Abstract

Obstetrical hematology represents challenges not only for the patient, but also for her progeny. In particular, bleeding disorders, both congenital and acquired, not only present problems both for delivery and in the immediate postpartum period, but also may have significant implications for the fetus and neonate. Women with congenital bleeding disorders or who are carriers of X-linked or autosomal disorders should be counseled prior to conception so that pregnancy can be safely undertaken with careful preparation. A treatment plan should be set up by a specialized care team that includes the hematologist, obstetrician, and anesthesiologist; the patient should be followed closely during pregnancy, through delivery, and in the immediate postpartum period. Acquired disorders of hemostasis that occur with pregnancy may present particular diagnostic difficulties and require rapid diagnosis and management.

Learning Objectives
  • List methods of preterm diagnosis of congenital bleeding disorders

  • Understand management strategies of factor deficiencies in pregnancy

  • Discuss the differential diagnosis of thrombocytopenia in pregnancy and its management

Women with a variety of congenital and acquired bleeding disorders are commonly referred to the hematologist by the obstetrician to help with management of pregnancy, in particular to prepare with delivery. Careful planning and monitoring during gestation is essential in patients with known abnormalities. Acquired abnormalities of hemostasis may present particular difficulties with diagnosis and management. With specialized expert care, the majority of women with these disorders can safely deliver a healthy infant.

Congenital disorders of hemostasis

Women with inherited bleeding disorders face hemostatic challenges during various stages of pregnancy. Women who are carriers may have abnormally low factor levels and be at risk as well. Bleeding may occur at the time of delivery and postpartum, but the patient may also be at risk following spontaneous pregnancy loss, during diagnostic procedures, and during termination of pregnancy. Women with inherited blood disorders planning a pregnancy should be evaluated by a hematologist and a high-risk obstetrician expert in the management of these disorders.

Congenital disorders of hemostasis require consideration not only for the bleeding risks of the mother: the risk of the fetus having inherited the bleeding tendency must also be taken into consideration. Women at risk of being carriers should have their status determined prior to actively seeking conception. For autosomal-recessive disorders, paternal testing may be indicated as well. Carrier state and the risk of her fetus should be determined early in pregnancy by genetic testing. Chorionic villus sampling for diagnosis of hemophilia and other inherited bleeding disorders can be performed between 11 and 14 weeks of pregnancy. Amniocentesis can be done between the 15th and 20th week of pregnancy; both carry a risk of miscarriage between 1% and 2%.1  For X-linked recessive disorders, fetal sex determination can be performed in the first trimester by real-time polymerase chain reaction identification of Y-chromosome–specific sequences using cell-free fetal DNA in maternal plasma for genetic conditions affecting a particular sex such as hemophilia and may obviate the need for more invasive testing of a female fetus.2  Umbilical cord blood testing should be obtained at the time of delivery to avoid venipuncture and ensure early testing.

von Willebrand disease

Despite autosomal inheritance, women are more commonly diagnosed with von Willebrand disease (VWD) because of presentation at menarche or postpartum bleeding. Normally, factor VIII (FVIII) and von Willebrand factor (VWF) increase throughout pregnancy, sharply during the third trimester. For this reason, most patients with type 1 and some patients with type 2 VWD do not require prophylactic administration of concentrates prior to delivery. However, levels fall sharply immediately following delivery, by as much as 29%,3  and there is a considerable risk of postpartum hemorrhage and late bleeding. Bleeding may occur late and patients should be counseled to report heavy bleeding which may occur for a month or more postpartum. Patients with type 3 VWD and FVIII levels that are low or unmeasurable will require replacement at the time of delivery to prevent hemorrhage and should continue to receive replacement therapy 3 to 4 times daily for at least 3 to 5 days or longer.4  FVIII levels are considered the best predictors of bleeding risk and FVIII levels should be tested early in the third trimester and again later in the third trimester if levels are low, and monitored for 1 to 2 weeks after delivery. Bleeding risk decreases significantly at FVIII levels above 40 U/dL5  and factor replacement should be given along with VWF replacement at the time of delivery if factor levels are <50 U/dL.6  Plasma-derived VWF-containing concentrates should be infused to increase FVIII and VWF levels and maintain them at >50 U/dL. Vonvendi, recombinant VWF, was approved in late 2015.7 

The use of desmopressin (DDAVP) antepartum is controversial because of a theoretical risk of vasoconstriction and placental insufficiency. DDAVP may be associated with hyponatremia and seizure, and tachyphylaxis occurs after repeated dosing due to depletion of endothelial stores. DDAVP is sometimes administered to patients with type 1 VWD at delivery, particularly with caesarean section and for several days afterward. Patients with type 2B VWD may develop severe thrombocytopenia, and are at risk of a fall in platelets. Although a risk of thrombosis has been theorized with administration of DDAVP in these patients, this has not been reported to date. VWF concentrates may be required for delivery and afterward, as well as platelet transfusions, if bleeding does not respond completely to VWF. Published evidence-based guidelines for VWD make recommendations for management during pregnancy including the more uncommon subtypes.5 

James and colleagues measured VWF and FVIII levels after delivery in 35 pregnancies in 32 women with VWD, 15 of whom were treated with DDAVP and VWF concentrate, and compared them to 40 normal pregnancies.8  Although levels of VWF were higher in women with VWD immediately postpartum, their levels fell rapidly after 4 hours and they had lower VWF levels, lower hematocrits, and significantly greater blood loss than the normal controls. Treated patients had the lowest levels. Our current approach of predicting and preventing postpartum hemorrhage appears to be inadequate and in need of further research to determine optimal monitoring and therapy.

Coagulation factor deficiencies

During pregnancy, FVIII levels increase in most hemophilia A carriers, however, FIX levels are unchanged in carriers of hemophilia B.9  Factor levels should be tested at ∼28 and 34 weeks. Carriers of hemophilia are at risk of postpartum hemorrhage if they have reduced levels at term, and factor replacement is recommended if levels are below 50 U/dL. Patients with borderline levels may be treated with tranexamic acid, alone or in combination with DDAVP and factor concentrates.10  Epidural anesthesia can be safely performed when factor concentrations are in the normal range if there are no other contraindications.

There are little data on bleeding risk in women with rare bleeding disorders. In women with FXIII and fibrinogen deficiencies, there may be abnormal placental implantation; an increased risk of antepartum hemorrhage due to placental abruption has been reported.11 

Other factor deficiencies may also result in bleeding or pregnancy loss. FXI deficiency may be associated with increased risk of miscarriage and postpartum bleeding but high-quality data regarding prophylaxis are not available.12  Prophylactic replacement for women with fibrinogen and FXIII deficiency may increase the chance for successful pregnancy outcome. Similarly, prophylaxis for deficiencies of FX, FV, and FVII are not well characterized, but may be indicated in women with a history of bleeding complications.13-15 

Inherited disorders of platelet number or function

Although women with inherited thrombocytopenia and their progeny are potentially at risk of bleeding, little evidence exists to guide management. A retrospective study of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia found that the thrombocytopenia and bleeding tendency did not worsen during pregnancy. There was no difference from normal women in terms of miscarriages, fetal bleeding, nor preterm births.16  The degree of thrombocytopenia in the newborn was similar to that in the mother. Although no mother died, the risk of hemorrhage was increased overall; bleeding varied from mild to very severe and was most closely related to the bleeding history prior to pregnancy. Of 156 affected neonates, only 7 bled at the time of delivery; however, 2 died of cerebral hemorrhage. The fetus with Bernard-Soulier syndrome has been reported to bleed antepartum with fatal consequences, and in utero bleeding risk should be considered. Similarly, little evidence exists for management of inherited platelet function disorders. Patients with Glanzmann thrombasthenia appear to be at the highest risk of bleeding whereas other defects appear less likely to result in hemorrhage at the time of delivery.17,18  It is important to recognize that patients may be alloimmunized to HLA due to prior transfusion or through pregnancy and may be refractory to platelet transfusion. It is prudent to check for HLA antibodies and the availability of HLA-matched platelets for these patients. Patients with Bernard-Soulier syndrome or Glanzmann thrombasthenia may also be refractory to platelet transfusion due to antibodies against glycoprotein Ib/IX/V or glycoprotein IIb, and testing by a laboratory specializing in these disorders is indicated.

Mode of delivery

The bleeding risk and optimal mode of delivery of a patient with a known bleeding disorder or a hemophilia carrier should be discussed by a team of physicians including the obstetrician, hematologist, anesthesiologist, and pediatrician. The laboratory should be notified of any specialized testing that will need to be done urgently and the transfusion service and pharmacy alerted to any anticipated special needs.

The optimal mode of delivery remains controversial. Although it is agreed that there is no indication for caesarean section in mild bleeding disorders, whether it is indicated in carriers with severe hemophilia who are pregnant with a boy with hemophilia remains under debate.19  Many experts believe vaginal delivery of the hemophilic infant is associated with increased risk of intracranial hemorrhage and recommend planned caesarean delivery to decrease fetal risk if the fetus is known to be affected or the state of inheritance unknown.20  Delivery using vacuum extraction or forceps should be avoided as they are associated with an increased risk of hemorrhage.21  Fetal scalp electrodes, venous sampling, or other invasive procedures should be avoided and cord blood sampling performed at the time of delivery.

Acquired disorders of hemostasis

Thrombocytopenia

Thrombocytopenia is second only to anemia as the most common hematologic abnormality encountered during pregnancy.22  Mild thrombocytopenia is relatively frequent during pregnancy and has generally no consequences for either the mother or fetus. Three large series involving >26 000 women suggest that the incidence of thrombocytopenia at the end of pregnancy varies from 6.6% to 11.6%.23-25  However, counts <100 × 109/L are observed in only 1% of pregnant women.

Gestational or “incidental” thrombocytopenia accounts for 70% to 80% of isolated thrombocytopenia cases and likely results from various mechanisms, including hemodilution and accelerated clearance.26  This is a diagnosis of exclusion and the thrombocytopenia is mild to moderate, with two-thirds of cases having platelet counts between 130 × 109/L and 150 × 109/L. The thrombocytopenia is usually self-limited and rarely requires therapy. An alternative etiology should be sought for platelet counts <80 × 109/L27  and a diagnosis of gestational thrombocytopenia is unlikely if the platelet count is <50 × 109/L.28,29  There ought not to be a past history of thrombocytopenia except during a previous pregnancy, the thrombocytopenia resolve spontaneously after delivery, and the child be unaffected. Because gestational thrombocytopenia is not immune mediated, it does not improve with corticosteroids or IV immunoglobulin (IVIg) and if an increase in the platelet count is for some reason necessary, platelet transfusion would be required. Gestational thrombocytopenia must be distinguished from primary immune thrombocytopenia which is managed quite differently and can have significant implications for the health and care of the neonate.

Immune thrombocytopenia may be primary, associated with another autoimmune condition such as systemic lupus erythematosus or antiphospholipid antibody syndrome, and rarely due to lymphoproliferative malignancy.27  Thrombocytopenia in systemic lupus erythematosus during pregnancy was predictive of higher disease activity and associated with severe organ damage, early onset preeclampsia, and higher pregnancy loss in some studies.30  Evaluation of thrombocytopenia presenting in the first or early second trimester is similar to that in a nonpregnant patient with evaluation of the peripheral blood film, and testing for associated thyroid or liver disease, infection, and other autoimmune disorders and serology. Testing for platelet antibodies is not recommended. Table 1 lists recommended testing for thrombocytopenia in pregnancy.

Table 1.

Laboratory evaluation of thrombocytopenia in pregnancy

Evaluation Tests 
Recommended tests Complete blood count 
Peripheral blood smear review 
Direct antiglobulin (Coombs) test (DAT) 
Reticulocyte count 
Liver function tests 
Viral screen (HIV, HCV, HBV, CMV) 
Creatinine 
Consider testing Antinuclear antibody 
Antiphospholipid antibodies, lupus anticoagulant 
Thyroid function tests 
Helicobacter pylori (stool antigen or breath test) 
Coagulation testing 
Quantitative immunoglobulins 
VWD panel (for VWF type 2b) 
ADAMTS-13 level 
Not routinely recommended Antiplatelet antibody 
Bone marrow aspiration 
Peripheral blood flow cytometry 
Thrombopoietin level 
Evaluation Tests 
Recommended tests Complete blood count 
Peripheral blood smear review 
Direct antiglobulin (Coombs) test (DAT) 
Reticulocyte count 
Liver function tests 
Viral screen (HIV, HCV, HBV, CMV) 
Creatinine 
Consider testing Antinuclear antibody 
Antiphospholipid antibodies, lupus anticoagulant 
Thyroid function tests 
Helicobacter pylori (stool antigen or breath test) 
Coagulation testing 
Quantitative immunoglobulins 
VWD panel (for VWF type 2b) 
ADAMTS-13 level 
Not routinely recommended Antiplatelet antibody 
Bone marrow aspiration 
Peripheral blood flow cytometry 
Thrombopoietin level 

CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus.

Immune thrombocytopenia may present for the first time or be exacerbated during pregnancy.31  It is the most common cause of thrombocytopenia presenting in the first trimester and may be mild or severe and refractory to treatment. Therapy should be directed toward maintaining a safe platelet count in the mother as it does not appear to affect the neonatal risk of thrombocytopenia. Generally, a platelet count of 30 000 is considered safe until approaching term when counts need to be monitored more closely in anticipation of delivery. IVIg and corticosteroids are first-line therapies and appear to increase platelet counts with similar efficacy and relatively little toxicity for the mother or neonate.32  Patients refractory to either of these treatments may benefit by a combination of the 2. Options for treatment of the refractory patient are limited by fetal risk. Azathioprine may be used as a steroid-sparing agent. Use of anti-RhD immune globulin, cyclosporine, and rituximab have all been reported with good outcomes but cannot be routinely recommended. There are several reports of romiplostim therapy in severe refractory thrombocytopenia in pregnancy but further evidence of its safety in pregnancy is required.33 

Maternal therapy and platelet count are poor predictors of the neonate’s platelet count. The only reliable predictor is the platelet count and course of thrombocytopenia of that of an older sibling.34 

The optimal platelet count at delivery has not been established. A platelet count of 75 × 109/L to 80 × 109/L in the absence of other hemostatic abnormalities is recommended by most guidelines.27  For uncomplicated deliveries, a platelet count of 50 000 is generally adequate and safe for caesarean section should it become necessary. Mode of delivery should be based upon obstetrical indications only, as the risk of intracranial hemorrhage is low, generally <1%.27  As in all deliveries with a potentially affected fetus, instrumentation, vacuum extraction, and forceps should be avoided. Most reports have found that severe thrombocytopenia (platelet counts <50 × 109/L) occurs in ∼10% of newborns; however, a recent report suggests that it may be as high as 30%.35  Nadir platelet counts typically occur 2 to 5 days after birth so the neonate should be monitored carefully. Treatment consists of IVIg, sometimes accompanied by platelet transfusions. Although breastfeeding is generally felt to be safe and not contraindicated, prolonged thrombocytopenia in the neonate has been shown to occur due to transfer of primarily IgA antiplatelet antibodies targeting αIIbβ3 integrin.36  If thrombocytopenia persists for >3 months in a breastfed infant, the mother should be asked to discontinue breastfeeding and pump and store the milk for a period of several weeks. Reinitiation of breastfeeding and recurrence of thrombocytopenia may suggest antibody transfer.

Thrombotic microangiopathies of pregnancy

Preeclampsia, hemolysis, elevated liver enzymes, and low platelets, and acute fatty liver of pregnancy are frequently associated with sudden deterioration in maternal and fetal conditions and the mainstay of treatment is delivery of the fetus.37  Reversal of the coagulopathy by transfusion with plasma, cryoprecipitate, and platelets may be required for delivery and postpartum. The target platelet count for caesarean section differs but 30 × 109/L to 50 × 109/L is generally recommended. Thrombotic thrombocytopenic purpura may also occur in pregnancy due to congenital deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) or an autoimmune etiology. The treatment does not differ from that in the nonpregnant patient. Hemolytic uremic syndrome may also present for the first time in pregnancy and may be difficult to distinguish from thrombotic thrombocytopenic purpura.

Disseminated intravascular coagulation may complicate pregnancy with placental implantation abnormalities, retained products of conception, or infection. Treatment is generally supportive of the coagulopathy and resolution of the underlying etiology.

Acquired coagulation factor deficiencies

Rarely, spontaneous autoantibody-mediated factor deficiencies may present in pregnancy.38  Generally, the deficiency is severe and associated with bleeding. Factor replacement may require high doses of concentrate and immune suppression. In patients with mechanical valves, an acquired VWF deficiency may occur and these patients should be screened early in pregnancy or in the planning phase of conception and managed similarly to patients with congenital deficiency.5 

Postpartum hemorrhage requires rapid response, and obstetrical services should develop protocols in preparation for these events. A recent review of the management of postpartum hemorrhage outlines recent progress in readiness, recognition, and management.39 

Conclusion

The diagnosis and management of bleeding disorders in pregnancy must take into consideration risks to the mother and the fetus and the special care considerations that occur during different stages of pregnancy, delivery, and postpartum. With proper planning and care delivered by an experienced knowledgeable team, the majority of women can carry a pregnancy to term and safely deliver a healthy neonate.

Correspondence

Terry B. Gernsheimer, Division of Hematology, University of Washington, 1959 NE Pacific St, Box 356330, Seattle, WA 98195; e-mail: bldbuddy@uw.edu.

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Author notes

Conflict-of-interest disclosure: T.B.G. has received research funding from the National Heart, Lung, and Blood Institute, has consulted for Amgen Corporation, Momenta Pharmaceuticals, Syntimmune, and UCB Bioscience, and has received honoraria from Amgen Corporation.

Off-label drug use: None disclosed.