: 01 October 2018. Selection criteria: Randomised and quasi-randomised controlled trials investigating the efficacy of DDAVP versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible. Data collection and analysis: No trials matching the selection criteria were eligible for inclusion. Main results: No trials matching the selection criteria were eligible for inclusion. Authors' conclusions: No randomised controlled trials were identified investigating the relative effectiveness of DDAVP for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high-quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with DDAVP.Given the ethical considerations, future randomised controlled trials are unlikely. However, other high-quality controlled studies (such as risk allocation designs, sequential design, parallel cohort design) to investigate the risks and benefits of using DDAVP in this population are needed.Given that there are unlikely to be any trials published in this area, this review will no longer be regularly updated.
Article
Background: Active management of the third stage of labour involves giving a prophylactic uterotonic, early cord clamping and controlled cord traction to deliver the placenta. With expectant management, signs of placental separation are awaited and the placenta is delivered spontaneously. Active management was introduced to try to reduce haemorrhage, a major contributor to maternal mortality in low-income countries. This is an update of a review last published in 2015. Objectives: To compare the effects of active versus expectant management of the third stage of labour on severe primary postpartum haemorrhage (PPH) and other maternal and infant outcomes.To compare the effects of variations in the packages of active and expectant management of the third stage of labour on severe primary PPH and other maternal and infant outcomes. Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the World health Organization International Clinical Trials Registry Platform (ICTRP), on 22 January 2018, and reference lists of retrieved studies. Selection criteria: Randomised and quasi-randomised controlled trials comparing active versus expectant management of the third stage of labour. Cluster-randomised trials were eligible for inclusion, but none were identified. Data collection and analysis: Two review authors independently assessed the studies for inclusion, assessed risk of bias, carried out data extraction and assessed the quality of the evidence using the GRADE approach. Main results: We included eight studies, involving analysis of data from 8892 women. The studies were all undertaken in hospitals, seven in higher-income countries and one in a lower-income country. Four studies compared active versus expectant management, and four compared active versus a mixture of managements. We used a random-effects model in the analyses because of clinical heterogeneity. Of the eight studies included, we considered three studies as having low risk of bias in the main aspects of sequence generation, allocation concealment and completeness of data collection. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes, which is reflected in the cautious language below.The evidence suggested that, for women at mixed levels of risk of bleeding, it is uncertain whether active management reduces the average risk of maternal severe primary PPH (more than 1000 mL) at time of birth (average risk ratio (RR) 0.34, 95% confidence interval (CI) 0.14 to 0.87, 3 studies, 4636 women, I2 = 60%; GRADE: very low quality). For incidence of maternal haemoglobin (Hb) less than 9 g/dL following birth, active management of the third stage may reduce the number of women with anaemia after birth (average RR 0.50, 95% CI 0.30 to 0.83, 2 studies, 1572 women; GRADE: low quality). We also found that active management of the third stage may make little or no difference to the number of babies admitted to neonatal units (average RR 0.81, 95% CI 0.60 to 1.11, 2 studies, 3207 infants; GRADE: low quality). It is uncertain whether active management of the third stage reduces the number of babies with jaundice requiring treatment (RR 0.96, 95% CI 0.55 to 1.68, 2 studies, 3142 infants, I2 = 66%; GRADE: very low quality). There were no data on our other primary outcomes of very severe PPH at the time of birth (more than 2500 mL), maternal mortality, or neonatal polycythaemia needing treatment.Active management reduces mean maternal blood loss at birth and probably reduces the rate of primary blood loss greater than 500 mL, and the use of therapeutic uterotonics. Active management also probably reduces the mean birthweight of the baby, reflecting the lower blood volume from interference with placental transfusion. In addition, it may reduce the need for maternal blood transfusion. However, active management may increase maternal diastolic blood pressure, vomiting after birth, afterpains, use of analgesia from birth up to discharge from the labour ward, and more women returning to hospital with bleeding (outcome not pre-specified).In the comparison of women at low risk of excessive bleeding, there were similar findings, except it was uncertain whether there was a difference identified between groups for severe primary PPH (average RR 0.31, 95% CI 0.05 to 2.17; 2 studies, 2941 women, I2 = 71%), maternal Hb less than 9 g/dL at 24 to 72 hours (average RR 0.17, 95% CI 0.02 to 1.47; 1 study, 193 women) or the need for neonatal admission (average RR 1.02, 95% CI 0.55 to 1.88; 1 study, 1512 women). In this group, active management may make little difference to the rate of neonatal jaundice requiring phototherapy (average RR 1.31, 95% CI 0.78 to 2.18; 1 study, 1447 women).Hypertension and interference with placental transfusion might be avoided by using modifications to the active management package, for example, omitting ergot and deferring cord clamping, but we have no direct evidence of this here. Authors' conclusions: Although the data appeared to show that active management reduced the risk of severe primary PPH greater than 1000 mL at the time of birth, we are uncertain of this finding because of the very low-quality evidence. Active management may reduce the incidence of maternal anaemia (Hb less than 9 g/dL) following birth, but harms such as postnatal hypertension, pain and return to hospital due to bleeding were identified.In women at low risk of excessive bleeding, it is uncertain whether there was a difference between active and expectant management for severe PPH or maternal Hb less than 9 g/dL (at 24 to 72 hours). Women could be given information on the benefits and harms of both methods to support informed choice. Given the concerns about early cord clamping and the potential adverse effects of some uterotonics, it is critical now to look at the individual components of third-stage management. Data are also required from low-income countries.It must be emphasised that this review includes only a small number of studies with relatively small numbers of participants, and the quality of evidence for primary outcomes is low or very low.
Article
A study has been undertaken in 72 women to provide systematic information on the changes that occur in a wide range of haemostatic variables during and after pregnancy. Factors VII, VIII :C, VIIIR:Ag, X, fibrinogen and α1 antitrypsin, rose markedly throughout pregnancy. Factors II and V and α2 macroglobulin all rose early on but then decreased steadily. Antithrombin III: C and Ag fell slightly. There was a marked decrease in fibrinolytic activity from 11-15 weeks onwards. Levels of fibrin degradation products rose from 21-25 weeks onwards. The rise in coagulation factors that occurs could be due to increased synthesis or increased activation by thrombin, or to both. The findings are consistent with a mild degree of local intravascular coagulation from early on in pregnancy in some women.
Article
Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.
Article
Congenital von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS) reflect conditions caused by von Willebrand factor (VWF) deficiency and/or defects. VWD is the most common inherited bleeding disorder and AVWS arises from a variety of causes. Since VWF stabilizes and protects factor VIII (FVIII) in the circulation, this is also reduced in many patients with VWD. The treatment of VWD and AVWS therefore primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail the use of VWF concentrates (currently plasma-derived) and/or FVIII concentrates (currently plasma-derived or more increasingly recombinant forms), and/or desmopressin to release endogenous VWF in subgroups of patients. For AVWS additional treatment of the underlying condition is also required. Adjunct therapies include antifibrinolytics. Globally, various formulations exist for both VWF and FVIII concentrates and are differentially available based on manufacturer marketing or regulatory approvals/clearances in different geographies. Also, guidelines for treatment of VWD vary for different localities and recombinant VWF is undergoing clinical trials. The current review provides an overview of the treatment of VWD as currently practiced in developed countries, and also provides a glimpse towards the future. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.