The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives.
ABSTRACT: Pregnancy has been linked to various microangiopathies, including primary atypical haemolytic uraemic syndrome (aHUS). Complement dysregulation, often linked to rare variants in complement genes, is key for primary aHUS to manifest and may play a role in pregnancy complications of the mother and fetus. The burden of such complications is unknown, making counselling of women with primary aHUS and asymptomatic relatives difficult. We analyzed the maternal and fetal outcomes of 39 pregnancies from 17 women with primary aHUS and two asymptomatic relatives. Seven out of 39 pregnancies were complicated by pregnancy-associated aHUS. Five out of 32 pregnancies not linked to pregnancy-associated aHUS were complicated by pre-eclampsia or HELLP. Rare genetic variants were identified in 10 women (asymptomatic relatives, n = 2) who had a total of 14 pregnancies, including 10 uncomplicated pregnancies. Thirty-five out of 39 pregnancies resulted in live birth. Eight out of 19 women had progressed to end-stage kidney disease, with an incidence of 2·95 (95% confidence interval, 1·37-5·61) per 100 person-years after the first pregnancy. Thus, we emphasized the frequency of successful pregnancies in women with primary aHUS and asymptomatic relatives. Pregnancies should be monitored closely. Rare genetic variants cannot predict the risk of a given pregnancy.
Project description:Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1-4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.
Project description:In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.
Project description:BACKGROUND:Autonomous ovarian activation with recurrent estrogen-producing cysts is a hallmark feature of the rare bone and endocrine disorder fibrous dysplasia/McCune-Albright syndrome. Precocious puberty in girls with McCune-Albright syndrome has been well-described, however long-term effects on gynecologic and reproductive function are unknown. Concerningly, case reports have described poor skeletal outcomes associated with pregnancy in women with fibrous dysplasia. METHODS:Thirty-nine women with fibrous dysplasia/McCune-Albright syndrome were evaluated as part of a natural history study. Clinical, radiographic, and biochemical data were reviewed. Women were contacted to obtain detailed menstrual and reproductive histories. RESULTS:Abnormal uterine bleeding affected 77% of women (30/39), and was associated with severe anemia requiring blood transfusion in 3 cases. Nine women underwent hysterectomy for management of bleeding, including 67% (6/9) at the unusually young age of less than age 35?years. Infertility affected 43% of women (9/21), including 2 women who developed primary ovarian insufficiency after undergoing surgical treatment of ovarian cysts. Of 25 spontaneous pregnancies in 14 women, 35% (8) were unplanned. Among the 14 pregnancies, pregnancy was associated with no change in bone pain in 7 subjects (53%), increased bone pain in 4 subjects (31%), and decreased bone pain in 2 subjects (15%). No additional skeletal complications were reported during pregnancies. CONCLUSIONS:Women with fibrous dysplasia/McCune-Albright syndrome report a high prevalence of gynecologic morbidity and reduced fertility. There is no clear association between pregnancy and poor skeletal outcomes in this population.
Project description:<b>Background: </b>HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is a severe variant of hypertensive disorders of pregnancy affecting approximately 1% of all pregnancies, and has significant maternal and fetal morbidity. Previously, we showed that upregulation of the alternative pathway of complement (APC) plays a role in HELLP syndrome. We hypothesize that HELLP syndrome follows a 2-hit disease model similar to atypical hemolytic uremic syndrome (aHUS), requiring both genetic susceptibility and an environmental risk factor. Our objective was to perform a comparative analysis of the frequency of APC activation and germline mutations in affected women and to create a predictive model for identifying HELLP syndrome.<br><br><b>Methods: </b>Pregnant women with HELLP syndrome, and healthy controls after 23 weeks of gestation were recruited, along with aHUS and thrombotic thrombocytopenic purpura participants. We performed a functional assay, the mHam, and targeted genetic sequencing in all groups.<br><br><b>Results: </b>Significantly more participants with rare germline mutations in APC genes were present in the HELLP cohort compared with controls (46% versus 8%, P = 0.01). In addition, significantly more HELLP participants were positive for the mHam when compared with controls (62% versus 16%, P = 0.009). Testing positive for both a germline mutation and the mHam was highly predictive for the diagnosis of HELLP syndrome.<br><br><b>Conclusion: </b>HELLP syndrome is characterized by both activation of the APC and frequent germline mutations in APC genes. Similar to aHUS, treatment via complement inhibition to mitigate maternal and fetal morbidity and mortality may be possible.<br><br><b>Funding: </b>National Heart Lung and Blood Institute grants T32HL007525 and R01HL133113.
Project description:<h4>Background</h4>Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum.<h4>Methods</h4>This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (?18?years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [?150?×?10<sup>9</sup>/L], lactate dehydrogenase normalization [?246?U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status.<h4>Results</h4>Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1-45.2] years) were diagnosed with aHUS and received ?1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5?days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21?days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred.<h4>Conclusions</h4>Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183?days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment.<h4>Trial registration</h4>Clinical trial identifier: NCT02949128 .
Project description:Mutations in ACTA2 predispose to thoracic aortic aneurysms and dissection as well as coronary artery and cerebrovascular disease. Here we examined the risk of aortic dissections, stroke and myocardial infarct with pregnancy in women with ACTA2 mutations. Of the 53 women who had a total of 137 pregnancies, eight had aortic dissections in the third trimester or the postpartum period (6% of pregnancies). One woman also had a myocardial infarct that occurred during pregnancy that was independent of her aortic dissection. Compared to the population-based frequency of peripartum aortic dissections of 0.6%, the rate of peripartum aortic dissections in women with ACTA2 mutations is much higher (8 out of 39; 20%). Six of these dissections initiated in the ascending aorta (Stanford type A), three were fatal. Three women had ascending aortic dissections at diameters less that 5.0 cm (range 3.8-4.7 cm). Aortic pathology showed mild to moderate medial degeneration of the aorta in three women. Of note, five of the women had hypertension either during or before the pregnancy. In summary, the majority of women with ACTA2 mutations did not have aortic or other vascular complications with pregnancy. However, these findings show that pregnancy is associated with significant risk for aortic dissection in women with ACTA2 mutations. Women with ACTA2 mutations who are planning to get pregnant should be counseled about this risk of aortic dissection, and proper clinical management should be initiated to reduce this risk.
Project description:OBJECTIVE:To assess the accuracy of transvaginal sonographic cervical length (CL) in predicting spontaneous preterm birth in women with twin pregnancies. STUDY DESIGN:Systematic review and metaanalysis of predictive test accuracy. RESULTS:Twenty-one studies (16 in asymptomatic women and 5 in symptomatic women) with a total of 3523 women met the inclusion criteria. Among asymptomatic women, a CL <or=20 mm at 20-24 weeks' gestation was the most accurate in predicting preterm birth <32 and <34 weeks' gestation (pooled sensitivities, specificities, and positive and negative likelihood ratios of 39% and 29%, 96% and 97%, 10.1 and 9.0, and 0.64 and 0.74, respectively). A CL <or=25 mm at 20-24 weeks' gestation had a pooled positive likelihood ratio of 9.6 to predict preterm birth <28 weeks' gestation. The predictive accuracy of CL for preterm birth was low in symptomatic women. CONCLUSION:Transvaginal sonographic CL at 20-24 weeks' gestation is a good predictor of spontaneous preterm birth in asymptomatic women with twin pregnancies.
Project description:Aims:We aimed to assess the relation between number of pregnancies and cardiac structure, function, and arrhythmic events in women with arrhythmogenic cardiomyopathy (AC). Methods and results:We included female AC patients in a cross-sectional study. Number of pregnancies and pregnancy related symptoms were recorded. Ventricular arrhythmias were defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy. Right and left ventricular dimensions and function, including strain analyses, were assessed by echocardiography and magnetic resonance imaging. We created a new AC severity score to grade the severity of AC disease. We included 77 women (age 47?±?16, 43 probands and 34 AC mutation positive female relatives), 19?±?14?years after last pregnancy. Median number of pregnancies was 2 (0-4); 19 had no previous pregnancies, 16 had 1 pregnancy, 30 had 2, and 12 had ?3 pregnancies. Presence of a definite AC diagnosis (P?=?0.36), severity of AC disease (P?=?0.53), and arrhythmic events (P?=?0.25) did not differ between groups of pregnancies. Number of pregnancies was related to increased right ventricular outflow tract diameter in single variable analyses [odds ratio (OR) 1.76, 95% confidence interval (CI) 1.08-2.87; P?=?0.02], but not when adjusted for body surface area and age (OR 1.56, 95% CI 0.91-2.66; P?=?0.11). The number of pregnancies was not associated with any other measures of cardiac structure and function. Conclusion:Higher number of pregnancies did not seem to relate to a worse phenotype in women with AC.
Project description:PURPOSE:The Copenhagen Primary Care Laboratory Pregnancy (CopPreg) database was established based on data from The Danish Medical Birth Register and the Copenhagen Primary Care Laboratory (CopLab) database. The aim was to provide a biomedical and epidemiological data resource for research in early disease programming (eg, parental clinical biomarker levels and pregnancy/ birth outcomes or long-term health in the offspring). PARTICIPANTS:The cohort consisted in total of 203 608 women (with 340 891 pregnancies) who gave birth to 348 248 children and with 200 590 related fathers. In this paper, we focused on women and fathers who had clinical test requisitions prior to and during pregnancy, and on all children. Thus, the cohort in focus consisted of 203 054 pregnancies with requisitions on 147 045 pregnant women, 39 815 fathers with requisitions during periconception and 65 315 children with requisitions. FINDINGS TO DATE:In addition to information on pregnancy and birth health status and general socio-demographic data, over 2.2 million clinically relevant test results were available for pregnancies with requisitions, over 1.5 million for children and over 600 000 test results were available for the fathers with requisitions during periconception. These were ordered by general practitioners in the primary care setting only and included general blood tests, nutritional biomarkers (macronutrients and micronutrients) and hormone tests. Information on tests related to infections, allergies, heart and lung function and sperm analyses (fathers) were also available. FUTURE PLANS:The CopPreg database provides ready to use and valid data from already collected, objectively measured and analysed clinical tests. With several research projects planned, we further invite national and international researchers to use this vast data resource. In a coming paper, we will explore and discuss the indication bias in our cohort.
Project description:BACKGROUND:Pregnancy-associated stroke is a rare but life-threatening event, with an estimated incidence of 30/100000 deliveries. Data on the risk of stroke recurrence and the risk of other adverse pregnancy outcomes are essential for adequate counselling and surveillance in subsequent pregnancies. The aim of this systematic review is to describe the implications of a pregnancy-associated stroke for the future health of these women. METHODS:We searched Ovid Medline, PubMed, Cochrane Library and CINAHL for articles published in 1980-2018. Articles including women with pregnancy-associated stroke and information on at least one of the following outcomes were included: 1) recurrence of stroke during subsequent pregnancy, 2) number and course of subsequent pregnancies and their outcomes and 3) subsequent cardiovascular health. RESULTS:Twelve articles were included in the review, with six providing information on subsequent pregnancies, four on subsequent maternal health and two on both. The included articles varied greatly in terms of study design, length of follow up and reported outcomes. We found 252 women with pregnancy-associated stroke for whom the outcomes of interest were reported: 135 women with information on subsequent pregnancies and 123 women with information on future health. In total, 55 pregnancies after stroke were found. In the majority of studies, the incidence of pregnancy complications was comparable to that of the general population. The risk of stroke recurrence during pregnancy was 2%. Data on subsequent health of these women were limited, and the quality of the data varied between the studies. CONCLUSIONS:Data on subsequent pregnancies and health of women with a history of pregnancy-associated stroke are limited. Further research on this topic is essential for adequate counselling and secondary prevention.