From www.bloodjournal.org by guest on October 3, 2017 For personal use only BLOOD The Joumal of The American Socikty of Hematology DECEMBER 1, 1992 VOL 80, NO 11 REVIEW ARTICLE Pregnancy-Associated Thrombocytopenia: Pathogenesis and Management By Keith R McCrae, Philip Samuels, and Alan D Schreiber T HE INCREASED utilization of automated blood counts by obstetricians has led to the realization that pregnancy may often be complicated by the development of thrombocytopenia Thrombocytopenia in pregnant individuals may result from the effects of several diverse processes, which may be either physiologic or pathologic In addition to disorders that may cause thrombocytopenia in nonpregnant women, pregnant patients are at risk for the development of thrombocytopenia caused by syndromes such as preeclampsia, which are unique to pregnancy Thus, determining the significance of thrombocytopenia in a pregnant patient depends on the accurate identification of its underlying cause In this report we review the major causes of thrombocytopenia that occur during pregnancy, and discuss their pathogenesis and management These include the syndromes of immune thrombocytopenic purpura (ITP), preeclampsia and the HELLP syndrome (hemolysis, elevated liver function tests, low platelets), thrombotic thrombocytopenic purpura (TTP), and the hemolytic uremic syndrome (HUS) Other causes of thrombocytopenia in pregnancy, such as systemic lupus erythematosus (SLE), type I1 von Willebrand disease (vWD), and disseminated intravascular coagulation will be discussed only briefly It is likely that ihe pathophysiology of these diverse syndromes involves complex interactions between platelets and the vessel wall, antiplatelet antibodies and IgG-containing immune complexes The integrity of the maternal and fetal reticuloendothelial systems, as well as the efficiency of platelet production by megakaryocytes within fetal and maternal bone marrow (BM), also play important roles in determining the severity of thrombocytopenia that may develop in a particular individual These considerations highlight the need to further clarify the complex processes that influence the maternal and fetal platelet counts during pregnancy ITP ITP is the most common cause of thrombocytopenia in the first and second trimesters of pregnancy.' Because the incidence of this disease is greatest in females during their childbearing the concurrence of pregnancy and ITP is not unusual Although it has been estimated that ITP affects only to of every 10,000 pregnancie~,~ recent reports describing large cohorts of pregnant women suggest that the true incidence of ITP in pregnancy may be Blood, Vol80, No 1 (December l), 1992:pp 2697-2714 substantially higher.5 Pregnancy has generally not been believed to impact significantly on the development or severity of ITP6;however, we and others have observed that thrombocytopenia in individual patients with ITP often worsens during pregnancy and improves after delive~y,~ suggesting that pregnancy may lead to exacerbations of the disease in some cases.1.6 These observations are similar to those reported in autoimmune hemolytic anemia, which may result from accelerated erythrocyte clearance caused by the effects of the hormonal milieu of pregnancy on reticuloendothelial cell function.6 The pathophysiology of ITP has been summarized in several excellent reviews?-15 Harrington et all6 initially demonstrated that the disorder was humorally mediated when he developed thrombocytopenia after infusing himself with plasma from a patient with ITP HarringtonI7 also showed that the humoral mediator of ITP was present in the gamma globulin fraction of serum, and Shulmanls subsequently provided evidence that this mediator was IgG These observations were confirmed with the eventual development of assays such as the platelet antiglobulin test.19 With the subsequent development of more specific techniques for the detection and characterization of plateletreactive antibodies, such as immunoblotting, immunoprecipitation, and antigen immobilization assays (MAIPA), it has been found that these antibodies recognize distinct epitopes expressed on platelet-surface glycoproteins, including the glycoprotein (GP) IIb/IIIa and Ib/IX complexes.20-22In some cases, these antibodies may also activate complement.19 Once coated with antibody, target platelets are removed from the circulation by binding to Fcy receptors expressed by macrophages within the reticuloendothelial From the Deparlments of Medicine, Pathology and Laboratory Medicine, and Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia Submitted July 7,1992; accepted September 3, 1992 Supported by grants from the National Institutes of Health (HD 00882, HL 40378, A L 22193, and HL 28207), and the American Heart Association (AHA) (90-0960, with funds contributed by the Pennsylvania Affiliate) Address reprint requests to Dr Keith R McCrae or Dr Alan D Schreiber, Hematology-Oncology Division, Silverstein 7, Hospital of the University of PA, 3400 Spruce St, Philadelphia, PA 19104 1992 by The American Society of Hematology 0006-4971I92 I801 1-0030$3.00/0 2697 From www.bloodjournal.org by guest on October 3, 2017 For personal use only 2698 system, primarily the spleen.u Platelets from approximately 90% of patients with ITP display increased levels of platelet surface-associated IgG,10311J9although platelets from patients with thrombocytopenia resulting from other causes may display similar a b n o r m a l i t i e ~ Because ~ ~ ~ ~ the immune destruction of platelets has not been established in all patients with increased levels of platelet-associated IgG, the utility of such measurements remains a topic of debate,24,26and antigen-specific assays may ultimately prove more useful in making a diagnosis of ITP.14 However, at the present time, an otherwise healthy patient with isolated thrombocytopenia, normal-appearing or mildly enlarged platelets on the peripheral blood film, and a bone marrow containing normal or increased numbers of megakaryocytes is presumed to have ITP, providing that a history of recent ingestion of drugs associated with the development of thrombocytopenia is not present.14 One caveat to this assumption is the association of early, asymptomatic human immunodeficiency virus (HIV) infection in individuals not previously known to be infected with the virus, with the development of t h r o m b o c y t ~ p e n i a ~This ~ - ~ ~HIV-associated thrombocytopenic syndrome may also be immunemediated, perhaps involving binding of immune complexes containing antiidiotypic antibodies reactive with anti-HIV gp120 antibodies to platelet^,^^,^^ or cross-reactivity of antibodies directed against HIV glycoproteins with the platelet GPIIb/IIIa ~ o m p l e x ~ ~ ~ ~ The pathogeneis of ITP in children and adults may differ Children with ITP most often present acutely with severe thrombocytopenia, accompanied by petechiae and bleeding, usually following a viral infection.35This form of ITP is generally self-limited.12In contrast, adults generally present with milder bleeding symptoms such as menorrhagia or easy bruisability, and are often diagnosed only after thrombocytopenia has been detected on routine automated blood counts ITP in adults runs a chronic course, and long-term therapy with glucocorticoids or other modalities is usually required to maintain an adequate platelet count.1° Many adults with ITP require splenectomy, which results in remission in approximately 70% of patients.I4 The aspect of ITP that is unique to the pregnant patient is that the fetus, as well as the mother, may be affected by this disorder Several early reports documented the development of transient thrombocytopenia in the infants of women with ITP,16,36,37 and in 1979 Kernoff et aP8 detected elevated levels of platelet-associated IgG in the cord blood of such a thrombocytopenic infant Maternal plateletreactive IgG appears to be actively transported to the fetal circulation subsequent to its binding to Fcy receptors on the syncytiotrophoblast cells of the p l a ~ e n t a ~Once ~ - ~ *in the fetal circulation, maternal platelet-reactive IgG binds to relevant epitopes on fetal platelets, and the antibodycoated cells are then cleared by macrophages within the fetal reticuloendothelial system However, the degree of fetal thrombocytopenia does not necessarily correlate directly with the amount of platelet-reactive IgG in cord blood,43,44and thus several other factors, such as the relative affinity of maternal antibodies for fetal platelets, the maturity of the fetal reticuloendothelial system, and the McCRAE, SAMUELS, AND SCHREIBER ability of the fetal bone marrow to compensate for increased platelet destruction all interact to determine the degree of fetal t h r ~ m b o c y t o p e n i a Because ~ ~ * ~ ~ ,fetal ~ blood is relatively inaccessible to routine examination, and quantitative analyses of the variables mentioned above are not possible, the goal of developing a reliable method for predicting the degree of fetal thrombocytopenia has not been achieved This topic is a focus of current investigation, since fetal and neonatal thrombocytopenia may cause severe morbidity.47The most devastating consequence of neonatal thrombocytopenia is intracranial hem0rrhage,4~*~’ which may be accompanied by profound neurologic sequelae A general assumption is that head trauma associated with passage of the fetus through the birth canal during labor and delivery is a major factor precipitating this catastrophy, although this has been questioned by some investigators.46 Despite the inability to reliably predict the platelet counts of infants born to mothers with ITP, much information of use in the management of this syndrome has accumulated First, thrombocytopenia (platelet count < 150,OOO/~L)in infants born to mothers with a definite history of ITP is relatively common, occurring in 15% to 65% of infants born to women with this disorder.5,43,46,48-50-52 Moreover, between 6% and 70% of these infants will have severe thrombocytopenia (platelet count < 50,000/ ~ L ) , p ~ 3and ~ ~ 7thus ~ ~ -be ~ ~at potential risk for intracranial hemorrhage Second, some investigators have noted that infants born to mothers with ITP who have previously given birth to infants without thrombocytopenia tend not to be thrombocytopeni~.5~.~~ Third, the maternal platelet count does not correlate with that of the f e t ~ ~ , and ~ ~women , ~ ~ , ~ ~ , ~ with a prior history of ITP, or with ITP in remission (eg, following splenectomy), may still deliver severely thrombocytopenic infant^.^,^^,^^ This likely occurs because asplenic patients in clinical remission may not necessarily be in immunologic remission, and circulating platelet-reactive IgG may be present in their plasma Fourth, several studies have shown that the level of maternal platelet-associated IgG is not a reliable predictor of the neonatal platelet ~ o u n t J In ~ , ~contrast, ~ reports from one g r o ~ phave ~ ~ , ~ ~ suggested that the amount of circulating antiplatelet antibody in maternal serum may be useful in this regard; however, these observations need to be confirmed by other^!^,^,^^ The utility of measuring circulating maternal anti-platelet IgG in predicting the development of fetal thrombocytopenia must also be examined in the light of reports in which dizygotic twins born to mothers with ITP were found to have discordant platelet c o ~ n t s These ~~,~~ observations emphasize the fact that although transplacental passage of maternal platelet-reactive IgG into the fetal circulation plays a central role in the development of fetal thrombocytopenia, several additional variables interact to determine the ultimate fetal platelet count at the time of delivery In recent years, several investigators have reported the development of mild to moderate thrombocytopenia in otherwise healthy pregnant patients with no prior history of ITP The pathogenesis of thrombocytopenia in this disor- From www.bloodjournal.org by guest on October 3, 2017 For personal use only THROMBOCYTOPENIA IN PREGNANCY 2699 der, which has been termed “pseudo ITP,”S7 “ i n ~ i d e n t a l ” ~ , ~To ~ meet the criteria for a diagnosis of preeclampsia, the or “ge~tational”~5 thrombocytopenia, is not understood patient must have a blood pressure of at least 140/90, as This syndrome may represent either the de novo developwell as proteinuria of > 0.3 g/24 h or 10 mg/dL in at least ment of ITP during pregnancy, or an acceleration of the two random specimens collected hours apart.@ Patients physiologic pattern of increased platelet destruction that with elevated blood pressure in the absence of proteinuria occurs during Because some patients with are considered to have pregnancy-induced hypertension incidental thrombocytopenia have elevated levels of platelet(PIH).@ Although early classification schemes included associated IgG and/or circulating IgG antiplatelet antibodonly primagrividas, PIH and preeclampsia occasionally ie~,S2,5~ this disorder is not easily distinguishable from occur in multiparous women,69sometimes associated with a classical ITP.S3However, the recognition and diagnosis of change of male partners.7oFor unknown reasons, preeclampthis syndrome is important, because infants born to individsia is most frequently observed in women less than 20 or uals with incidental thrombocytopenia appear to have a greater than 30 years old.67,71Between 15% and 50% of markedly reduced risk of developing thrombocytopenia patients with preeclampsia develop thrombocytopenia at when compared to infants born to patients with a history of some point in the course of their i l l n e s ~ , ~making ~-~~ ITP antedating p r e g ~ ~ a n c y For ~ , ~example, ~ , ~ ~ ~in~a series preeclampsia a common cause of significant thrombocytopeof 1,357 healthy pregnant women, 112 (8.3%) were found to nia during the third trimester of pregnancy have platelet counts less than 15O,OOO/pL, with the lowest Although the pathogenesis of preclampsia is poorly platelet count being 97,000/pL.58 The incidence of thromunderstood, the observation that this disorder may develop bocytopenia in the infants of these 112 thrombocytopenic in patients with hydatidiform moless2 and usually remits women (4.3%) was not statistically different from that of soon after delivery suggests that the disease is initiated and infants born to healthy pregnant women who did not mediated by factor(s) released from or contained within the develop thrombocytopenia during pregnancy (1.5%) Furpla~enta.~3-= Additional studies suggest that in many cases thermore, none of the infants born to these thrombocytopeof preeclampsia, placentation, the process by which fetal nic women had either platelet counts less than lOO,OOO/pL trophoblasts invade uterine tissue and remodel the uterine or any hemorrhagic complications Similar results were spiral arteries,86-8sis disordered, with an apparent defiobtained in an additional study involving 300 healthy ciency in the remodeling of these vessels by trophopregnant women with incidentally detected thrombocytopeb l a s t ~ Deficient ~ ~ , ~ placentation leads to the formation of a nia (lowest platelet count 43,OOO/pL) and their off~pring.~ uteroplacental vasculature that is unable to deliver adeOnly 4% of these infants had thrombocytopenia and none quate amounts of maternal blood to the placenta and fetus, had hemorrhagic complications An additional in ultimately leading to the development of placental ischwhich neonatal thrombocytopenia was noted in only of 74 emia.&l In response to progressive ischemia, the placenta infants born to mothers with incidental thrombocytopenia may release diminished amounts of physiologic mediators (with none of these infants having platelet counts < 50,000/ necessary for maintenance of the normal gestational hemopL), supports these observations These studies suggest dynamic state, or, alternatively, release pathologic factors that the risk of severe thrombocytopenia in infants born to that may contribute to the clinical manifestations of premothers with incidential thrombocytopenia is ~ m a 1 , 5and ~ , ~ ~ e~lampsia.83.8~ It has been suggested that imbalances in the it has therefore been suggested that patients with this metabolism and release of prostaglandins by both placental syndrome should not be subjected to percutaneous umbiliand extraplacental tissues may play a prominent role in the cal blood sampling (PUBS) for measurement of the fetal pathogenesis of preeclampsia Both the diminished producplatelet co~nt.~l-63 However, it should be noted that rare tion of prostacyclin (PG12) and PGE?, and augmented patients with apparent incidental thrombocytopenia have production of thromboxane (TXA2) and PGFk have been delivered thrombocytopenic infants2O Therefore, further reported in this disorder, potentially contributing to the studies designed to clarify the pathogenesis of this disorder development of hypertension, reduced uteroplacental blood are warranted The primary goal of such studies should be flow, and platelet a ~ t i v a t i o n s ~ Other ~ ~ - ~ 3potential mediathe development of noninvasive assays that could be pertors of the preeclamptic state include the vasoconstrictors formed on maternal blood and allow clinicians to accurately end0thelin-19~-~6 and serotonin,97 the latter presumably distinguish incidental thrombocytopenia from ITP Such released from activated platelets in the microvasculature studies should also include long-term follow-up of women However, the relative importance of these mediators and with presumed incidental thrombocytopenia, particularly the relationship between deficient placentation, uteroplathose with platelet counts less than 75,OOO/pL, to detercental ischemia, and the development of preeclampsia mine whether a subgroup of these individuals ultimately remains uncertain Furthermore, additional studies have developes ITP implied that the pathogenesis of preeclampsia may primarily involve alterations in immune function.98Antibodies PREECLAMPSIA AND THE HELLP SYNDROME against laminin,* collagen,lW endothelial cellsloland smooth muscle cells,lo2 as well as increased levels of plateletPreeclampsia is the most common medical disorder of associated IgG,lo3 have all been observed in the sera of pregnancy64 and contributes significantly to maternal and preeclamptic patients Whether these antibodies are actufetal morbidity and mortality.65This disorder affects approxally involved in the pathogenesis of the syndrome is unimately 5% to 13% of pregnancies, most commonly those of primigravidas, and usually occurs in the third t r i m e ~ t e r ~ ~ known ~~ From www.bloodjournal.org by guest on October 3, 2017 For personal use only 2700 McCRAE, SAMUELS, AND SCHREIBER disease."' Relevant to these observations, others have The pathogenesis of preeclampsia-associated thrombocyobserved that plasma levels of both tissue plasminogen topenia is equally unclear Patients with preeclampsia who develop thrombocytopenia appear to manifest a state of activator (tPA) and plasminogen activator inhibitor type I (PAI-1) are increased in preeclamptic patient^.^^^,^^^ Fiaccelerated platelet destruction which exceeds that observed in the course of normal pregnancy The observations nally, the FVII-related antigen (vWF)/FVIIIc ratio has that the mean platelet volumes in these patients are usually been reported to be elevated in most patients with severe increased77and that bone marrow specimens obtained from preeclampsia.120These findings appear to reflect primarily patients with preeclampsia-associated thrombocytopenia the elevated levels of vWF subsequently reported in this reveal normal to increased numbers of megakaryocyte^'^^ disorder,121,122 rather than significant reductions in factor VIIIc However, occasional patients demonstrate altersuggest the presence of young platelets in the circulation ations in this ratio before the development of other manifesand a compensated thrombocytolytic state The increased tations of preeclampsia, perhaps indicative of subclinical rate of platelet destruction observed in this disorder may endothelial dysfunction.123Although these findings may result from several potential mechanisms These include provide insight into the pathogenesis of preeclampsia in pathologically increased adherence of circulating platelets some individuals, no specific coagulation assay has been to damaged or activated endothelium, activation of the coagulation system with accelerated thrombin generation shown to either reliably predict or confirm the diagnosis of leading to platelet activation and enhanced platelet clearpreeclampsia, though it has been proposed that coagulation ance, or removal of IgG-coated platelets by the reticuloenindices derived from several individual coagulation assays dothelial system In the latter situation, the plateletmay be more useful in this regard.11sJ24Taken together, these studies show that subtle degrees of activation of the associated IgG may represent antiplatelet antibody, or coagulation system occur in many patients with preeclampmore likely, circulating immune complexes, elevated levels sia; in some of these cases, it is likely that this process of which have been reported in preeclampsia.loSJM contributes to the development of thrombocytopenia by the Activation of both the coagulation and fibrinolytic sysinduction of thrombin-mediated platelet activation Howtems, occasionally leading to the development of disseminated intravascular coagulation (DIC), occurs in some ever, some investigators believe that in many cases of patients with preeclampsia, and may play a role in stimulatpreeclampsia, activation of coagulation is insufficient to ing platelet activation and accelerated c l e a r a n ~ e ~ In ~ J ~ ~account J ~ ~ for the degree of thrombocytopenia observed.72 This view is supported by experimental data comparing the the antepartum state, procoagulant processes appear to results of serial measurements of plasma fibrinopeptides predominate and may contribute to the development of (sensitive markers of the effects of thrombin on fibrinogen), microthrombi and fibrinoid necrosis, which occur primarily in the liver and placenta.lo9However, clinically evident DIC with levels of P-thromboglobulin (PTG) and platelet factor occurs in only the most severe cases, and measurement of (PF4) (platelet granule proteins released on platelet the prothrombin time (PT), partial thromboplastin time activation).125J26These studies indicate that in some pa(PTT), fibrin degradation products (FDP), and fibrinogen tients with preeclampsia-associated thrombocytopenia, levels in preeclamptic patients usually yields normal remarked elevations in the plasma levels of platelet granule proteins occur in the presence of relatively minor differs u l t ~ Nevertheless, ~ ~ ~ - ~ ~more ~ sensitive assays of procoagulant activity have shown that the coagulation system beences in fibrinopeptide levels, suggesting that accelerated platelet clearance and thrombocytopenia in many patients comes activated to a subtle degree in many preeclamptic patients who manifest neither the clinical nor the classic may occur by mechanisms distinct from thrombin-mediated platelet activation.125J26 laboratory manifestations of DIC For example, antithrombin I11 (AT 111) levels were reported to be significantly An additional clue to the pathogenesis of preeclampsiareduced (Thus, ~ , ~ ~the most useful means of differentiating infants were born to mothers in this group In contrast, no these syndromes is, by definition, the antenatal h i ~ t o r y ~ ~ thrombocytopenic ,~~ infants were born to any of the 18 Thrombocytopenia developing in patients with an antenatal mothers who did not have circulating antiplatelet IgG history of ITP most likely results from ITP, and places these Thus, in this series, the risk of a pregnant patient with a individuals at an increased risk of delivering a thrombocytohistory of ITP and elevated levels of circulating antiplatelet penic neonate Patients with no antenatal history of ITP IgG delivering a thrombocytopenic infant was 26% A who develop mild to moderate thrombocytopenia during patient with an identical clinical history, but without an gestation likely have incidental thrombocytopenia Howelevated level of platelet-associated IgG, had a 0% chance ever, some patients without an antenatal history of ITP of delivering a thrombocytopenic infant, though the confidence interval for this probability prediction ranged from develop severe thrombocytopenia during gestation, with to 18% Thus, even a negative test for circulating plateletplatelet counts less than 50,0OO/pL reported? Although these patients are considered to have gestational thromboreactive IgG obtained by a laboratory with extensive expericytopenia based on their history, they may in fact have ITP, ence in this assay, cannot exclude a significant risk (up to and postpartum follow-up studies of such patients to approximately 20%) of delivering a severely thrombocytopedetermine whether their thrombocytopenia resolves after nic infant Based on the results of this study and t h e r s , ~ J ~ ~ delivery have not been performed We not believe that a we cannot recommend that decisions regarding the mode of sufficient number of such patients has been reported to delivery of the fetus of a thrombocytopenic mother with justify application of the same management principles to ITP be based solely on the results of antiplatelet antibody them as to the broad group of patients with less severe tests Furthermore, despite uncontrolled studies that have incidental thrombocytopenia We recommend, instead, that noted elevations in the fetal platelet count after maternal patients without a preceding history of ITP, but with treatment with p r e d n i ~ o n e , ~other ~ ~ ~studies ~ have not platelet counts less than 75,OOO/pL, be considered to found this agent to be of benefit.43,50Although some potentially suffer from de novo ITP, with their risk of investigators have suggested that the greater efficiency of delivering a thrombocytopenic neonate increased accordbetamethasone or dexamethasone in crossing the placenta ingly might render these corticosteroids superior to prednisone After the etiology of maternal thrombocytopenia has in the treatment of fetal thromb0cytopenia,2~~~~~ controlled been determined as accurately as possible, the physician studies have not supported these assumptions.238.240 Finally, IVIg does not predictably increase fetal platelet must decide on the optimal manner for delivery of the fetus counts,5°,241,242 despite its efficacy in maternal ITP The results of several studies have shown that patients with The inability to identify easily measurable maternal incidental thrombocytopenia have little risk of delivering a factors that provide accurate information concerning the thrombocytopenic infant,5,52,58 and therefore the mode of fetal platelet count, as well as the lack of efficacy of delivery for these individuals should be dictated only by obstetrical concerns In contrast, the physician caring for maternal medical therapy in the treatment of fetal thrombopatients with ITP must attempt to identify those individuals cytopenia, leads us to recommend sampling of the fetal with this disorder who are at greatest risk for delivery of a blood before or at the time of delivery in the offspring of all From www.bloodjournal.org by guest on October 3, 2017 For personal use only 2706 thrombocytopenic women with ITP Fetal blood sampling may be performed by either PUBS61,62,243 or fetal scalp sampling.43,244,245 The former technique involves withdrawal of fetal blood from the umbilical vein, under ultrasound guidance This technique is more accurate than fetal scalp sampling because contamination of the sample by amniotic fluid or maternal blood is less of a concern However, the procedure is technically difficult, and may be associated with postpuncture bleeding in up to approximately 38% of fetuses.246Although this bleeding is usually of short duration and contained within Wharton’s jelly, PUBS has also been associated with fetal complications that may necessitate emergency cesarean s e ~ t i o n , 6and ~ , ~may ~ ~uncommonly lead to fetal death.248For these reasons, PUBS should only be performed by physicians experienced in this technique, in a setting where cesarean section can be performed emergently if necessary Another theoretical concern regarding PUBS is that the fetal platelet count may decrease in the interval between the procedure and delivery, though this remains unproven Most authorities allow delivery of the fetus by the vaginal route if the fetal platelet count is known to be greater than approximately 50,000/pL.43 Because of its relative safety compared with PUBS, scalp sampling as a means of determining the fetal platelet count has been advocated by some investigator^.“^,^^^,^^^ This technique involves removal of blood, via capillary tube, from a small laceration made in the fetal scalp However, for the scalp to be accessible for this procedure the fetal membranes must be ruptured, the maternal cervix fully dilated, and the fetal head firmly engaged in the maternal pelvis, and thus already under considerable pressure Furthermore, inaccurate platelet counts may frequently be obtained by this method because of contamination with maternal blood or amniotic fluid However, in the hands of experienced inve~tigators,4~ correlations between fetal scalp and umbilical cord platelet counts have been good, and a normal fetal scalp platelet count in the setting of maternal thrombocytopenia provides evidence that the fetus is not thrombocytopenic Our recommendations concerning the mode of delivery of the offspring of thrombocytopenic patients with immunemediated thrombocytopenia are summarized as follows First, we recommend that patients with apparent incidental thrombocytopenia and platelet counts greater than 75,000/ pL undergo routine vaginal delivery unless obstetrical indications dictate otherwise Second, until additional neonatal outcomes are reported, we recommend that women with apparent incidental thrombocytopenia and platelet counts of less than 75,OOO/pL be considered to potentially have ITP Third, we not recommend that measurements of either platelet-associated IgG or circulating platelet antibodies alone be used in determining the mode of delivery of the fetus of a thrombocytopenic mother with ITP Finally, we recommend that all such fetuses undergo PUBS for determination of the platelet count Those with platelet counts greater than 50,000/ pL may be delivered vaginally, whereas those with lower counts should be delivered by cesarean section We realize that many of McCRAE, SAMUELS, AND SCHREIBER these recommendations are arbitrary, and acknowledge the concerns of those who feel that the risk of fetal blood sampling may in fact outweigh the risk of intracranial hemorrhage resulting from the trauma of vaginal delive r ~ ! ~ , ~However, ~ , ~ ~insufficient ~ , ~ ~ data are presently available to allow definitive resolution of these conflicting viewpoints Management of preeclampsia and the HELLP syndrome The major role in the management of preeclampsia and the HELLP syndrome falls to the obstetrician, with the involvement of the hematologist limited to cases complicated by coagulopathy and severe thrombocytopenia The overall approach to both of these syndromes involves medical stabilization of the patient, followed by delivery of the fetus as soon as possible.81,142,143,148,251 Although the manifestations of preeclampsia or HELLP in some patients may reverse with conservative management,252-254 this outcome appears to be unusual in most series.142-144,148 In addition, some patients with these disorders, particularly those with HELLP, may unpredictably experience sudden and severe clinical d e t e r i ~ r a t i o n ,particularly ~~~ in the presence of disseminated intravascular c o a g ~ l a t i o n Because ~~ most cases of preeclampsia and HELLP develop after 34 weeks of gestation, by which time the fetal lung has usually matured adequately to support independent lack of fetal lung maturity is usually not a reason to delay delivery However, if necessary, betamethasone may be administered to the patient upon presentation, and delivery delayed for 24 to 48 hours to allow the full effect of this agent in enhancing fetal lung maturity to ensue.143Isolated reports have demonstrated that administration of aspirin may occasionally reverse preeclampsia-associated thrombocytopenia in some i n d i v i d ~ a l s ,though ~~ it is uncertain whether such therapy improves fetal outcome However, in the rare patient who develops preeclampsia or the HELLP syndrome in the mid to late second trimester, such a trial may be warranted, based on the poor fetal outcome predicted in this situation Although major hemorrhage in patients with preeclampsia or the HELLP syndrome occurs rarely, minor bleeding is common, and postoperative oozing after cesarean section occurs freq~ent1y.I~~ In some cases, bleeding may result from the effects of a coagulopathy, such as disseminated intravascular coagulation.255Therapy of bleeding resulting from thrombocytopenia in this setting requires the administration of platelets; however, because the pathophysiology of thrombocytopenia occurring in these syndromes involves accelerated platelet destruction, the survival of transfused platelets is sh0rt.1~~ Therefore, routine platelet transfusion in the absence of bleeding, with the goal of maintaining an arbitrary platelet count, is recommended only in cases of extreme thrombocytopenia with platelet counts less than approximately 20,000/pL.’48 However, most authorities recommend attempting to increase the patient’s platelet count to at least 50,00O/pL before cesarean ~ e c t i n The l~~ infusion of additional platelets immediately at the start of this procedure may also help improve hemostasis.143One group has noted that steroid administration before delivery From www.bloodjournal.org by guest on October 3, 2017 For personal use only 2707 THROMBOCYTOPENIA IN PREGNANCY may increase platelet counts in some patients with apparent preeclampsia.8l After delivery of the patient with preeclampsia or HELLP, platelet counts usually continue to decrease for an additional 24 to 48 hours, after which they begin a rapid recovery.74.145-147,257 In one series, 90% of a group of 61 patients with preeclampsia-associated thrombocytopenia had increasing platelet counts by the third day after while in another, all 25 patients with thrombocytopenia resulting from preeclampsia had achieved a platelet count greater than lOO,OOO/pL within 95 hours postpart ~ m ~In’a study of 158 patients with HELLP, all patients whose platelet counts recovered spontaneously did so within days, with rebound thrombocytosis developing in all patients.147However, occasional patients with preeclampsia-associated thrombocytopenia manifest persistently low platelet counts for a prolonged period after delivery, often in the presence of continued multisystem dysfunction and increasing LDH e ~ e l s In l ~ one ~ report, thrombocytopenia in seven such patients resolved after plasma exchange therapy,’& with another report describing a similar response in an additional ~ a t i e n t 2Thus, ~ ~ despite the fact that the efficacy of this therapy has not been demonstrated in a randomized trial, plasma exchange therapy in patients with severe thrombocytopenia and evidence of an ongoing preeclampsia of HELLP-like illness lasting more than to days postpartum should be considered The presence of thrombocytopenia at the time of delivery in the offspring of preeclamptic patients is unusual, with most infants of preeclamptic mothers who develop thrombocytopenia probably doing so at some point after delive r ~ Furthermore, ~ ~ ~an increased ~ ~ ~ incidence of intracranial hemorrhage in the offspring of preeclamptic patients, even when delivered vaginally, has not been observed Therefore, no specific precautions are recommended concerning management of the platelet count in these infants, other than close monitoring for several days after delivery, particularly in those with associated medical pr0b1ems.l~~ Management of TTP and HUS in pregnancy Before the early 1980s, the maternal and fetal outcomes in cases of pregnancy complicated by TTP were exceptionally p 0 r l ~ ~ However, in 1984, the successful use of plasma infusions to manage two consecutive pregnancies in a women with chronic, relapsing TTP was first reported.259 Since this report, several others describing successful therapy of TTP during pregnancy have appeared.lS5 One report described two patients with chronic, relapsing TTP and prior fetal deaths who experienced successfulpregnancies when treated prophylactically with aspirin and dipyridamole, and with plasma infusion for mild relapses.260Another report described a successful pregnancy outcome in a patient with TTP who did not respond to plasma infusions, but responded dramatically to plasma exchange261and was subsequently managed with aspirin and dipyridamole The successful management of a pregnancy in a patient with chronic relapsing TTP and a prior history of fetal death, using regular infusions of plasma, cryosupernatant and a high molecular weight plasma fraction (HMW-F) has also been reported.262The amount of plasma required to maintain this patient’s disease in remission was substantially greater during pregnancy than antepartum, and the use of HMW-F significantly reduced the volume of infusions needed to maintain a remission Thus, although a large experience in the treatment of pregnant patients with TTP has not been reported, it appears that the prognosis for such patients has improved since the widespread use of plasma therapy for this disorder The therapy of adult HUS occurring in the peripartum or postpartum setting, as well as in other situations, has been much less satisfying than that of TTP Because of the rarity of this syndrome, only anecdotal reports concerning its therapy have appeared Supportive care remains the mainstay of therapy for adult HUS.165,259 In many cases this involves dialysis, with particularly close attention to fluid management The use of platelet function inhibitors has been reported to be associated with clinical improvement in four adults with HUS, two cases of which occurred during pregnancy.263Another report described the efficacy of therapy with heparin and antiplatelet agents in 11 adults with HUS264;4 patients were left with chronic renal failure, and died (one with intracranial hemorrhage), demonstrating the risk of administering anticoagulant therapy in this setting Furthermore, randomized studies in children have not shown heparin to be of benefit in the therapy of HUS, and suggest that its use may actually be detrimental.265 Similar results have been reported with thrombolytic agents.266Anecdotal reports have suggested that prostacyclin infusions267and vincristine268may benefit occasional patients with HUS, but these remain unconfirmed Finally, isolated reports of successful therapy of HUS with plasma infusion and/or exchange have appeared,ls5 though this modality does not appear to be as efficacious in this disorder as in TTP REFERENCES Kelton JG: Management of the pregnant patient with idiopathic thrombocytopenicpurpura Ann Intern Med 99:796,1983 Carloss HW, McMillan R, Crosby WH: Management of pregnancy in women with immune thrombocytopenic purpura J Am Med Assoc 244:2756,1980 Moise KF Jr: Autoimmune thrombocytopenic purpura in pregnancy 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Am J Obstet Gynecol 158:430, 1988 45 Moise KJ, Cotton DB: Discordant fetal platelet counts in a twin gestation complicated by idiopathic thrombocytopenic purpura Am J Obstet Gynecol156:1141,1987 46 Cook RL, Miller RC, Katz VL, Cefalo RC: Immune thrombocytopenic purpura in pregnancy: A reappraisal of management Obstet Gynecol78:578, 1991 47 Andrew M, Castle V, Saigal S, Carter C, Kelton JG: Clinical impact of neonatal thrombocytopenia J Peds 110:457, 1987 48 Territo M, Finkelstein J, Oh W, Hobel C, Kattlove H: Management of autoimmune thrombocytopenia in pregnancy and the neonate Obstet Gynecol41:570,1973 49 Kitzmiller J L Autoimmune disorders: Maternal, fetal, and neonatal risks Clin Obstet Gynecol21:385, 1978 From www.bloodjournal.org by guest on October 3, 2017 For personal use only THROMBOCYTOPENIA IN PREGNANCY 50 Kaplan C, Daffos F, Forestier F, Tertian G, Catherine N, Pons JC, Tchernia G: Fetal platelet counts in thrombocytopenic pregnancy Lancet 336:979,1990 51 Burrows RF, Kelton 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