Embed Size (px)
Citation preview
Autoimmunity Reviews xxx (2015) xxx–xxx
AUTREV-01700; No of Pages 6
Contents lists available at ScienceDirect
Autoimmunity Reviews
j ourna l homepage: www.e lsev ie r .com/ locate /aut rev
Review
Systemic vasculitis and pregnancy: A multicenter study on maternal andneonatal outcome of 65 prospectively followed pregnancies
Micaela Fredi a,1, Maria Grazia Lazzaroni a,1, Chiara Tani b, Véronique Ramoni c, Maria Gerosa d, Flora Inverardi c,Paolo Sfriso e, Paola Caramaschi f, Laura Andreoli a, Renato Alberto Sinico g, Mario Motta a, Andrea Lojacono a,Laura Trespidi h, Francesca Strigini b, Antonio Brucato i, Roberto Caporali c, Andrea Doria e, Loic Guillevin j,Pier Luigi Meroni d, Carlomaurizio Montecucco c, Marta Mosca b, Angela Tincani a,⁎a Spedali Civili,University of Brescia, Brescia, Italyb University of Pisa, Pisa, Italyc University of Pavia, IRCCS Policlinico S.Matteo, Pavia, Italyd University of Milano, Istituto Ortopedico Gaetano Pini, Milan, Italye University of Padova, Padova, Italyf Azienda Ospedaliera Universitaria Integrata, Verona, Italyg Ospedale San Carlo Borromeo, Milano, Italyh Clinica Ostetrica L.Mangiagalli, Fondazione IRCSS Cà Granda Ospedale Maggiore Policlinico, Milano, Italyi Ospedale Papa Giovanni XXIII, Bergamo, Italyj University Paris Descartes, National Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Hôpital Cochin, Paris, France
⁎ Corresponding author at: Rheumatology and Clinical0303995085.
E-mail address: [email protected] (A. Tincani).1 Drs. Fredi and Lazzaroni contributed equally to this w
http://dx.doi.org/10.1016/j.autrev.2015.03.0091568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Fredi M, et al, Syprospectively followed pregnancies, Autoim
a b s t r a c t
a r t i c l e i n f oArticle history:
Received 12 February 2015Accepted 31 March 2015Available online xxxxKeywords:PregnancySystemic vasculitis
Objective: Systemic vasculitis (SV) are uncommon diseases that rarely affect women during their reproductiveage; little data,mainly retrospective, is available on this topic. The aimof our studywas to evaluatematernal/neo-natal outcome and disease course before, during and after pregnancy.Methods: Sixty-five pregnancies in 50womenwith SVwere followed by amultispecialistic team in 8 institutionsbetween 1995 and 2014. Clinical data on pregnancy, 1 year before and 1 year after delivery was retrospectivelycollected. The rate of pregnancy complications was compared to that of a General Obstetric Population (GOP) of3939 women.
Results: In 2 patients the diagnosis of SV was done during pregnancy; 59 out of the remaining 63 started whenmaternal disease was quiescent. We recorded 56 deliveries with 59 live births, 8 miscarriages and 1 fetaldeath. In SV, preterm, particularly early preterm (b34 weeks) deliveries and cesarean sections appeared signifi-cantly more frequent than in GOP (11.3% vs 5.0%, p = 0.049 and 48.2% vs 31.0%, p = 0.009).Vasculitis-related complications occurred in 23 pregnancies (35.4%), with 5 severe events (7.7%) including 3cases of transient ischemic attack (TIA). Data about the post-partum period were available for 56 pregnancies:12 flares (21.4%) occurred, with 1 severe event (1.8%).Conclusion: SV patients can have successful pregnancies (especially during a disease remission phase) despite anincreased rate of preterm delivery. Severe flareswere limited, but the occurrence of 3 TIA suggests that particularattention should be given to possible thrombotic complications in SVpatients during pregnancy and puerperium.© 2015 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Immunology, Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, Italy. Tel.: +39 0303995487; fax: +39
ork.
stemic vasculitis and pregnancy: A multicenter study on maternal and neonatal outcome of 65mun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.009
2 M. Fredi et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.1. Pregnancy outcome and course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2. SV during pregnancy and after delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Financial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1. Introduction
Systemic vasculitis (SV) include a group of disease that share inflam-matory damage of the vesselwall. Theprocess involving blood vessels ofdifferent sizes can affect various organs or systems, generating variableclinical pictures. The severity can also vary frommild to life-threateningmanifestations and the course of disease can be self-limiting, relapsing-remitting or chronic.
Themost common classification is based upon the size of the vesselsinvolved and has been recently updated in the 2012 InternationalChapel Hill Consensus Conference on the Nomenclature of Vasculitides[1].
In the last decades, increasing knowledge in the diagnosis andmanagement of SV has led to reduction in mortality and morbidity ofthese patients; the consequent improvement in quality of life couldinclude for young women the possibility to carry out with success oneor more pregnancies. However, SV are a rare diseases and, unlike otherrheumatic diseases, do not preferentially affect women during their re-productive age (with the exception of Takayasu arteritis), so that preg-nancy in these patients is still an uncommon event. Consequently mostof the published data is derived from case reports with retrospective de-sign considered of limited significance [2–6]. A recent study included aconsiderable number of pregnancies, where data was collected througha self-administered anonymous internet-based survey [7].
Pregnancy in women with SV requires a constant and careful man-agement by both rheumatologists/internists and obstetricians, becauseof the pregnancy-related modifications (immunological, cardiovascularand thrombophilic) that can affect the course of the disease and of thecomplex relationship between the disease and the pregnancy outcome.In addition, the treatment assessment needs attention because of thefetotoxicity of many drugs employed in these serious medical condi-tions. On the other hand, the choice of drugs compatible with pregnan-cy, hopefully performed during a pre-conceptional counseling, needs toguarantee the maternal disease control.
The aim of the present study was to retrospectively evaluate a seriesof prospectively followed pregnancies inwomenwith SVwhose clinicaldata before, during and after pregnancies was accessible. Duringgestation all the patients attended a multispecialistic clinic withrheumatologists/internists and gynecologists in a tertiary referral hospi-tal where an experienced Neonatal Intensive Care Unit (NICU) wasavailable.
2. Patients and methods
2.1. Patients
Our study includes data of 65 pregnancies in 50 SVwomen regularlyattending one of the 8 participating centers between 1995 and 2014.Seven centers were in Italy (Spedali Civili of Brescia, Ospedale SantaChiara of Pisa, Policlinico San Matteo, Pavia, Ospedale Papa GiovanniXXIII, Bergamo, Azienda Ospedaliera of Padova, Istituto OrtopedicoGaetano Pini and Clinica Ostetrica L.Mangiagalli/Fondazione IRCSS CàGranda Ospedale Maggiore Policlinico, Milano, Policlinico G.B. Rossi,Verona) and one in France (Hôpital Cochin, Paris).
Clinical data prospectively recorded from these patients in each cen-ter were retrospectively reviewed using a common data collection
Please cite this article as: Fredi M, et al, Systemic vasculitis and pregnaprospectively followed pregnancies, Autoimmun Rev (2015), http://dx.do
sheet. Only patients with clinical and laboratory data available beforepregnancy (up to 1 year), during the 3 trimesters and the post-partumperiod (up to 1 year) were included.
Criteria of inclusion were the International Study Group Criteria forBehçet's disease [8] (BD) (25 patients with 31 pregnancies), the ACRcriteria for eosinophilic granulomatosis with polyangiitis [9] (EGPA)(9 patients with 11 pregnancies), Takayasu arteritis [10] (TAK)(6 patients with 8 pregnancies), granulomatosis with polyangiitis [11](GPA) (4 patients with 5 pregnancies), polyarteritis nodosa [12](PAN) (2 patients with 2 pregnancies) and IgA vasculitis [13](Henoch–Schönlein) (IgAV) (1 patient with 2 pregnancies); Cogan'soriginal criteria were used for Cogan Syndrome (CS) [14] (1 patientwith 1 pregnancy).We also included 2 pregnancies in 1 patientwith cu-taneous Polyarteritis Nodosa (c-PAN) and 3 in 1 patient with ANCA-associated neuropathy (AAN); these last 2 forms were defined accord-ing to the clinical features.
Clinical and laboratory features and therapymodificationswere con-sidered in order to divide flares of disease into 3 groups of severity:
- mild flares in case of new clinical manifestations that do not modifythe quality of life of the patient; these were detected by the clinicalexamination and treated with symptomatic drugs, without require-ment of major modifications of the treatment such as the increase ofcorticosteroids or immunosuppressive drugs;
- moderate flares if maternal conditions implied modifications intherapy, with necessity to introduce or increase corticosteroids(any dosage) and/or immunosuppressive drugs;
- severe flares in case of new symptoms or worsening of the clinicalconditions requiring hospitalization and/or causing organ damage.
The general obstetric population (GOP) was used as a control groupand included all the women (n = 3939) that delivered in a single year(2009) in oneparticipating center. In this control sample, itwas not pos-sible on the basis of deliveries alone, to calculate the number of startedpregnancies and therefore the prevalence of miscarriages and fetaldeaths was obtained from the literature [15].
This study was approved by the local Ethics Review Boards. All thesubjects gave their written consent to use the data for research.
2.2. Statistical analysis
Student's 2-tailed t-test for continuous variables and Chi-square orFisher's exact tests for categorical variables were used. A multivariateanalysis was conducted by a logistical regression model (Statview);p values less than 0.05 were considered significant. Odds Ratio (OR)and 95% Confidence Interval (CI 95%) were calculated.
3. Results
3.1. Pregnancy outcome and course
The 65 recorded pregnancies ended with the delivery of 59 new-borns, including 3 twin pregnancies. Spontaneous conception occurredin 61 cases, while 4 requiredmedically assisted procedures. Median dis-ease duration at conceptionwas76months (range 10–240months) andmaternal mean age was 31.4 years, not significantly different from GOP
ncy: A multicenter study on maternal and neonatal outcome of 65i.org/10.1016/j.autrev.2015.03.009
3M. Fredi et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
(30.9 years). Most patients (43, 86%) were Caucasians but 2 Afro–Americans, 2 Hispanics, and 3 Asians were included.
Table 1 shows the pregnancy outcomes compared to GOP. The globalrate of preterm deliveries (b37weeks of gestation)was 28.5% and earlypreterm delivery was 16.1%. Even excluding the 3 twin pregnancies,preterm delivery was significantly increased in SV patients comparedto GOP (24.5% vs 11.9%, p=0.010). In addition SV patients had a higherprevalence of early preterm delivery (defined as delivery before34weeks of gestation) than the GOP (11.3% vs 5.0%, p=0.049). Univar-iate and multivariate analysis showed no correlation of preterm deliv-ery with maternal age, race, disease duration, antiphospholipidantibodies positivity, corticosteroid use or folic acid uptake during preg-nancy, smoke, anamnestic preterm delivery, disease flare during preg-nancy and active disease at the conception. Corticosteroid use resultedmore frequent in patients who delivered preterm than in women whogave birth at term although not reaching statistical significance (69%vs 49%, p not significant). The 16 preterm deliveries (including twinpregnancies) were iatrogenic in 6 cases (37.5%), due to preterm prema-ture rupture of membranes (pPROM) in 5 (31.2%) and spontaneous(due to the onset of unstoppable contractions in the absence of the rup-ture of membranes) in 5 (31.2%).
Cesarean sections were significantly more frequent in patients thanin GOP (48.2% vs 31.0%, p = 0.009). Eleven of the cesarean sections(40.7%) were performed because of the concerns of clinicians about
Table 1Pregnancy outcomes.
SV total BD EGPA TAK
No. women 50 25 9 6Pregnancy total no. 65 31 11 8
Age at conception,mean ± SD yearsa
31.4 ± 4.8 31.7 ± 5.2 32.4 ± 2.7 31.7 ± 4.5
Live births, no. 56 (86.9) 28 (90.3) 10 (90.1) 6 (75)Miscarriage (b10 weeks), no. c 8 (12.3) 2 (6.4) 1 (9.9) 2 (25)Fetal deaths (N10 weeks), no. c 1 (1.5) 1 (3.2) 0 (0) 0 (0)Voluntary and therapeuticabortions, no.
0 (0) 0 (0) 0(0) 0 (0)
Deliveries total no. 56 28 10 6Twin pregnancies, no. 3 (5.3) 0 (0) 2 (20) 1 (16.6)
IUGR, no. 2 (3.6) 0 (0) 2 (20) 0 (0)Preterm premature rupture ofmembranes, no.b
3 (5.3) 0 (0) 1(10) 2 (33)
Preterm deliveries b37 weeks, no. b 16 (28.5) 6 (21.4) 2 (20) 3 (50)Preterm deliveries34–36.6 weeks, no.b
7 (12.5) 4 (14.3) 0 (0) 0 (0)
Preterm deliveries b34 weeks, no.b 9 (16.1) 2 (7.1) 2 (20) 3 (50)Gestational diabetes, no.d 7 (12.5) 6 (21.4) 0 (0) 1 (16.6)Gestational hypertension, no. 4 (7.1) 2 (7.1) 0 (0) 2 (33.3)Preeclampsia, no. 2 (3.6) 1 (3.5) 0 (0) 0 (0)Eclampsia, no. 0 (0) 0 (0) 0 (0) 0 (0)Cesarean section, no. 27 (48.2) 10 (35.7) 7 (70) 5 (83)
Newborn total no. 59 28 12 7VLBW, no. b 6 (10.2) 1 (3.5) 2 (16.6) 1(14.2)SGA, no.b 11 (18.6) 2 (5.3) 4 (33.3) 3 (4.3)
*Except where indicated otherwise, values are the number (%) based on the category. IUGR= iin the b5th percentile); Preterm premature rupture of membranes was defined as rupture ohypertension after 20 weeks of gestation, without proteinuria. Preeclampsia was defined as hdefined as generalized convulsion and/or coma in the setting of preeclampsia with no other nb10th percentile for gestational age. VLBW = very low birth weight, b1500 g at birth. NA =eosinophilic granulomatosis with polyangiitis; TAK = Takayasu arteritis; GPA = granulomatoSchönlein purpura; c-PAN= cutaneous-panarteritis nodosa; AAN = ANCA-associated neuropa
a p value was determined by Student's t-test (all others are by Chi-square test with Yates' cob For the items with this symbol, comparison with general obstetric population was done exc In this control population it was not possible, on the basis of deliveries alone, to calculate t
deaths was obtained from the literature [14].d In this control sample it was not possible, on the basis of deliveries alone, to calculate the n
from literature [22].e OR = 2.39;CI 95% = 1.21–4.67.f OR = 2.43; CI95% = 0.92–6.03.g OR = 2.07; CI95% = 1.18–3.62.
Please cite this article as: Fredi M, et al, Systemic vasculitis and pregnaprospectively followed pregnancies, Autoimmun Rev (2015), http://dx.do
maternal disease, although there was no real medical/obstetricalindication.
The 3 twin pregnancies (2 EGPA, 1 TAK) all resulted in early pretermdelivery with emergency cesarean sections before 32 weeks, in 2 casesdue to a pPROM and in the other case due to a severe flare of maternaldisease.
Eight newborns were admitted to NICU for the following reasons:respiratory distress syndrome (5 newborns), necrotizing enterocolitisthat required bowel resection (1 newborn), premature birth before32 weeks of gestation (1 newborn) and low birth weight (1 newborn);5 of them were born prematurely (2 from a twin pregnancy).
Infants that are small for gestational age (SGA) and very low birthweight (VLBW) were more frequent in patients group than in GOP(18.6% vs 9.7% and 10.2% vs 1.1% respectively), but excluding the twinnewborns the differences were not statistically significant. Onenewborn had a congenital malformation with hip dysplasia andcryptorchidism.
In our population 7 patients (1 TAK, 3 BD, 1 EGPA, 1HSS and 1ANCA-associated neuropathy) had 8 miscarriages (12.3%) and 1 fetal death(1.5%); none of these patients was positive for antiphospholipid anti-bodies. No voluntary or therapeutic abortions were observed.
Four pregnancies were induced through medically assistedprocedures: 2 by oocyte donation, 1 by in vitro fertilization and 1 by in-trauterine insemination. Two cases of infertilitywere independent from
GPA PAN CS IgAV c-PAN AAN GOP p value,SVvsGOP
4 2 1 1 1 1 NA5 2 1 2 2 3 NA25.6 ± 5.8 29 ± 1.4 33 ± 0 30 ± 0 33 ± 0 34 ± 0 30.9 ± 4.3 NAa
5 (100) 2 (100) 1 (100) 0 (0) 2 (100) 2 (66) NA NA0 (0) 0 (0) 0 (0) 2 (100) 0 (0) 1(33) (8.1–9.5) NAc
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) (5) NAc
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) NA NA
5 2 1 0 2 2 39390 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 128 (3.2) NS0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 58 (1.5) NS0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 126 (3.2) NSb
2 (40) 2 (100) 0 (0) 0 (0) 0 (0) 1 (50) 470 (11.9) 0.010b,e
2 (40) 0 (0) 0 (0) 0 (0) 0 (0) 1 (50) 274 (7.0) NSb
0 (0) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 196 (5.0) 0.049 b,f
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) (6–7) NA0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 123 (3.1) NS0 (0) 1 (50) 0 (0) 0 (0) 0 (0) 0 (0) 43 (1.1) NS0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) NS2 (40) 1(50) 1(100) 0 (0) 0 (0) 1(50) 1222 (31.0) 0.009g
5 2 1 0 2 2 40730 (0) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 43 (1.1) NSb
0 (0) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 394 (9.7) NSb
ntrauterine growth restriction (assessed by ultrasound as a fetal abdominal circumferencef the membranes before 37 weeks of gestation. Gestational hypertension was defined asypertension after 20 weeks of gestation, with proteinuria b300 mg/24 h. Eclampsia waseurologic condition. SGA = small for gestational age was defined as a birth weight in thenot available or not assessable; NS = not significant. BD = Behçet's disease; EGPA =
sis with polyangiitis; PAN = panarteritis nodosa; CS = Cogan disease; IgAV = Henoch–thy; GOP = general obstetric population; SV = Systemic vasculitis.rrection).cluding multiple pregnancies (three pregnancies, six newborns).he number of started pregnancies and therefore the prevalence of miscarriages and fetal
umber of gestational diabetes, therefore the prevalence of this complication was obtained
ncy: A multicenter study on maternal and neonatal outcome of 65i.org/10.1016/j.autrev.2015.03.009
Table 3Disease flares during the year after delivery.
Type ofvasculitis
Pregnancies withflare, no. (%)
Number ofpregnancies
Severity
Mild Moderate Severe
BD 8 (30.8) 26 2a 5b 1c
EGPA 2 (20.0) 10 0 2d 0GPA 1 (20.0) 5 0 1e 0IgAV 1 (50.0) 2 1f 0 0
3 8 1
*Except where indicated otherwise, values are the number (%) based on the category.a Oral and/or genital aphtosis (2).b Arthritis (2), erythema nodosum(1),worsening of vision loss (1), arthritis and signs of
possibile neuro-Behçet at RMN (1).c Neuro-Behçet with neurological symptoms (1).d Worsening of the upper airways involvement(2).e Worsening of the renal function (1).f Purpura (1).
4 M. Fredi et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
maternal disease, while one was due to a primary ovarian failure afterhigh cyclophosphamide dose (more than 50 g in a patient with GPA)and the other one was related to the age of a TAK patient who reacheda sustained remission only when 40 years old. An EGPA patient devel-oped ovarian hyperstimulation syndrome after in vitro fertilizationwith embryo transfer. These 4 pregnancies (3 singleton, 1 twin) endedin 5 live births, including 3 premature babies delivered at 30 (twin)and 35 weeks respectively. Only 1 out of the 7 patients treated withcyclophosphamide before conception suffered from primary ovarianfailure: the 6 unaffected patients were exposed to relatively low cumu-lative drug dose (range 5–18 g).
We observed 7 cases of gestational diabetes (12.5%), 4 out of thesewere taking corticosteroids during pregnancy (mean dosage 60 mgprednisone weekly, range 35–100 mg).
Corticosteroids during gestation were used in 32 pregnancies(49.2%), cyclosporine in 9 (13.8%), azathioprine in 4 (6.2%), cyclosporineand azathioprine in 1 pregnancy (1.5%) and hydroxychloroquine in1 pregnancy (1.5%). In 22 pregnancies (33.8%) low-dose aspirin (LDA)was administered: in 4 cases because of previous arterial or venousthrombosis and in 18 cases for primary prophylaxis of vascular eventsand for fetal protection. Low-molecularweight heparin always associat-ed with LDAwas used in 6 cases (9.2%) consisting in 4 BDwith previousvenous thrombosis and 2 TAK affected by severe carotid stenosis. Finally33 pregnancies (50.8%) were treated with folic acid during all the3 trimesters.
3.2. SV during pregnancy and after delivery
In the months before conception SV was quiescent or stable in themajority of the cases (93.8%); 4 pregnancies in 3 patients (1 GPA with2 pregnancies, 1 PAN and 1 BD) started while the disease was not incomplete remission.
Flares of SV were reported in 23 pregnancies (35.4%) during the 3trimesters; they are shown in Table 2 divided for disease and for sever-ity. Considering severity, we observed 10 mild (15.4%), 8 moderate(12.3%) and 5 severe events (7.7%). The severe ones occurred inwomen with BD (3 cases), TAK (1 case), EGPA (1 case). The clinicalmanifestations included 3 cases of transient ischemic attack (TIA)(2 BD, 1 TAK, identified as recurrence in 2 patients), an optic neuritisin a BD and a cardiac failure in an EGPA (recurrences in both cases).
We also reported 2 cases of onset of SV during pregnancy: 1 BDwithoral ulcers, erythema nodosum and thrombophlebitis during the firsttrimester and 1 PAN with cardiac failure, abdominal microaneurismsand arterial hypertension during the second trimester. The first
Table 2Disease flares during pregnancy.
Type ofvasculitis
Pregnancies withflare, no.
Number ofpregnancies
Severity
Mild Moderate Severe
BD 14 (45.2) 31 8a 3b 3c
EGPA 4 (36.4) 11 1d 2e 1f
TAK 2 (25.0) 8 0 1g 1h
GPA 2 (40.0) 5 1i 1j 0PAN 1 (50.0) 2 0 1k 0
10 8 5
*Except where indicated otherwise, values are the number (%) based on the category.a Oral and/or genital aphtosis (8).b Erythema nodosum (2), episcleritis (1).c TIA (2), optic neuritis (1).d Mild worsening of asthma (1).e Worsening of asthma and urticarial rash (1), pulmonary infiltrates (1).f Heart failure (1).g Claudicatio abdominis and chest pain (1).h TIA (1).i Nasal inflammation (1).j Nasal inflammation and tracheal stenosis (1).k Worsening of arterial hypertension (1).
Please cite this article as: Fredi M, et al, Systemic vasculitis and pregnaprospectively followed pregnancies, Autoimmun Rev (2015), http://dx.do
pregnancy required a cesarean section (38 weeks) for placental abrup-tion with admission of the newborn to NICU, while the second one re-quired a severe preterm delivery (32 weeks).
Maternal disease flares occurred in all the 4 pregnancies that startedwhile the disease was still active. These flares included 1mild (nasal in-flammation in 1 GPA), 2 moderate (worsening of arterial hypertensionin 1 PAN, asthma and tracheal stenosis in 1 GPA) and 1 severe (a TIAin 1 BD).
Data about the post-partum period (up to 12 months) were avail-able for 46womenwith 56 pregnancies, 9were lost at follow-up or con-ceived again in the first year after the previous pregnancy. Twelve flares(21.4%) occurred in the post-partum, but only one of them was classi-fied as severe as detailed in Table 3.
In consideration of the wide temporal period of the study, we com-pared the 25 pregnancies occurred before 2005 with the 40 ones oc-curred after that year. We found no statistical significant differences inthe incidence of obstetric complications (including preterm deliveryand cesarean section) or in the rate of disease flares.
4. Discussion
Our study suggests that SV patients can have successful pregnancies,although obstetrical and maternal risks have to be considered.
We reported 65 pregnancies with a rate of abortions and fetal deathsimilar to what was described in general population [15]; none of thepatients had a positivity for antiphospholipid antibodies, an establishedrisk factor for pregnancy morbidity [16]. In our cohort 3 twin pregnan-cies occurred, with a rate comparable to that observed in our GOP; allendedwith a severe pretermdelivery (between 30 and 32weeks of ges-tation) but this is not surprising since a rate of more than 50% pretermdeliveries is currently reported in multiple pregnancies [17]. Moreover,1 out of the 3 was induced by in vitro fertilization, that could be an ad-ditional risk for preterm birth [18].
We observed an increased risk of pretermdelivery of singleton preg-nancies and in particular early preterm delivery (before 34 weeks ofgestation). Preterm birth is the first cause of neonatal mortality andlong-term neurological impairments in children [19]; in our cohort, 5out of 19 preterm babies had early-onset complications that requiredadmission in NICU; none of these babies died. We did not identify riskfactors significantly associatedwith preterm birth: in particular, the fre-quency of corticosteroids was not significantly higher among patientsthat had a preterm delivery as expected [20,21] and folic acid resultednot protective, in contrast with what recently had been reported [22].We collected only onenon-major congenitalmalformation,with a prev-alence of 1.53%, comparable with that described in general population[23].
The rate of cesarean sections in our population was of nearly 50%,significantly higher than that of the local GOP (48.2% vs 31.0%).
ncy: A multicenter study on maternal and neonatal outcome of 65i.org/10.1016/j.autrev.2015.03.009
5M. Fredi et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
According to a recent report (European perinatal Health) [24], Italy isoneof the European countrieswith the highest rate of cesarean sections,reaching 38% on national scale. Even compared to this data, our cohortshowed a higher rate.
We observed that nearly 40% of cesareans were performed becauseof the clinicians' worries about SV related risks. No real medical or ob-stetrical indications were given, other than it was considered a saferway to deliver. The indication for a cesarean section in these patientsshould instead be very cautious, considering the increased risk of deepvenous thrombosis that is associated with this modality of delivery[25,26].
Gestational diabetes mellitus occurred in 7 patients (12.5%), a ratesimilar to what has been reported in healthy pregnant women [27].Five out of our patients conceived before the beginning of a systematicscreening for gestational diabetes in pregnant women in Italy. Even ex-cluding these pregnancies, the rate remained stable (14%). Chronic cor-ticosteroids assumption can be an additional risk in developinggestational diabetes [20]; in our cohort 4 out of 7 patientswith this com-plication were assuming medium dosage of corticosteroid (60 mgweekly). No patients required insulin injections and no large for gesta-tional age babies were delivered.
Assisted reproductive technology methods were used to achievepregnancy in 4 cases (6%), in 1 case due to high dose cyclophosphamide.Ovarian protection, with the use of a gonadotropin-releasing hormoneagonist, has to be considered for all patients treated with cyclophospha-mide and today, alternative treatments can be offered. In fact, the diseaseonset of these patients goes back to the early 90s, when the access toeffective (but non-toxic) drugs for remission and maintenance waslimited. Notably, primary ovarian failure was reported only in 1 out ofthe 7 women who previously received cyclophosphamide, possibly be-cause of the lower cumulative dose received by the6 unaffected patients.
Patients should be also informed about the possible complicationslinked tomedically assisted procedures that can increase the difficultiesof pregnancies that per se are at higher risk. In fact, half of these preg-nancies ended preterm and 1 woman experienced an ovarian hyper-stimulation syndrome, that is associated to an increased risk ofvascular complications even in healthy women.
Inmore than 60% of the pregnanciesmaternal disease remained qui-escent; in particular no case of maternal death was recorded.
However, 5 patients developed a severe worsening of their condi-tion, including 3 TIA in 1 patient with TAK and in 2 with BD; no associ-ated thrombophilic factors were observed, but 2 of thesewomen had ananamnestic history of multiple TIA (BD patients).
We observed only arterial events,while the literature reportsmainlyvenous thrombosis [2]. Importantly all the events occurred despite theassumption of anti-platelet therapy (LDA). Vasculitis are characterizedper se by an increased risk of thromboembolic events [28], which be-comes higher during pregnancy and puerperium that are well-knownthrombophilic conditions even in normal women. Following this obser-vation, a more effective prophylactic treatment would be advisable inthese patients, particularly if anamnestic episodes were reported.
The limited data available about small vessel vasculitis (EGPA, GPA,MPA) and PAN pregnancy outcomes show a high rate of obstetric com-plications and maternal disease flares [2]. Data about the 16 patientswith EGPA and GPA in our series are similar to those formerly reported,in particular all GPA patientswith active disease at the conception expe-rienced a relapse.
We observed an onset of PAN during pregnancy with cardiovascularand intestinal involvement. This patient delivered prematurely, but al-though the occurring of life-threatening complications, she was treatedand survived. To our knowledge this is one of the few cases of survival inpatients with an onset of PAN during pregnancy [2,29].
We also collected 1 pregnancy in a patient with CS, which representthe fourth case reported up to now [2]. This patient was in remission atpregnancy onset, she was treated with low dose of corticosteroids, cy-closporine plus azathioprine and LDA; the pregnancy was uneventful.
Please cite this article as: Fredi M, et al, Systemic vasculitis and pregnaprospectively followed pregnancies, Autoimmun Rev (2015), http://dx.do
Disease complications rate in our series of TAK was much higherthan that reported in literature (25% vs b5%) [2,30], but our results areof limited power because of the small number of TAK pregnancies col-lected in this study.
Behçet's diseasewas themost represented vasculitis in our population(31 pregnancies, 48%), with also a disease onset during pregnancy. Previ-ous case series of pregnancies in womenwith BD showed generally goodoutcomes [2,3], with a low prevalence of maternal and neonatal compli-cations. We observed gestational diabetes (6 cases, 86% of all gestationaldiabetes in our cohort), hypertension (2, 7.1%) and preeclampsia(1, 3.5%). In additiondiseaseflareswere observed in 45.2% of BDpregnan-cies, a rate higher than that recently reported (30% [2] and 35.5% [3]), butsevere events occurred only in 3 pregnancies (2 TIA, 1 optic neuritis).
We also focused our attention on the puerperium. The diseasecourse during this period has already been studied in other systemic au-toimmune diseases, such as rheumatoid arthritis, systemic lupus ery-thematosus or systemic sclerosis [31–34,22], but is not well defined inSV. Post-partum period is characterized by several hormonal changes.These mainly consist in high estrogens and prolactin levels that can beresponsible for immune system activation [35].
In our study 12 patients out of 56 (21.4%) experienced a flare duringthe first year after pregnancy, but a comparison with previous dataseems difficult because of very few observations of this period in SV re-ported [2,3]. However, we found a rate of reactivations lower than thatobserved during pregnancy (35.4%). In this respect, it has to be consid-ered that after a delivery the treatment can be modified allowing theuse of higher dosage of corticosteroids or immunosuppressive drugscontraindicated before and during pregnancy. In fact, in 8 out of44 patients without any post-partum flare, the treatment was signifi-cantly enhanced: in 4 cases corticosteroids dosage was increased andin the other 4 new immunosuppressive therapy was added. This couldhave had an important role on the better control of maternal diseasein the period after delivery.
Our study has several limitations. We included patients with differ-ent types of vasculitis but BD represented nearly half of pregnanciesand this could have influenced our results. However, the other vasculitisare evenmore rare andmay have a later onset, therefore a pregnancy inthese patients is very unusual. The studymay have been limited also bythe retrospective evaluation of data that on the other hand,were obtain-ed from prospectively collected clinical charts. Other limitations derivefrom the wide temporal range of the pregnancies and the multicentricnature of this study that implies possible heterogeneity in the data.However, only in the frame of a long multicenter observation it's possi-ble to obtain a number of data that allows defining at least some generalconsiderations on pregnancies in SV.
In fact, our study established some conclusions that can guide thephysician's counseling of these patients.
In the counseling of a young woman affected by SV, we need to in-quire about her family planning and her desire to be a mother, inorder to get the best chance for the pregnancy as soon as the treatmentand the disease activity allow it. The treatment with gonadotoxic drugsmust be limited and eventually ovarian protection has to be considered.According to our results, in the largemajority of the cases the pregnancyis successful, with a moderate risk of preterm delivery. Disease flaresduring and after pregnancy are possible but in few cases seem to be se-vere; persistent disease activity at time of conception can predict theworsening of maternal condition. In addition, during the pre-pregnancy counseling, physicians need to carefully consider thromboticrisk factors such as previous events or the presence of genetic/acquiredthrombophilia, suggesting the possible need of prophylactic antithrom-botic treatment in pregnancy and puerperium.
Financial support
None.No conflicts of interest to declare.
ncy: A multicenter study on maternal and neonatal outcome of 65i.org/10.1016/j.autrev.2015.03.009
6 M. Fredi et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
Take-home messages
• SV patients can have successful pregnancies despite an increased rateof preterm delivery.
• Severe disease flares are rare, but can occur, especially as recurrences.• Family planning has to be discussed in young patients affected by SV.
References
[1] Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 Revised Interna-tional Chapel Hill Consensus Conference nomenclature of vasculitides. ArthritisRheum 2013;65:1–11.
[2] Gatto M, Iaccarino L, Canova M, Zen M, Nalotto L, Ramonda R, et al. Pregnancy andvasculitis: a systematic review of the literature. Autoimmun Rev 2012;11(6):A447–59.
[3] Noel N, Wechsler B, Nizard J, Costedoat-Chalumeau N, Boutin DLTH, DommerguesM, et al. Behçet's disease and pregnancy. Arthritis Rheum 2013;65(9):2450–6.
[4] Tuin J, Sanders JSF, de Joode AAE, Stegeman CA. Pregnancy in women diagnosedwith antineutrophil cytoplasmic antibody-associated vasculitis: outcome for themother and the child. Arthritis Care Res 2012;64:539–45.
[5] Iskender C, Yasar O, Kaymak O, Yaman ST, Uygur D, Danisman N. Behçet's diseaseand pregnancy: a retrospective analysis of course of disease and pregnancy out-come. J Obstet Gynaecol Res 2014;40:1598–602.
[6] Østensen M, Andreoli L, Brucato A, Cetin I, Chambers C, Clowse M, et al. State of theart: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev 2015;14:376–86.
[7] Clowse ME, Richeson RL, Pieper C, Merkel PA. Pregnancy outcomes among patientswith vasculitis. Arthritis Care Res 2013;65(8):1370–4.
[8] The international study group for Behçet disease. Criteria for diagnosis of Behçet dis-ease. Lancet 1990:1078–80.
[9] Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990criteria for the classification of Churg–Strauss syndrome (allergic granulomatosisand angiitis). Arthritis Rheum 1990;33(8):1094–100.
[10] Arend WA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33(8):1129–34.
[11] Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33(8):1101–7.
[12] Lightfoot RW, Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al. TheAmerican College of Rheumatology 1990 criteria for the classification of polyarteritisnodosa. Arthritis Rheum 1990;33(8):1088–93.
[13] Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990criteria for the classification of Henoch–Schönlein purpura. Arthritis Rheum 1990;33(8):1114–21.
[14] Cogan D. Syndrome of nonsyphilitis interstitial keratitis and vestibuloauditorysymptoms. Arch Ophtalmol 1945;33:144–9.
[15] Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age andfetal loss: population based register linkage study. BMJ 2000;320(7251):1708–12.
Please cite this article as: Fredi M, et al, Systemic vasculitis and pregnaprospectively followed pregnancies, Autoimmun Rev (2015), http://dx.do
[16] de Jesus GR, Agmon-Levin N, Andrade CA, Andreoli L, Chighizola CB, Porter TF, et al.14th International Congress on Antiphospholipid Antibodies Task Force report onobstetric antiphospholipid syndrome. Autoimmun Rev Aug 2014;13(8):795–813.
[17] Stock S, Norman J. Preterm and term labour in multiple pregnancies. Semin FetalNeonatal Med 2010;15(6):336–41.
[18] McDonald S, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of in vitro fertiliza-tion twins: a systematic review and meta-analyses. Am J Obstet Gynecol 2005;193(1):141–52.
[19] Bogges KA. Pathophysiology of preterm birth: emerging concepts of maternal infec-tion. Clin Perinatol 2005;32:561–9.
[20] Østensen M, Förger F. How safe are anti-rheumatic drugs during pregnancy? CurrOpin Pharmacol 2013;13(3):470–5.
[21] de Steenwinkel FD, Hokken-Koelega AC, Hazes JM, Dolhain RJ. The influence of foetalprednisone exposure on the cortisol levels in the offspring. Clin Endocrinol 2014;80(6):804–10.
[22] Taraborelli M, Ramoni V, Brucato A, Airò P, Bajocchi G, Bellisai F, et al. Brief report:successful pregnancies but a higher risk of preterm births in patients with systemicsclerosis: an Italian multicenter study. Arthritis Rheum 2012;64(6):1970–7.
[23] Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. RareDiseases Epidemiology. Netherlands: Springer; 2010 349–64.
[24] European Perinatal Health Report. Health and care of pregnantwomen and babies inEurope in 2010. http://www.europeristat.com/reports/european-perinatal-health-report-2010.html.
[25] Greer Ian A. Thrombosis in pregnancy: updates in diagnosis and management. ASHeducation program book 2012.1; 2012. p. 203–7.
[26] Sultan AA, Tata LJ, West J, Fiaschi L, Fleming KM, Nelson-Piercy, et al. Risk factors forfirst venous thromboembolism around pregnancy: a population-based cohort studyfrom the United Kingdom. Blood 2013;121(19):3953–61.
[27] Sacks DA, Hadden DR, Maresh M, Deerochanawong C, Dyer AR, Metzger BE, et al.Frequency of gestational diabetes mellitus at collaborating centers based onIADPSG consensus panel–recommended criteria the hyperglycemia and adversepregnancy outcome (HAPO) study. Diabetes Care 2012;35(3):526–8.
[28] Tomasson G, Monach PA, Merkel PA. Thromboembolic disease in vasculitis. CurrOpin Rheumatol 2009;21(1):41.
[29] Pagnoux C, Le Guern V, Goffinet F, Diot E, Limal N, Pannier E, et al. Pregnancies insystemic necrotizing vasculitides: report on 12 women and their 20 pregnancies.Rheumatology 2011;50(5):953–61.
[30] Pagnoux C, Mahendira D, Laskin CA. Fertility and pregnancy in vasculitis. Best PractRes Clin Rheumatol 2013;27(1):79–94.
[31] Barrett JH, Brennan P, Fiddler M, Silman A. Breast‐feeding and post-partum relapsein women with rheumatoid and inflammatory arthritis. Arthritis Rheum 2000;43(5):1010–5.
[32] Doria A, Tincani A, Lockshin M. Challenges of lupus pregnancies. Rheumatology2008;47(Suppl. 3):iii9–iii12.
[33] Alijotas-Reig J, Ferrer-Oliveras R, Ruffatti A, Tincani A, Lefkou E, BerteroMT, et al. TheEuropean registry on obstetric antiphospholipid syndrome (EUROAPS): a survey of247 consecutive cases. Autoimmun Rev May 2015;14(5):387–95.
[34] Efe C, Kahramanoğlu-Aksoy E, Yilmaz B, Ozseker B, Takci S, Roach EC, et al. Pregnan-cy in women with primary biliary cirrhosis. Autoimmun Rev Sep 2014;13(9):931–5.
[35] Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. AutoimmunRev 2007;6(8):537–42.
ncy: A multicenter study on maternal and neonatal outcome of 65i.org/10.1016/j.autrev.2015.03.009
