Original Article
Estimation of the Risk of Thrombocytopenia in the Offspring of Pregnant Women with Presumed Immune Thrombocytopenic Purpura
N Engl J Med 1990; 323:229-235July 26, 1990
- Abstract
- Abstract
Background and Methods.
The optimal management of immune thrombocytopenic purpura during pregnancy remains controversial because the risk of severe neonatal thrombocytopenia remains uncertain. We studied the outcome of the index pregnancy in 162 women with a presumptive diagnosis of immune thrombocytopenic purpura to determine the frequency of neonatal thrombocytopenia and to determine whether neonatal risk could be predicted antenatally by history or platelet-antibody testing.
Results.
Two maternal characteristics were identified as predicting a low risk of severe neonatal thrombocytopenia: the absence of a history of immune thrombocytopenic purpura before pregnancy, and the absence of circulating platelet antibodies in the women who did have a history of the condition. Eighteen of 88 neonates (20 percent; 95 percent confidence interval, 13 to 30 percent) born to women with a history of immune thrombocytopenic purpura had severe thrombocytopenia (platelet count <50×109 per liter at birth), as compared with 0 of 74 (0 percent; 95 percent confidence interval, 0 to 5 percent) born to women first noted to have thrombocytopenia during pregnancy (P<0.0001). Among the women with a history of immune thrombocytopenic purpura, 18 of 70 neonates (26 percent; 95 percent confidence interval, 16 to 38 percent) born to those with circulating platelet antibodies had severe thrombocytopenia, as compared with 0 of 18 infants (0 percent; 95 percent confidence interval, 0 to 18.5 percent) born to those without circulating antibodies (P<0.02). Thus, the risk of severe neonatal thrombocytopenia in the offspring of women without a history of immune thrombocytopenic purpura before pregnancy and of women with a history of the condition in whom circulating platelet antibodies are not detected was 0 percent (95 percent confidence intervals, 0 to 5 and 0 to 18.5 percent, respectively).
Conclusions.
The absence of a history of immune thrombocytopenic purpura or the presence of negative results on circulating-antibody testing in pregnant women indicates a minimal risk of severe neonatal thrombocytopenia in their offspring. (N Engl J Med 1990; 323: 229–35.)
Article Activity
- Article
IMMUNE thrombocytopenic purpura occurs frequently in young women and may first be diagnosed during the childbearing years or pregnancy. In some women with immune thrombocytopenic purpura, pregnancy and childbirth are complicated by severe neonatal thrombocytopenia, which can lead to intracranial hemorrhage.1 2 3 4 5 The actual incidence of neonatal thrombocytopenia and bleeding is uncertain because there have been no large prospective studies, and the published experience may primarily reflect the clinical course of the more severely affected pregnant women referred to larger medical centers.3 , 6 The problem is compounded by recent evidence that mild thrombocytopenia (platelet count, 100 to 150×109 per liter) occurs commonly during pregnancy and presents little risk to the mother or newborn.7 , 8
Unfortunately, the correlation between maternal and fetal platelet counts is poor,3 and there is no readily available noninvasive means to identify pregnancies in which newborns will be at risk for severe thrombocytopenia. A wide range of recommendations have therefore been made for managing pregnancies complicated by immune thrombocytopenic purpura, including antenatal maternal therapy with corticosteroids3 , 9 , 10 or intravenous gamma globulin, delivery by cesarean section,4 and direct determination of fetal platelet counts during labor11 , 12 or, more recently, in utero.13 14 15 16 17 What is needed is a means to identify women who should undergo invasive testing (with the attendant risk of complications and false positive results), antenatal therapy, or cesarean section,13 , 16 , 18 19 20 and women who should be allowed to give birth without intervention.
The current study was undertaken to estimate the risk of neonatal thrombocytopenia and hemorrhage in infants born to mothers with immune thrombocytopenic purpura or presumed immune thrombocytopenic purpura, and to determine whether platelet-antibody testing in conjunction with a maternal history of the condition can be used to identify neonates at risk for thrombocytopenia.
Methods
We studied 162 consecutive pregnant women meeting our study criteria who presented either to the Hospital of the University of Pennsylvania or one of its teaching affiliates (n = 130) or to New York Hospital (n = 32) between 1979 and 1989 during the course of 176 pregnancies. Eighty-eight patients had a history of immune thrombocytopenic purpura antedating the pregnancy, and 74 presented during pregnancy with more than one platelet count of less than 150×109 per liter without another explanation. None of these 74 women had abnormal bleeding, and 56 (76 percent) had a normal platelet count documented before or during the first trimester of pregnancy. There was no evidence of ppregnancy-induced hypertension, disseminated intravascular coagulation, systemic lupus erythematosus, or other systemic illness in any patient, and none were taking medications known to cause thrombocytopenia. Data from an additional 17 patients were excluded from analysis because an isolated platelet count of less than 150×109 per liter was not confirmed on subsequent determinations.
On the basis of the clinical outcomes reported by Scott et al.,21 neonatal platelet counts between 100 and 150×109 per liter were considered to represent mild thrombocytopenia, 50 to 99×109 per liter moderate thrombocytopenia, and less than 50×109 per liter severe thrombocytopenia. For the purposes of this study we used a platelet count of less than 100×109 per liter as the definition of neonatal thrombocytopenia. Maternal platelet counts just before delivery and neonatal platelet counts on the day of delivery were analyzed. In order to ensure independent observations, only the outcome of the first pregnancy after the discovery of thrombocytopenia was used in the statistical analyses.
Platelet-antiglobulin tests were performed in the same laboratory on samples from both institutions with a radioimmunoassay as previously reported.22 Antiglobulin tests were performed within two weeks of delivery in all patients, or closer to term if there was a change in either the platelet count or therapy. The amount of platelet-associated IgG, IgM, and C3 bound to platelets and the amount of platelet-bindable IgG in plasma were determined by measuring the percentage of binding (mean +2 SD) of each Radio-labeled reagent to platelets obtained from more than 200 normal donors and 26 women in the third trimester of uncomplicated pregnancies. Values in study patients that were more than 2 SD above the mean for the normal, nonpregnant population were considered to be abnormal. Values in all 26 healthy pregnant women studied concurrently at term fell in this normal range. Platelets from each patient bound an amount of 125I-labeled normal rabbit IgG not having antihuman IgG activity that was within the range of binding to platelets from normal donors.22
Statistical analyses included Pearson's correlations and two-tailed Fisher's exact tests. Ninety-five percent confidence intervals for the sensitivity, specificity, and predictive values of the diagnostic tests were determined as previously described.23 Unless otherwise noted, values given are means ±SD.
Results
Clinical Characteristics of the Mothers
We studied 162 women who gave birth to 178 neonates during 176 pregnancies (2 women delivered twins), including 149 women with a single pregnancy, 12 women with 2 pregnancies, and 1 woman with 3 pregnancies. The mode of delivery was selected by the obstetrician. Among the index pregnancies, 124 infants (77 percent) were delivered by cesarean section, whereas 38 were delivered vaginally.
Seventy-eight patients (60 percent) from the Hospital of the University of Pennsylvania and 10 (31 percent) from New York Hospital were given a diagnosis of immune thrombocytopenic purpura before the index pregnancy. The remaining women with thrombocytopenia were identified during pregnancy. At the time of delivery the results of at least one platelet-antiglobulin test were positive in each of these 162 pregnant women. The distribution of platelet counts at the time of delivery in the 74 mothers with no history of immune thrombocytopenic purpura before pregnancy and in the 88 mothers with such a history is shown in Table 1Table 1
Platelet Counts at Delivery in Women with Presumed Immune Thrombocytopenic Purpura.. The number of mothers with platelet counts of more than 150×109 per liter was higher in the group previously given a diagnosis of immune thrombocytopenic purpura because many of these mothers were taking glucocorticoids or had undergone splenectomy and were in clinical remission.All therapy for immune thrombocytopenic purpura was initiated and guided only by maternal indications (Table 2Table 2
Maternal and Neonatal Platelet Counts, According to Maternal Therapy.*). Of the 35 patients who received prednisone as their only treatment, therapy was started before pregnancy in 16 because of a low platelet count and started during pregnancy in 19 because of a falling platelet count. Thirteen of the latter 19 women were first discovered to have thrombocytopenia during the index pregnancy. The mean dose of prednisone in these 13 women was 34 mg per day (range, 5 to 60). Three women also received intravenous gamma globulin during pregnancy. Each had previously undergone splenectomy and was also taking prednisone. The relation between maternal therapy and the neonatal platelet count is discussed below.Neonatal Outcome
Thirty-five of the 88 mothers with a previous diagnosis of immune thrombocytopenic purpura (40 percent; 95 percent confidence interval, 29 to 51 percent) and 3 of the 74 mothers found to have thrombocytopenia during the index pregnancy (4 percent; 95 percent confidence interval, 1 to 11 percent) delivered an infant with a platelet count below 100×109 per liter (Fig. 1Figure 1
Identification of High-Risk and Low-Risk Neonates in the Study. and 2Figure 2
Relation between the Results of the Indirect Antiglobulin Test and Neonatal Platelet Count.). All 18 newborns with platelet counts below 50×109 per liter on the day of delivery were born to mothers with a history of immune thrombocytopenic purpura before pregnancy. An additional 20 infants were born with platelet counts between 100 and 150×109 per liter, including 9 born to the 74 women with no history of the condition.Ten of the 162 infants delivered in the index pregnancy (6 percent; 95 percent confidence interval, 3 to 11 percent) had bleeding complications, 5 (3 percent; 95 percent confidence interval, 1 to 7 percent) of which were considered serious, including central nervous system bleeding (n = 2), gastrointestinal bleeding (n = 2), and a bloody pericardial effusion (n = 1) (Table 3Table 3
Complications in Neonates Born to Mothers with a History of Immune Thrombocytopenic Purpura and Detectable Circulating Antibodies.).An intracranial hemorrhage was detected in two neonates born to women given a diagnosis of immune thrombocytopenic purpura before pregnancy in whom circulating antibodies were detected. One infant, with a platelet count of 7×109 per liter, died as a result of this complication. This infant was delivered vaginally in 1982. The mother was taking 70 mg of prednisone daily, and her platelet count was 186×109 per liter when she went into labor at term. The patient's labor was normal, and the delivery was spontaneous. An intracranial hemorrhage was diagnosed when the infant experienced respiratory distress and decreased responsiveness. The other infant with an intracranial hemorrhage was delivered vaginally with a platelet count of 78×109 per liter. An ultrasound examination of the head was performed because of the decreased neonatal platelet count, although the infant was asymptomatic. The child's development was normal at six months of age.
The overall rate of intracranial hemorrhage in newborns delivered vaginally by mothers who were given a diagnosis of immune thrombocytopenic purpura before the pregnancy was 2 of 17 (12 percent; 95 percent confidence interval, 1 to 36 percent). An intracranial hemorrhage was not suspected on clinical grounds in any of the 71 newborns (0 percent; 95 percent confidence interval, 0 to 5 percent) delivered by cesarean section whose mothers were given a diagnosis of immune thrombocytopenic purpura before pregnancy.
Relation between Maternal Presentation and Neonatal Platelet Count
No clinically important correlation was observed between maternal platelet counts at term and neonatal platelet counts at birth for the group as a whole or for the subgroups of mothers with platelet counts below 150×109 or below 100×109 per liter. The associations were weak regardless of maternal therapy. No single maternal platelet count could be used as a threshold to identify all fetuses at risk of severe thrombocytopenia at birth. If a maternal platelet count below 100×109 per liter had been used as the sole screening criterion, 9 of the 18 cases of severe neonatal thrombocytopenia would not have been identified (Table 4Table 4
Screening Criteria for Neonatal Thrombocytopenia.). The platelet count at term in these nine mothers ranged from 136×109 to 287×109 per liter. Seven of the nine mothers had had a splenectomy, and three were also receiving prednisone, but the remaining two were not receiving any therapy at the time of delivery.Only weak correlations were observed between the levels of platelet-associated IgG, IgM, and C3 measured in the direct antiglobulin tests in the mother and the neonatal platelet counts (r = 0.07, 0.18, and 0.15, respectively). The correlations between the results of the direct antiglobulin tests and the neonatal platelet counts were not statistically significant, irrespective of maternal history, therapy, or platelet count at term (data not shown). No level of platelet-associated IgG, IgM, or C3 and no combination of direct tests identified all fetuses at risk of severe thrombocytopenia (data not shown).
Screening for Neonatal Thrombocytopenia
We analyzed the maternal studies to determine which, if any, maternal characteristics predicted the presence or absence of severe neonatal thrombocytopenia. Only two variables were identified: history of immune thrombocytopenic purpura and the presence of circulating antiplatelet antibodies at term.
History of Immune Thrombocytopenic Purpura
Each of the 18 neonates with severe thrombocytopenia was born to a mother in whom a diagnosis of immune thrombocytopenic purpura had been made before pregnancy (Fig. 1 and 2). None of the 74 women discovered to have thrombocytopenia during the index pregnancy gave birth to an infant with a platelet count below 50×109 per liter, and only 3 had infants with platelet counts between 50 and 100×109 per liter. Maternal platelet counts in these three women were 53×109, 92×109, and 119×109 per liter. Overall, the positive predictive value of a maternal history of immune thrombocytopenic purpura was 40 percent (95 percent confidence interval, 29 to 51 percent) for delivering a neonate with a platelet count below 100×109 per liter, and 20 percent (95 percent confidence interval, 13 to 30 percent) for delivering a neonate with a count below 50×109 per liter (Table 4). The risk that a woman without a history of immune thrombocytopenic purpura would deliver a neonate with moderate thrombocytopenia was 4 percent (95 percent confidence interval, 1 to 11 percent), and the risk for severe thrombocytopenia was 0 percent (95 percent confidence interval, 0 to 5 percent), regardless of the maternal platelet count (Table 4). For the 29 women with no history of immune thrombocytopenic purpura and a platelet count below 100×109 per liter at term, the risk that a neonate might be born with severe thrombocytopenia was also 0 percent, but the 95 percent confidence interval was wider for this smaller group (0 to 12 percent).
Detection of Circulating Antibodies
Detection of circulating antibodies (platelet-bindable IgG) in the mother by the indirect antiglobulin test also helped to estimate the risk of neonatal thrombocytopenia. Overall, 46 of 162 mothers (28 percent) had negative results on indirect antiglobulin testing at the time of delivery (Fig. 1 and 2). No neonates with platelet counts below 50×109 per liter were born to these 46 mothers, although one child was born with a platelet count of 52×109 per liter. Therefore, the predictive value of negative test results for delivering an infant with a platelet count of 50×109 or more per liter in the entire sample (n = 46) and in the subgroup of mothers with a history of immune thrombocytopenic purpura before pregnancy (n = 18) was 100 percent (95 percent confidence intervals, 92 to 100 percent and 82 to 100 percent, respectively) regardless of all other clinical data (Table 4). This means that the risk of severe neonatal thrombocytopenia in the offspring of women with a history of immune thrombocytopenic purpura but no circulating antibodies at term was 0 percent (95 percent confidence interval, 0 to 18 percent).
The utility of positive results on the indirect test depended on the maternal history (Fig. 1 and 2 and Table 4). Positive results had little usefulness in women first found to have thrombocytopenia during the index pregnancy. The test results were positive in 27 of 44 such mothers with platelet counts of 100×109 or more per liter and in 19 of 30 mothers with platelet counts of less than 100×109 per liter. Nevertheless, none of these 46 mothers with positive results on the indirect test gave birth to a neonate with severe thrombocytopenia, and only 2 had infants with moderate thrombocytopenia.
The test results were positive at term in 70 of 88 women with an earlier diagnosis of immune thrombocytopenic purpura (Fig. 1 and 2). Eighteen of the 70 firstborn infants delivered by these mothers had platelet counts below 50×109 per liter (positive predictive value, 26 percent; 95 percent confidence interval, 16 to 38 percent).
Overall, 35 of the 38 neonates with thrombocytopenia (platelet count <100×l09 per liter) and all 18 of those with severe thrombocytopenia were delivered to women with a history of immune thrombocytopenic purpura who had positive results on the indirect test at the time of delivery (Fig. 1). Two of the remaining three neonates with moderate thrombocytopenia were born to mothers found to have thrombocytopenia during the index pregnancy and positive results on the indirect test. Conversely, 89 of the 92 firstborn infants delivered by mothers without a history of immune thrombocytopenic purpura (n = 74) or with a history of the condition but negative results on the indirect test (n = 18) had neonatal platelet counts of more than 100×109 per liter, and all 92 had platelet counts of more than 50×109 per liter at birth (Fig. 1).
Relation between Neonatal Platelet Count in Index and Subsequent Pregnancies
Thirteen women with a history of immune thrombocytopenic purpura were followed during a subsequent pregnancy, including one during two subsequent gestations. Eleven of these women gave birth to a neonate with a normal platelet count during the index pregnancy. Only one infant with thrombocytopenia (platelet count, 80×109 per liter) was born during the 12 subsequent pregnancies in these 11 women. One of the two women who had given birth to an infant with thrombocytopenia during her first pregnancy (platelet count, 12×109 per liter) was subsequently delivered of an infant with severe thrombocytopenia (platelet count, 10×109 per liter). Both infants had bleeding complications after birth (Table 3). None of the four women with negative results on the indirect test at the time of the second delivery had a neonate with thrombocytopenia.
Discussion
The optimal care of pregnant women with immune thrombocytopenic purpura remains uncertain, because there is a poor correlation between maternal and neonatal platelet counts2 3 4 5 , 12 and there is no noninvasive method to predict severe neonatal thrombocytopenia.4 , 5 , 14 This has led obstetricians to use fetal-scalp sampling,11 , 12 percutaneous umbilical-blood sampling,13 14 15 16 17 , 24 and cesarean section25 in women with immune thrombocytopenic purpura, although the risk-to-benefit ratio of the various methods of management has not been defined. For example, few infants with severe thrombocytopenia have been identified when percutaneous umbilical-blood sampling has been performed routinely in all mothers with thrombocytopenia or all women with a history of immune thrombocytopenic purpura. Moreover, the procedure is not widely available and can lead to emergency cesarean section and fetal morbidity.13 14 15 16 17 , 19 , 20 Therefore, a noninvasive method is needed to identify patients at low risk of neonatal thrombocytopenia, in order to avoid both unnecessary invasive tests and unnecessary cesarean sections.
Our study was conducted over an 11-year period to amass a sufficiently large series of unselected patients to define the natural history of immune thrombocytopenic purpura in pregnancy.1 2 3 4 5 , 9 , 24 By including patients with severe immune thrombocytopenic purpura and previous complications as well as many patients with mild thrombocytopenia, immune thrombocytopenic purpura in prolonged clinical remission before pregnancy, or thrombocytopenia that occurred for the first time during pregnancy, our series may reflect the natural history of immune thrombocytopenic purpura and presumed immune thrombocytopenic purpura, as seen by obstetricians and hematologists in the community, more accurately than previous smaller series. However, our experience may still be biased by the pattern of referral to our institutions. Within these constraints, our study indicates that the absence of a history of immune thrombocytopenic purpura, the absence of detectable circulating platelet antibodies at term, or both identify women at low risk of giving birth to a child with severe thrombocytopenia.
Since the advent of automated blood-count determinations, mild maternal thrombocytopenia has been detected commonly at term during otherwise normal pregnancies. This finding appears to be of little consequence to the mother or fetus.7 , 8 However, since most of the women in those series had platelet counts of more than 100×109 per liter, the applicability of this experience to patients with more profound thrombocytopenia remains uncertain.
At the present time there is no way to differentiate such gestational thrombocytopenias from immune thrombocytopenic purpura, since positive results on platelet-antiglobulin tests were equally common in both populations in our study. However, our study provides some guidelines for managing pregnancies when the history is unknown. Among the women with no history of immune thrombocytopenic purpura, no neonates with severe thrombocytopenia were born to the 42 mothers with platelet counts between 100 and 150×109 per liter at term or to the 21 mothers with platelet counts between 75 and 100×109 per liter. Therefore, we believe that intervention will benefit few women found to have platelet counts higher than 75×109 per liter who have no history of immune thrombocytopenic purpura, regardless of the results of their antiglobulin tests or documentation of a previous normal platelet count. However, in our series only 18 of the 74 women without a history of this condition (24 percent) had not had a normal platelet count documented before term. Such women may be more likely to have "classic" autoimmune, antibody-mediated thrombocytopenia, with the attendant risk of severe neonatal thrombocytopenia, although the diagnosis cannot be made in the individual patient until after delivery.10
There is insufficient information to estimate the risk of neonatal thrombocytopenia in women who first present during pregnancy with platelet counts below 75×109 per liter. None of the 10 neonates born to such women in our series had severe thrombocytopenia. Although exceptions may occur, we believe that such neonates will be born to mothers who have detectable circulating antibodies.
Women who had been given a diagnosis of immune thrombocytopenic purpura before pregnancy had a 20 percent risk of delivering a child with severe thrombocytopenia (Fig. 1 and 2). Detection of circulating platelet antibodies in these women did not add significantly to the positive predictive value of the history alone (P>0.2) (Table 4). In contrast, none of the 18 neonates whose mothers had a positive history but no circulating antibodies had severe thrombocytopenia (0 percent; 95 percent confidence interval, 0 to 18.5 percent). In addition, none of the four women without circulating antibodies during a second pregnancy gave birth to a neonate with thrombocytopenia. Therefore, in this situation, we believe that routine cesarean section will benefit few neonates, and the extent to which fetal-scalp sampling, percutaneous umbilical-blood sampling, or maternal therapy will be useful will require additional study. In contrast, if circulating antibodies are detected in pregnant women with a history of the condition, it seems prudent to deliver their children by cesarean section unless an adequate fetal platelet count is documented. We emphasize that the clinical recommendations we make on the basis of the results of platelet-antibody tests can only be applied to laboratories that have had sufficient experience to validate their results clinically.
The diagnostic tests that we used (Table 4) provide predictive values that depend on the prevalence of neonatal thrombocytopenia in the study group. The prevalence of neonatal thrombocytopenia may be lower in the general community, notwithstanding our attempt to study "typical" patients with immune thrombocytopenic purpura. If the prevalence is lower, it would be anticipated that the predictive value of positive test results will be lower, but the predictive value of negative results will be higher.26 Because it is unlikely that a higher prevalence of neonatal thrombocytopenia will be found outside referral centers such as ours, negative results on an indirect antiglobulin test effectively indicate a minimal risk of severe neonatal thrombocytopenia in most clinical settings. However, although our single-number statistical estimate of this risk is 0 percent, the actual risk of severe neonatal thrombocytopenia, although low, is unlikely to be zero in the population as a whole.23
Generally, our patients underwent a planned, elective cesarean section at term if the mother had clinical or serologic evidence of immune thrombocytopenic purpura. Because so many of our patients (124 of 162) had been delivered by cesarean section, our study cannot address the relative risk of neonatal morbidity associated with vaginal delivery as compared with cesarean section. There were no bleeding complications in any mother after cesarean section. However, neonates with moderate or severe thrombocytopenia were born to only 13 and 11 percent of these mothers, respectively. In retrospect, therefore, approximately three quarters of the surgical procedures were performed without benefit to the neonate or mother. However, since 5 of the 18 neonates with severe thrombocytopenia had clinically important bleeding, any decision to forgo cesarean section in an individual patient must take into consideration the uniformly good outcome of the 124 infants and mothers delivered by this method. Had we applied the criterion of clinical history to our sample, percutaneous umbilical-blood sampling or cesarean section would have been considered in only 54 percent of our patients. Had we also excluded women with negative results on the indirect antiglobulin test, this figure would have been reduced to 43 percent, without any change in neonatal morbidity.
Inability to identify the small percentage of fetuses with severe thrombocytopenia by noninvasive means has previously precluded formulating rational management plans for individual mothers with immune thrombocytopenic purpura or thrombocytopenia discovered during pregnancy and has hindered the development of cooperative studies of antenatal therapy. This study and others8 may help to define the risk of neonatal thrombocytopenia on the basis of readily accessible data and to identify women in whom treatment, invasive testing, or operative delivery should receive consideration.
Note added in proof: The finding that maternal history is important in assessing the risk of neonatal thrombocytopenia has been corroborated in a recent publication by Burrows and Kelton.27
Source Information
From the Department of Obstetrics and Gynecology (P.S., M.T.M.), Cancer Center (L.E.B.), and Departments of Medicine and Laboratory Medicine (A.T., D.B.C.), University of Pennsylvania School of Medicine, Philadelphia; and the Departments of Pediatrics (J.B.B.) and Obstetrics and Gynecology (M.L.D.), Cornell University School of Medicine, New York. Address reprint requests to Dr. Samuels at the Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.
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