Frequency and severity of pregnancy complications in women with hereditary thrombotic thrombocytopenic purpura

Critical complications of pregnancy in women with hereditary thrombotic thrombocytopenic purpura (TTP) have been recognized since hereditary TTP was first described,1 and they continue to be frequently reported.2 However, the frequency of complications, their severity, and when they occur during pregnancy are not known. It remains uncertain if women with hereditary TTP can have uncomplicated pregnancies. These issues are critical for physicians who care for women with hereditary TTP. To address these issues, we reviewed all case reports of patients with hereditary TTP whose diagnosis was confirmed by documentation of ADAMTS13 activity <10% and biallelic ADAMTS13 mutations. The case reports were identified by searching MEDLINE and PubMed from 2001 (when ADAMTS13 was first described) to March 20, 2020. This search was initially performed in 20193 and updated for this study. We identified 80 articles describing 180 patients. We believe that the pregnancy data are valid because the objectives of most reports were to describe new ADAMTS13 mutations. Forty-four women were pregnant preceding their diagnosis of hereditary TTP. Nine women in two publications were omitted because they were only listed in a table, without text descriptions. Our analysis included 35 women who had 61 pregnancies (two twin pregnancies). Major complications were defined as life-threatening, requiring urgent hospitalization. Other complications were defined as minor. The data are summarized in Table 1. Table S1 presents all relevant data from each report. Patients are identified by their numbers in Table S1. Thirty-four (97%) of the 35 women had severe complications during one or more pregnancies. Thirty-one of these 34 women had severe complications with their first pregnancy. The other three women had spontaneous pregnancy losses at 5 to 11 weeks' gestation of their first pregnancy; all three had severe complications with their second pregnancy. Of the 31 women who had severe complications during their first pregnancy, 21 had no report of a subsequent pregnancy. Forty-nine (84%) of the 58 pregnancies (excluding three pregnancies with elective induced termination) had severe complications. Gestational age was reported for 41 (84%) of the 49 severe complications; they occurred from seven to 37 weeks' gestation (median, 23 weeks). Twelve (29%) occurred at <20 weeks' gestation, when preeclampsia rarely occurs4; seven (17%) occurred in the first trimester (<13 weeks' gestation). Among the 49 pregnancies with severe complications, outcome was reported for 48 infants, including both twin pregnancies; 16 (33%) infants survived. Eleven patients had previous symptoms suggestive of hereditary TTP (severe neonatal hemolysis, recurrent thrombocytopenia and anemia); two patients had been previously diagnosed with recurrent acquired TTP. In 22 patients, pregnancy complications may have been the initial symptoms of hereditary TTP. Only one woman, Patient 34, did not have severe pregnancy complications. She had two pregnancies, both with minor complications and with term deliveries of healthy infants. Although the description of her pregnancies is limited, it is apparent that severe complications did not occur. Only three women had uncomplicated pregnancies, each following an initial pregnancy with severe complications. Patient 28 had an uncomplicated second pregnancy followed by two pregnancies with induced terminations. Patient 7 had severe complications with her second and fourth pregnancies but her third pregnancy had no reported complications. Patients 7 and 28 were treated with aspirin throughout their uncomplicated pregnancies because of previous diagnoses of antiphospholipid syndrome and HELLP (hemolysis, elevated liver function tests, and low platelets) syndrome. Although aspirin and other antiplatelet agents were commonly used for treatment of TTP in the era preceding routine plasma exchange, their efficacy is uncertain. Patient 30 had two subsequent pregnancies, both without reported complications. Although these four uncomplicated pregnancies were each reported in only a single sentence with no description of clinical or laboratory data, it seems apparent that severe complications did not occur. All four children were healthy. Two (6%) of the 34 women died from severe complications of their initial pregnancy. Patient 17 was admitted at gestational week 20 (with twins) because of mild thrombocytopenia (platelet count, 66 000/μL) and anemia (hemoglobin, 9.3 g/dL) with intrauterine fetal death of one twin. One day after admission she had sudden back pain; her other twin died; then she developed bradycardia and died. Hereditary TTP was diagnosed from autopsy tissue. Patient 21 was admitted at gestational week 21 with seizures, severe thrombocytopenia (platelet count, 16 000/μL) and anemia (hemoglobin, 5.4 g/dL). Her fetus had died. Then TTP was diagnosed and plasma exchange begun. She died 32 hours after admission. Her ADAMTS13 activity was <10%; her ADAMTS13 mutations were implied from her parents' mutations. The risk of death with pregnancy may be greater than 6%. In the reports of 4 of these 29 families, an older sister had previously died from pregnancy complications but TTP was not suspected; ADAMTS13 activity was not measured, and ADAMTS13 sequencing was not done (Table S1 legend). If these four women had been documented to have hereditary TTP and included in our analysis, the frequency of deaths during pregnancy would have increased to 16%. The severe complications almost always had the typical clinical features of TTP. They were similar to the symptoms of preeclampsia with severe features, but were often more severe and/or occurred earlier than 20 weeks' gestation. The clinical similarities of TTP and preeclampsia with severe features are consistent with their similar pathologic abnormalities. In both disorders, the placental pathology is described as maternal vascular malperfusion.5 The diagnosis of TTP should be considered and ADAMTS13 activity should be measured in all women who have unusually severe or atypical preeclampsia. 5 When TTP is diagnosed during pregnancy, both hereditary and acquired, autoimmune TTP should be considered. 6 When a woman has had a previous episode of TTP that was not confirmed as acquired TTP by recovery of ADAMTS13 activity, plasma prophylaxis during a subsequent pregnancy is appropriate. Also, all sisters of patients with hereditary TTP should have their ADAMTS13 activity measured to diagnose or exclude hereditary before planning pregnancy. When hereditary TTP is diagnosed, plasma prophylaxis is required for all subsequent pregnancies. We begin plasma prophylaxis as soon as pregnancy is documented. We adjust the amount of plasma and interval of infusions to maintain the patient's normal platelet count and to prevent evidence for hemolysis. We also follow fetal development with Doppler assessment of uterine and fetal arteries. We continue plasma prophylaxis for 6 weeks postpartum.5 Prophylactic plasma can prevent exacerbations of TTP but it cannot prevent the occurrence of preeclampsia.5 The authors received no support for this project. The authors declare no conflict of interest with the content of this paper. Table S1. Pregnancy outcomes in women with previously undiagnosed hereditary TTP Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.