Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome : Journal of the American Society of Nephrology

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Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome

Gaggl, Martina1; Aigner, Christof1; Csuka, Dorottya2; Szilágyi, Ágnes2; Prohászka, Zoltán2; Kain, Renate3; Haninger, Natalja1; Knechtelsdorfer, Maarten4; Sunder-Plassmann, Raute5; Sunder-Plassmann, Gere1; Schmidt, Alice1

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Journal of the American Society of Nephrology 29(3):p 1020-1029, March 2018. | DOI: 10.1681/ASN.2016090995
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Pregnancy presents a challenge for the maternal immune system because of the need to protect the fetus from pathogens while preventing alloimmune injury by facilitating tolerance to paternal antigens. The challenge is focused on the feto-maternal interface in the placenta and requires a precise control of adaptive and innate immunity, including the complement system as exemplified by women with atypical hemolytic uremic syndrome (aHUS).

aHUS is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or of the proteins that regulate it, and pregnancy can provoke life-threatening episodes.1,2 Pregnancy-related aHUS (p-aHUS) affects one in 25,000 pregnancies in the general population,3 which contrasts with an incidence of 20% in women with preexisting aHUS in whom it causes significant maternal mortality and morbidity.4 Classically, p-aHUS presents in the postpartum period and was believed to have little effect on fetal outcome. However, preeclampsia, eclampsia, and HELLP syndrome (hemolysis–elevated liver enzymes–low platelet) are all strongly linked to complement dysregulation and consequently to aHUS that has been complicated by worse fetal outcomes.5

Despite the risks, current consensus proposes that each pregnancy should be considered individually and carefully planned.4 However, the knowledge base is small, and it needs to be expanded before women with aHUS can be given robust advice about pregnancy.6 Here we present data on pregnancies from well characterized patients with aHUS, recruited into the Vienna Thrombotic Microangiopathy (TMA) cohort.

In total, we document 27 pregnancies in 14 women, including nine pregnancies in four women that were followed prospectively.


Clinical Aspects of p-aHUS

By the end of June of 2015, a total of 92 patients had been entered into the Vienna TMA Cohort. These included 30 (33%) with aHUS, of whom 20 were female; one with Shiga toxin–producing Escherichia coli (STEC)–HUS; and 61 with other causes of TMA (Figure 1). Fourteen of the 20 women with aHUS had been pregnant, and together they had had 27 pregnancies, of which nine (in four women) were followed prospectively and are described in detail in the Supplemental Data.

Figure 1.:
Pregnancies among patients with aHUS. Flowchart of the Vienna TMA Cohort. *Developed p-aHUS in subsequent pregnancies.

The 14 women with aHUS who had pregnancies were aged 29±12 years (mean±SD) at diagnosis (Table 1). They segregated into three groups, depending on the timing of pregnancy in relation to diagnosis (Figure 1). Group A (14%) consisted of two individuals (A.1 and A.2) in whom aHUS was diagnosed before their first pregnancies, which occurred 6 and 14 years later. Group B (36%) contained five individuals (B.1 to B.6) who had had at least one uncomplicated pregnancy before their first episode of aHUS, that occurred a median of 6 years (range, 2–23 years) after their last pregnancy. Group C (50%) comprised seven women (C.1 to C.7) who presented with aHUS during or immediately after pregnancy. In five of these women, p-aHUS occurred during their first pregnancy, in the second trimester in two, the third trimester in two, and in the puerperium in one. Notably, patient C.6 initially presented with aHUS 1 year after the birth of her first baby and, after an uneventful second pregnancy, subsequently developed another episode during her third pregnancy. Patient C.7 presented with p-aHUS in the puerperium of her second pregnancy.

Table 1. - Manifestation of aHUS, treatment, and renal function during pregnancies in 14 women
Patient Onset of aHUS Preg Prior First Preg
CKD Stage Adverse Events Maintenance Treatment As of 2015 (End of Study)
Age Treatment During Preg After Preg Prior First Preg After Preg Age CKD Stage Mainten. Treatment
A.1 3 supportive, PEX 2 CKD-G1 1: none, with PI 1: none none 1: none 24 CKD-G1 none
2: proteinuria,
hypertension, with PI 2: persistent
proteinuria 2: none
A.2 24 none 3 CKD-G1T 1: none (KTX) 1: none none 1: none 33 CKD-G2T none
2: none (KTX) 2: none 2: none
3: none (IUFD gw 31) 3: none 3: none
B.1 28 PEX, ecul 1 unknown 1: none 1: none none 1: none 31 CKD-G4 none
B.2 39 none 2 unknown 1: none 1: none none 1: none 43 CKD-G3bT ecul
2: hypertension 2: none
B.3 37 PEX 2 unknown 1: none 1: none none 1: none 41 normal none
2: none 2: none
B.4 34 PEX 1 unknown 1: none 1: none none 1: none 42 CKD-G4T ecul
B.5 57 none 2 unknown 1: none 1: none none 1: none 60 CKD-G2 none
2: none 2: none
C.1 20 PEX 3 normal 1: none 1: p-aHUS none 1: none 23 CKD-G1 none
2: none, with PI 2: none 2: none
3: none, with PI 3: none 3: none
C.2 31 none 3 CKD-G3b 1: increasing creatinine, preeclampsia, fetal death 1: p-aHUS none 1: none 53 CKD-G5D none
2: none, spont. abortion 2: none 2: none
3: none, spont. abortion 3: none 3: none
C.3 28 none 1 CKD-G3b/4T 1: preeclampsia gw 26 1: p-aHUS none 1: none 42 CKD-G5D none
C.4 24 PEX 1 normal 1: spont. abortion 1: p-aHUS none 1: none 27 normal none
C.5 33 none 1 normal 1: proteinuria, HELLP 1: p-aHUS none 1: none 42 CKD-G5D none
C.6 19 PEX 3 normal 1: none 1: aHUS (+12 mo) none 1: PI 32 CKD-G4T ecul
2: none, with PI (KTX) 2: none 2: PI
3: none, with PI (KTX) 3: p-aHUS (+1 d) 3: ecul
C.7 27 PEX 2 unknown 1: none 1: none none 1: none 33 CKD-G1T ecul
2: none 2: p-aHUS (+6 d) 2: PEX
Preg, pregnancy; mainten., maintenance; PEX, plasma exchange; PI, plasma infusion; KTX, kidney transplant; IUFD, intrauterine fetal death; gw, gestational week; ecul, eculizumab; spont., spontaneous.

Overall, seven pregnancies (26%) were complicated by episodes of TMA (p-aHUS), whereas 20 (74%) were not. Accordingly, the incidence of p-aHUS was 6.94 episodes per 1000 weeks at risk (95% confidence interval [95% CI], 2.79 to 14.27). In three patients, episodes of TMA appeared to be provoked by recognized triggers: infection in patient C.6; bleeding in C.1; and curettage after a spontaneous abortion in patient C.4. In addition, three women (C.3, C.4, and C.5) were considered to have preeclampsia or HELLP syndrome before the definitive diagnosis of p-aHUS was made. One individual (C.7) had an induced preterm delivery, but we have no information about why this was considered necessary.

Complement Gene Mutations

Mutations in genes that encode complement alternative pathway proteins, or the molecules that regulate this pathway, were detected in 10 of 14 (71%) in our p-aHUS cohort, a frequency within the range of 50%–80% reported for aHUS more generally.7,8 Details of the mutations are shown in Table 2. On the basis of in silico analysis, functional studies, or previous association with aHUS, three of the patients (A.2, B.5, C.1) have mutations that are recognized as highly likely to be pathogenic and a further two (A.1, C.4) are recognized as probably pathogenic. The remaining five patients had rare variants that are also likely to be pathogenic.

Table 2. - Results of genetic investigations in 14 women with aHUS
Patient Gene Alteration in Protein Domain In Silico Predictions on Possible Functional Effect Minor Allele Frequency a Functional Effect Risk Haplotype Copy Number of CFH, CFHR1,-R2, -R3, and -R5
A.1 CFI p.G342E serine
protease probably damaging, 1 damaging, 2 
deleterious, 3 disease causing 4 0% not characterized 42 het CFH H3 no alteration
CD46 p.D257Vfs a 42 SCR4 disease causing 4 0% FS causing, damaging 43
A.2 CFI p.I416L serine
protease benign, 1 tolerated, 2 neutral, 3 
disease causing 4 0.01%–1.29% quantitative Factor I Deficiency 42,44–47 none het dele CFHR1,-R3
B.1 none na na na na het CFH c.-331C>T het dele CFHR1,-R3
B.2 none na na na na hom CFH H3 no alteration
B.3 CD46 p.E234K SCR4 benign, 1 tolerated, 2 neutral, 3 poly 4 0% not characterized 7 het CFH H3 no alteration
B.4 C3 p.D61N MG1 probably damaging, 1 tolerated, 2 
neutral, 3 poly 4 0% not characterized b het CFH H3 no alteration
B.5 CD46 p.A353V TM benign, 1 tolerated, 2 neutral, 3 poly 4 0.29%–1.73% deficient cell surface control of AP 48–52 none no alteration
C.1 C3 p.K104E MG1 benign, 1 tolerated, 2 neutral, 3 poly 4 0% not characterized het CFH H3 no alteration
C3 p.D1457H MG8 probably damaging, 1 damaging, 2 
deleterious, 3 poly 4 0.34% not characterized
C.2 THBD p.E560Q probably damaging, 1 tolerated, 2 
neutral, 3 disease causing 4 0.01%–0.02% not characterized het CFH H3 no alteration
C.3 none na na na na het CFH H3/H8 na
C.4 CFHR5 p.E163Rfs a 34 SCR3 disease causing 4 0.09%–0.30% FS causing, damaging 53,54 none no alteration
C.5 none None na na na na hom CFH H3 no alteration
C.6 CFH p.N516K SCR9 probably damaging, 1 tolerated, 2 
deleterious, 3 poly 4 0.02%–0.04% not characterized 42,44,48,55 het CFH H3
hom p.E936D no alteration
C.7 CFH p.D748Nfs a 10 SCR13 disease causing 4 0% FS causing, damaging het CFH H3
CD46 p.A353V TM benign, 1 tolerated, 2 neutral, 3 poly 4 0.29%–1.73% deficient cell surface control of AP 48–52 no alteration
CFH, complement factor H; CFHR1–5, CFH related protein 1–5; CFI, complement factor I; het, heterogeneous; CD46, cluster of differentiation 46; SCR, short consensus repeat; FS, frameshift; dele, deletion; na, not applicable; hom, homogenous; poly, polymorphism; MG, macroglobulin; TM, transmembrane; AP, alternative pathway; THBD, thrombomodulin.
aMinor allele frequency was included on the basis of the Exome Sequencing ( and 1000 Genomes Projects (reported by dbSNP; for patient C.3 only CFH was analyzed and CFH c.-331C>T was not included (CFH-H3/H8); CFHR5 was sequenced only in patients C.4 and C.5.
bp.K65Q at a near site affects the C3 binding to factor H and membrane cofactor protein.

The genes CFH, CFI, and CD46 are inherited together with other regulators of complement activation as part of a gene cluster on chromosome 1. Penetrance of pathogenic CFH, CFI, and CD46 mutations for aHUS is incomplete but is increased when they are inherited on a particular haplotype (CFH-H3).7 Ten of the 14 patients in the p-aHUS cohort inherited the CFH-H3 risk haplotype that included a complement mutation in seven individuals. Notably, the two patients without complement mutations were the only ones that were homozygous for CFH-H3 (Table 2).

Specific mutations had no discernable effect on the timing of p-aHUS in relation to pregnancy. Thus, recognized disease-causing mutations were present in both women who developed aHUS years before they first became pregnant (A.1 and A.2); in at least three of the five women who had uncomplicated pregnancies before developing clinically severe aHUS (group B); and in five of the seven women in group C who presented with p-aHUS.

Pregnancy in Women with aHUS

We analyzed 18 pregnancies retrospectively (patients B.1 to B.5 and C.1 to C.7), none of which were managed with prophylactic infusions of fresh frozen plasma (FFP) or other preventative therapy. Six of these pregnancies (33%) were complicated by p-aHUS (Table 1).

None of the eight pregnancies in individuals in group B were complicated by p-aHUS. However, patient B.2 developed hypertension without proteinuria (Table 1). During their first pregnancies, patients C.2 and C.3 (who had received a renal allograft) were both diagnosed clinically as having preeclampsia, but proved to have TMA on renal biopsy (p-aHUS), and subsequently progressed to ESRD. Patient C.4 developed p-aHUS with ARF triggered by curettage after spontaneous abortion. She was treated with eight therapeutic plasma exchanges, and her renal function recovered completely. Patient C.5 developed typical clinical signs of p-aHUS after a stillbirth and an initial diagnosis of HELLP syndrome; no specific treatment was given, and she developed progressive CKD. Finally, patient C.7 presented with p-aHUS after an uneventful second pregnancy and developed ESRD despite therapeutic plasma exchange.

Nine pregnancies were followed prospectively (A.1, A.2, C.1, and C.6), one of which led to p-aHUS (C.6). Patient A.1 was originally diagnosed as having STEC-HUS when she presented with TMA at the age of three. She subsequently had 22 further episodes before a definitive diagnosis of aHUS was made when she was shown to have inherited a CFI and CD46 mutation on the CFH-H3 susceptibility haplotype. She has had two pregnancies, both treated with prophylactic FFP (3 ml/kg twice monthly; Table 3). The first pregnancy was uncomplicated, but she developed hypertension and significant proteinuria during the second, although her serum creatinine concentration remained stable (Table 4). There were no signs of complement activation during either pregnancy.

Table 3. - Details about aHUS treatment of four women during pregnancies and postpartum period
Patient Preg Year Prospectively Followed Maintenance Plasma Therapy before Pregnancy Plasma Therapy during Pregnancy Start (Gestational Week) Stop (Postpartum Week) TMA Episode
A.1 1 2009 yes none 3 ml/kg twice monthly 15 continued no
2 2012 yes none 3 ml/kg twice monthly 13 continued no
A.2 1 2010 yes none 2.5 ml/kg twice monthly 14 continued no
2 2011 yes none none no
3 2014 yes none none no
C.1 1 2011 a no none none yes
2 2014 yes none 10 ml/kg twice monthly 21 14 no
3 2015 yes none 10 ml/kg twice monthly 15 24 no
C.6 1 2002 a no none none no b
2 2013 yes 25 ml/kg monthly 25 ml/kg twice monthly 14 19 no
3 2015 yes 25 ml/kg monthly 25 ml/kg monthly 1 c yes
Preg, pregnancy.
aPregnancy before follow-up at our department.
bPresented with acute and chronic TMA in renal biopsy 12 mo after delivery.
cSwitch to eculizumab.

Table 4. - Renal function, BP, and signs of microangiopathic hemolytic anemia during 11 pregnancies
Patient Preg Gestational/pp. week a Kidney Function Signs of Microangiopathic Hemolytic Anemia Hypertension
A.1 1 13 28 36 3 S-Crea 0.67 0.69 0.69 0.93 Hb 11.1 10.4 10.1 11.7 BP 125/75 120/80 125/80 127/75
UPE 386 320 397 488 PLC 234 182 170 299 Med none
LDH 143 171 165 164
2 14 28 36 3 S-Crea 0.71 0.66 0.71 0.85 Hb 11.8 11.5 10.6 11.8 BP 130/70 130/80 130/80 130/80
UPE 776 727 2208 1178 PLC 237 254 225 317 Med none N N N
LDH 143 202 235 237
A.2 1 13 28 36 5 S-Crea 0.95 0.91 1.06 1.16 Hb 10.1 10.2 10.6 12.1 BP 125/88 125/79 147/105 120/80
UPE 56 112 155 91 PLC 263 172 137 182 Med M M M none
LDH 180 157 207 164
2 14 27 39 2 S-Crea 0.86 0.85 0.85 1.15 Hb 10.5 10.6 11.2 10.9 BP 120/80 120/80 140/90 140/100
UPE 47 164 280 65 PLC 308 254 194 332 Med N N N, M N, M
LDH 169 143 215 215
3 12 28 33 1 S-Crea 0.71 0.8 0.78 0.92 Hb 10.4 10.7 11.9 9.3 BP 125/75 123/84 123/84 130/89
UPE 104 127 145 102 PLC 349 233 258 304 Med N, M N, M N, M N, M
LDH 171 154 191 209
C.1 1 8 25 40 1 S-Crea na 0.5 2.2 Hb 14.1 11.0 9.2 8.0 BP 115/75 110/70 na PRES
UPE neg neg na 362 PLC na na 254 52 Med none na
LDH na 188 1964
2 20 27 37 5 S-Crea 0.76 0.74 0.72 0.9 Hb 12.3 12.1 9.8 11.2 BP 110/90 125/85 125/78 125/78
UPE 110 169 253 390 PLC 235 240 240 368 Med M M M none
LDH 184 164 268 194
3 13 27 37 3 S-Crea 0.74 0.71 0.79 0.89 Hb 11.3 8.9 12.5 11.2 BP 138/102 123/65 126/81 121/71
UPE 373 342 456 290 PLC 333 284 222 335 Med M M M M
LDH 185 205 191 na
C.6 1 8 23 36 na S-Crea na Hb 14.1 12.3 na na BP 110/70 110/70 120/80 na
UPE neg neg neg na PLC 272 243 na na Med none
LDH na
2 14 28 38 3 S-Crea 1.46 1.71 2.01 1.96 Hb 10.0 8.4 8.9 9.3 BP 130/85 130/88 132/83 140/93
UPE 101 85 202 366 PLC 279 236 191 398 Med U, H, N U, L, N U, L, N U, Ca, A
LDH 154 na 184 215
3 13 29 37 1 S-Crea 1.66 2.06 2.42 7.53 Hb 9.9 8.5 9.6 6.8 BP 155/95 133/71 135/90 158/82
UPE 212 244 2848 7653 PLC 263 177 178 108 Med U, L, N U, L, N U, L, N U, Ca, A
LDH 146 182 246 592
Preg, pregnancy; pp., postpartum; S-Crea, serum creatinine (mg/dl); Hb, hemoglobin (mg/dl); BP, BP (mmHg); UPE, urinary protein excretion (mg/g creatinine); PLC, platelet count (G/L); Med, medication; LDH, lactate dehydrogenase (U/L); N, Nifedipin; M, Methyldopa; na, not available; PRES, posterior reversible encephalopathy syndrome; neg, urine dipstick negative; U, urapidil; H, hydrochlorothiazide; L, labetolol; Ca, carvedilol; A, amlodipine;
aColumns 1–3 refer to gestational week; column 4 refers to postpartum week.

After repeated episodes of TMA according to renal biopsy, patient A.2, aged 24, presented with ESRD and later successfully received a renal allograft. After this she had three pregnancies all of which were followed prospectively. The first was managed with prophylactic FFP (2.5 ml/kg FFP twice monthly) and was uncomplicated. Prophylactic FFP was not given during either of the subsequent pregnancies: the second was completely uncomplicated, but the third resulted in a late intrauterine death, probably caused by in utero infection. There was no evidence of complement activation during any of the three pregnancies.

Patient C.1 has compound C3 mutations and has inherited the CFH-H3 susceptibility haplotype. Originally, she presented elsewhere with p-aHUS after her first pregnancy and was treated with 26 plasma exchanges over 41 weeks, but did not require maintenance therapy after she recovered. Her two subsequent pregnancies were managed by us with twice monthly prophylactic infusions of FFP (10 ml/kg), during the pregnancy and into the puerperium (Table 3). Neither pregnancy was complicated by p-aHUS, despite an infection with influenza H1N1—a known trigger for aHUS—during the third pregnancy (Table 4). However, she did have decreased serum C3c concentrations for at least 6 months postpartum, despite normal C3 concentrations and otherwise unremarkable laboratory values.

Patient C.6 has a CFH mutation on a CFH-H3 haplotype and developed aHUS complicated by renal failure 12 months after an apparently uncomplicated pregnancy. She received a renal allograft and was treated thereafter with monthly prophylactic infusions of FFP (25 ml/kg monthly). She had two further pregnancies. In the first, we increased the prophylactic FFP infusions from once to twice a month from the first trimester until the 19th postpartum week (Table 3), and supplemented this with 1600 ml FFP infusions on the day of her caesarian section and the day after (Table 4). She continued her maintenance prophylactic treatment with FFP during her third pregnancy and was again infused with 1600 ml FFP before and after her caesarean section. Despite this, she developed TMA within hours after surgery, possibly provoked by infection. The hemolysis and thrombocytopenia resolved rapidly with FFP infusions, but she developed ARF in the kidney transplant and a renal biopsy confirmed acute TMA (Figure 2). FFP alone has been reported to be ineffective in this situation,9–12 and so eculizumab was added, and this was followed by a steady improvement in serum creatinine. In retrospect, plasma haptoglobin had become undetectable around 4 weeks before the caesarian section, which might be suggestive of low levels of TMA despite the absence of symptoms or other evidence of microangiopathy (Table 4).

Figure 2.:
Renal TMA in a patient with aHUS. Biopsy specimen of renal allograft of patient C.6 after third pregnancy showing (A) arteriolar TMA (acid fuchsin orange G stain, 200× magnification) and (B) glomerular TMA (Periodic Acid-Schiff stain, 200× magnification). In comparison, a renal biopsy after her second pregnancy showed (C) a histologically normal glomerulum with interstitial fibrosis (acid fuchsin orange G stain, 400× magnification).

Fetal Outcome of 27 Pregnancies in Women with aHUS

The fetal outcomes of all 27 pregnancies are documented in Table 5. The median gestational week at birth was 38 (interquartile range, 33–40 weeks). Nineteen pregnancies (70%) resulted in a term live birth and there were two preterm live births. In addition, two preterm infants were stillborn, and four pregnancies resulted in spontaneous abortions before the 21st gestational week (C.2, C.4).

Table 5. - Outcomes of 27 pregnancies in 14 women with aHUS
Patient Preg Year Outcome Sex Gestational Age at Birth, wk Mode of delivery Birth Weight, g Birth Height, cm Head Circumference at Birth, cm Assessment
A.1 1 2009 live birth female 40+0 vaginal delivery 3010 53 33 AGA
2 2012 live birth male 38+2 vaginal delivery 3340 50 33 AGA
A.2 1 2010 live birth male 37+3 vaginal delivery 3110 51 33 AGA
2 2011 live birth male 40+3 vaginal delivery 3956 52 36 AGA
3 2014 stillbirth male 33+3 vaginal delivery 2230 46 35 AGA
B.1 1 2004 live birth female 38+0 C-section 2900 40 33 AGA
B.2 1 2003 live birth female 41+3 C-section 4090 52 35 AGA
2 2005 live birth male 40+2 C-section 3560 50 36 AGA
B.3 1 2001 live birth a unknown unknown C-section unknown unknown unknown unknown
2 2006 live birth a unknown unknown C-section unknown unknown unknown unknown
B.4 1 2005 live birth male 38+3 C-section 3665 52 36.5 AGA
B.5 1 1981 live birth male 40+? emergency C-section 3270 unknown unknown AGA
2 1989 live birth female 40+5 vaginal delivery 3500 50 34 AGA
C.1 1 2011 live birth female 40+6 emergency C-section 4450 53 38 LGA
2 2014 live birth female 37+3 C-section 3130 49 35 AGA b
3 2015 live birth female 38+0 C-section 3150 51 33.5 AGA
C.2 1 1993 fetal death/abortion na 18 vaginal delivery na na na na
2 1999 spontaneous abortion na 7 vaginal delivery na na na na
3 2000 spontaneous abortion na 9+6 vaginal delivery na na na na
C.3 1 2002 live birth/premature female 26+? emergency C-section 888 unknown unknown AGA c
C.4 1 2012 spontaneous abortion na 18+3 vaginal delivery na na na na
C.5 1 2006 stillbirth male 31+1 emergency C-section 1210 na na SGA
C.6 1 2002 live birth male 39+0 C-section 3760 53 37 AGA
2 2013 live birth male 38+3 C-section 3030 51 33 AGA
3 2015 live birth female 38+0 C-section 3240 49 34 AGA
C.7 1 2002 live birth male 40+3 vaginal delivery unknown unknown unknown unknown
2 2009 live birth male 35+? vaginal delivery unknown unknown unknown unknown
Preg, pregnancy; AGA, appropriate for gestational age; C-section, caesarian section; ?, unknown; LGA, large for gestational age; na, not applicable; SGA, small for gestational age.
aLost to follow-up.
bIntermediate care unit stay.
cIntensive care unit stay.

Seven pregnancies were complicated by p-aHUS: two were full term live births (C.1, C.6); three were preterm births, two live births (C.3, C.7) and one stillbirth (C.5); and there were two early spontaneous abortions due to fetal death (C.2, C.4).

In total there were 21 live infants: 16 with birth weights appropriate for gestational age, and one who was large for gestational age; the weights of the remaining four infants are unknown. The overall rate of adverse fetal outcomes in the aHUS cohort was 22 per 100 pregnancies (95% CI, 10 to 41) and was 70 per 100 for those whose pregnancies were complicated by p-aHUS (95% CI, 33 to 93).

Renal Outcome and Pregnancy in aHUS

At the end of the study in June of 2015, the renal status of the 14 women in our aHUS pregnancy cohort was as follows: six have native kidneys (normal kidney function, two; CKD-G1, two (one had had p-aHUS); and CKD-G2 and CKD-G4, one each), whereas the remaining eight progressed to ESRD (caused by p-aHUS in one). Seven of these received renal allografts, of which three have stable renal function with CKD-G1T to -G3T, two have CKD-G4T, and two developed ESRD (caused by p-aHUS in one) (Table 1). The rate of ESRD in all 14 women from first pregnancy until 2015 was 6.36 per 100 person-years (95% CI, 2.56 to 13.11; Table 1).


Pregnancy is a critical condition for women with aHUS because of its well documented ability to trigger episodes of TMA with the attendant risk of irreversible renal failure. These risks led to many women being counseled not to have children and to a considerable number deciding to remain intentionally childless.13,14 Recently this approach has been criticized for being over-pessimistic,4 and this view is strongly re-enforced by our analysis of pregnancy in women with aHUS in the Vienna TMA cohort. Specifically, our results show that: (1) only a quarter of the 27 pregnancies studied were complicated by episodes of p-aHUS; (2) episodes of p-aHUS were three times more common in the retrospectively studied pregnancies (33%), which were managed like conventional low-risk pregnancies, compared with those who were studied prospectively (11%) in a specialized unit and in most cases treated with prophylactic FFP; and (3) fetal outcomes were excellent in those without antenatal episodes of p-aHUS. Our data show that the outcome of pregnancies in women with aHUS is much better than commonly appreciated.

The overall prevalence of p-aHUS was 26% in our cohort, with five out of seven presenting during the first pregnancy. Four were “classic” p-aHUS episodes presenting postpartum (three with an additional trigger) and three patients with an initial diagnosis of preeclampsia/HELLP. With an incidence of 3%–5%, preeclampsia is the most frequent complication after 20th gestational week,15 and its early clinical presentation can mimic p-aHUS, HELLP syndrome, thrombotic thrombocytopenic purpura, acute fatty liver of pregnancy, and SLE. Distinguishing between them can be challenging,4,16 but the most discriminatory laboratory tests have been summarized.17 Glomerular endotheliosis is the morphologic hallmark of preeclampsia,18 whereas thrombosis within vessels and glomeruli is the central feature in aHUS,19 and HELLP syndrome leads to acute tubular necrosis.20,21 The physiologic changes during pregnancy complicate interpretation of hematologic tests,22 proteinuria,23 and serum concentrations of complement factors, because the reference ranges established for nonpregnant subjects are inappropriate during pregnancy.24,25

In a large, multicenter study of women with p-aHUS, Bruel et al.26 reported that 58% of episodes occurred during first pregnancy, whereas in our study 71% of episodes of p-aHUS occurred in the first pregnancy. However, both studies document that a previously uncomplicated pregnancy does not reduce the probability of developing p-aHUS in subsequent pregnancies. Similarly, neither the presence nor the nature of complement gene mutations appeared to influence the risk of p-HUS in either cohort. Currently, there are no factors that can be used to predict the risk of developing p-aHUS in a given pregnancy, other than the presence of one of the disease triggers identified in nonpregnant patients with aHUS. Caesarian section was recently proposed as a particular risk factor for p-aHUS.12 Although the proportion of caesarian sections in our cohort was more than twice as high (65% for deliveries ≥21 weeks of gestation) compared with the general population,27 only three out of 15 (20%) caesarean sections were associated with postpartum p-aHUS, and all three had additional potential triggers (bleeding, infection, stillbirth).

The goal for the management of pregnancy in aHUS is to minimize the risk of an episode of TMA and mitigate the injury caused should one develop. Two approaches have been suggested: prophylactic infusions of FFP,6 perhaps coupled with plasma exchange as recommended for patients with thrombotic thrombocytopenic purpura28; or alternatively expectant management with immediate treatment with eculizumab should an episode of TMA occur. This is feasible because the safety of eculizumab in pregnancy has been established in patients with paroxysmal nocturnal hemoglobinuria,29,30 and in a small number of individuals with p-aHUS.31–38

In the absence of data from randomized, controlled trials, we have adopted a pragmatic approach and have increased the maintenance dose of prophylactic FFP for those already receiving it,39 and have introduced it for those who were not. Our standard regimen is to infuse FFP (10–20 ml/kg body wt every other week40), starting at 15th gestational week, and continue at the original dose for at least 12 weeks postpartum. Additionally, we have infused FFP on the day of delivery and again 1 day later. None of the six pregnancies in patients treated in this way were complicated by p-aHUS and none were accompanied by evidence of dysregulated complement activity. In addition, there were three pregnancies in which we did not use prophylactic FFP or increase maintenance dose; one of these was associated with p-aHUS and the two others were not. Accordingly, the prophylactic use of FFP during pregnancy in women with aHUS appears safe, but effectiveness to prevent p-aHUS needs yet to be determined.

Despite good outcome of pregnancies, the long-term renal prognosis was poor. However, it is impossible to know whether pregnancy influenced this prognosis or whether it simply reflects the natural history of aHUS more generally. The latter would be consistent with data from a recent international study in which women with complement gene mutations progressed more frequently to dialysis-dependent renal failure.26

In conclusion, our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of TMA is essential, but currently, the available data do not allow firm recommendations about the best strategy to prevent them.

Concise Methods


Patients presenting with laboratory signs of TMA or/and biopsy-proven TMA in renal tissue are eligible to be enrolled in the Vienna TMA cohort of the Division of Nephrology and Dialysis at the Medical University of Vienna. Our study includes all enrolled female patients with at least one reported pregnancy until 2015. All patients enrolled in the study gave written informed consent, investigations are in accordance with the Declaration of Helsinki, and the ethics committee of the Medical University of Vienna approved the study. Subjects were classified as aHUS in the case of: laboratory signs of TMA, sequence variations within complement regulatory protein genes, and absence of secondary forms of TMA.41 Disease definitions, classifications, and calculations are detailed in the Supplemental Material. Data collection was on the basis of chart review. With respect to pregnancies, data were obtained by personal interview, review of hospital charts, and the Austrian mother/child book.

Laboratory Methods

Laboratory work-up was carried out at the Department of Laboratory Medicine, Medical University of Vienna, and at the 3rd Department of Internal Medicine, Research Laboratory, Semmelweis University in Budapest. Genetic investigations were performed according to standard procedures and as detailed in the supplement (,



Published online ahead of print. Publication date available at

This article contains supplemental material online at

We would like to thank Prof. Andrew Rees and Prof. Lisa Schulkind for editing the manuscript.

This work was partly supported by the National Research Fund (Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal) of Hungary, PD116119 (to D.C.).


1. Fakhouri F, Roumenina L, Provot F, Sallée M, Caillard S, Couzi L, Essig M, Ribes D, Dragon-Durey MA, Bridoux F, Rondeau E, Frémeaux-Bacchi V: Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 21: 859–867, 201020203157
2. Robson JS, Martin AM, Ruckley V, Macdonald MK: Irreversible post-partum renal failure. A new syndrome. Q J Med 37: 423–435, 19685676880
3. Dashe JS, Ramin SM, Cunningham FG: The long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet Gynecol 91: 662–668, 19989572207
4. Fakhouri F, Vercel C, Frémeaux-Bacchi V: Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy. Clin J Am Soc Nephrol 7: 2100–2106, 201222879435
5. Lynch AM, Salmon JE: Dysregulated complement activation as a common pathway of injury in preeclampsia and other pregnancy complications. Placenta 31: 561–567, 201020427084
6. Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Frémeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodríguez de Córdoba S, Roumenina LT, Sethi S, Smith RJ; Conference Participants: Atypical hemolytic uremic syndrome and C3 glomerulopathy: Conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference. Kidney Int 91: 539–551, 201727989322
7. Rodríguez de Córdoba S, Hidalgo MS, Pinto S, Tortajada A: Genetics of atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost 40: 422–430, 201424799305
8. Nester CM, Thomas CP: Atypical hemolytic uremic syndrome: What is it, how is it diagnosed, and how is it treated? Hematology (Am Soc Hematol Educ Program) 2012: 617–625, 201223233643
9. Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T: Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 36: 673–681, 201020865645
10. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C: Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368: 2169–2181, 201323738544
11. Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, Delmas Y, Douglas K, Furman RR, Gaber OA, Goodship T, Herthelius M, Hourmant M, Legendre CM, Remuzzi G, Sheerin N, Trivelli A, Loirat C: Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 87: 1061–1073, 201525651368
12. Huerta A, Arjona E, Portoles J, Lopez-Sanchez P, Rabasco C, Espinosa M, Cavero T, Blasco M, Cao M, Manrique J, Cabello-Chavez V, Suñer M, Heras M, Fulladosa X, Belmar L, Sempere A, Peralta C, Castillo L, Arnau A, Praga M, Rodriguez de Cordoba S: A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome [published online ahead of print September 11, 2017]. Kidney Int doi:S0085-2538(17)30482-928911789
13. Tong A, Brown MA, Winkelmayer WC, Craig JC, Jesudason S: Perspectives on pregnancy in women with CKD: A semistructured interview study. Am J Kidney Dis 66: 951–961, 201526452499
14. Tong A, Jesudason S, Craig JC, Winkelmayer WC: Perspectives on pregnancy in women with chronic kidney disease: Systematic review of qualitative studies. Nephrol Dial Transplant 30: 652–661, 201525523452
15. Williams D, Davison J: Chronic kidney disease in pregnancy. BMJ 336: 211–215, 200818219043
16. August P: Obstetric nephrology: Pregnancy and the kidney--inextricably linked. Clin J Am Soc Nephrol 7: 2071–2072, 201223221097
17. Sibai BM: Imitators of severe preeclampsia. Obstet Gynecol 109: 956–966, 200717400860
18. Spargo BH, Lichtig C, Luger AM, Katz AI, Lindheimer MD: The renal lesion in preeclampsia. Perspect Nephrol Hypertens 5: 129–137, 197663936
19. Stillman IE, Karumanchi SA: The glomerular injury of preeclampsia. J Am Soc Nephrol 18: 2281–2284, 200717634433
20. Abraham KA, Kennelly M, Dorman AM, Walshe JJ: Pathogenesis of acute renal failure associated with the HELLP syndrome: A case report and review of the literature. Eur J Obstet Gynecol Reprod Biol 108: 99–102, 200312694980
21. Pourrat O, Touchard G, Robert R, Badia P, Bauwens M, Hauet T, Patte D: A kidney biopsy is clearly mandatory to confirm the indication of plasma exchanges in adult haemolytic uraemic syndrome. Ann Med Interne (Paris) 145: 369–372, 19947985952
22. Townsley DM: Hematologic complications of pregnancy. Semin Hematol 50: 222–231, 201323953339
23. Airoldi J, Weinstein L: Clinical significance of proteinuria in pregnancy. Obstet Gynecol Surv 62: 117–124, 200717229328
24. Baines MG, Millar KG, Mills P: Studies of complement levels in normal human pregnancy. Obstet Gynecol 43: 806–810, 19744208314
25. Reggia R, Ziglioli T, Andreoli L, Bellisai F, Iuliano A, Gerosa M, Ramoni V, Tani C, Brucato A, Galeazzi M, Mosca M, Caporali R, Meroni PL, Tincani A: Primary anti-phospholipid syndrome: Any role for serum complement levels in predicting pregnancy complications? Rheumatology (Oxford) 51: 2186–2190, 201222923750
26. Bruel A, Kavanagh D, Noris M, Delmas Y, Wong EKS, Bresin E, Provôt F, Brocklebank V, Mele C, Remuzzi G, Loirat C, Frémeaux-Bacchi V, Fakhouri F: Hemolytic uremic syndrome in pregnancy and postpartum. Clin J Am Soc Nephrol 12: 1237–1247, 201728596415
27. Heim K: Geburtenregister Österreich, Geburtsjahr 2012. Available at:, 2014. Accessed August 1, 2017
28. Scully M, Thomas M, Underwood M, Watson H, Langley K, Camilleri RS, Clark A, Creagh D, Rayment R, Mcdonald V, Roy A, Evans G, McGuckin S, Ni Ainle F, Maclean R, Lester W, Nash M, Scott R, O Brien P; collaborators of the UK TTP Registry: Thrombotic thrombocytopenic purpura and pregnancy: Presentation, management, and subsequent pregnancy outcomes. Blood 124: 211–219, 201424859360
29. Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R: Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 373: 1032–1039, 201526352814
30. Hallstensen RF, Bergseth G, Foss S, Jæger S, Gedde-Dahl T, Holt J, Christiansen D, Lau C, Brekke OL, Armstrong E, Stefanovic V, Andersen JT, Sandlie I, Mollnes TE: Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology 220: 452–459, 201525468724
31. Servais A, Devillard N, Frémeaux-Bacchi V, Hummel A, Salomon L, Contin-Bordes C, Gomer H, Legendre C, Delmas Y: Atypical haemolytic uraemic syndrome and pregnancy: Outcome with ongoing eculizumab. Nephrol Dial Transplant 31: 2122–2130, 201627587606
32. Ardissino G, Wally Ossola M, Baffero GM, Rigotti A, Cugno M: Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol 122: 487–489, 201323884270
33. Mussoni MP, Veneziano FA, Boetti L, Tassi C, Calisesi C, Nucci S, Rigotti A, Panzini I, Ardissino G: Innovative therapeutic approach: Sequential treatment with plasma exchange and eculizumab in a pregnant woman affected by atypical hemolytic-uremic syndrome. Transfus Apher Sci 51: 134–136, 2014
34. Delmas Y, Bordes C, Loirat C, Frémeaux-Bacchi V, Combe C: Post-partum atypical haemolytic-uraemic syndrome treated with eculizumab: Terminal complement activity assessment in clinical practice. Clin Kidney J 6: 243–244, 201326019860
35. Zschiedrich S, Prager EP, Kuehn EW: Successful treatment of the postpartum atypical hemolytic uremic syndrome with eculizumab. Ann Intern Med 159: 76, 201323817717
36. Cañigral C, Moscardó F, Castro C, Pajares A, Lancharro A, Solves P, de la Rubia J, Carpio N, Sanz MA: Eculizumab for the treatment of pregnancy-related atypical hemolytic uremic syndrome. Ann Hematol 93: 1421–1422, 201424306089
37. Kourouklaris A, Ioannou K, Athanasiou I, Panagidou A, Demetriou K, Zavros M: Postpartum thrombotic microangiopathy revealed as atypical hemolytic uremic syndrome successfully treated with eculizumab: A case report. J Med Case Reports 8: 307, 201425219386
38. De Sousa Amorim E, Blasco M, Quintana L, Sole M, de Cordoba SR, Campistol JM: Eculizumab in pregnancy-associated atypical hemolytic uremic syndrome: Insights for optimizing management. J Nephrol 28: 641–645, 201525712233
39. Thomas MR, Robinson S, Scully MA: How we manage thrombotic microangiopathies in pregnancy. Br J Haematol 173: 821–830, 201627019232
40. Licht C, Weyersberg A, Heinen S, Stapenhorst L, Devenge J, Beck B, Waldherr R, Kirschfink M, Zipfel PF, Hoppe B: Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 45: 415–421, 200515685522
41. George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 371: 1847–1848, 201425372103
42. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschênes G, Lebranchu Y, Zuber J, Loirat C: Genetics and outcome of atypical hemolytic uremic syndrome: A nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8: 554–562, 201323307876
43. Sullivan M, Rybicki LA, Winter A, Hoffmann MM, Reiermann S, Linke H, Arbeiter K, Patzer L, Budde K, Hoppe B, Zeier M, Lhotta K, Bock A, Wiech T, Gaspert A, Fehr T, Woznowski M, Berisha G, Malinoc A, Goek ON, Eng C, Neumann HP: Age-related penetrance of hereditary atypical hemolytic uremic syndrome. Ann Hum Genet 75: 639–647, 201121906045
44. Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, Fakhouri F, Provost F, Fridman WH, Thervet E, Legendre C, Zuber J, Frémeaux-Bacchi V: Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant 8: 1694–1701, 200818557729
45. Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ: Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 31: E1445–E1460, 201020513133
46. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C; French Society of Pediatric Nephrology: Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18: 2392–2400, 200717599974
47. Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautés-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V: Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77: 339–349, 201020016463
48. Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, Pinto S, Goodship TH, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M; European Working Party on Complement Genetics in Renal Diseases: Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24: 475–486, 201323431077
49. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G; International Registry of Recurrent and Familial HUS/TTP: Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108: 1267–1279, 200616621965
50. Sartz L, Olin AI, Kristoffersson AC, Ståhl AL, Johansson ME, Westman K, Fremeaux-Bacchi V, Nilsson-Ekdahl K, Karpman D: A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome. J Immunol 188: 2030–2037, 201222250080
51. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship TH, Atkinson JP: Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111: 624–632, 200817914026
52. Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Müslümanoğlu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH: Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A 100: 12966–12971, 200314566051
53. Vernon KA, Goicoechea de Jorge E, Hall AE, Fremeaux-Bacchi V, Aitman TJ, Cook HT, Hangartner R, Koziell A, Pickering MC: Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency. Am J Kidney Dis 60: 121–125, 201222503529
54. Monteferrante G, Brioschi S, Caprioli J, Pianetti G, Bettinaglio P, Bresin E, Remuzzi G, Noris M: Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. Mol Immunol 44: 1704–1708, 200717000000
55. Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, Katz LM, Sethi S, Smith RJ: Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol 7: 265–274, 201222223606

atypical hemolytic uremic syndrome; aHUS; pregnancy; TMA; complement-mediated

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