REPRODUCTIVE HEALTH IN WOMEN WITH BLEEDING DISORDERS

T R E AT M E N T O F H E M O P H I L I A
APRIL 2009 • NO 48
REPRODUCTIVE HEALTH IN
WOMEN WITH BLEEDING
DISORDERS
Rezan A. Kadir
Department of Obstetrics and Gynaecology
The Royal Free Hospital, London, U.K.
Andra H. James
Division of Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
Duke University Medical Center, Durham,
North Carolina, U.S.A.

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Published by the World Federation of Hemophilia (WFH), 2009
© World Federation of Hemophilia, 2009
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The Treatment of Hemophilia series is intended to provide general information on the treatment and
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Statements and opinions expressed here do not necessarily represent the opinions, policies, or
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Treatment of Hemophilia Monographs
Series Editor
Dr. Sam Schulman

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Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Menorrhagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Clinical assessment of menorrhagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Assessment of bleeding disorders in women with menorrhagia . . . . . . . . . . . . . . . . . . . . . . . . .2
Other Gynecological Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Dysmenorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Hemorrhagic ovarian cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Endometriosis and other gynecological conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Management of Menorrhagia in Women with Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Hormonal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Hemostatic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Surgical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Management of acute adolescent menorrhagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Pregnancy in Women with Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Preconception counselling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Prenatal diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Antenatal management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
Management of labour and delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
Postpartum management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Impact of Bleeding Disorders on Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

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Reproductive Health in Women with Bleeding Disorders
Rezan A. Kadir and Andra H. James
Introduction
condition [9]. With respect to other bleeding disorders,
the prevalence of menorrhagia in women with severe
Bleeding disorders can result from thrombocytopenia,
platelet dysfunction has been reported to be 51% in
platelet function disorders, abnormal collagen (such
women with Bernard-Soulier syndrome [10] and 98%
as in Ehlers-Danlos syndrome), and clotting factor
in women with Glanzmann thrombasthenia [11];
deficiencies, including a deficiency of von Willebrand
59% in women with factor XI deficiency [12]; 57% in
factor (VWF). Bleeding disorders may be acquired
carriers of hemophilia [6]; and 35-70% in women
or inherited. Mild inherited bleeding disorders are
with other rare factor deficiencies [13].
common, while severe inherited bleeding disorders
are rare, affecting as few as one in 5,000 to one in
In addition to heavy menstrual loss, women with
1,000,000 people [1] .
bleeding disorders also suffer from prolonged
bleeding (more than seven days), excessive passage
Hemophilia is the commonest severe bleeding disorder.
of large clots, and flooding during menstruation [6].
Hemophilia A (factor VIII deficiency) and B (factor IX
Adolescent girls and perimenopausal women may
deficiency) are X- linked disorders that together affect
suffer the most, as menstrual cycles are often anovu-
one in 5,000 men. Women are affected as carriers of
latory (i.e. no egg is released) during these repro-
hemophilia. Carriers may also have low factor levels
ductive stages. This leads to irregular shedding of
and experience significant bleeding symptoms [2].
the endometrium and predisposes to increased and
In women, von Willebrand disease (VWD) is the
prolonged menstrual bleeding. Perimenopausal women
most common inherited bleeding disorder. VWD
are also more likely to have pelvic pathology, such
and other inherited bleeding disorders are autosomal
as fibroids and endometriosis, which increase the risk
disorders and equally likely to affect women and
of bleeding and the magnitude of menstrual problems.
men. Two large prospective epidemiological studies
reported a 0.8-1.3% prevalence of mild VWD in the
Clinical assessment of menorrhagia
general population [3, 4]. However, women are
The only way to get an accurate measurement of
more likely to be symptomatic due to the bleeding
menstrual blood loss is to assess hemoglobin content
challenges of menstruation and childbirth. This
using the alkaline hematin method, a complex and
monograph will review the common obstetric and
expensive laboratory test. Since it is not feasible to
gynecological challenges in women with bleeding
use in clinical practice, the pictorial blood assessment
disorders and their management.
chart (PBAC) has been used as a semi-objective
alternative [14]. The PBAC (seen in Figures 1 and 2)
consists of a series of diagrams representing lightly,
Menorrhagia
moderately, and heavily soiled towels and tampons.
The numbers at the top of the chart represent the
Menorrhagia, or heavy menstrual bleeding, is the
days of the menstrual cycle. Women are instructed
most common symptom that women with bleeding
to mark the appropriate box each time a towel
disorders experience. It is defined as bleeding that
and/or tampon is discarded, after comparing its
lasts for more than seven days or results in the loss
degree of saturation with those depicted on the
of more than 80 mL of blood per menstrual cycle [5].
chart. Passage of clots and episodes of flooding are
also recorded. Lightly stained towels or tampons
Most of the data about the prevalence of menorrha-
obtain a score of 1, moderately stained towels or
gia in women with bleeding disorders come from
tampons a score of 5, completely soaked tampons a
reports of women with VWD. The prevalence of
score of 10, and completely soaked towels a score of
menorrhagia in these reports ranges from 74-92% [6-8].
20. A total score of greater than 100 per cycle has
Women with VWD are five times more likely to
been shown to be a reasonably good predictor of
experience menorrhagia than women without the
menstrual blood loss of more than 80 mL [14].

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2
Reproductive Health in Women with Bleeding Disorders
Figure 1: Assessment of menstrual blood loss using the pictorial blood
assessment chart (PBAC)
Patient name:
Date of birth: DD/MM/YY
Date of start: DD/MM/YY

Towel
1 2 3 4 5 6 7 8

























Clots / Flooding








(small/large)

Tampon
1 2 3 4 5 6 7 8

























Clots / Flooding








(small/large)












Score: ______
Scoring system
Towels
1 point
For each lightly stained towel
5 points
For each moderately soiled towel
20 points
If the towel is completely saturated with blood

Tampons
1 point
For each lightly stained tampon
5 points
For each moderately soiled tampon
10 points
If the tampon is completely saturated with blood

Clots
1 point
For small clots (½ inch )
5 points
For large clots (1 inch )

Flooding
5 points
For any episode of flooding
A drawback of the chart is that it must be completed
laboratory reference), or the need for changing a pad
prospectively and results are not available at the
or tampon more than hourly (flooding) [19]. The
time of an initial evaluation. Additionally, the validity
presence of these features in the menstrual history
of the chart and its ease of use have been questioned
may help identify women who suffer from heavy
by some investigators [15, 16]. Nonetheless, the PBAC
menstrual bleeding.
is a simple and inexpensive tool and has been used
successfully to monitor response to treatment [17, 18].
Assessment of bleeding disorders in women
with menorrhagia
In most situations, practitioners must rely on menstrual
Menstruation is an important hemostatic challenge
history and clinical impression. Variables that can best
that can be associated with excessive bleeding in the
predict a menstrual blood loss of more than 80 mL
presence of any hemostatic defect. Therefore, menor-
are passage of clots greater than one inch (2.5 cm) in
rhagia can be the presenting symptom of a bleeding
diameter, low ferritin (according to the investigators’
disorder (especially in its mild form) in otherwise

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Reproductive Health in Women with Bleeding Disorders
3
Figure 2: Assessment of menstrual blood loss using the pictorial blood
assessment chart (PBAC): Example of a completed chart
Patient name: Jane Smith
Date of birth: 14/03/1978
Date of start: 25/08/2006

Towel
1 2 3 4 5 6 7 8
//
/ / / /
/// //
// //

Clots / Flooding






½” x 3
1” x 1

Tampon
1 2 3 4 5 6 7 8
/ // /
// /// //
/ ////

Clots / Flooding









Score: 208
asymptomatic women. Women with bleeding disorders
– Notable bruising without injury (and > 2 cm
commonly present with adolescent menorrhagia,
in diameter)
typically at menarche — the first hemostatic challenge
– Minor wound bleeding (i.e. from trivial cuts
for these young girls.
lasting for > 5 minutes)
– Bleeding in the oral cavity or gastrointestinal
The prevalence of VWD in women presenting with
tract without an obvious anatomic lesion
menorrhagia is reported to be 13% (95% confidence
– Prolonged or excessive bleeding following
interval 11-16%), according to a systematic review of
dental extraction
11 studies including 988 women [20]. The data on the
– Unexpected post-surgical bleeding
prevalence of platelet dysfunction in women presenting
– Recurrent midcycle pain due to ovulation
with menorrhagia are very limited but it has been
bleeding
reported to be as high as 47% [21]. Other less common
– Hemorrhage requiring blood transfusion
inherited bleeding disorders have also been identified
– Postpartum hemorrhage, especially secondary
in women presenting with menorrhagia, such as carriers
postpartum hemorrhage (after 24 hours).
of hemophilia, factor XI deficiency, and other rare
• Failure to respond to conventional management
bleeding disorders. Therefore, menorrhagia should
of menorrhagia and prior to any surgical inter-
alert clinicians to the possibility of a bleeding disorder.
vention for menorrhagia.
A full hematological evaluation is not necessary and
In patients whose symptoms warrant further inves-
not practical for all women with menorrhagia.
tigation, the initial hematological assessment should
Clinicians should take a thorough bleeding history
include:
and consider testing in the presence of:
• Full blood count/complete blood cell count
• Menorrhagia since menarche
• Blood group
• Family history of a bleeding disorder
• Ferritin level
• Personal history of one, but usually several, of
• Activated partial thromboplastin time (aPTT)
the following symptoms:
• Prothrombin time (PT)
– Epistaxis (generally bilateral epistaxis, > 10
• Assessment of VWF (measured with ristocetin
minute duration once in the last year, possibly
cofactor activity and antigen) and FVIII levels.
necessitating packing or cautery)

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4
Reproductive Health in Women with Bleeding Disorders
If the initial hemostatic tests are normal, platelet
implants in the pelvic cavity and organs outside of
function (aggregation and release) tests should be
the uterus. There are several possible reasons why
performed if available. Further hemostatic assessment,
women with bleeding disorders would be more likely
including specific coagulation factor profile, is con-
to be diagnosed with endometriosis. Although there
sidered on the basis of the degree and severity of
is disagreement regarding the cause of endometriosis,
personal bleeding symptoms and family history.
the prevailing theory is that it results from retrograde
menstruation (the backward flow of menstrual blood).
Heavy menstrual bleeding is a risk factor for retro-
Other Gynecological Conditions
grade menstruation and endometriosis. Women with
bleeding disorders have heavier menstrual bleeding,
Dysmenorrhea
more retrograde menstruation and, possibly, more
Dysmenorrhea (painful periods) is a common gyne-
endometriosis. Another possible explanation is that
cological complaint for all women, but women with
women with bleeding disorders are more likely to
bleeding disorders more commonly suffer from period
experience symptomatic bleeding from the implan-
pain. Moderate to severe dysmenorrhea has been
tation of endometrial tissue.
reported in half of these women [6, 7]. Treatment
would usually involve non-steroidal anti-inflammatory
There is no strong evidence that women with bleeding
drugs (NSAIDs), but these should be avoided in
disorders are more likely to develop endometriosis,
women with bleeding disorders due to the drugs’
fibroids (leiomyoma), polyps, or endometrial hyper-
antiplatelet activity. Alternative analgesia such as
plasia (excessive growth of lining of the uterus), but
acetaminophen or paracetamol and codeine-based
in a survey by the U.S. Centers for Disease Control of
products may be used. The combined oral contra-
102 women with VWD, these gynecological problems
ceptives may also help reduce dysmenorrhea, as
were more commonly reported by affected women
may the levonorgestrel intrauterine system
compared to the controls [23]. Since most of these
(Mirena® IUS) (see “Hormonal therapy” below).
pathologies often present with bleeding, women
with bleeding disorders are more likely to be symp-
Hemorrhagic ovarian cysts
tomatic and therefore diagnosed.
When a woman ovulates, a small amount of bleeding
may occur with rupture of the follicle and formation
of the corpus luteum. This may be associated with
Management of Menorrhagia in Women
abdominal and pelvic pain (known as Mittelschmerz,
with Bleeding Disorders
a German word that means “middle pain”). Women
with bleeding disorders are more likely to have sig-
Since abnormal bleeding may be a sign of a gyneco-
nificant bleeding at ovulation with resulting pain,
logical problem other than a bleeding disorder, a full
hemorrhagic ovarian cysts, broad ligament hematomas,
gynecological evaluation is required prior to treatment
or even hemoperitoneum (significant bleeding into
of menorrhagia [5, 24]. With the exception of NSAIDs,
the abdominal and pelvic cavity). There have been
which affect platelet function and systemic hemo-
many case series of hemorrhagic ovarian cysts in
stasis [25] and are not generally prescribed for patients
women with inherited bleeding disorders, with a
with bleeding disorders [26], other gynecologic
prevalence ranging from 2-25% [13].
treatment options may be suitable depending on the
woman’s age, gynecological conditions, and repro-
Although these gynecological complications can be
ductive plans (see Figure 3 for treatment algorithm).
treated surgically, conservative management with
the use of appropriate hemostatic agents (tranexamic
Hormonal therapy
acid, desmopressin, and coagulation factor replacement)
is advisable in women with bleeding disorders [22].
Levonorgestrel intrauterine system
Combined oral contraceptives suppress ovulation and
The levonorgestrel intrauterine system (LNG-IUS,
have been successfully used to prevent recurrences.
Mirena®) is the most effective medical treatment for
menorrhagia [27] and has been shown to be useful
Endometriosis and other gynecological conditions
for reducing menstrual blood loss in women with
Endometriosis is a painful condition in which
bleeding disorders [17, 28]. It is also an effective and
endometrial tissue, the tissue which lines the uterus,
reversible method of contraception, making it an

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Reproductive Health in Women with Bleeding Disorders
5
Figure 3: Algorithm of management of menorrhagia


Would the patient like to

preserve fertility?




Yes
No





Would the patient like to
In women with pelvic

become pregnant now?
pathology or for whom

other measures have

failed, can also consider

surgical options*:

• Endometrial
ablation

• Hysterectomy

Yes
No


*Consider hemostatic

evaluation prior to surgery



Hemostatic measures*
Hormonal measures
• Antifibrinolytic drugs (tranexamic
• Levonorgestrel
IUS
acid and aminocaproic acid)
• Combined oral contraceptives
• DDAVP (intranasal or
• Progestins
subcutaneous)
• GnRH therapy
• Clotting
factor
replacement

*can also be used in women who do not wish

to get pregnant, either alone or in

combination with hormonal therapies
ideal treatment for women with menorrhagia who
bleeding disorders, there is a potential risk of bleeding
wish to preserve their fertility. The licensed duration
at the time of insertion and hemostatic coverage
of its use is five years in many countries. However,
may be required.
effective and safe extended use of the same LNG-IUS
for up to eight years has been reported [29, 30]. This
Combined hormonal contraceptives
gives a long grace period before replacing the system,
Combined hormonal contraceptives reduce menstrual
which is especially important for women living in
blood loss by thinning the endometrium and possibly
areas where medical care is not readily available.
by increasing factor VIII and VWF levels. Combined
hormonal contraceptive methods currently available
The main problem with the LNG-IUS is irregular
include the combined oral contraceptive (COC) pill,
bleeding or spotting, especially in the first three to
transdermal contraceptive patches, and vaginal rings.
six months of use, leading to discontinuation of
They provide reliable birth control and cycle control
treatment. Proper counselling and patient education
and reduce dysmenorrhea and other menstrual
may increase tolerance. In women with inherited
complaints. In women with bleeding disorders, they

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6
Reproductive Health in Women with Bleeding Disorders
have an added advantage of controlling ovulation
use, but GnRH analogues may be an alternative
bleeding and midcycle pain. Continuous use of
option to surgery for young women with resistant
these therapies (rather than the traditional 21-day
menorrhagia or severe bleeding disorders. If used
course) is safe and can be used to control timing and
for more than six months, hormone replacement
frequency of menstruation as well as menstruation-
therapy should be added to counteract low estrogen
associated symptoms [31]. This can be very useful
levels.
for girls and women with severe menstrual problems
that interfere with school/work attendance and
Hemostatic therapy
performance. Serious side effects of hormonal con-
Hemostatic therapies have been reported to be
traceptives include hypertension, liver dysfunction,
effective in controlling menorrhagia in women with
and thrombosis. Women with bleeding disorders,
bleeding disorders. Hemostatic therapies include
however, may have a low inherited thrombotic risk.
DDAVP (1-desamino-8-D-arginine vasopressin), a
Other side effects include nausea, headache, breast
synthetic vasopressin that stimulates the release of
tenderness, breakthrough bleeding, skin reactions,
VWF from endothelial cells, antifibrinolytic medica-
and depression.
tions (tranexamic acid and aminocaproic acid), and
coagulation factor concentrates. Hemostatic agents
Oral progestogens
constitute the main treatment option for women
Oral progestogens such as medroxyprogesterone
who are trying to conceive, though they are also
acetate and norethisterone are recommended treat-
used in women who do not wish to get pregnant,
ments for menorrhagia when used as a 21-day
either alone or in combination with hormonal therapy.
course (days 5-26). Shorter courses such as luteal
phase progesterone treatments are not effective.
Oral tranexamic acid (1g, 3-4 times a day during the
Compliance is usually poor with oral progestogens
menstrual period) is usually well tolerated but side
due to side effects such as fatigue, mood changes,
effects include nausea, headache, and diarrhea.
weight gain, bloating, depression, and irregular
DDAVP can be given by intravenous or subcutaneous
bleeding. In high doses, oral progestogens can be
injection or intranasally as a spray. For management
used with DDAVP or clotting factor to treat acute
of menorrhagia, it is usually administered as a nasal
menorrhagia in women with bleeding disorders.
spray (150-300 mcg daily for a maximum of 3-4 days,
usually during days with the heaviest blood flow).
Progestin-only contraceptives
Side effects are related to a vasomotor effect and
Progestin-only contraceptives such as Depo-Provera®
include tachycardia, flushing, and headache. With
(medroxyprogesterone acetate) injections, progestin-
repeated doses there is a small risk of hyponatremia
only pills, and the Implanon® implant also reduce
and water intoxication due to an antidiuretic effect.
endometrial proliferation and may reduce menstrual
Therefore, fluid restriction during treatment is
blood loss or suppress menstruation, but they are
essential. Both tranexamic acid and DDAVP alone
associated with a high rate of irregular bleeding and
or in combination have been reported to be effective
spotting. Insertion of the Implanon® implant could
in controlling menorrhagia in women with bleeding
also cause bleeding in women with bleeding disorders
disorders [18].
and might require preventative treatment with a
hemostatic agent.
Clotting factor replacement may be required to control
menorrhagia as regular prophylaxis in some women
Medroxyprogesterone acetate is now also available
with severe factor deficiencies not responding to
in a subcutaneous formulation, depo-subQ provera
other treatments.
104™, providing an alternative to the intramuscular
formulation, which can result in intramuscular
Surgical treatment
bleeding in a woman with a severe bleeding disorder.
Surgery may be required in the presence of pelvic
pathology and for women who do not tolerate medical
Gonadotropin-releasing hormone (GnRH) analogues
treatment or in whom this is unsuccessful. Women
These drugs stop ovulation and are effective for
with inherited bleeding disorders are more likely to
reducing menstrual flow and duration. Hypoestrogenic
have bleeding complications both peri-operatively
side effects (such as hot flashes and a reversible loss
and delayed (7-10 days later), even with relatively
of bone density) and cost prohibit their long-term
minor procedures such as hysteroscopy and biopsy.

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