Progress in the Management of Pregnancy with Paroxysmal Nocturnal Hemoglobinuria: A Review

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired complement-mediated hemolytic disease characterized by intravascular hemolysis, thrombosis, smooth muscle dystonia, and so on. Thrombosis is the principal cause of death in PNH patients. During the perinatal period, pregnant PNH patients have increased morbidity and mortality with a heightened risk of complications, including significant preterm birth. The management of pregnancy complicated by PNH is difficult. Therefore, early diagnosis, standardized treatment protocols, and improving perinatal outcomes are crucial. However, there is a lack of consensus on treating patients with PNH during pregnancy. This article reviews 32 studies of pregnancy affected by PNH, focusing on the clinical presentation, diagnosis, and treatment strategies of PNH, to provide guidance for obstetricians on how to handle pregnant patients with PNH, and to offer academic support for the management of PNH patients. We found that Eculizumab has become the primary choice for treating PNH, effectively controlling intravascular hemolysis and reducing the frequency of blood transfusions necessary to stabilize the condition, with no severe threat to the safety of the mother and fetus.

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare somatic mutation hemolytic disease with the clinical characteristics of intravascular hemolysis, venous thrombosis, and smooth muscle dystonia, contributing to bone marrow failure, even multiple organ damage in the progression of the disease.¹

The core of the pathophysiological mechanism of PNH disease is the abnormal activation of complement, which causes blood cell destruction and the occurrence of hemolysis. The root cause was traced to a mutation in the phosphatidylinositol glycan complementation class A (PIGA) gene encoded on Xp22.2.² Clinical manifestations mainly include intravascular hemolysis, anemia, hemoglobinuria, thrombogenesis, abdominal pain, dysphagia, pulmonary hypertension, renal impairment, and so on.³ Diagnosis is mainly achieved by flow cytometry.⁴

In general, pregnancy is discouraged for women with confirmed PNH.⁵ More complications are reported in pregnant women with PNH, such as preterm birth, stillbirth, fetal growth restriction, preeclampsia, and low platelet count (HELLP) syndrome.^6
–8 Furthermore, preexisting PNH symptoms can also worsen during pregnancy. Several case reports have revealed high mortality rates; the maternal mortality rate is 8%–20%, mainly owing to venous thrombosis, whereas the fetal mortality rate is 4%–9% largely because of premature births.^2,3,9,10

Eculizumab, a humanized monoclonal antibody combined with complement C5, is currently considered the first choice for treating PNH during pregnancy, which can significantly reduce PNH complications and improve the median survival rate, and its efficacy and safety have been confirmed in some published studies.^2,6,9,11 Additional treatments include anticoagulation therapy and supportive care.^12,13

Despite promising case reports, lack of authoritative expert consensus and management guidelines remains for pregnant patients with PNH. This review aims to elaborate on the pathophysiology, clinical manifestations, laboratory examinations, diagnosis, and therapy for pregnant PNH patients, strengthening the awareness of the disease and improving the perinatal management period to reduce the incidence of adverse pregnancy outcomes.

Materials and Methods

An extensive search of all published articles from 2000 to 2022 was performed using the PubMed and Cochrane databases. The search terms included “paroxysmal nocturnal hemoglobinuria” and “paroxysmal nocturnal hemoglobinuria” combined with “pregnancy” and “clinical symptoms,” “complications,” “morbidity,” “mortality,” “management,” “treatment,” “Eculizumab,” “prognosis,” “delivery,” and “postpartum,” respectively. A total of 108 relevant studies included reviews, systematic reviews, clinical trials, and case reports. According to the innovative content of the literature and the comprehensive influence, 31 high-quality literature studies were screened for review and summary.

Pathophysiology

Mutations in the PIGA gene linked to the X chromosome result in the deficiency or absence of glycosylphosphatidylinositol-anchored proteins (GPI-APs) on the blood cell membrane surface, of which the most closely associated with PNH disease are CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis).² Their primary function is to prevent activated complement action and to protect cells from being destroyed by complement activity.^9,14

CD59 and CD55 act on an alternative pathway to complement. CD59 can directly interact with the membrane attack complex (MAC), reducing the amount of MAC formation, and preventing lytic pore formation by blocking C9 aggregation. The CD55 accelerates the destruction rate of the membrane-bound C3 convertase.¹⁰

The process of intravascular hemolysis in PNH is described briefly as follows: the lack of CD55 results in the reduction of C3 convertase deactivation increasing the activity of C3 convertase on the surface of PNH cells. Subsequently, the terminal complement pathway is activated by a cascade of amplification eventually resulting in the formation of the MAC, the effect of which is exacerbated by CD59 deficiency.¹ Consequently, cells lacking CD55 and CD59 are vulnerable to destruction by complement attack, triggering complement-mediated intravascular hemolysis. This process is given in Figure 1.

FIG. 1.

Complement-mediated intravascular hemolysis. The activation pathways of complement include the classical pathway, alternative pathway, and lectin pathway. Their common terminals are activation of the C3 and C5 convertases and then the formation of MAC via amplification. MAC attaches to the target cell membrane, causing the cell to rupture and lyse. CD55 and CD59 inhibit complement activation by blocking the formation of C3 convertases and MAC, respectively. PNH erythrocytes lacking both CD55 and CD59 are lysed by complement attack, leading to the development of intravascular hemolysis. Eculizumab suppresses complement activation by binding to C5. MAC, membrane attack complex; PNH, paroxysmal nocturnal hemoglobinuria.

The germination of PNH originates from the amplification of hemopoietic stem cells (HSCs) lacking GPI-APs. HSCs carrying somatic PIGA mutations grow and differentiate; as a result, the correspondingly generated blood cells naturally lack GPI-APs on their surfaces. The final differentiated cells can be myeloid or lymphoid cells such as leukocytes, erythrocytes, platelets, or sundry lymphocytes. Owing to the absence of a nucleus in red cells, erythrocytes are more sensitive to complement attacks and are easily lysed, resulting in the intravascular hemolysis typical of PNH. Except for this deterioration, thrombosis, bone marrow failure, and progression to myelodysplastic syndromes are nonerythroid presentations of PNH, which indicates that PNH results from the clonal expansion of one or several HSCs that obtain an acquired PIGA mutation.¹⁵

Adverse Influence of PNH in Pregnancy

Women of childbearing age are a high-incidence group of PNH.¹³ Complement activation increases dramatically during pregnancy, especially after 20 weeks of gestation, and can be more significant if patients suffer preeclampsia.⁷ Therefore, intravascular hemolysis is frequently more severe for those who are pregnant. The incidence rate of anemia and platelet reduction is also more common, reaching 74% and 80%.¹¹ Because maternal blood is in a hypercoagulable state during pregnancy, venous thrombosis and fatal thrombotic events in the abdominal or cerebral veins may lead to higher maternal mortality.¹² An additional pregnancy-related complication includes an increased risk of abortions. In Bastos et al. study, >45% of PNH pregnancy outcomes are miscarriages or spontaneous interruptions.²

Poor fetal outcome prognoses are closely related to preterm birth. In a report by Fieni et al., only half of all surveyed pregnancies progressed to term,¹⁴ and low birth weight among infants (birth weight <3 kg) was described in 53% of cases.³ Termination of pregnancy via cesarean section is necessary when mother or fetus is accompanied by serious complications, which is the main cause of preterm birth. The indications typically for termination of pregnancy include platelet reduction, thrombosis, fetal respiratory distress, and so on.¹² In addition, many patients cannot undergo transvaginal delivery because of smooth muscle dystonia associated with PNH, making an elective cesarean section the preferred option.⁶

Generally speaking, monitoring and managing pregnant women with PNH comes with many risks and challenges for obstetricians, necessitating collaboration between multidisciplinary teams including hematologists, intensive care unit specialists, anesthesiologists, nurse experts, and neonatal specialists.

Clinical Manifestations

Various symptoms present in PNH are principally determined by the lack of GPI-AP on the erythrocyte cell membrane.⁹

Intravascular hemolysis

As the alternative complement pathway in which C3 is involved is constantly activated, patients with PNH will suffer from persistent chronic hemolysis.⁹ Breakthrough hemolysis frequently occurs in the second trimester of pregnancy, and infection, surgery, strenuous exercise, excessive pressure, and alcohol consumption are all exacerbating factors.^2,4,16

Intravascular hemolysis is often accompanied by moderate to severe anemia, platelet reduction, increased reticulocyte count, indirect bilirubin, and decreased serum-bound globin. At the same time, elevated lactate dehydrogenase (LDH) levels are often >10 times higher than normal values.¹

Hemoglobinuria is a typical clinical manifestation of intravascular hemolysis. Depending on the hemoglobin content, urine color ranges from dark yellow, and red to black. In addition, severe fatigue often accompanies but is not proportional to the degree of anemia.⁹ Fatigue is most intense during episodes of hemolysis. In a series of cases, 75% of pregnant women who presented with fatigue were unable to be relieved by rest.³

Thrombosis

Thrombosis is the main cause of mortality and morbidity in PNH, responsible for ∼40%–67% of known causes of death. Thrombosis in PNH is affected by multiple interacting mechanisms, such as activation of platelets, consumption of nitric oxide (NO), and endothelial dysfunction.¹⁷

Although thrombosis in PNH can occur anywhere, venous thrombosis is more common than arterial thrombosis,^9,15 and hepatic vein thrombosis (Budd–Chiari syndrome) occurs most commonly. Hill et al. proposed that the CD59 negative neutrophils tend to localize in liver microvessels. Patients may present with acute or chronic abdominal pain, or display no significant symptoms.¹⁷ Sagittal and cavernous sinus veins are additional common thrombosis locations, and patients can develop severe headaches of unknown origin.¹⁴ Therefore, the possibility of thrombosis must not be dismissed when pregnant women present with unexplained abdominal pain, headache, or lower limb pain.

Prophylactic anticoagulation and complement inhibitor therapy is recommended for prompt use among high-risk pregnant women. In contrast, therapeutic anticoagulation should be applied for patients who develop thrombosis, and thrombolytic therapy should be considered for those with Budd–Chiari syndrome.¹⁴ In the meantime, hemolysis indicators should be monitored regularly and vessel patency assessed by computed tomography.

Smooth muscle dystonia

Abdominal pain, back pain, and dysphagia nervosa are common manifestations of PNH and they are linked to increased free hemoglobin.⁹

Therefore, the content of NO in the tissue decreases, leading to the spasm of smooth muscle.¹⁴ In a study by Fu et al., the symptoms of smooth muscle dystonia are more severe in patients with PNH granulocyte clones of high size and those with significantly elevated LDH levels.¹⁸

Other manifestations

Chronic renal insufficiency

Patients with PNH are at increased risk for chronic kidney dysfunction. Studies by Hillmen et al. indicated that PNH patients are six times more likely to suffer from chronic kidney disease than the general population.¹⁹ The possible mechanism of kidney injury includes thrombosis and deposition of ferritin particles, which impair the function of renal tubules. Besides, the reduction of NO concentration also plays an important role by leading to increased renal vascular resistance, subsequently decreased glomerular filtration rate, and impairment of renal function finally.²⁰ One clinical trial has shown that Eculizumab can reduce intravascular hemolysis and normalize NO levels, thereby improving glomerular filtration rate and renal function.²¹

Pulmonary artery hypertension

Pulmonary artery hypertension may be caused by thrombogenesis or a reduction of the NO clearance rate.⁹ Studies have reported that almost half of PNH patients with signs of hemolysis had NT-proBNP levels >160 pg/mL, suggesting both pulmonary artery hypertension and right ventricular dysfunction. Fatigue and severe dyspnea are prominent clinical features. In a study by Hill A., et al., 66% of patients with PNH reported having dyspnea, whereas 72% described it as moderate to severe.²²

Diagnosis and Classification of PNH

PNH is usually diagnosed before pregnancy, and the difficulty in the diagnosis during the perinatal period lies in pregnancy complications, of which symptoms similar to PNH, including preeclampsia, HELLP syndrome, and gestational platelet reduction.¹⁴ As such, the diagnosis of PNH should be considered for pregnant women with unexplained anemia, severe platelet reduction, and signs of intravascular hemolysis. It is important to distinguish HELLP syndrome from PNH crisis, as both can present as abdominal pain, anemia, and abnormal laboratory results such as increased LDH and decreased platelet count,²³ making the identification of the two diseases confusing. HELLP often is secondary to preeclampsia, accompanied by proteinuria, high liver enzymes as well as hypertension, while flow cytology tests can be negative.

Traditional diagnostic tests for PNH include the Ham test, sucrose hemolysis, and complement lysis assay. These trials have been gradually abandoned because their sensitivity and specificity are generally lower than with flow cytometry.¹² Since the late 1980s, flow cytometric analysis has been the most sensitive and informative method for the diagnosis of PNH. It not only recognizes the presence of defective cells but also ascertains their specific percentage and degree. For a precise diagnosis, qualitative and quantitative detection of at least two GPI-APs is recommended to exclude the single somatic GPI-APs defect. The detection of CD55 and CD59 molecules in erythrocytes and granulocytes is more commonly used.

It is noteworthy that blood transfusion affects the proportion of red blood cells that lack GPI-APs. So flow cytometric analysis should be implemented before transfusion or during transfusion cessation (at least 1 month) to obtain accurate information.⁴ Although the proportion of abnormal granulocytes is not influenced by red cell transfusion, it can more accurately reflect the clone size of PNH. Furthermore, the clone size of PNH positively correlates with the occurrence of thromboembolic events. A retrospective study by Hill et al. observed that the risk of thrombosis was 44% in patients with PNH clones >50%, whereas it was 5.8% in patients with PNH clones <50%.²⁴ Therefore, observing the clone size of PNH cells can help evaluate the risk of thrombosis so as to manage PNH patients better.¹⁴

In addition to flow cytometry, clinical symptoms of hemolysis and laboratory indicators are also important diagnostic basis. However, flow cytometry can be helpful in confirming the diagnosis of the disease in patients with PNH who have no obvious clinical manifestations and no abnormal laboratory test results.

Treatment

Complement inhibition therapy

Terminal complement inhibition is extremely effective in controlling intravascular hemolysis from PNH. It substantially eliminates the risk of thrombosis and stabilizes hemoglobin levels, reducing the requirement for blood transfusions.^2,11,15 At the same time, it can significantly improve renal dysfunction caused by PNH, improving life quality dramatically.²¹

Eculizumab and Ravulizumab are currently the only drugs approved by the Food and Drug Administration (FDA) for treating PNH by complementing protein C5 inhibitors and reducing erythrocytic cellular lysis effectively. Of importance, Eculizumab is the drug of first choice for pregnant patients with PNH.¹⁶ Before its advent, the mortality of pregnant women with PNH was as high as 20%. Surprisingly, among data evaluated by the International PNH Interest Group from 75 pregnancies in 61 women with PNH undergoing treatment with Eculizumab, there were no maternal deaths and only 3 fetal deaths (accounting for 4%).¹¹ The perinatal mortality rate has decreased significantly. Moreover, Eculizumab was demonstrated to have a minimal effect on the fetus. Kelly et al. examined 20 fetal cord blood samples, only 7 of which had traces of Eculizumab; none of the 10 breast milk.¹¹ This suggests that Eculizumab does not cross the placenta at high enough doses to affect complement activation and is not excreted into breast milk, which has relatively reliable safety for the fetus.

Eculizumab is administered once weekly as an intravenous infusion at an induction dose of 600 mg for 4 weeks, followed by a maintenance dose of 900 mg every 2 weeks.²⁵ Dosage adjustments may depend on the patient's hemolysis symptoms, dynamic changes in the LDH or other indicators that reflect the hemolysis situations, and the size of PNH clonal cells.²⁶ An emerging prophylactic strategy focuses on advancing dose escalation or reducing medication intervals to make sure the concentration of serum Eculizumab reaches the level where the drug could block the complement (pharmacodynamic analysis ≥35 μg/mL) if facilities for monitoring drug levels be available.²⁶ In the study of Hill et al., the interval of administration is shortened to 12 days with the dose of 900 mg maintained, hemolytic activity can be completely suppressed in PNH patients whose serum Eculizumab level does not reach 35 μg/mL previously.²⁷

Breakthrough hemolysis occurs typically beyond the second trimester, usually 1–2 days before the next regular dose, and is accompanied by an abnormal increase in LDH levels. To avoid maternal and infant complications, shorter administration intervals (12–13 days) or higher doses of 1200 mg or both may be required.

There are currently no clinical studies regarding the initiation of Eculizumab during pregnancy. It is recommended that patients treated with Eculizumab before pregnancy can continue their medication during pregnancy, whereas for those who were never treated with Eculizumab or were first diagnosed with PNH during pregnancy, severe anemia, thrombosis, frequent episodes of pain, debilitating fatigue, worsening of renal insufficiency, or dyspnea are the indications for starting treatment, regardless of the PNH clone size.¹⁶ In addition, advanced prophylactic treatment can reduce the risk of hemolysis and thrombosis, and improve renal function, pulmonary artery pressure, pregnancy outcomes, and survival rate.⁹ Moreover, treatment should be extended to the postpartum period. If Eculizumab therapy is discontinued abruptly, the risk of thrombosis may increase compensatively. In the International PNH Group report, 10 patients stopped Eculizumab treatment 12 weeks after delivery, 2 of whom developed thrombosis.

One patient developed mesenteric thrombosis 4 weeks after cessation of Eculizumab therapy, whereas another developed Budd–Chiari syndrome after 8 weeks. Fortunately, Eculizumab treatments resumed immediately after thrombus detection, which resulted in no long-term complications.¹¹

The most severe adverse event associated with Eculizumab has been reported to increase the risk of Neisseria meningiditis infection, resulting from the blockade of terminal complement.⁹ As recommended by the European Medicines Agency, meningitis vaccines should be administered prophylactically before initiating complement inhibitor therapy.^16,23 However, the vaccine is classified as a C-class drug during pregnancy, which must be carefully used after a comprehensive assessment.¹¹ So, doctors are required to be vigilant if patients display fever, chills, muscle pain, and other symptoms. In addition, up to 27% of Eculizumab-treated patients may experience breakthrough hemolysis.¹⁷ Other common adverse events include headache, nasopharyngitis, and upper respiratory tract infection.²⁸ Although treatment courses must be individualized and fully balance the pros and cons of utilization for each patient, the benefits far outweigh the concurrent risks. Further studies are required to standardize the treatment protocols to continue improving outcomes for patients with PNH.²

Ravulizumab also is available as a PNH treatment with the advantage of longer dose intervals of 8 weeks compared with Eculizumab.²⁸ However, no clinical studies have been conducted on the application of Ravulizumab during pregnancy. New complement inhibitors like Pegcetacoplan and Danicopan are being developed and undergoing clinical trials.¹⁶ But the clinical experience of utilization during pregnancy is still undetermined. Overall, the clinical use of complement inhibition therapy in the perinatal period has achieved a breakthrough. Eculizumab can significantly reduce maternal and infant complications associated with complement activation. But more comprehensive clinical studies are still needed on how to minimize and control the adverse effects of complement inhibitor.

Supportive therapy

Basic supportive therapy is essential for health care facilities or regions without access to Eculizumab and includes transfusions of erythrocytes and platelets, folic acid and iron supplements, glucocorticoids, and so on.

The demand for the transfusion of red blood cells and platelets during pregnancy is both significantly increased.¹¹ It should be noted in particular that transfusion of blood products rich in complement should be avoided to prevent iatrogenic hemolysis. A better solution is an infusion of washed red blood cells and platelets.⁴

Folic acid and ferrous sulfate are usually given during pregnancy. They can sustain enough erythrocyte production to improve anemia, and folic acid can prevent fetal neural tube malformation.

Glucocorticoids remain the first-line drugs for controlling breakthrough intravascular hemolysis in PNH patients in areas where Eculizumab is not widely available. A study by Fu et al. reported that corticosteroids combined with hematopoietic growth factor therapy reduced the incidence of acute hemolysis and stabilized the condition in most patients, with an overall treatment response rate as high as 79.01%.¹⁸ In addition, small doses of glucocorticoids during short periods of pregnancy can promote fetal lung maturation. However, long-term use increases adverse effects, including iatrogenic Cushing syndrome, infection, osteoporosis, and hyperglycemia, which may pose additional risks to pregnant women. Many physicians do not use corticosteroids for any PNH patients given the lack of efficacy data and the risk of steroid-induced complications.¹⁴ In conclusion, glucocorticoids may prevent acute hemolysis from worsening in the near future, but its possible adverse effects require vigilance. Clinicians need to evaluate the pros and cons of glucocorticoids in a comprehensive manner.

Anticoagulation therapy

Recent studies indicate that 29%–44% of PNH patients had at least one thromboembolic event during their disease course.² Therefore, anticoagulation therapy for PNH patients with high-risk pregnancies is recommended to avoid death or adverse outcomes owing to thrombosis, especially for those with a previous history of thrombosis, recurrent abortion, or other risk factors.²⁹ As long as pregnancy complicated by PNH is confirmed and contraindications are excluded, prophylactic anticoagulation should begin immediately and continue until 6–12 weeks postpartum.³⁰

Low molecular weight heparin (LMWH) is usually recommended. Compared with unfractionated heparin (UFH), LMWH can lead to a lower incidence of drug-induced platelet reduction.^4,9 Furthermore, LMWH does not cross the placenta or produce teratogenic side effects and is generally tolerated well by PNH patients.³¹ Coumarins are contraindicated owing to possible teratogenesis through the placenta in the first trimester and bleeding risk in late pregnancy. In a clinical study of 39 PNH patients treated with anticoagulation therapy of warfarin by Hill et al., 2 patients suffered severe bleeding events, whereas 1 patient experienced intracranial hemorrhage that ultimately resulted in death.²⁴ Nevertheless, warfarin can be administered in the postpartum period as it is not excreted in breast milk. Low-dose (<150 mg/day) aspirin is safe during pregnancy but does not provide adequate protection against thromboembolic events in patients with PNH.⁶

Anticoagulation can be stopped briefly during delivery considering the risk of bleeding. However, tissue damage, tissue factor release, and platelet activation during delivery can lead to complement overactivation, so patients with PNH have an increased risk of thrombosis during this period.²⁹ Therefore, it is essential to minimize the interval of anticoagulation therapy and restart when feasible. The delivery time should be arranged in advance, and the anticoagulant should be converted from LMWH to the continuous infusion of UFH before delivery. UFH should cease 2–4 hours after the start of delivery and be restarted after delivery. If a cesarean section is chosen, UFH should be discontinued 6 hours before surgery and reused when receiving adequate hemostasis after delivery. LMWH can be restarted 48 hours after surgery, with full-dose anticoagulation for at least 6 months to prevent the development of puerperal venous thrombosis.⁶ Subsequently, patients with a history of thromboembolism should be treated with long-term anticoagulant therapy, and warfarin can be chosen as the main anticoagulant drug.⁴

The balance between bleeding and thrombosis during anticoagulant therapy plays a vital role in managing patients with PNH. Monitoring coagulation indicators is essential. The initiation and termination time of anticoagulant therapy needs to be closely monitored.

Conclusion

PNH is a rare disease characterized by intravascular hemolysis. Health education for women with PNH is a priority, and they need to be fully aware of the high risks and adverse pregnancy outcomes, particularly if untreated. Although flow cytometry is the primary method of diagnosis, frequent monitoring of hemoglobin, platelets, coagulation indexes, and LDH levels is essential during pregnancy to identify emerging intravascular hemolysis. Eculizumab is the most effective and safe treatment while anticoagulation and supportive therapy should be initiated simultaneously or as adjuvant therapy. However, owing to the rarity of the disease, relevant clinical research on the subject remains insufficient. There is no consensus on how to address the adverse effects of Eculizumab and further studies could focus on these areas to ensure better outcomes in pregnant women with PNH.

Footnotes

Authors' Contributions

Study concept and design: B.Z., R.C., and Y.M. Literature search: X.S., J.W., L.L., and Y.X. Drafting of the article: B.Z. and R.C. Critical revision of the article: all authors. All authors read and approved the final version of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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