Bleeding disorders in pregnancy require consideration of maternal bleeding and hemorrhagic complications in the newborn. Data on the fetus are often lacking, and the practitioner must base decisions on past experience and the mother’s previous reproductive history.
DISSEMINATED INTRAVASCULAR COAGULATION
Life-threatening bleeding is seen with some pregnancy-unique complications, resulting in disseminated intravascular coagulation (DIC). Because of the changes in coagulation factor levels, D-dimer, and platelet count during pregnancy, the normal range for tests routinely used to diagnose DIC in a nonpregnant state cannot be extrapolated directly to DIC in pregnancy. Serial measurement of the prothrombin time (PT), partial thromboplastin time (PTT), D-dimer, and fibrinogen are likely to be more helpful than measuring a single value.32 The DIC score developed by the International Society on Thrombosis and Hemostasis has been modified for pregnancy and this score may be more useful in identifying DIC.33
Complications of pregnancy that lead to DIC include placental abruption, a retained dead fetus, and amniotic fluid embolism (Chap. 129). Although amniotic fluid embolism is a significant cause of maternal death in developed countries, the mortality decreased from 86 percent in 1979 to less than 30 percent in 1994 and 1995, perhaps from a better supportive therapy.34 Amniotic fluid embolism is most likely to occur in older multiparous women whose pregnancies have gone beyond the 40th week and during tumultuous labor. Amniotic fluid enters the maternal circulation through tears in the chorioamniotic membranes, injury to the uterine veins, or uterine rupture. Its onset is heralded by maternal vascular collapse with dyspnea, hypotension, and cardiac arrhythmias followed by DIC that is manifested by oozing from intravenous lines, hematuria, hemoptysis, and excessive uterine bleeding. Atypical presentations have also been reported in which there is rapid deterioration of the fetus, followed by maternal respiratory and cardiovascular deterioration with development of DIC.35
In amniotic fluid embolism, DIC appears to involve an abnormal host response to exposure to various foreign antigens with the subsequent release of endogenous mediators which drive the clinical manifestations.36 Treatment is not significantly different than in other cases of DIC with bleeding (Chap. 129); however, there are some reports of successful management with uterine artery embolization.37
Placental abruption has also led to development of DIC, and the spectrum of hemostatic failure is broad and appears to be related to the degree of placental separation.38 Volume resuscitation, delivery of the fetus, and infusion of blood products to correct the maternal coagulation defect are indicated. Regional anesthesia is contraindicated because of the risk of bleeding in the epidural space and of the pooling of blood in the lower limb vascular bed, which could worsen hypovolemia.38 Fetal trophoblast cells have distinct properties which may activate coagulation including expression of tissue factor, suppression of fibrinolysis, and exposure of anionic phospholipids.39 Finally, intrauterine fetal death can also lead to DIC. Thromboplastic substances and specifically tissue factor released from dead fetal tissues into the maternal circulation are thought to trigger DIC; however, this is not usually detectable by laboratory tests until 3 or 4 weeks after fetal demise. Overt DIC is present in approximately 50 percent of women who retain a dead fetus for 5 weeks or longer.40
Although von Willebrand disease (VWD) is transmitted in an autosomal dominant fashion, women appear to be disproportionately affected with bleeding symptoms, primarily menorrhagia and postpartum hemorrhage (Chap. 126). In normal women and in types 1 and 2 (but not type 3) VWD patients, levels of factor VIII and VWF rise during pregnancy, with the most pronounced increase in the third trimester.39 As a result, prophylactic administration of VWF-containing factor concentrates at delivery is often unnecessary in type 1 and type 2 VWD patients; however, the risk of postpartum hemorrhage is significant (13–29 percent) as levels fall rapidly after birth.41 Thus in type 1 patients, factor VIII levels should be tested not only late in the third trimester, but also for 1 to 2 weeks postpartum. These patients should be monitored for increases in menstrual blood flow for at least 1 month. Risk of bleeding appears to be minimal when factor VIII levels are greater than 50 U/dL. There are several reports of severe thrombocytopenia developing late in pregnancy in patients with type 2B VWD,42,43 and at least one of these patients developed a pulmonary embolus while receiving cryoprecipitate for postpartum hemorrhage. Despite the possible risk of thrombosis, these patients may require treatment with plasma-derived VWF-containing concentrates at delivery or postpartum if there is abnormal bleeding, and with platelets if thrombocytopenic bleeding is not controlled with infusion of VWF concentrate. Type 3 VWD patients require infusion of a plasma-derived VWF-containing concentrate at delivery, typically 40 to 80 IU/kg, followed by doses of 20 to 40 IU/kg daily for a week then tapered over the next few weeks.44 Use of desmopressin acetate (DDAVP) antepartum is controversial because of the theoretical risk of vasoconstriction and placental insufficiency and the risk of maternal hyponatremia. Guidelines for management of VWD at delivery and during the puerperium have been published and are also reviewed in Chap. 126.45,46
COAGULATION FACTOR DEFICIENCIES
Carriers of hemophilia A and B generally have factor levels approximately 50 percent of normal; however, a wide range of values have been reported as a result of random inactivation of the X chromosome (Chaps. 10 and 123).47,48 Ideally, carriers are identified before pregnancy when prenatal counseling can be offered. Baseline factor levels should be tested at the first visit during pregnancy and again in the third trimester, but it should be noted that factor IX levels generally do not rise during the course of the pregnancy.47 The sex of the fetus should be determined to guide the obstetrician at delivery. With the recognition that maternal serum contains cell free fetal DNA, genomic strategies have been developed to determine fetal gender as early as 7 weeks of gestation. Similarly, strategies to determine whether a male fetus is affected by hemophilia based on testing of maternal blood have now been developed and will doubtless enter the clinical arena in the near future.49 Cranial hemorrhage is the commonest site of bleeding in newborns with severe hemophilia, and has the highest potential for long-term serious sequelae. Risk factors for cranial hemorrhage include prolonged labor and use of instruments during delivery.48 To protect a potentially affected or known hemophiliac fetus, vacuum extraction should be avoided at delivery and forceps should be used only with caution. All intramuscular injections should be withheld from the newborn until hemophilia testing is completed. If an infant’s hemophilia status is not known, testing should be done on cord blood to avoid potential bleeding or bruising after a blood draw.48 The mother’s factor level should be followed for a few days after delivery and menstrual bleeding should be monitored to ensure adequate hemostasis.
There is also an association between pregnancy and acquired hemophilia caused by factor VIII autoantibodies (Chap. 127). This condition usually appears 1 to 4 months postpartum, but emerges during pregnancy in up to 14 percent of patients.50 In general, the Bethesda titer of the inhibitor is low and in most cases the inhibitor disappears spontaneously. Inhibitors can recur in subsequent pregnancies.51
Rarely, pregnant women with factor deficiencies other than factors VIII and IX may be identified. The most important of these to recognize is deficiency of factor XIII, which is associated with habitual hemorrhagic abortions and postpartum hemorrhage. In rare pregnancies reaching term, bleeding complications, including intracranial hemorrhage in the infant, have been observed.52,53 Treatment of this deficiency with fresh-frozen plasma, cryoprecipitate, or plasma-derived factor XIII concentrates (now available in the United States) prevents abortion in women, although there are no controlled studies.54 Most authorities recommend more frequent prophylactic therapy during pregnancy (every 3 weeks vs. every 5–6 weeks) with booster doses during labor or before cesarean section to ensure a level of 5 percent or greater.55 Although rare, congenital afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia (Chap. 125) can cause hemorrhagic and thrombotic pregnancy complications. Most experts recommend fibrinogen replacement (using cryoprecipitate or fibrinogen concentrate) to maintain a level of 60 to 100 mg/dL during pregnancy and for 6 weeks postpartum.56
CAUSES OF THROMBOCYTOPENIA
Thrombocytopenia in pregnancy is relatively common, with up to 5 percent of all pregnant women exhibiting asymptomatic thrombocytopenia.57 Many causes of thrombocytopenia in pregnancy are identical to those seen in the nonpregnant state, with some predisposing to bleeding whereas others predispose to clotting. However, there are several conditions leading to thrombocytopenia that are unique to pregnancy, including gestational thrombocytopenia, preeclampsia/HELLP syndrome/eclampsia, and acute fatty liver of pregnancy.
Gestational and Immune Thrombocytopenia
Gestational thrombocytopenia and idiopathic thrombocytopenic purpura (ITP) are best discussed together as they can be difficult to differentiate and, in fact, may be two extremes of a spectrum of disease. In general, gestational thrombocytopenia is asymptomatic and is said to occur later in pregnancy and be less severe than ITP. Most sources suggest that gestational thrombocytopenia occurs in the second and third trimesters, with platelet counts rarely falling below 70,000/μL.58 Gestational thrombocytopenia can sometimes be diagnosed with certainty only after delivery; usually there is no past history of low platelets, except perhaps with previous pregnancies, the platelet count returns to normal after delivery, and there is no association with fetal thrombocytopenia. It is not clear whether or not gestational thrombocytopenia is a variant of immune-mediated platelet destruction (Chap. 117).58
In contrast to gestational thrombocytopenia, ITP can occur at any point in pregnancy and the fall in platelet count can be severe. Diagnosis is essentially the same as it would be in any patient in that alternative causes of thrombocytopenia must be ruled out. As in other cases, treatment of ITP in pregnancy must take into account the severity of the thrombocytopenia and the presence or absence of symptoms. In general, platelet counts less than 10,000/μL require treatment regardless of the trimester; platelet counts of 30,000 to 50,000/μL without bleeding require no treatment, and platelet counts of 10,000 to 30,000/μL in later trimesters or in the presence of bleeding require treatment. Although glucocorticoid and intravenous immunoglobulin are safe in pregnancy, they may have no effect on fetal counts and should only be used to treat the mother.59 Splenectomy for ITP in pregnancy is best done in the second trimester if platelet counts are extremely low and unresponsive to treatment.58 One small study evaluated the safety of anti-D antibodies during pregnancy; all 10 of the women studied achieved a platelet count greater than 30,000/μL, but larger studies are needed before this intervention can be recommended.60 Similarly, there are case reports of rituximab administration for treatment of refractory ITP in pregnancy; at least one report demonstrated transient inhibition of neonatal B-lymphocyte development.61 There are no adequate and well-controlled studies of either eltrombopag or romiplostim in pregnant women and both are considered pregnancy category C drugs. In animal studies, both drugs crossed the placental and fetal effects included thrombocytosis, postimplantation loss, increase in fetal mortality, but no major structural malformations were reported.62 Case reports describing the use of romiplostim in pregnancy have appeared and in one report the newborn had severe thrombocytopenia at birth complicated by intracranial hemorrhage.63 Maternal platelet counts of greater than 50,000/μL usually are safe for both vaginal and cesarean delivery. In most cases, spinal anesthesia should not be used if the platelet count is less than 75,000/μL.64 Less than 5 percent of babies born to mothers with ITP have platelet counts less than 20,000/μL, although there does seem to be some correlation between very severely depressed maternal platelet count and severe thrombocytopenia in the newborn.65 No clear recommendations can be given for measuring fetal platelet count prior to or at delivery as measurements are fraught with error; however, if the fetal platelet count is known to be less than 20,000/μL, cesarean section is probably reasonable. Newborns of mothers with ITP should be monitored for 5 to 7 days after delivery to ensure that the platelet count does not drop (Chap. 117).
Eclampsia and HELLP Syndrome
The spectrum of hypertensive disorders of pregnancy ranging from preeclampsia to severe preeclampsia and HELLP syndrome to eclampsia (see Chap. 51) may also result in thrombocytopenia, although thrombosis is more of an issue than is bleeding. There is some debate in the literature as to whether thrombocytopenia can be diagnosed in preeclampsia without HELLP syndrome; however, data from one large study57 indicated that approximately 15 percent of cases of preeclampsia are complicated by thrombocytopenia. In general, the symptoms of preeclampsia, including hematologic manifestations, resolve with delivery; however, in a small proportion of cases they persist, worsen, or even develop immediately postpartum. When symptoms persist postpartum, the differentiation from thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome becomes more difficult. Some data suggest that maternal recovery from the HELLP syndrome is accelerated by administration of intravenous dexamethasone66; however, a meta-analysis demonstrated no clear advantage to the use of glucocorticoids to decrease maternal or perinatal morbidity or mortality.67 A collaborative randomized controlled trial of glucocorticoids in HELLP syndrome (COHELLP) is underway to determine the effectiveness of dexamethasone to accelerate the postpartum recovery of patients with class I HELLP syndrome.68 Observation or treatment of HELLP with glucocorticoids alone postpartum should probably not persist beyond the third postpartum day. If the patient is not clearly improving, plasma exchange should be initiated as one would do for thrombotic thrombocytopenic purpura (TTP).69,70 Although not associated with hypertension, acute fatty liver of pregnancy is another rare disorder that can present in the third trimester with severe liver dysfunction, but thrombocytopenia, if present, is generally mild and does not require treatment (Chaps. 51, 117, and 129).