paroxysmal nocturnal hemoglobinuria ( pnh ) is a rare acquired clonal stem cell disorder characterized by intravascular hemolysis and thrombophilia . pregnancy in pnh is associated with increased maternal and fetal morbidity and mortality due to thromboembolism , infection and premature birth . the terminal complement cascade inhibitor eculizumab has become the standard treatment in patients with symptomatic pnh . there are limited published data regarding the use of eculizumab in pregnancy in either animal studies or in humans . we report a patient with pnh who became pregnant while on eculizumab , required dose escalation during the third trimester to control breakthrough hemolysis , and successfully delivered a healthy baby . eculizumab levels were measured at cambridge biomedical using a manual elisa method in which the microtitre plates are coated with c5 , then blocked . after incubation and washing , mouse anti - human igg4 horseradish peroxidase ( hrp ) was added as the conjugate . then the substrate 3,3,5,5-tetramethylbenzidine ( tmb ) was added and the color reaction was halted using a stop reagent . the pharmacodynamics of eculizumab were determined by measuring the capacity of the patients serum to lyse chicken erythrocytes in a standard total human serum - complement hemolytic assay . a 30 year old chinese female presented with pancytopenia and direct antiglobulin negative hemolytic anemia in 2010 . she was diagnosed with hypoplastic myelodysplastic syndrome due to dysplastic feantures noted on the bone marrow aspirate and biopsy , although with normal cytogenetics . a pnh clone was identified by flow cytometry with type i rbc 93.9% ( reference range  99.0 to 100.0% ) , type ii rbc 0.10% ( reference range  0.00 to 0.99% ) and type she was treated with cyclosporine , horse anti - thymocyte globulin , steroids and standard dose eculizumab with a good response . her lactate dehydrogenase ( ldh ) levels returned to normal with a simultaneous improvement in her hemoglobin level from 6  g /dl to 12  g / dl . two years after the initial diagnosis , she was noted to have a decline in hemoglobin from 12  g / dl to 7  g / dl with a simultaneous rise in ldh to 1027 u / l and undetectable haptoglobin ( fig . a repeat bone marrow aspiration and biopsy showed focal erythroid hyperplasia , mild dyserythropoiesis , normal myelopoiesis , small lymphoid aggregate , and increased iron stores . she required an average of 1 unit of packed red blood cell transfusion per week for symptomatic anemia ( fig . , her serum eculizumab level was found to be less than 11 ug / ml ( therapeutic>99  ug / ml ) . pharmacodynamic ( pd ) assay showed no complement blockade by eculizumab . she was re - induced with eculizumab 900  mg iv weekly x 4 doses , followed by 1200  mg iv every 2 weeks . repeat eculizumab level after 5 weeks was 100  ug / ml with complete complement blockade by pd assay and her hemolysis was controlled ( fig . she had an elective cesarean section at 36 weeks and gave birth to a healthy female baby with apgar score 9/9 . she continued on eculuzimab 1200  mg every 2 weeks for 3 months postpartum with stable hemoglobin and no evidence of active hemolysis . she remains stable on eculizumab , the dose of eculizumab was reduced to 900  mg every 2 weeks a 30 year old chinese female presented with pancytopenia and direct antiglobulin negative hemolytic anemia in 2010 . she was diagnosed with hypoplastic myelodysplastic syndrome due to dysplastic feantures noted on the bone marrow aspirate and biopsy , although with normal cytogenetics . a pnh clone was identified by flow cytometry with type i rbc 93.9% ( reference range  99.0 to 100.0% ) , type ii rbc 0.10% ( reference range  0.00 to 0.99% ) and type she was treated with cyclosporine , horse anti - thymocyte globulin , steroids and standard dose eculizumab with a good response . her lactate dehydrogenase ( ldh ) levels returned to normal with a simultaneous improvement in her hemoglobin level from 6  g /dl to 12  g / dl . two years after the initial diagnosis , she was noted to have a decline in hemoglobin from 12  g / dl to 7  g / dl with a simultaneous rise in ldh to 1027 u / l and undetectable haptoglobin ( fig . a repeat bone marrow aspiration and biopsy showed focal erythroid hyperplasia , mild dyserythropoiesis , normal myelopoiesis , small lymphoid aggregate , and increased iron stores . she required an average of 1 unit of packed red blood cell transfusion per week for symptomatic anemia ( fig . , her serum eculizumab level was found to be less than 11 ug / ml ( therapeutic>99  ug / ml ) . pharmacodynamic ( pd ) assay showed no complement blockade by eculizumab . she was re - induced with eculizumab 900  mg iv weekly x 4 doses , followed by 1200  mg iv every 2 weeks . repeat eculizumab level after 5 weeks was 100  ug / ml with complete complement blockade by pd assay and her hemolysis was controlled ( fig . 2 ) . her hemoglobin rose to 10.8  g / dl without further blood transfusion . she had an elective cesarean section at 36 weeks and gave birth to a healthy female baby with apgar score 9/9 . she continued on eculuzimab 1200  mg every 2 weeks for 3 months postpartum with stable hemoglobin and no evidence of active hemolysis . she remains stable on eculizumab , the dose of eculizumab was reduced to 900  mg every 2 weeks sthe median age at diagnosis of pnh is 34 years , so affected females are often in the reproductive age group . there are 6 reported cases of successful pregnancies in pnh patients being treated with eculizumab [ 47 ] . breakthrough hemolysis manifested itself with patients experiencing hemoglobinuria prior to their next scheduled dose of eculizumab . both of these patients were treated by reducing the interval between subsequent doses from 14 days to 12 days in one case and to 7 days in the other case . one of them suffered breakthrough hemolysis and was treated by reducing the duration between eculizumab doses to 7 days . it has been noted that the dose of eculizumab required to block complement during the latter stages of pregnancy is greater than in the non - pregnant state . her eculizumab level was sub - therapeutic and a pharmacodynamic assay demonstrated the absence of complement blockade . rather than reducing the time interval between doses , we opted to escalate the dose of eculizumab . higher doses of eculizumab have been needed to control atypical hemolytic uremic syndrome ( ahus )   and catastrophic antiphospholipid syndrome . in ahus , the recommended dose of eculizumab is 33% higher than for pnh in order to completely block the complement cascade . utilizing this escalated dose of eculizumab , we successfully achieved therapeutic eculizumab levels with adequate complement blockade ( fig . this dose of eculizumab was also recently reported in a pregnant patient with ahus and found to be safe . pregnancy activates the complement cascade , with increased terminal complex formation in the third trimester . we hypothesize that loss of control of complement - mediated hemolysis with eculizumab during the second and third trimester appears to be due to the physiologic expansion of intravascular volume which occurs during pregnancy . our patients serum eculizumab level was clearly subtherapeutic , reflecting the dilution which had occurred . it therefore does not appear to cross the placenta nor be excreted in breast milk , which is consistent with previous reports [ 47 ] . forty - five percent of pregnancies in women with pnh result in spontaneous miscarriage and 6% in maternal mortality due to fatal thrombotic events . because of the risk of life threatening thrombotic complications , pregnant women with pnh should receive full anticoagulation during pregnancy and for at least 46 weeks postpartum . our case highlights that breakthrough hemolysis can occur early in gestation and that pregnant patients with pnh require close monitoring . many pnh patients require either a shortening of dose interval or treatment with higher doses of eculizumab in order to control hemolysis as pregnancy progresses . all authors were involved in drafting the article or revising it critically for important intellectual content .
pregnancy in women with paroxysmal nocturnal hemoglobinuria ( pnh ) is associated with increased maternal and fetal morbidity and mortality . 
 there is limited published experience regarding therapy of pnh during pregnancy . 
 we describe a case of a 30 year old female with hypoplastic myelodysplastic syndrome and pnh . 
 after two years of treatment with eculizumab , she became pregnant . 
 she developed breakthrough hemolysis at 20 weeks gestation . 
 pharmacokinetic and pharmacodynamic studies demonstrated a subtherapeutic eculizumab level with absence of complement blockade . 
 escalation of her eculizumab dose successfully controlled hemolysis and restored therapeutic eculizumab level and activity . 
 she delivered a healthy baby at 36 weeks .