General obstetrics. Introduction

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1 DOI: /j x General obstetrics Prevalence of undiagnosed autoimmune rheumatic diseases in the first trimester of pregnancy. Results of a two-steps strategy using a self-administered questionnaire and autoantibody testing A Spinillo, a F Beneventi, a OM Epis, b L Montanari, a D Mammoliti, a V Ramoni, a E Di Silverio, a C Alpini, c R Caporali, b C Montecucco b a Department of Obstetrics and Gynecology b Department of Rheumatology and c Department of Laboratory Medicine, IRCCS Fondazione Policlinico San Matteo, University of Pavia, Pavia, Italy Correspondence: Dr A Spinillo, Department of Obstetrics and Gynecology, IRCCS Fondazione Policlinico San Matteo, University of Pavia, Piazzale Golgi, 19, Pavia, Italy. spinillo@smatteo.pv.it Accepted 26 August Published OnlineEarly 26 October Objective To evaluate the prevalence of undiagnosed rheumatic diseases in the first trimester of pregnancy. Design We screened for rheumatic diseases in 1210 consecutive pregnant women during the first trimester of pregnancy using a 10-item questionnaire. Setting A university hospital in northern Italy. Population One hundred and thirty-seven (11.3%) women who answered positively to at least one question constituted the cases and were compared with 107 negative controls. Methods Cases and controls were tested for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibody, anti-b2- glycoprotein I antibodies and lupus anticoagulant) and were evaluated by a rheumatologist for a definite diagnosis of rheumatic disease. Main outcome measures Prevalence of undiagnosed rheumatic disease in the first trimester of pregnancy. Results The overall rate of positivity to the antibodies tested was 43.1% (59/137) among cases and 9.3% (10/107) in the controls (P < 0.001). A definitive diagnosis of rheumatic disease was made in 35 cases (25.5%) and in none of the controls (P <0.001). In stepwise logistic regression analysis, photosensitivity (adjusted OR 5.72; 95% CI ), erythema or malar rash (adjusted OR 3.91; 95% CI ) and history of two or more miscarriages (adjusted OR 5.6; 95% CI ) were independent predictors of a definitive diagnosis of rheumatic disease (area under receiving operator curve = 0.814; 95% CI ). Birthweight was lower (3180 g ± 475 compared with 3340 g ± 452, P = 0.008), and overall serious pregnancy complications (miscarriage, fetal growth restriction, delivery before 34 weeks of pregnancy and severe preeclampsia) were higher among cases (12/137) than controls (2/107) (adjusted OR 5.60; 95% CI ; P = 0.021). Conclusions A two-step screening process with a self-administered questionnaire proved to be a useful method to screen for undiagnosed rheumatic diseases during the first trimester of pregnancy. Keywords Autoimmune rheumatic disease, fetal growth restriction, screening. Please cite this paper as: Spinillo A, Beneventi F, Epis O, Montanari L, Mammoliti D, Ramoni V, Di Silverio E, Alpini C, Caporali R, Montecucco C. Prevalence of undiagnosed autoimmune rheumatic diseases in the first trimester of pregnancy. Results of a two-steps strategy using a self-administered questionnaire and autoantibody testing. BJOG 2008;115: Introduction Autoimmune rheumatic diseases or connective tissue diseases are a heterogeneous group of chronic disorders of undetermined aetiology characterised by inflammation of various tissues, production of non-organ-specific autoantibodies and clinical manifestations including nephritis, neurological disorders, thrombosis and arthritis. Signs and symptoms are not disease-specific and some may be mild and, therefore, misdiagnosed. 1 ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 51

2 Spinillo et al. Autoimmune rheumatic diseases affect predominantly women during childbearing age and can have significant negative effects on both maternal and neonatal outcomes. 2 5 Rheumatic diseases often relapse during the second and third trimesters of pregnancy and within 3 months after delivery. In addition, compared with controls, pregnant women with autoimmune rheumatic diseases have increased risks of fetal loss, stillbirth, preterm delivery, pre-eclampsia, intrauterine growth restriction, low birthweight and development of neonatal lupus. 1,4,5 Identification of autoimmune rheumatic diseases early during pregnancy could be important both for enabling close monitoring of the potential complications associated with these diseases and for establishing effective preventive and therapeutic strategies. The aim of the study was to develop a self-administered questionnaire, regarding only the most common clinical manifestations of rheumatic diseases (ten items) and to identify potential cases of autoimmune rheumatic diseases in a population of pregnant women. Methods Subjects for the study were recruited from among pregnant women attending the ultrasonography clinic of our Department for their first-trimester ultrasound scan. We enrolled all women attending the clinic each Friday during a 2-year period (May 2004 to April 2006). The study was approved by the local Institutional Review Board of our Department; women with known autoimmune rheumatic disease were excluded from the study. Prior to the medical evaluation, each woman was asked to complete the screening questionnaire, which was developed using the most common symptoms of connective tissue diseases according to commonly used classification criteria for systemic lupus erythematosus (SLE), 6,7 rheumatoid arthritis, 8,9 primary Sjögren s syndrome, 10 systemic sclerosis, 11 polymyositis/dermatomyositis, 12 mixed connective tissue diseases, 13 primary antiphospholipid syndrome, 14 necrotising small vessel vasculitis, 15 undifferentiated connective tissue disease (UCTD) and overlapping syndrome. 16 The screening questionnaire included ten items phrased in readily understandable language concerning the presence or absence of the different symptoms. The questionnaire takes between 5 to 7 minutes to complete (Table 1). The study was planned with a case control design. Women who answered positively to one or more of the questions constituted the cases. They were tested for the presence of autoantibodies including antinuclear antibody (ANA), antidouble-stranded DNA (dsdna), anti-extractable nuclear antigen (ENA), anticardiolipin antibody (acl), anti-b2- glycoprotein I antibodies (ab2gpi) and lupus anticoagulant (LA) according to standardised methods, as previously described. 17 Table 1. Items of the questionnaire: women were asked to answer yes or no to all the questions 1 Have you ever had generalised or localised reddening of your skin after exposure to sunlight? 2 Have you ever had an obvious or prominent rash on your cheeks or nose? 3 Do your hands or feet become white in the cold and then blue or pink? 4 (a) Have you ever had painful and swollen joints? (b) Do you suffer from stiffness lasting one hour or more in the morning? 5 Have you ever had pericarditis or pleuritis? 6 Do you have a dry mouth? 7 Do you feel like you have sand in your eyes? 8 Have you ever had painful white mouth ulcers? 9 Have you ever had thrombophlebitis? 10 Have you had two or more miscarriages or stillbirths? ANAs were tested by a standard indirect immunofluorescence technique using a BX 51 Olympus fluorescence microscope at 40 magnification. Serum was first diluted 1:80 in phosphate-buffered saline (PBS) and overlaid onto fixed Hep-2 cell slides (Immuno Concept, Sacramento, CA, USA) in a moist chamber for 30 minutes at room temperature. Slides were then rinsed and washed twice in PBS for 10 minutes. A fluorescein-labelled antibody specifically directed towards human immunoglobulin G (IgG) (g chains) (Delta Biologicals, Pomezia, Italy) was used as the fluorescent conjugate. The positive samples (titre 1:80) were then evaluated at increasing dilutions in PBS up to 1:640. Anti-dsDNA antibodies were determined by both indirect immunofluorescence and a quantitative enzyme-linked immunosorbent assay (ELISA). The immunofluorescence assay was performed at 1:10 serum dilution in PBS using Crithidia luciliae as the substrate (INOVA, San Diego, CA, USA) and fluorescein-labelled antihuman IgG (g-chain specific) as the fluorescent conjugate. ELISA was performed using a commercially available kit (Axis-Shield, Dundee, UK) according to the manufacturer s recommendations. Alkaline phosphatase-labelled murine monoclonal antibodies to both human IgG and IgM (heavy and light chains) were used. The absorbance was read at 550 nm. Serum samples were evaluated in triplicate, and the median value was considered. The upper limit of normal, according to the specifications of the manufacturer, was 30 UI/ml. ENA antibodies were evaluated in triplicate by commercially available ELISA kits according to the manufacture s recommendations. The following single ENA specificities wereinvestigated:sm,rnp,ssa(ro),ssb(la),scl-70andjo1. Commercially available ELISA kits (Orgentec Diagnostika, Mainz, Germany) were used to detect acl (IgG and IgM) and ab2gpi (IgG and IgM) by means of a peroxidase-conjugated 52 ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology

3 Rheumatic diseases in the first trimester of pregnancy solution of either polyclonal rabbit antihuman IgG (heavy and light chains) or polyclonal rabbit antihuman IgM (heavy and light chains) according to the manufacturer s instructions. The absorbance was read at 450 nm. Serum samples were evaluated in triplicate; the upper limits of normal were 10 U/ml for IgG acl, 7 U/ml for IgM acl and 8 U/ml for both ab2gpi IgG and IgM. LA was assayed by activated partial thromboplastin time, diluted Russell s viper venom time and kaolin clotting time according to recently published guidelines. 14 The group of controls was recruited from among women who answered negatively to the questionnaire. To ensure random sampling, the first five consecutive women with negative responses to all the items in the questionnaire each month were tested for autoantibodies and served as controls. Cases and controls were referred to the Rheumatology Unit of our hospital for further clinical assessment including a careful history and a physical examination. Statistical analyses were carried out with the Mann Whitney U test and chi-square analysis to compare continuous and categorical variables. Univariate odds ratios and exact 95% CIs were used to evaluate the association between categorical variables and outcomes. To identify independent predictors of the outcome studied, we used stepwise logistic regression analysis. The items contained in the questionnaire were categorised as binary variables (yes, no) and introduced as explanatory terms in the logistic models studied together with potential confounders. Logistic regression was also used to test for trend across ordered categories, while adjusting for potential confounders. In all the analyses, a P value of 0.05 was considered statistically significant. The statistical analyses were carried out with SPSS 13.0 (SPSS Inc., Chicago, IL, USA). Since this was not a randomised study, we did not compute a preliminary sample size. However, given a 10% prevalence of positivity to the autoantibodies tested among controls, a sample size of 100 cases and 100 controls permits to detect an odds ratio of 4 or more with a power of 94.9%, at the values of a =0.05andb = 0.1. Results During the 2 years of the study, 55 women (4.3%) out of the 1265 enrolled did not complete the questionnaire and were excluded from the analysis. The mean maternal age was 32.4 years (±4.6 SD), and the gestational age at enrolment was 11.3 weeks (±1.2 SD). One hundred and thirty-seven women (11.3%) answered positively to at least one item of the questionnaire and constituted the cases. The mean age among cases was 32.9 years (±4.2 SD) and 50 (36.5%) of these women reported one or more previous term pregnancy. The frequency of the different items of the questionnaire among cases are shown in Table 2. Photosensitivity, erythema and Raynaud s phenomenon were the most frequent symptoms reported. Thirteen (10.8%) out of the 120 women recruited as controls refused autoantibodies testing and/or Table 2. Rates of symptoms among 137 women who gave at least one positive answer to the items in the questionnaire Photosensitivity 39 (28.5%) Erythema and/or malar rash 25 (18.2%) Raynaud s phenomenon 25 (18.2%) Painful and swollen joints 6 (4.4%) Serositis 1 (0.7%) Dry mouth 11 (8.0%) Dry eyes 8 (5.8%) Painful mouth ulcers 5 (3.6%) Thrombophlebitis 2 (1.4%) Pregnancy loss (2) 9 (6.6%) rheumatologic examination and were excluded from the study. The mean age of controls was 31.8 years (±4.3 SD) (P = compared with the cases), and 49 women (45.8%) reported one or more previous pregnancy (P = 0.18 compared with the cases). Maternal age and history of a previous term pregnancy were inserted as confounding factors in all the subsequent multivariable analyses. The overall rate of positivity to the antibodies tested was 43.1% (59/137) among cases and 9.3% (10/107) among the controls (adjusted OR 10.4; 95% CI ; P < 0.001). The only antibodies found in controls were ANA. Among the women who answered positively to questionnaire, 25.5% (35/137) were found to be positive for ANA, 3.6% (5/137) for dsdna, 8% (11/137) for ENA, 4.4% (6/137) for acl IgG, 9.5% (13/137) for acl IgM, 0.7%, 5.1% (7/137) for ab2gpi IgG and 14.6% (20/137) for ab2gpi IgM. Nine (81.8%) of 11 women who were positive for ENA had the anti-ro specificity. Thirty-five (25.5%) cases and none of the controls (P < 0.001) were definitively diagnosed as having a rheumatic disease. The overall prevalence of a definite rheumatic disease was 2.9% (35/1210). The rheumatic diseases diagnosed were UCTD, primary antiphospholipid syndrome, primary Sjögren s syndrome, rheumatoid arthritis and SLE in 20.4% (28/137), 1.5% (2/137), 1.5% (2/137), 0.7% (1/137) and 1.5% (2/137) of the women, respectively. The relationship between the items of the questionnaire, the presence of antibodies or the diagnosis of a rheumatic disease is reported in Table 3. In univariate analysis, the items describing the occurrence of photosensitivity, erythema or malar rash, dry mouth and a history of two or more miscarriages were significantly correlated with positivity to antibody testing or with a definite diagnosis of a rheumatic disease. To identify the best predictive items contained in the questionnaire, we constructed a stepwise logistic model. Basal model included maternal age (discrete variable) and previous term pregnancy (categorical variable). All the items of the questionnaire were included in the subsequent stepwise logistic model as binary (yes, no) explanatory variables with either ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 53

4 Spinillo et al. Table 3. Univariable association between symptoms, autoantibody testing and definite diagnosis of a rheumatic disease Antibodies Disease Positive (n 5 69) Negative (n 5 175) OR (95% CI) Positive (n 5 35) Negative (n 5 209) OR (95% CI) Photosensitivity ( ) ( ) Erythema and/or malar rash ( ) ( ) Raynaud s phenomenon ( ) ( ) Painful and swollen joints ( ) ( ) Serositis ( ) ( ) Dry mouth ( ) (1 9.3) Dry eyes ( ) ( ) Painful mouth ulcers ( ) ( ) Thrombophlebitis ( ) ( ) Pregnancy loss (2) (1 9.7) ( ) the result of antibody testing or a definite diagnosis of rheumatic disease as outcome variables. The results of this modelling are reported in Table 4. In multivariable analysis, photosensitivity, erythema or malar rash and a history of two or more miscarriages were independent predictors of both positivity to antibody testing and a definite diagnosis of a rheumatic disease. The simultaneous presence of these three symptoms was associated with a high specificity in the diagnosis of the presence of autoantibodies or rheumatic disease. However, the presence of one of the three symptoms was associated with 85.7% (95% CI ) sensitivity (30/35) and 70.3% (95% CI ) specificity (147/209) in the definite diagnosis of a rheumatic disease. When stepwise analysis was repeated with anti-ro positivity as an outcome variable, photosensitivity (adjusted OR 6.1; 95% CI ) and dry mouth (adjusted OR 4.22; 95% Table 4. Multivariable association between symptoms, autoantibody testing and definite diagnosis of a rheumatic disease Antibodies OR (95% CI)* Disease OR (95% CI)* Photosensitivity 4.48 ( ) 5.72 ( ) Erythema 5.1 ( ) 3.91 ( ) Pregnancy loss (2) 5.6 ( ) 5.6 ( ) Area under ROC curve ( ) ( ) Sensitivity 46.4% ( ) 34.3% ( ) Specificity 97.1% ( ) 95.2% ( ) ROC, receiving operator curve. *Odds ratio and 95% CI as obtained by logistic regression analysis including terms for photosensitivity, erythema, pregnancy loss (2), previous term pregnancies (categorical variables) and maternal age (discrete variable). CI ) were the explanatory variables, which correlated best with the outcome. Table 5 reports the association between the number of items of the questionnaire with a positive response and the occurrence of antibodies or rheumatic disease. After adjustment for the confounding effect of maternal age and previous term pregnancy, there was a significant linear trend relating an increasing number of positive answers to the prevalence of antibodies or rheumatic disease. The adjusted odds ratios of positive antibody testing or definite rheumatic disease among women who answered positively to two or more of the items of the questionnaire were 5.61 (95% CI ) and 6.55 (95% CI ), respectively. Table 6 reports the main obstetric outcome variables among cases and controls. Birthweight was significantly lower among cases than controls. Six cases and none of the controls (P = by Fisher s exact test) were delivered before 34 weeks of pregnancy. A moderate-to-severe pregnancy complications (miscarriage, fetal growth restriction, delivery before 34 weeks of pregnancy and severe pre-eclampsia) were recorded in 8.8% (12/137) of cases and 1.9% (2/107) controls (adjusted OR 5.6; 95% CI ; P = 0.021). Discussion and conclusion Rheumatic diseases include a group of heterogeneous autoimmune diseases that occur predominantly among women of childbearing age. The first trimester of pregnancy could be an appropriate period to screen for rheumatic diseases in a highly motivated and at risk population. Pregnancy and lactation can modulate rheumatic disease activity. However, rheumatic diseases are associated with increased risks of fetal losses, preeclampsia, fetal growth restriction and neonatal complications. 1 6 In the past decade, several antenatal pharmacological treatments have been shown to reduce some fetal and 54 ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology

5 Rheumatic diseases in the first trimester of pregnancy Table 5. Association between number of symptoms, positivity to autoantibodies and diagnosis of rheumatic disease Antibodies Disease Positive (n 5 69), n (%) Negative (n 5 175), n (%) P for trend* Positive (n 5 35), n (%) Negative (n 5 209), n (%) P for trend* Number of symptoms None 10 (14.5) 97 (55.4) 107 (51.2) One 14 (20.3) 36 (20.6) 9 (25.7) 41 (19.6) Two 30 (43.5) 28 (16.9) 17 (48.6) 41 (19.6) Three 8 (11.6) 10 (5.7) 6 (17.1) 12 (5.7) More than three 7 (10.1) 4 (2.3), (8.6) 8 (3.8), Area under ROC curve** ( ) ( ) Sensitivity** 65.2 ( ) 74.3 ( ) Specificity** 76 ( ) 70.8 ( ) ROC, receiving operator curve. *As obtained by logistic regression analysis including terms for number of symptoms, maternal age (discrete variables) and previous term pregnancies (categorical variable) **Positive response to two or more items versus others. Results obtained by logistic regression analysis as reported above. neonatal complications associated with rheumatic diseases. 18 Congenital heart block, neonatal lupus or maternal thrombosis associated with rheumatic diseases can be efficaciously prevented by appropriate maternal treatments. 19,20 For this reason, the identification of women with asymptomatic rheumatic diseases or also simply those with potentially dangerous autoimmune antibodies could have important preventive implications with regards to several complications of pregnancy. In our evaluation of a questionnaire-based screening strategy for detecting rheumatic diseases among asymptomatic pregnant women, we used a two-step process. The first step was a self-administered questionnaire, whereas the second step included both screening for autoantibodies and referral to a rheumatologist. The validity of this approach has been Table 6. Main obstetric and neonatal data in cases and controls Cases (n 5 137) Controls (n 5 107) P value Mean (SD) Mean (SD) Gestational age (weeks) 38.8 (1.8) 39.2 (1.5) Birthweight (g) 3180 (475) 3340 (452) n(%) n (%) Miscarriage 3 (2.2) 0.26 Pre-eclampsia 4 (2.9) 2 (1.9) 0.7 Gestational diabetes 3 (2.2) 0.26 Fetal growth restriction 2 (1.5) 0.51 Preterm delivery 10 (7.3) 2 (1.9) 0.07 (,37 weeks) Overall complications 17 (12.4) 3 (2.8) extensively confirmed for the diagnosis of SLE, rheumatoid arthritis and Sjogren s syndrome in population studies both in Europe and in other countries. 21,22 The rate of false negatives using this method is very low in the nonpregnant population. 21 To our knowledge, this is the first study that attempts to apply the two-step screening process for rheumatic diseases to pregnant women, and the accuracy of this method in this particular population should, therefore, be further confirmed. A similar two-step testing, including a self-completed questionnaire followed by ANA test was applied to a cohort of infertile women by Geva et al., 2 showing a 1.5% prevalence of undiagnosed SLE in this population. In our study, classical disturbances associated with the first trimester of pregnancy (nausea, vomiting, backache, sialorrhoea, etc.) did not impair the detection of true rheumatic diseases. The overall prevalence of rheumatic diseases in our population is consistent with the prevalences of individual diseases reported in other studies. 1 In particular, in European countries, the prevalences of SLE, rheumatoid arthritis and primary Sjögren s syndrome in adult women are between %, 0.2 1%, and %, respectively UCTD was the more frequent rheumatic disease diagnosed by rheumatologist in our population. The high rate of this syndrome could have important maternal and fetal implications. According to several studies, approximately 10 to 20% of women diagnosed with UCTD will develop a definite rheumatic disease during the subsequent 5 years. 16,25 However, the disease remains undifferentiated in almost 75% of cases. 25 Little is known about the influence of pregnancy and lactation on the course of UCTD. A small study indicated that the risk of flares during a 1-year period of observation was more than three times higher in pregnant women than in nonpregnant ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 55

6 Spinillo et al. ones. 26 In addition, 80% of the women with UCTDs also have autoantibodies, mostly anti-ssa/ro, anti-ssb/la and antidsdna. 25 Anti-SSA/Ro and/or anti-ssb/la antibodies are associated with the occurrence of neonatal lupus, a rare transient lupus dermatitis, and isolated congenital heart block. 20 Congenital heart block is the most important and irreversible manifestation of neonatal lupus, occurring in 1 2% of anti- SSA/Ro antibody-positive pregnancies. 27 Arrhythmias caused by congenital heart block are associated with a 16 19% fetal mortality rate. These arrhythmias are caused by the binding of anti-ssa/ro to heart conduction tissue and the consequent inflammatory/fibrotic reaction. 19,20 This condition must be monitored carefully by serial fetal echocardiograms starting at weeks of gestation Another finding that could have important implications is the relatively high rate of autoantibodies among women who answered positively to questionnaire. Antiphospholipid antibodies are directed against trophoblast and are associated with an increased rate of placental thrombosis. 1,3,28 These two phenomena are responsible for the high rate of fetal losses, fetal growth restriction and other pregnancy complications among women with antiphospholipid syndrome. 29 These findings are confirmed by the higher rates of placental complications among women who responded positively to the questionnaire than among the negative controls. In conclusion, a two-step screening process with a simple, self-administered questionnaire proved to be a useful strategy for identifying undiagnosed rheumatic diseases in women during the first trimester of pregnancy. The accuracy of the screening method was similar to that reported in the nonpregnant population. The validity of this approach should obviously be confirmed in larger studies, but standardised questions on rheumatic symptoms could help in the identification and referral of pregnant women at risk of rheumatic diseases. Contribution to authorship A.S., F.B., C.M., O.M.E.: Conception of the study, analysis of data, drafting of the manuscript, final approval. L.M., R.C.: Design of the study, Revision of the manuscript, final approval. D.M., V.R., E.D.S., C.A.: Acquisition of data, revision of the manuscript, final approval. Details of ethical approval Approved by Department of Obstetrics and Gynecology, January j References 1 Saar P, Hermann W, Müller-Ladner U. Connective tissue diseases and pregnancy. Rheumatology 2006;45: Geva E, Lerner-Geva L, Burke M, Vardinon N, Lessing JB, Amit A. Undiagnosed systemic lupus erythematosus in a cohort of infertile women. Am J Reprod Immunol 2004;51: Mavragani CP, Dafni UG, Tzioufas AG, Moutsopoulos HM. 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