The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab

Kelly, Richard; Arnold, Louise; Richards, Stephen J.; Hill, Anita; Bomken, Charlotte; Hanley, John; Loughney, Andrew; Beauchamp, Jon; Khursigara, Gus; Rother, Russell P.; Chalmers, Elizabeth; Fyfe, Andrew; Fitzsimons, Edward J.; Nakamura, Ryotaro; Risitano, Antonio M.; Schubert, Jörg; Norfolk, D. R.; Simpson, Nigel; Hillmen, Peter

doi:10.1111/j.1365-2141.2010.08099.x

Cited by 118 publications

(95 citation statements)

References 15 publications

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“…35 Importantly, eculizumab seems to be administrable safely in pregnancy in the long term. 36,37 In our study, we found similar C5a levels in healthy pregnant and non-pregnant women and could not detect any association between C5a levels and obstetric parameters, such as fetal birthweight or gestational week at delivery; of note, these pregnancies were without complications.…”

Section: Discussionmentioning

confidence: 54%

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

et al. 2016

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BACKGROUND: Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. METHODS: The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n ‫؍‬ 19) and in pregnancy with asthma (pregnant subjects with asthma; n ‫؍‬ 22), compared with healthy non-pregnant (n ‫؍‬ 21) and healthy pregnant women (n ‫؍‬ 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). RESULTS: Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257-3.052) ng/mL versus 1.84 (IQR 1.576 -2.563), 1.783 (IQR 0.6064 -2.786), and 2.024 (IQR 1.232-2.615) ng/mL, respectively (P ‫؍‬ .02 in all cases). C5a correlated negatively with FEV 1 (r ‫؍‬ ؊0.44, P ‫؍‬ .039) and FVC values (r ‫؍‬ ؊0.64, P ‫؍‬ .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the nonpregnant asthma group (n ‫؍‬ 12, r ‫؍‬ 0.78, P ‫؍‬ .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9 -1,224] and 910.7 [IQR 614.5-1076] g/mL vs 559.7 [IQR 388.7-783.1] g/mL, P ‫؍‬ .002 and P ‫؍‬ .004, respectively) but not in the pregnant asthma group compared with the non-pregnant asthma group (median 687.4 [IQR 441.6 -947.6] g/mL, P ‫؍‬ .10). CONCLUSIONS: Asthma during pregnancy increases the circulating level of pro-inflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level (detected in pregnancy both in healthy and subjects with asthma).

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Section: Discussionmentioning

confidence: 54%

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

et al. 2016

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“…Several recent reports suggest that eculizumab, a humanized monoclonal antibody that binds to the terminal complement protein C5 has the potential to prevent PNH-associated complications in pregnant women receiving anticoagulation therapy and is well tolerated. [29][30][31] However, further, larger studies are required in this setting to confirm these findings. …”

Section: Discussionmentioning

confidence: 57%

Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience

Guibert¹,

Latour²,

Varoqueaux³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundPregnancy in women with paroxysmal nocturnal hemoglobinuria is rare, with few reports on maternal and fetal mortality rates. Design and MethodsA specific questionnaire designed to solicit data on pregnancies in women with paroxysmal nocturnal hemoglobinuria was sent to all members of the French Society of Hematology in January 2008. ResultsWe identified 27 pregnancies in 22 women at 10 French Society of Hematology centers between 1978 and 2008. The median age was 21.5 years at diagnosis of paroxysmal nocturnal hemoglobinuria and 27 years at pregnancy. None of these women had received eculizumab during their pregnancy. Maternal complications, consisting mostly of cytopenias requiring transfusions, occurred in 95% of cases. Two cases of severe aplastic anemia (de novo in one case and relapse in the other) were recorded. No thrombotic events occurred during pregnancy, whereas 4 postpartum thromboses (16%) were recorded, 2 of which were fatal (maternal mortality rate 8%). Most patients received antithrombotic prophylaxis during pregnancy and postpartum (n=16; 64%). Delivery was preterm in 29% of cases, and birth weight was less than 3 kg in 53% of cases. Fetal mortality rate was 4%. ConclusionsPregnancy during paroxysmal nocturnal hemoglobinuria is associated with increased maternal and fetal mortality rates (8% and 4%, respectively, in this series). Maternal mortality is related to postpartum thromboses. Prophylactic anticoagulation is recommended during pregnancy and for six weeks postpartum.

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“…Nonetheless, preliminary data from HPN patients treated with eculizumab during pregnancy suggest that its use may be safe, at least in the short term, for the fetus (60)(61)(62). In contrast, potential infectious complications may be of concern.…”

Section: Tma In Pregnancy: the Great Paradigm Shiftmentioning

confidence: 99%

Obstetric Nephrology

Fakhouri

Vercel

Frémeaux‐Bacchi

2012

Clinical Journal of the American Society of Nephrology

141

121

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Summary AKI in pregnancy remains a cause of significant fetomaternal mortality and morbidity, particularly in developing countries. Hypertensive complications of pregnancy (preeclampsia/eclampsia or hemolysis, elevated liver enzymes, and low platelets count syndrome) are the leading cause of AKI in pregnancy worldwide. Thrombotic microangiopathy is another peculiar and devastating cause of AKI in pregnancy. During the last decade, our understanding, and in some cases, our management, of these causes of AKI in pregnancy has dramatically improved. For instance, convincing data have linked pre-eclampsia/eclampsia to an increase in circulating antiangiogenic factors soluble Flt 1 and endoglin, which induce endothelial cell dysfunction, hypertension, and proteinuria. Several distinct pathogenic mechanisms underlying thrombotic microangiopathy, including thrombotic microangiopathy occurring during pregnancy, have been established. Thrombotic microangiopathy, which can present as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, can be reclassified in four potentially overlapping subtypes: disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 deficiency-related thrombotic microangiopathy, complement alternative pathway dysregulation-related thrombotic microangiopathy, secondary thrombotic microangiopathy (verotoxin and antiangiogenic drugs), and thrombotic microangiopathy of undetermined mechanism. In most cases, pregnancy is only a precipitating factor for thrombotic microangiopathy. Treatment of thrombotic microangiopathy occurring during pregnancy should be tailored to the underlying pathogenic mechanism: (1) restoration of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 serum activity in the setting of thrombotic thrombocytopenic purpura through plasma exchanges and in some cases, B cell-depleting therapy and (2) inhibition of complement alternative pathway activation in atypical hemolytic uremic syndrome using antiC5 blocking antibody (eculizumab).

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The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab

Cited by 118 publications

References 15 publications

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience

Obstetric Nephrology

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