Bleeding Disorders: Impact on Reproduction


Bleeding disorders can create problems with reproductions.

Inherited bleeding disorders in women and girls represent unique management challenges for the ob/gyn. Conditions such as von Willebrand disease (VWD) can increase risk of menorrhagia and postpartum hemorrhage, whereas inherited thrombophilias can predispose patients to thrombosis during pregnancy or if they are exposed to estrogen-containing contraceptives or postmenopausal hormone therapy. Incidence of medical and pregnancy-related complications is increased in women with sickle cell disease and those who are carriers of the X-linked condition hemophilia. Clearly, inherited bleeding disorders impact the health of women and girls at every stage of their reproductive lives (Table).

Management of reproductive issues in requires knowledge of both reproductive physiology and hematology. Ob/gyns may not be familiar with a particular blood disorder or the latest therapy for its management, whereas hematologists most likely are not prepared to manage impact on aspects of reproduction including menstruation, ovulation, gestation, and delivery.

This article reviews some key concerns for ob/gyns faced with caring for women with common nonmalignant blood disorders.


Prevalence and consequences

Menorrhagia is common in women with bleeding disorders and prevalence ranges from 10% to 100%, depending on the specific bleeding disorder.1 Bleeding disorders also are more prevalent in women with menorrhagia:
Studies indicate that 5% to 32% of women with menorrhagia have bleeding disorders. Although menorrhagia is the most common reproductive-tract manifestation of a bleeding disorder, it is not the only sign. Women with bleeding disorders also appear to have an increased risk of developing hemorrhagic ovarian cysts and possibly endometriosis.

Women suspected of having a bleeding disorder (or who are hemophilia carriers) should undergo diagnostic testing before becoming pregnant to ensure appropriate preconception counseling and pregnancy management. During pregnancy, women with bleeding disorders may have an increased risk of bleeding complications. At delivery, affected women are more likely to experience postpartum hemorrhage, particularly delayed or secondary postpartum hemorrhage.

As women with bleeding disorders age, they may be more likely to experience conditions that present with bleeding, such as fibroids, endometrial hyperplasia, and polyps.1 They are also more likely to undergo hysterectomy and to have the procedure at a younger age. In a survey of women with VWD enrolled in US hemophilia treatment centers, 25% reported having had a hysterectomy, compared with 9% of matched controls.2 Women with bleeding disorders are at risk of the same obstetric and gynecologic problems that affect all women, but they appear to be disproportionately affected by conditions that manifest with bleeding (see “Resources for physicians”).1

von Willebrand disease

VWD is the most common inherited bleeding disorder.1 It is caused by deficiency in or dysfunction or absence of von Willebrand factor, which is necessary for platelet adhesion at sites of vascular injury and for protection of clotting factor VIII from proteolysis in the circulation.3 VWD manifests with mucocutaneous bleeding, including uterine bleeding. The prevalence of VWD in the general population ranges from 0.6% to 1.3%, depending upon the number of individuals with bleeding symptoms, family history, and laboratory abnormalities. VWD affects both men and women, but its implications for women are more serious than for men because they experience menstruation, pregnancy, and childbirth. 4 Among women with menorrhagia, prevalence of VWD is reportedly 5% to 20%, and it may be as high as 36% in adolescents with menorrhagia.4 VWD is often overlooked in women and girls because of lack of awareness among providers and patients. Bleeding symptoms often manifest in the reproductive tract, so clinicians may diagnose and treat the condition as a gynecologic problem without appreciating the contribution of the underlying bleeding disorder.

In 2004, the National Heart, Lung, and Blood Institute of the National Institutes of Health convened a panel of experts to develop evidence-based practice guidelines for diagnosis, evaluation, and management of VWD by primary care providers and specialists. The guidelines were published in 2008 and excerpted for ob/gyns in Obstetrics and Gynecology in 2009.5 Other consensus guidelines have been published by various government agencies and hemophilia organizations, as summarized in Thrombosis Research in 2009.6 The American College of Obstetricians and Gynecologists (ACOG) issued a Committee Opinion on VWD in women in 2009.7


Hemophilia is the most common severe inherited bleeding disorder, but as an X-linked condition, it affects almost exclusively men and boys; women are carriers. Hemophilia is caused by a deficiency of clotting factor VIII (80% of cases) or clotting factor IX (20% of cases). Female carriers of hemophilia may or may not have clinical manifestations of a bleeding disorder and their bleeding symptomatology ranges widely, from asymptomatic to severe. Clinicians must be aware that hemophilia carriers are at risk of having an affected male infant. Ob/gyns may be the only knowledgeable providers who can inform a carrier about opportunities for preimplantation genetic diagnosis or molecular analysis of fetal DNA.

Ob/gyns must consider the risk of fetal intracranial hemorrhage at the time of delivery in a potentially affected male infant.8 Most affected male infants delivered vaginally to hemophilia carriers do not suffer a head bleed, but the outcome of labor cannot be predicted. Planned vaginal delivery puts a woman at risk of an abnormal labor and operative vaginal delivery, both of which predispose to intracranial hemorrhage. Cesarean delivery reduces the risk of intracranial hemorrhage by an estimated 85%, and the risk can be nearly eliminated by performing elective cesarean before labor. After maternal and fetal risks associated with planned vaginal versus planned cesarean delivery have been discussed with a hemophilia carrier pregnant with a male fetus, she should also be offered the option of elective caesarean.8 At the time of cesarean, vacuum-assisted delivery should be avoided.


In 2010, the Foundation for Women & Girls with Blood Disorders, a nonprofit 501(c)3 organization, was launched to ensure that all women and girls with blood disorders are correctly diagnosed and optimally treated and managed at every life stage. Its strategy is to improve healthcare provider education across disciplines. Ob/gyns can find additional information, pose questions, or request resources through Below is a professional bibliography compiled by the Foundation.

Resources for Physicians

Patient Education Resources

Immune thrombocytopenia

Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia, defined as a peripheral blood platelet count less than 100 x 109/L in the absence of any obvious initiating or underlying cause.9 Approximately 1 in 10,000 individuals are affected by ITP, but the prevalence is higher in women aged 30 to 60.9,10 Depending on their degree of thrombocytopenia, women and girls who are not pregnant have an increased risk of heavy menstrual bleeding and other abnormal reproductive-tract bleeding.11 The prevalence of ITP during pregnancy has been reported to be 1 in 1,000 to 10,000. In affected patients, despite the potential hemostatic challenges of pregnancy-a time when clotting factors are elevated-platelet counts drop by approximately 10%.9 During pregnancy, therefore, women with ITP are vulnerable to exacerbation or relapse.

Management during pregnancy requires maintaining a platelet count sufficient to avoid bleeding complications (>20-30 x 109/L), to allow regional anesthesia (>75 x 109/L), and to avoid excess bleeding at delivery (>50 x 109/L). During pregnancy, corticosteroids and intravenous immunoglobulin are considered first-line therapy, with splenectomy, azathioprine, and anti-RH(D) as alternatives. Other options for immunosuppressant medications are limited because of possible teratogenicity.9 Fortunately, risk of fetal thrombocytopenia is not substantially different in women with versus without ITP,12 so delivery recommendations are based on obstetric indications.

Although the concept is counterintuitive, ITP is a hypercoagulable state. Patients with ITP have approximately a 1.6-fold increased risk of venous thromboembolism (VTE) and a 1.4-fold increased risk of arterial thrombosis. Especially if other risk factors are present, women with ITP may benefit from some form of thromboprophylaxis at delivery, such as use of pneumatic compression devices. Postulated mechanisms of primary ITP-induced thrombosis include increased microparticle thrombogenicity after peripheral destruction of platelets and antiphospholipid antibody activity.10


Resources for Physicians

Patient Education Resources

Thrombotic disorders

Approximately 0.5 to 2 per 1,000 pregnant women experience thromboembolism.13 In the United States and Western Europe, thrombotic pulmonary embolism is one of the leading causes of maternal death.14 During pregnancy, approximately 80% of thromboembolism cases are venous and about 20% are arterial.15 Risk of VTE is increased 4- to 5-fold during pregnancy and postpartum, and it is substantially higher in women with thrombophilia. An estimated 20% to 50% of patients who experience VTE during pregnancy and postpartum have thrombophilia, and the condition is associated with increased risk of adverse pregnancy outcomes.16-18

In women who are not pregnant, the prevalence of VTE is approximately 1 in 10,000 per year. Studies indicate that it is increased by 2- to 6-fold in users of combined hormonal contraception, depending upon the dose of estrogen and type of progestin.19-22 The risk is substantially higher in women with thrombophilia. Both observational studies and randomized controlled trials have shown a 2- to 4-fold increase in risk of VTE associated with postmenopausal hormone therapy, and positivity for Factor V Leiden further increases that risk.23-28

Options for contraception, management of menorrhagia, and postmenopausal symptoms are limited in women with a history of thrombosis because of their risk of recurrent thrombosis, which is further increased by exposure to estrogen. Conversely, women on anticoagulation have bleeding risks with menstruation and ovulation that are similar to those in women with bleeding disorders. Optimal management of these patients requires an understanding of the risks of thrombosis with hormonal contraceptives and of bleeding with anticoagulants. Hot flashes, sleeplessness, mood changes, and vaginal dryness or atrophy may require nonhormonal strategies. Vaginal dryness or atrophy may be the most difficult to manage without hormones, but can be treated with new vaginal preparations that have minimal or no systemic absorption.29,30


Resources for Physicians

Patient Education Resources

Sickle cell disease

Sickle cell disease (SCD), which affects 1 in 600 African Americans, is the most common hemoglobinopathy in the United States. In women with SCD, pregnancy is associated with an increased incidence of medical and pregnancy-related complications.31 Rates of mortality in pregnant women with SCD have been falling consistently since the 1970s, but remain higher than in unaffected women.32 SCD complicates only 0.1% of pregnancies, yet it accounts for 1% of all maternal deaths.31

Multiple case control and at least 2 population-based series have documented an increased risk of growth restriction, preterm delivery, and stillbirth in women with SCD.31,33 Risks are reduced, but not eliminated, with fetal surveillance, including ultrasound monitoring for growth and antepartum testing, which may lead to planned early delivery. Women with SCD have frequent exposure to blood products, and a recent study showed a 5.3% rate of alloimmunization among them.34 Alloimmunized women are at risk of fetal anemia because of maternal antibodies that target fetal red cell antigens, which may lead to hemolytic disease in the fetus or neonate. Regular use of pain-relieving opioids can result in fetal exposure and neonatal withdrawal syndrome after delivery.35 Compared with women without SCD, affected women are more likely to experience preeclampsia, VTE, and serious infections during pregnancy.31,33,34 Forty percent to 50% of women with SCD require at least one hospital admission during pregnancy.34,36-37

Women with SCD who have partners with S hemoglobin, C hemoglobin, or β-thalassemia trait are at risk of having an infant with SCD. Once again, ob/gyns may be the only knowledgeable providers who can counsel affected women about options for genetic testing.

For women with SCD who are not pregnant, hormonal contraceptives protect against pregnancy and may provide noncontraceptive benefits, such as decreased menstrual blood flow with improvement in hemoglobin levels. The primary risk associated with hormonal contraceptives-particularly combined hormonal contraceptives containing estrogen-is VTE. Caution should be used when prescribing combined hormonal contraceptives, however, because studies show that children with SCD have a 9% risk of overt stroke and a 22% risk of silent stroke (silent cerebral infarct) before age 18.38-40 This may be problematic for women with SCD because 10% to 20% have had VTE or stroke by the age of 18. Systematic reviews of the literature have consistently demonstrated the safety of progestin-only hormonal contraception for patients with SCD (and for women with a history of thrombosis).41-43


Resources for Physicians

Patient Education Resources


Ob/gyns managing reproductive issues in women and girls with bleeding disorders must be knowledgeable about both reproductive physiology and hematology. Ob/gyns should be alert for menorrhagia in patients with bleeding disorders and bleeding disorders in patients with menorrhagia. Optimal management of women with a history of thrombosis requires an understanding of both the risks of thrombosis with hormonal therapy and the consequences of bleeding with anticoagulants.

Preconception counseling, including genetic counseling, is a requirement for women with bleeding disorders and the potential impact of the disorders must be taken into consideration during prenatal care and when planning for delivery (see “Patient education resources”).

Take-Home Messages:

◾ Women with bleeding disorders are at disproportionate risk of obstetric and gynecologic conditions that manifest with bleeding.

◾ Preconception counseling, which should include genetic counseling, is essential in women diagnosed with bleeding disorders.

Power Points:

◾ Postpartum hemorrhage, particularly delayed or secondary postpartum hemorrhage, is more likely to occur in women with bleeding disorders.

◾ Pregnant hemophilia carriers with an affected male fetus should be offered the option of an elective cesarean delivery, which nearly eliminates the risk of intracranial hemorrhage in the neonate.

Other organizations for blood disorders

R e f e r e n c e s

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  • Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical, reproductive and psychosocial experiences of women diagnosed with von Willebrand’s disease receiving care in haemophilia treatment centres: a case-control study. Haemophilia. 2003;9(3):292-297.

  • Nichols WL Jr, Hultin MB, James AH, et al. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2007.

  • James AH. Women and bleeding disorders. Haemophilia. 2010;16(suppl 5):160-167.

  • James AH, Manco-Johnson MJ, Yawn BP, Dietrich JE, Nichols WL. Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines. Obstet Gynecol. 2009;114(3):674-678.

  • James AH. Guidelines for bleeding disorders in women. Thromb Res. 2009;123(suppl 2):S124-S128.

  • American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 451: Von Willebrand disease in women. Obstet Gynecol. 2009;114(6):1439-1443.

  • James AH, Hoots K. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is caesarean delivery. Haemophilia. 2010;16(3):420-424.

  • Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186.

  • Sarpatwari A, Bennett D, Logie JW, et al. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica. 2010;95(7):1167-1175.

  • Levens ED, Scheinberg P, DeCherney AH. Severe menorrhagia associated with thrombocytopenia. Obstet Gynecol. 2007;110(4):913-917.

  • Sainio S, Kekomäki R, Riikonen S, Teramo K. Maternal thrombocytopenia at term: a population-based study. Acta Obstet Gynecol Scand. 2000;79(9):744-749.

  • James A; Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118(3):718-729.

  • Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol. 2010;116(6):1302-1309.

  • James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194(5):1311-1315.

  • Dilley A, Austin H, El-Jamil M, et al. Genetic factors associated with thrombosis in pregnancy in a United States population. Am J Obstet Gynecol. 2000;183(5):1271-1277.

  • Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342(6):374-380.

  • Lockwood C, Wendel G; Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 124: inherited thrombophilias in pregnancy. Obstet Gynecol. 2011;118(3):730-740.

  • Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997;349(9045):83-88.

  • Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344(8935): 1453-1457.

  • Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995;346(8990):1582-1588.

  • Venous thromboembolic disease and combined oral contraceptives: results of international multicentre casecontrol study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995;346(8990):1575-1582.

  • Grady D, Cummings SR. Postmenopausal hormone therapy for prevention of fractures: how good is the evidence? JAMA. 2001;285(22):2909-2910.

  • Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348(9033):977-980.

  • Hemminki E, McPherson K. Impact of postmenopausal hormone therapy on cardiovascular events and cancer: pooled data from clinical trials. BMJ. 1997;315(7101): 149-153.
  • Barrett-Connor E, Stuenkel CA. Hormone replacement therapy (HRT)-risks and benefits. Int J Epidemiol. 2001;30(3):423-426.

  • Cushman M, Kuller LH, Prentice R, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292(13):1573-1580.

  • Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655): 1227-1231.

  • Bachmann GA. The clinical platform for the 17betaestradiol vaginal releasing ring. Am J Obstet Gynecol. 1998;178(5):S257-S260.

  • Committee on Practice Bulletins-Gynecology. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 84: prevention of deep vein thrombosis and pulmonary embolism. Obstet Gynecol. 2007;110(2 pt 1): 429-440.

  • Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol. 2008;199(2):125.e1-125.e5.

  • Powars DR, Sandhu M, Niland-Weiss J, Johnson C, Bruce S, Manning PR. Pregnancy in sickle cell disease. Obstet Gynecol. 1986;67(2):217-228.

  • Barfield WD, Barradas DT, Manning SE, Kotelchuck M, Shapiro-Mendoza CK. Sickle cell disease and pregnancy outcomes: women of African descent. Am J Prev Med. 2010;38(4 suppl):S542-S549.

  • Ngô C, Kayem G, Habibi A, et al. Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions. Eur J Obstet Gynecol Reprod Biol. 2010;152(2):138-142.

  • Kellogg A, Rose CH, Harms RH, Watson WJ. Current trends in narcotic use in pregnancy and neonatal outcomes. Am J Obstet Gynecol. 2011;204(3):259.e1-259.e4.

  • Yu CK, Stasiowska E, Stephens A, Awogbade M, Davies A. Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic. J Obstet Gynaecol. 2009;29(6):512-516.

  • 37. Al Jama FE, Gasem T, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Pregnancy outcome in patients with homozygous sickle cell disease in a university hospital, Eastern Saudi Arabia. Arch Gynecol Obstet. 2009;280(5):793-797.

  • Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288-294.

  • Buchanan GR, DeBaun, MR, Quinn CT, Steinberg MH. Sickle cell disease. Hematology Am Soc Hematol Educ Program. 2004:35-47.

  • Pegelow CH, Macklin EA, Moser FG, et al. Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood. 2002;99(8): 3014-3018.

  • Manchikanti Gomez A, Grimes DA, Lopez LM, Schulz KF. Steroid hormones for contraception in women with sickle cell disease. Cochrane Database Systematic Reviews, 2007 (2) Art. No.: CD006261. DOI: 0.1002/14651858.CD006261. pub2.

  • Legardy JK, Curtis KM. Progestogen-only contraceptive use among women with sickle cell anemia: a systematic review. Contraception. 2006;73(2):195-204.

  • Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception. 1998;57(5):315-324.
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