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/lp/ou_press/de-novo-antineutrophil-cytoplasmic-antibody-associated-vasculitis-in-Z3GZcoEmSR
- Publisher
- Oxford University Press
- Copyright
- © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.
- ISSN
- 2048-8505
- eISSN
- 2048-8513
- DOI
- 10.1093/ckj/sfy011
- Publisher site
- See Article on Publisher Site
Abstract
Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Clinical Kidney Journal, 2018, vol. 11, no. 5, 659–666 doi: 10.1093/ckj/sfy011 Advance Access Publication Date: 15 March 2018 Original Article ORIGI N AL A R TICLE De novo antineutrophil cytoplasmic antibody- associated vasculitis in pregnancy: a systematic review on maternal, pregnancy and fetal outcomes 1 2 2 3 Nicole L. Veltri , Michelle Hladunewich , Arrti Bhasin , Jocelyn Garland and Benjamin Thomson 1 2 Division of Internal Medicine, Department of Medicine, Queen’s University, Kingston, ON, Canada, Division of Nephrology, Department of Medicine, University of Toronto, Toronto, ON, Canada and Division of Nephrology, Department of Medicine, Queen’s University, Kingston, ON, Canada Correspondence and offprint requests to: Nicole L. Veltri; E-mail: 12nlv@queensu.ca; Twitter handle: @queensuim ABSTRACT Background. De novo antineutrophil cytoplasmic antibody-associated vasculitis typically arises in post-reproductive years, but can occur during pregnancy. Concerns of treatment-related teratogenicity persist, while efficacy and safety of new therapies including intravenous immunoglobulin (IVIG) and rituximab are uncertain. There remains a paucity of maternal, fetal and pregnancy outcome data in these women, and therefore a lack of guidance on safe treatment for clinicians. Methods. We conducted a systematic review of the literature and a local, retrospective chart review of women with de novo antibody-associated vasculitis (AAV) in pregnancy. Cochrane, Embase and PubMed databases and relevant conference abstracts were searched. Patient demographics, clinical presentation, management and outcomes (maternal, fetal and pregnancy-related) were analyzed. Results. Twenty-seven cases of de novo AAV in pregnancy were included. Women presented were from 5 to 39 weeks’ gestation, of which a majority were in the second trimester (median 20 weeks). The median gravida of women was 2 and the median parity was 1. Women were treated with steroids (89%), cyclophosphamide (CYC) (37%), other immunosuppressive agents [azathioprine (AZA), IVIG, plasma exchange (PLEX)] or no therapy (11%). High rates of serious complications, including preeclampsia (29%) and maternal death (7%), were reported; however, most pregnancies resulted in live birth (73%). Prematurity was common; 73% of live births occurred prior to 37 weeks’ gestation and 40% prior to 34 weeks’ gestation. The majority of infants were born in the third trimester (median 34.5 weeks). Rates of pregnancy termination were high (23%) and only one intrauterine death was reported, shortly after initiation of therapy (4%). Congenital abnormalities were rare, with one infant having a solitary, pelvic kidney (6%) after maternal treatment with steroids, CYC and PLEX. Use of PLEX, IVIG and AZA increased after 2005, whereas CYC use decreased. Remission often occurred postpartum (60%). Conclusions. De novo AAV in pregnancy can result in uncomplicated pregnancies; however, serious maternal risks exist. Further data on potentially pregnancy compatible therapies such as IVIG and rituximab are needed in this population. Received: 23.10.2017. Editorial decision: 23.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 659 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 660 | N.L. Veltri et al. Keywords: ANCA, eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis, pregnancy Data extraction and quality assessment INTRODUCTION One investigator (N.V.) used the search strategy to identify rele- Antineutrophil cytoplasmic antibody (ANCA)-associated vascu- vant cases. Full reports of cases were obtained and each litides are a small vessel multi-system vasculitis characterized reviewed. Data were collected for study and patient characteris- by necrotizing inflammation of the blood vessel wall and the tics, induction and maintenance management strategy as well presence of ANCAs [1]. Although classically a disease of the as maternal, fetal and pregnancy outcomes. older population with peak incidence at age >40 years [1], ANCA associated vasculitis (AAV) can also be associated with preg- nancy. Immunosuppression with combinations of corticoste- Data synthesis and analysis roids (CORT) and other therapies, such as cyclophosphamide Patient characteristics included maternal and gestational age (CYC), azathioprine (AZA) and plasma exchange (PLEX), are the (GA), obstetric history (gravida and parity), medical and surgical mainstay of treatment for AAV, with new therapies emerging history. Information collected at presentation included symp- such as intravenous immunoglobulin (IVIG) and rituximab [2, 3]. toms at presentation, laboratory investigations, biopsy location However, immunosuppressive therapies vary in teratogenicity and results and treatment. and adverse risks, and thus have varying impact on maternal, Disease-related outcomes encompassed both disease sequelae fetal and pregnancy outcomes [2–5]. The advent of new induc- and outcomes of therapy. Disease sequelae included short- and tion immunosuppressive regimens raises the possibility that long-term manifestations in renal, pulmonary, hematologic, car- maternal, fetal and pregnancy outcomes have changed in preg- diac, neurologic, vascular, cutaneous, otolaryngologic and other nant women diagnosed with AAV. systems. There remain limited data on maternal, fetal and pregnancy Pregnancy-associated outcomes included (i) live birth versus outcomes of de novo AAV arising during pregnancy [6]. We per- fetal demise or therapeutic termination of pregnancy, (ii) pre- formed a systematic review and a local, retrospective chart maturity, (iii) documented congenital anomalies/birth defects, review of de novo ANCA-associated vasculitis in pregnancy to (iv) admission to neonatal intensive care unit (NICU), (v) mode evaluate management strategies, and fetal, maternal and of delivery: vaginal versus Caesarean section (C-section), (vi) pregnancy-related outcomes. need for emergent C-section or induction of labor (IOL), (vii) pre- term premature rupture of membranes (PPROM), (viii) intrauter- ine growth restriction (IUGR) and growth small for gestational age (SGA) with birth weight <10th centile, (ix) oligohydramnios, MATERIALS AND METHODS (x) preeclampsia and (xi) postpartum hemorrhage (PPH). Search strategy and case selection criteria For the purposes of this study, acute kidney injury (AKI) was defined as a 1.5-fold increase in serum creatinine, renal failure A systematic review of the literature was performed using requiring hemodialysis in a previously nondialysis-dependent Cochrane, Embase and PubMed databases from 1 January 1960 to patient or serum creatinine >100 umol/L with AKI or acute renal 1 February 2017, using English only. Conference abstracts were failure reported by the authors in the absence of defined previous searched from annual meetings of nephrology (American Society values. Anemia was defined as serum hemoglobin <11 g/dL. of Nephrology 2003–15, Canadian Society of Nephrology 2012–16 3 3 Leukocytosis was defined as white blood cell count >13.6 10 /mm and European Dialysis and Transplant Association 2002–15), 3 3 in the first trimester, 14.8 10 /mm in the second trimester and rheumatology (American Rheumatology Association 2012–16, 3 3 16.9 10 /mm in the third trimester [7]. Eosinophilia was defined as Canadian Rheumatology Association 2009–16 and European 3 3 serum eosinophils >0.6 10 /mm [7]. League Against Rheumatism 2002–16) and obstetrics (Fetal Analysis was performed using Microsoft Excel Version Medicine Foundation World Congress 2014–16 and Society 14.1.0. For data reported in ranges, median value and quartiles for Maternal-Fetal Medicine 2008–16). Search terms were were calculated if data were not normally distributed. ‘ANCA’, ‘Churg-Strauss’, ‘Eosinophilic’, ‘Gestation’, ‘Polyangiitis’, ‘Pregnancy’, ‘Pregnant’, ‘Vasculitis’ and ‘Wegener’s’. Cases that were referenced in articles, but not found in the primary search, Ethics were collected separately. Cases were included if AAV symptom Ethics approval was obtained through Queen’s University onset occurred during pregnancy with diagnosis either during Health Sciences Research Ethics Board (identification number pregnancy or postpartum (PP). Cases of drug-induced AAV were 6020107) and Sunnybrook Health Sciences Centre (REB PIN #146 excluded. Cases in which c-ANCA or p-ANCA were either not 2015). reported or negative were only considered to be cases of AAV if there was a diagnostic biopsy. A retrospective local chart review was performed of both RESULTS V R TM local electronic medical records, in NephroCare , Patient Care Selected studies TM System and Sunnybrook Health Sciences Centre Medical Records. Local electronic medical records were searched using Systematic review of literature yielded 153 abstracts, from the search term ‘ANCA’ and only charts of females diagnosed which 7 were excluded because of language (Figure 1). Local ret- with ANCA-associated vasculitis during child-bearing age (<50 rospective review of electronic patient medical records revealed years) were examined. Of those, only women who developed 13 patients, but only one developed de novo AAV in pregnancy symptoms and signs of AAV while pregnant who were diag- and was included in the review. A total of 27 cases of de novo nosed in pregnancy or PP were included. AAV during pregnancy were thus identified and included in this Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 De novo ANCA-associated vasculitis in pregnancy | 661 review. One case of de novo ANCA-negative pauci-immune glo- Patient characteristics merulonephritis (GN) was considered, but not included in this Maternal age ranged from 18 to 40 years at the time of pregnancy group because authors did not state whether the case was con- (median age 28 years) (Table 1). Women presented during their sidered AAV [8]. first to sixth pregnancy (median second) and were at anywhere from 5 to 39 weeks’ gestation (median 20 weeks). The medical Citations identified as potentially comorbidities in this group included asthma or atopy (5/16), sinus- relevant to literature review: itis (2/16) and thyroid disease (2/16), with other comorbidities Cochrane/Embase/PubMed: 123 including non-ANCA-associated leukocytoclastic vasculitis (1/16) Conference Abstracts: 30 and diabetes mellitus (1/16). No patients were reported to have Total: 153 preexisting renal, autoimmune or other pulmonary diseases. Abstracts excluded due to non- English language: 7 Investigations Laboratory abnormalities at presentation included anemia (15/ Abstracts reviewed: 146 18), leukocytosis (4/15), eosinophilia (4/12), AKI (9/25), and pres- ence of proteinuria (11/22) or hematuria (9/22). Bloodwork at Abstracts excluded: Diagnosis prior to pregnancy: 59 presentation included rheumatoid factor (RF) (3/5), antinuclear Review Article: 21 antibody (ANA) (3/11) and anti-double-stranded DNA (anti- Not relevant to pregnancy: 13 dsDNA) (1/5) (Table 1). Serum ANCA was positive in the majority Not ANCA vasculitis: 8 of women (19/27: 13/19 c-ANCA, 4/19 p-ANCA, 1/19 both). In one Drug-induced ANCA vasculitis: 5 Onset prior to conception: 4 case, serum ANCA was positive, but whether this was c-ANCA Postpartum symptom onset: 4 or p-ANCA was not reported [9]. In one case, the serum myelo- Serum/biopsy non-diagnostic: 3 peroxidase antibodies (MPO) titer was positive (153 U/mL), but serum ANCA was not reported [10]. Diagnosis was based on tis- Cases identified from local search: 1 sue biopsy, without serum ANCA reported, in seven cases. Anti- glomerular basement membrane (GBM) was negative in all Total abstracts included in case review: reported cases (0/6). Cochrane/Embase/PubMed: 23 When performed (24/27), biopsy sites were nasal cavity (9/ Conference Abstracts: 3 24), kidney (8/24), skin (4/24), lung (3/24), vascular (2/24) and Local cases: 1 Total: 27 myocardium (2/24). Three women had biopsies taken at multi- ple sites [11–13]. Biopsies were performed during pregnancy (17/ 24), PP (5/24) and at delivery (1/24). One histological sample was FIGURE 1: Flow of literature and local case search to identify cases of de novo ANCA vasculitis in pregnancy. examined in autopsy (1/24) [14]. Biopsy showed changes Table 1. Maternal and disease demographics for reported cases of de novo ANCA vasculitis in pregnancy Cases reported, n (%) Frequency, n (%) Median Range Maternal demographics Age (years) 25 (92.6) – 28 18–40 Gravida 16 (59.2) – 2 1–6 Parity 12 (44.4) – 1 0–5 GA at presentation (weeks) 25 (92.6) – 20 5–39 Asthma/atopy 16 (59.2) 5 (31.2) – – Sinusitis 16 (59.2) 2 (12.5) – – Thyroid disease 16 (59.2) 2 (12.5) – – Vasculitis 16 (59.2) 1 (6.25) – – Diabetes mellitus 16 (59.2) 1 (6.25) – – Disease demographics p-ANCA positive 19 (70.4) 6 (31.6) – – c-ANCA positive 19 (70.4) 15 (78.9) – – MPO positive 13 (48.1) 5 (38.5) – – PR3 positive 13 (48.1) 8 (61.5) – – Anti-GBM antibodies 6 (22.2) 0 (0.00) – – ANA positive 11 (40.7) 3 (27.3) – – Anti-dsDNA positive 5 (18.5) 1 (20.0) – – RF positive 5 (18.5) 3 (60.0) – – GPA diagnosis 24 (88.9) 16 (57.1) – – MPA diagnosis 24 (88.9) 4 (14.3) – – EGPA diagnosis 24 (88.9) 4 (14.3) – – Biopsy performed 27 (100) 24 (88.9) – – Biopsy location (%) Nasal 24 (89.3) 9 (37.5) – – Renal 24 (89.3) 8 (33.3) – – Skin 24 (89.3) 4 (16.7) – – Lung 24 (89.3) 3 (12.5) – – Vascular 24 (89.3) 2 (8.33) – – Cardiac 24 (89.3) 2 (8.33) – – Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 662 | N.L. Veltri et al. consistent with vasculitis in most women (20/24; 8/9 nasal, 7/8 well as AZA and CORT (2/27). In certain cases, CYC therapy was renal, 4/4 skin, 3/3 lung, 1/2 vascular, 2/2 myocardium). In all added to these regimens PP (4/17). In some cases, no antenatal seven cases in which biopsy results did not confirm vasculitis, therapy was given (3/27); however, in two of these cases either diagnosis was made by a combination of clinical and laboratory steroids (1/3) or a combination of CORT and CYC (1/3) was added data, including positive serologic markers (i.e. ANCA, MPO or PP. When given in pregnancy, CYC was given in the second tri- proteinase 3 antibodies (PR3)). mester (7/10) and third trimester (2/10); the timing of CYC ther- apy was not reported in one case (1/10) (Table 3). The frequency of PLEX, AZA and IVIG use was similar (5/27, 4/27 and 4/27, Induction and maintenance therapy respectively), and the use of PLEX and IVIG increased in fre- The most common antenatal induction therapy was CORT (24/ quency in later decades (Table 3). From before to after 2005, 27) followed by CYC (10/27), and the most common antenatal antenatal use of CYC induction therapy decreased (8/14 to 2/13), induction combination therapy was CYC and CORT (8/27) whereas antenatal use of AZA (1/14 to 3/13), PLEX (1/14 to 4/13) (Table 2). Other regimens included CORT monotherapy (7/27), as and IVIG (0/14 to 4/13) increased (Table 3). PP use of CYC Table 2. Induction therapy regimens for cases of de novo ANCA vasculitis in pregnancy Induction regimen Cases reported, n (%) Number treated, n (%) PP additional therapy, n (%) References – 27 (100) – – – CORT 6 other – 24 (88.9) 2 (8.33) – CYC 6 other – 10 (37.0) – – PLEX 6 other – 5 (18.5) 2 (40.0) – IVIG 6 other – 4 (14.8) 1 (25.0) – AZA 6- other – 4 (14.8) – – None – 3 (11.1) 2 (66.7) [10, 15, 16] CYC þ CORT – 8 (29.6) – [11, 17–23] CORT – 7 (25.9) 2 (28.6) [9, 14, 24–28] AZA þ CORT – 2 (7.41) – [12, 29] IVIG þ CORT – 1 (3.70) – [13] PLEX þ CORT – 1 (3.70) 1 (100) [30] CYC þ PLEX þ CORT – 1 (3.70) – [31] IVIG þ AZA þ CORT – 1 (3.70) – [32] IVIG þ PLEX þ CORT – 1 (3.70) 1, (100) [33] IVIG þ CYC þ PLEX þ CORT – 1 (3.70) – [34] PLEX þ AZA þ CORT – 1 (3.70) – [22] Table 3. Induction and maintenance therapy in de novo ANCA vasculitis in pregnancy stratified by timing in pregnancy and decade of publication Therapy, n (%) Symptom onset, n (%) CORT CYC PLEX AZA IVIG None Timing of therapy First trimester 7 (25.9) 4 (14.8) 0 (0) 3 (11.1) 0 (0) 1 (3.70) – Second trimester 10 (37.0) 13 (48.1) 7 (25.9) 1 (3.70) 2 (7.41) 0 (0) – Third trimester 6 (22.2) 5 (18.5) 2 (7.41) 0 (0) 1 (3.70) 2 (7.41) – Postpartum 0 (0.00) 2 (7.41) 5 (18.5) 0 (0) 0 (0.00) 0 (0) – Induction – 24 (88.9) 10 (37.0) 5 (18.5) 4 (14.8) 4 (14.8) 3 (11.1) Maintenance – 13 (61.9) 11 (52.4) 0 (0) 2 (9.52) 0 (0) 5 (23.8) Not reported 4 (14.8) 2 (7.41) 1 (3.70) 1 (3.70) 1 (3.70) 1 (3.70) – Timing of publication 1980–89 – 2 (100) 1 (50.0) 0 (0) 1 (50.0) 0 (0) 0 (0) (induction therapy) 1990–99 – 9 (100) 5 (55.6) 0 (0) 0 (0) 0 (0) 0 (0) 2000–09 – 8 (80.0) 2 (20.0) 1 (10.0) 2 (20.0) 2 (20.0) 2 (20.0) 2010–17 – 5 (83.3) 2 (33.3) 4 (66.6) 1 (16.7) 2 (33.3) 1 (16.7) Prior to 2005 – 14 (100) 8 (57.1) 1 (7.14) 1 (7.14) 0 (0) 0 (0) 2005 and later – 10 (76.9) 2 (15.4) 4 (30.8) 3 (23.1) 4 (30.8) 3 (23.1) Timing of publication 1980–89 – 1 (50.0) 1 (50.0) 0 (0) 0 (0) 0 (0) – (maintenance therapy) 1990–99 – 4 (44.4) 4 (44.4) 0 (0) 0 (0) 0 (0) – 2000–09 – 5 (50.0) 3 (30.0) 0 (0) 1 (10.0) 0 (0) – 2010–17 – 3 (42.8) 3 (42.8) 0 (0) 1 (14.3) 0 (0) – Prior to 2005 – 7 (50.0) 6 (42.8) 0 (0) 0 (0) 0 (0) – 2005 and later – 6 (46.2) 5 (38.5) 0 (0) 2 (15.4) 0 (0) – Percentage of total women. Percentage of total cases reported in the defined decade of publication. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 De novo ANCA-associated vasculitis in pregnancy | 663 increased from before to after 2005 (1/14 to 4/13). PLEX was relapse (4/17) occurred with tapering of therapy (2/4) and in sub- administered in 4–10 doses in reported cases (median 7; 4/5 sequent pregnancies (2/4). reported), and 5 doses of IVIG were administered in all cases (4/4 Maternal mortality was a reported complication of de novo reported). No woman received rituximab (0/27). The most com- AAV in pregnancy. One woman died shortly after presenting mon maintenance therapy was CORT and CYC (8/16), followed by with malaise, nasal obstruction, epistaxis and cutaneous ulcera- CYC monotherapy (3/16), CORT monotherapy (3/16), and CORT tions in her second trimester [12]. Nasal and cutaneous biopsies and AZA (2/16). The frequency of CYC usage as maintenance ther- were consistent with granulomatosis with Polyangiitis (GPA), so apy did not change from before to after 2005 (6/12 to 5/9). she was treated with prednisone and AZA induction therapy. During treatment, she developed bilateral intracranial hemato- mas and died. The second woman presented at 16 weeks’ gesta- Disease-related outcomes tion with rash, arthralgia and fevers, and was diagnosed with The most common manifestation of disease was pulmonary microscopic polyangiitis (MPA) with renal involvement with posi- involvement (20/25), which included radiographic changes (20/ tive MPO-ANCA and renal biopsy results [19]. She was treated 25), alveolar hemorrhage (4/25), pleural effusion (3/25) and res- with daily intravenous methylprednisolone and one dose of CYC, piratory failure requiring intubation (2/25) (Table 4). Renal and suffered a spontaneous abortion on Day 3 of therapy. She involvement was common (14/25), with AKI (9/25), proteinuria then developed ARDS secondary to an methicillin-resistant (11/22), hematuria (9/22), and the need for short-term (5/25) and staphylococcus aureus (MRSA) respiratory infection and died of long-term (2/25) hemodialysis. Additional serious maternal respiratory failure. complications included acute limb ischemia resulting in ampu- tation (2/26), splenic infarct (1/26), acute mesenteric ischemia Pregnancy-associated outcomes requiring partial small bowel resection (1/26) and cardiomyop- athy necessitating PP cardiac transplant (1/26) [15–18]. Infection The majority of pregnancies resulted in live birth (19/26; one case occurred in women treated with CYC (3/10), AZA (1/4), steroids unreported). The GA of the infants ranged from 28 to 39 weeks (5/24) and PLEX (1/5) (Table 5). Maternal death occurred in the (median 34.5 weeks). Prematurity (11/15 born<37 weeks and 6/ peripartum period (2/26) and resulted from acute respiratory 15<34 weeks) and SGA infants (34/15) were common. The loca- distress syndrome (ARDS) secondary to severe respiratory infec- tion of newborn admission was seldom explicitly reported, but tion and intracranial bleeding [12, 19]. Remission of disease NICU admission was reported in two cases. Only one case of a occurred during pregnancy (10/25) or PP (15/25). Antenatal birth defect, a solitary pelvic kidney (1/18), was reported [31]. remission occurred in most women treated with AZA (3/4) and Another case of possible skeletal dysplasia was reported, but test- less so with other therapies (2/4 IVIG, 5/10 CYC, 2/5 PLEX, 10/24 ing was pending at the time of publication [10]. Infant death was CORT and 0/3 none) (Table 4). Following remission, the majority not reported in any case (0/19). Several women underwent either of women continued maintenance therapy (16/23), and reported therapeutic termination of pregnancy (6/26) at 12–33 weeks or Table 4. Disease outcomes for cases of de novo ANCA vasculitis in pregnancy stratified by induction therapy Therapy, n (%) Cases Frequency, reported, n (%) n (%) CORT CYC PLEX IVIG AZA None Renal AKI 25 (92.6) 9 (38.5) 8 (88.9) 5 (55.6) 5 (55.6) 2 (22.2) 1 (11.1) 1 (11.1) Proteinuria 22 (81.4) 11 (47.8) 11 (100) 5 (45.4) 4 (36.4) 4 (36.4) 3 (27.3) 0 (0) Hematuria 22 (81.4) 9 (43.5) 9 (100) 4 (44.4) 4 (44.4) 3 (33.3) 3 (33.3) 0 (0) HD, short-term 25 (92.6) 5 (20.0) 4 (80.0) 2 (40.0) 3 (60.0) 2 (40.0) 0 (0) 1 (20.0) HD, long-term 25 (92.6) 2 (8.00) 1 (50.0) 1 (50.0) 0 (0) 0 (0) 0 (0) 1 (50.0) Pulmonary Radiologic changes 25 (92.6) 20 (80.0) 18 (90.0) 7 (35.0) 3 (15.0) 3 (15.0) 2 (10.0) 2 (10.0) Alveolar hemorrhage 25 (92.6) 4 (16.0) 3 (75.0) 2 (50.0) 2 (50.0) 0 (0) 0 (0) 1 (25.0) Pleural effusion 25 (92.6) 3 (12.0) 2 (66.7) 1 (33.3) 0 (0) 0 (0) 0 (0) 1 (33.3) Respiratory failure 25 (92.6) 2 (8.00) 1 (50.0) 1 (50.0) 1 (50.0) 0 (0) 0 (0) 1 (50.0) Hematologic Anemia 18 (66.7) 15 (83.3) 13 (86.7) 6 (40.0) 4 (26.7) 3 (20.0) 3 (20.0) 2 (13.3) Leukocytosis 15 (55.6) 4 (26.7) 4 (100) 3 (75.0) 1 (25.0) 0 (0) 0 (0) 0 (0) Eosinophilia 12 (44.4) 4 (33.3) 4 (100) 1 (25.0) 0 (0) 0 (0) 0 (0) 0 (0) Infectious Infection 26 (96.3) 5 (18.5) 5 (100) 3 (60.0) 1 (20.0) 0 (0) 1 (20.0) 0 (0) Neurologic Neuropathy 26 (96.3) 3 (11.1) 3 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Cardiac Cardiac transplant 26 (96.3) 1 (3.70) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100) Vascular Limb ischemia 26 (96.3) 2 (7.41) 1 (50.0) 1 (50.0) 0 (0) 0 (0) 0 (0) 1 (50.0) Splenic infarct 26 (96.3) 1 (3.70) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100) Mesenteric ischemia 26 (96.3) 1 (3.70) 1 (100) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) Cutaneous Cutaneous involvement 26 (96.3) 10 (37.0) 9 (90.0) 3 (30.0) 1 (10.0) 1 (10.0) 2 (20.0) 1 (10.0) ENT ENT involvement 26 (96.3) 13 (48.1) 13 (100) 6 (46.2) 0 (0) 2 (15.4) 2 (15.4) 0 (0) Disease remission Antenatal remission 25 (92.6) 10 (40.0) 10 (100) 5 (50.0) 2 (20.0) 2 (20.0) 3 (30.0) 0 (0) Remission post pregnancy 25 (92.6) 15 (60.0) 13 (86.7) 4 (26.7) 3 (20.0) 2 (13.3) 0 (0) 2 (13.3) Maintenance therapy 21 (77.8) 16 (76.2) 15 (93.8) 7 (43.8) 4 (25.0) 4 (25.0) 2 (12.5) 1 (6.25) Relapse 17 (63.0) 4 (23.5) 4 (100) 1 (25.0) 0 (0) 1 (25.0) 1 (25.0) 0 (0) Mortality Maternal death 26 (96.3) 2 (7.69) 2 (100) 1 (50.0) 0 (0) 0 (0) 1 (50.0) 0 (0) Percentage of number of cases with the indicated outcome that received the therapy, for example, 88.9% of patients with AKI received CORT. ENT, ear, nose and throat; HD, hemodialysis. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 664 | N.L. Veltri et al. Table 5. Pregnancy-related outcomes for cases of de novo ANCA vasculitis in pregnancy stratified by induction therapy Therapy, n (%) Cases reported, Frequency, n (%) n (%) Median CORT CYC PLEX IVIG AZA None Live birth 26 (96.3) 19 (73.1) 15 (78.9) 7 (36.8) 2 (10.5) 2 (10.5) 2 (10.5) 3 (15.8) GA at delivery (weeks) 15 (78.9) – 34.3 – – –––– Prematurity: delivery prior to 37 weeks 15 (78.9) 11 (73.3) 9 (81.8) 6 (54.5) 2 (18.2) 0 (0) 1 (9.09) 2 (18.2) Delivery prior to 34 weeks 15 (78.9) 6 (40.0) 5 (83.3) 4 (66.7) 1 (16.7) 0 (0) 1 (16.7) 1 (16.7) SGA 14 (51.8) 3 (21.4) 3 (100) 2 (66.7) 2 (66.7) 0 (0) 1 (33.3) 1 (33.3) NICU admission 2 (7.14) 2 (100) 2 (8.33) 1 (10.0) 1 (20.0) 0 (0) 1 (25.0) 0 (0) Solitary, pelvic kidney 18 (94.7) 1 (5.56) 1 (100) 1 (100) 1 (100) 0 (0) 0 (0) 0 (0) IUGR 17 (63.0) 1 (5.88) 1 (100) 0 (0) 1 (100) 0 (0) 1 (100) 0 (0) Oligohydramnios 17 (63.0) 1 (5.88) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) PPROM 17 (63.0) 4 (23.5) 4 (100) 3 (75.0) 1 (25.0) 0 (0) 0 (0) 0 (0) Preeclampsia 17 (63.0) 5 (29.4) 4 (80.0) 2 (40.0) 1 (20.0) 0 (0) 1 (20.0) 1 (20.0) Pregnancy termination 26 (96.3) 6 (23.1) 6 (100) 2 (33.3) 3 (50.0) 2 (33.3) 0 (0) 0 (0) Miscarriage 26 (96.3) 1 (3.85) 1 (100) 1 (100.0) 0 (0) 0 (0) 0 (0) 0 (0) GA at miscarriage or termination 6 (75.0) – 16 – – –––– IOL 17 (89.5) 7 (41.2) 7 (100) 4 (57.1) 1 (14.3) 2 (28.6) 1 (14.3) 0 (0) Vaginal delivery 17 (89.5) 10 (58.8) 9 (90.0) 5 (50.0) 1 (10.0) 2 (20.0) 1 (10.0) 1 (10.0) C-section 17 (89.5) 7 (41.2) 5 (71.4) 2 (28.6) 1 (14.3) 0 (0) 1 (14.3) 2 (28.6) Emergent C-section 17 (89.5) 4 (23.5) 2 (50.0) 0 (0) 1 (25.0) 0 (0) 1 (25.0) 2 (50.0) PPH 17 (89.5) 1 (5.88) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100) Percentage of number of cases with the indicated outcome that received the therapy, for example, 78.9% of cases resulting in live birth received CORT. miscarriage (1/26) (2/26) at 16 weeks. The miscarriage occurred on respectively [35]. In addition, in a study of 350 women with vascu- Day 3 of methylprednisolone and CYC therapy. In some cases, litic diseases encompassing AAV, polyarteritis nodosa, Behc ¸et’s pregnancy was complicated by preeclampsia (5/17), resulting in Disease and Takasayu’s arteritis, 18% of women experienced wor- either C-section (4/5) or IOL (1/5). PPROM (<37 weeks) was com- sening of symptoms, 59% were unchanged and 23% actually mon (5/17). The primary mode of delivery was vaginal (10/17) fol- experienced improvement of symptoms during pregnancy [36]. lowed by C-section (7/17), of which over half were emergent (4/7). The risk of relapse during pregnancy is unpredictable and bimo- Cases without induction therapy. All cases that underwent no dal, highest in the first/second trimester of pregnancy as well as 1 induction therapy throughout their disease course (3/27) occurred month PP [5]. Our results were consistent with these statistics; from 2005 onwards. One woman presented at 34 weeks’ gestation over 75% of women with de novo disease presented prior to the with fever, hemoptysis and leg pain, and subsequently developed third trimester (median GA at presentation 20 weeks) and four recurrent leg ischemia requiring amputation [15]. She delivered a other cases arose between 3 days and 3 months PP. healthy infant at 34 weeks’ gestation via C-section and was then This review confirms that maternal outcomes of de novo AAV in pregnancy were quite poor, even with treatment. Of 27 diagnosed with GPA with positive c-ANCA. She dramatically improved with prednisolone and CYC induction therapy. Another cases, over half (56%) reported serious maternal complications, woman presented at 10 weeks’ gestation with fatigue, vomiting including alveolar hemorrhage, respiratory failure, renal failure and oliguria and was found to have dialysis-dependent AKI [10]. resulting in short- or long-term hemodialysis, limb ischemia, She was diagnosed with MPA on the basis of positive MPO-ANCA mesenteric ischemia, severe cardiac failure requiring cardiac and a diagnostic renal biopsy; however, induction therapy was transplant and maternal death (Table 4). One woman died not administered given the risks of immunosuppressive treat- shortly after she developed bilateral intracerebral hematomas ment in pregnancy. She subsequently developed resistant hyper- as described above [12]. There were no preexisting medical tension with poor fetal growth and concerns regarding possible comorbidities reported that would have predisposed her to an skeletal dysplasia of the fetus, and emergent C-section was per- intracranial hemorrhage, suggesting that this was a complica- formed at 29 weeks’ gestation complicated by PPH. The final tion of severe GPA. This complication has been reported in GPA woman with a history of atopy and asthma presented with pro- in the nonpregnant population, however, is more common in gressive dyspnea at 39 weeks’ gestation and 2 months PP devel- MPA and EGPA [37, 38]. The second maternal death was in the oped respiratory failure and hemodynamic shock [16]. context of severe respiratory infection and ARDS as a complica- Echocardiogram revealed severe left ventricular dysfunction and tion of MPA [19]. There are obvious complications associated mitral regurgitation, and myocardial biopsy was consistent with with immunosuppression, and in our study, the infection rate eosinophilic granulomatosis with polyangiitis (EGPA). She was was as high as 21% in those treated versus 0% in those that treated with intravenous methylprednisolone and underwent went untreated. This can be compared with nonpregnant AAV successful cardiac transplant. patients treated with immunosuppressive therapy with infec- tion rates of 20–60% in observational studies [39]. However, in the subgroup of women who were not treated in pregnancy, DISCUSSION outcomes were very poor, as described above [10, 15, 16]. So, although many of the immunosuppressive therapies have risks It is unclear whether AAV symptoms are affected by pregnancy. and side effects, withholding treatment is likely not a viable The literature reports risk of flares of GPA during pregnancy in alternative in this condition. women with preexisting EGPA or GPA to be 36.4% and 40%, Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/659/4938690 by Ed 'DeepDyve' Gillespie user on 17 October 2018 De novo ANCA-associated vasculitis in pregnancy | 665 Our review showed a very high (73%) prematurity rate among throughout pregnancy. Fetal serum concentrations are negli- those with de novo AAV who did not opt for termination of preg- gible in the first trimester, but match maternal levels by 26 nancy (Table 5). Of those, over half (56%) delivered at under 34 weeks’ gestation and can actually exceed maternal levels at weeks’ gestation. This compares unfavorably with women who delivery [48, 49]. Rituximab use in pregnancy has not been asso- became pregnant while AAV disease was in remission, in whom ciated with fetal complications; however, there is a risk of prematurity rates were 23.2 and 28.5% in two studies [35, 36]. The maternal and fetal neonatal B-cell depletion and therefore, likelihood of prematurity did not appear related to the GA of pre- increased risk of infection [4, 48–50]. One case was reported of sentation. It is likely that prematurity was related to disease de novo ANCA-negative, pauci-immune GN. The authors did not severity and possibly choice of induction therapy. In our review, confirm that this was diagnostic for AAV; however, this particu- exposure to CYC was reported in 10/27 cases, resulting in 7/10 live lar case was refractory to steroids, rituximab and PLEX [8]. The births, 6/7 and 1/7 cases with and without prematurity, respec- outcome was pregnancy termination and maternal long-term tively. Prematurity was much more likely in women who suffered hemodialysis. Clearly, more data are needed to determine if rit- serious outcomes (8/15), as defined above, versus those who did uximab can improve pregnancy outcomes. not (3/11). In addition, renal involvement, a condition that is inde- pendently associated with prematurity, was more likely in cases Conclusion of prematurity (8/11) versus not premature (1/4) [40]. In conclusion, de novo AAV in pregnancy is associated with high Our review showed high rates of PPROM (24%) and C-section rates of maternal and fetal pregnancy-related complications. As delivery (41%) in women with de novo disease. This is higher than we attempt to move away from cytotoxic therapies in preg- previously reported C-section rates in women with preexisting nancy, there remains a paucity of literature on the outcomes AAV in remission at the time of conception (9–23%) [6, 41]. In one associated with the newer generation of therapies such as ritux- European study, the C-section rate was as high as 48.2% in imab. This review highlights the need for practitioners to con- women with vasculitis in remission at the time of conception tinue reporting cases of de novo AAV in pregnancy, especially [35]. However, in nearly 40% of these cases no medical or obstetri- those treated with rituximab. In addition, publishing cases cal indication was given, aside from C-section being considered a where serious maternal complications or death occur is impor- safer method of delivery. Emergent C-section rates in our study tant in order to identify women with high-risk features wherein (27.8%) are comparable to the literature, reported as high as 23% termination should be strongly recommended. When managing in a study of 19 pregnancies with previous diagnoses of systemic these patients, a multidisciplinary team is required to counsel necrotizing vasculitis, secondary to preeclampsia, cardiac failure patients and to optimize outcomes given the complexity of and infection [42]. For de novo AAV during pregnancy, delivery medical issues in this population. may be a definitive therapy, as remission during pregnancy occurred in under half (40%) and remission PP occurred in over half (60%) of cases. This suggests that, like in systemic lupus, AUTHORS’ CONTRIBUTIONS pregnancy potentiates disease activity, and in those presenting early in pregnancy, termination should be considered. In manuscript preparation, N.V. completed the literature review, CYC is traditionally one of the mainstays of induction therapy analysis, table and figure construction and manuscript prepara- in AAV, however it is mutagenic, teratogenic and embryolethal, tion. A.B. analyzed the data from the local case that was included especially in the first trimester of pregnancy [4]. In our study, one in our review. M.H. reviewed the manuscript and provided the case of de novo AAV with CYC exposure early in the second tri- local case in conjunction with A.B. J.G. reviewed the manuscript. mester resulted in fetal demise at 16 weeks’ gestation [19]. In B.T. was the principal investigator and was involved in data col- another case, an infant was born with a birth defect following lection, data analysis and manuscript preparation. treatment with CYC in the second trimester; a solitary pelvic kid- ney, which has not previously been reported in the literature as a CONFLICT OF INTEREST STATEMENT complication of CYC therapy. In human embryology, renal gene- sis begins at the fourth week of gestation and renal ascent occurs None declared. in Weeks 6–8. 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Journal
Clinical Kidney Journal – Oxford University Press
Published: Oct 1, 2018