paroxysmal nocturnal hemoglobinuria ( pnh ) is a rare , acquired clonal disorder of hematopoietic stem cells . these cells have somatic mutations in the x - linked phosphatidylinositol glycan ( pig)-a gene , which encodes an integral step in production of glycosylphosphatidylinositol ( gpi ) membrane anchor proteins . without these anchors , gpi - linked proteins such as the complement regulatory elements cd55 and cd59 are deficient , causing cells to be exquisitely susceptible to complement - mediated lysis 1 . classical manifestations of pnh include coombs - negative intravascular hemolysis , thrombophilia , and bone marrow failure . other common symptoms include fatigue , abdominal pain , pulmonary hypertension , erectile dysfunction , and renal insufficiency 1,2 . patients with pnh have traditionally been treated supportively with transfusions , folic acid , and anticoagulation ; in pnh with severe aplastic anemia ( saa ) , antithymocyte therapy may be used , with or without bone marrow transplant . the introduction of eculizumab , a humanized monoclonal antibody that binds complement protein c5 , led to considerable advances in the long - term management of pnh , with significant improvements in hemolysis , thrombosis , quality of life , and overall survival 24 . the median age at diagnosis of pnh is in the third decade , with a slight female preponderance 5 . as such retrospective analysis has suggested that 25% of women are diagnosed with pnh during pregnancy 6 . this may be , in part , due to the increased activity of complement noted even in normal pregnancy , which could provide a trigger 7 . in active pnh , cytopenias and thromboembolism can cause significant morbidity to mother and fetus , with thrombosis being the leading cause of death in pregnant women . reports of pregnant pnh patients in the preeculizumab era describe maternal and fetal mortality rates of 812% and 47% , respectively 8,9 . however , as pregnancy was an exclusion criterion for the clinical trials , randomized controlled data for pregnant women are unavailable 3,4 . case reports and series in the published literature document several patients who have been treated with eculizumab during some portion of their pregnancy and/or postpartum 1013 . physiologic changes during pregnancy can affect drug metabolism , including altered plasma volume , total body water , plasma proteins , and organ blood flow . eculizumab pharmacokinetic testing was assessed in 40 nonpregnant adult patients with pnh using a one - compartment model , without taking pregnancy - associated changes into account . pharmacodynamic analysis demonstrated near - complete inhibition of hemolysis with a sustained trough of 35  g / ml 14 . eculizumab metabolism has not been explicitly tested in pregnancy . in the largest case series of pregnant pnh patients , only three of the seven had documented eculizumab levels ( range : 63.2116.1  g / ml ) 11 . those who had levels measured either continued eculizumab antepartum / postpartum or were started in later trimesters and into the postpartum period . eculizumab was administered without interruption in the antepartum period but required increased dosing and frequency of infusions for management of breakthrough disease . in 2001 , an 18-year - old female with pancytopenia was referred to our clinic and diagnosed with saa . she had no histocompatible siblings so was treated with horse antithymocyte globulin ( atg ) and cyclosporine . due , in part , to noncompliance with cyclosporine , only a partial response was achieved , and she continued to require intermittent transfusions . a second course of horse atg was administered for worsening disease in 2006 , again with only a partial response . in january 2007 , flow cytometric evaluation demonstrated the first evidence of a pnh clone ( 23% of granulocytes ) with evidence of compensated intravascular coombs - negative hemolysis , worsening fatigue , and multiple episodes of dysuria , many culture - negative . consistent with this , her lactate dehydrogenase ( ldh ) , which was normal at diagnosis , became modestly elevated in mid-2006 and rose further near the end of the year , with levels between 563 and 619  u / l ( normal range : 100220 hemolysis continued to worsen ( ldh 10002000  u / l ) , and transfusion requirements increased to 410 units of red cell concentrate ( rcc ) per month . although our patient also had mild thrombocytopenia and occasional heavy menstrual periods , no platelet transfusions were required . she was immunized against meningococcus with a quadrivalent vaccine , and eculizumab was started in early december 2009 . following induction , she was maintained on the standard fortnightly dose of 900  mg . evidence of hemolysis resolved within a week ( ldh 200300  u / l ) , with marked improvement in fatigue and dysuria . she had a moderate reduction in transfusion requirements ( 24 units rcc per month ) with no increase in ldh or hemoglobinuria , likely reflecting extravascular hemolysis and the underlying saa . ongoing transfusions led to the development of transfusion - related iron overload and the eventual initiation of iron chelation therapy ( deferasirox ) . interestingly , erythropoiesis improved and she became transfusion independent in february 2011 , coinciding with the start of deferasirox . this is similar to results seen in some patients with myelodysplastic syndrome early after initiation of iron - chelation therapy 15 . in february 2013 , risks and benefits were discussed , and the decision was made to continue both cyclosporine and eculizumab throughout pregnancy , to initiate low - molecular - weight heparin ( lmwh ) prophylaxis ( tinzaparin 4500  units daily ) , and to discontinue deferasirox . in the second trimester , she developed symptomatic anemia without overt evidence of hemolysis and again required regular rcc transfusions . because of previously published experience with pregnancy 11 and the increased plasma volume anticipated in the second trimester , her eculizumab was increased from 900  to 1200  mg fortnightly in june 2013 . in august 2013 , despite the increased dose , she had her first episode of frank intravascular hemolysis with hemoglobinuria since starting eculizumab ( ldh 1073 u / l ) . one week before the planned delivery , she experienced antepartum hemorrhage with frequent contractions and required an urgent c - section . a healthy female infant was delivered approximately 4-week premature , with a normal age - adjusted preterm complete blood count . intraoperatively , the hemoglobin dropped to 79  g / l with an estimated blood loss volume of 800  ml . two units of rcc were subsequently transfused . in all , 25 rcc units were required during the pregnancy . four eculizumab infusions were given at the increased dose and frequency ( including two postpartum ) , with no further evidence of hemolysis , and then reduced back to her standard schedule . there were no thromboembolic episodes , and the lmwh was discontinued 6  weeks postpartum . we report here the first case of a canadian pnh patient on eculizumab followed through pregnancy . although no overt complications occurred , it was clear that pregnancy coincided with a return of transfusion dependence and overt intravascular hemolysis . increased transfusion requirements and hemolysis during pregnancy have been reported by other groups as well 6,11 . fortunately , no thromboembolic events or infections occurred in our patient , despite the increased frequency of both being reported in pnh pregnancies 6,8 . as well , similar to previous reports , no adverse fetal outcomes were noted with eculizumab exposure 11 . our case highlights the importance of regular , and perhaps more frequent , monitoring of hemolytic parameters to detect early disease activity . preemptive increases in eculizumab dose and/or frequency may prevent serious clinical manifestations of pnh and minimize maternal and fetal complications . such an anticipatory strategy could be assisted further by the ability to quantify eculizumab drug levels . data on eculizumab in pregnant pnh patients , monitored prospectively , will help in developing guidelines for treating this patient population . eculizumab could also be monitored in these cases via umbilical cord sampling , as previously reported in select cases 11 , although the engineered igg2 backbone should minimize placental transfer . such data would enrich the global registry and serve to improve care of pregnant pnh patients in the future .
key clinical messageparoxysmal nocturnal hemoglobinuria ( pnh ) results from reduced complement regulatory proteins on hematopoietic cells , predisposing patients to intravascular hemolysis , thrombophilia , and cytopenias . 
 women diagnosed in pregnancy can experience significant maternofetal complications . 
 trials of eculizumab in pnh excluded pregnant women . here , we report the first canadian patient taken through pregnancy on eculizumab .