Predictive factors of fetal congenital heart block in anti-SS-A antibody-positive pregnant women

Predictive factors of fetal congenital heart block in anti-SS-A antibody-positive pregnant women | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictive factors of fetal congenital heart block in anti-SS-A antibody-positive pregnant women Chiaki Heshiki, Yutaka Nagai, Miki Miyagi, Akira Oku, Akari Kanemura, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2302813/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Identifying predictive factors of fetal congenital heart block (CHB) in pregnant women with positive anti-SS-A antibodies is important to manage the cases properly. Methods We retrospectively reviewed the medical records of 59 anti-SS-A antibody-positive women undergoing perinatal management at our hospital from January 2011 to November 2021. Univariate and multivariate analyses were performed to investigate predictive factors for the development of fetal CHB. Results Of 59 women with positive anti-SS-A antibodies, 9 had fetal CHB. In univariate analysis, fetal CHB was associated with diagnosing connective tissue disease (OR 0.109, p = .009) and positive anti-SS-A antibodies after conception (OR 31.333, p = .0002). In multivariate analysis, diagnosing connective tissue disease was a protective factor (OR 0.049, p = .025), and positive anti-SS-A antibody after conception was a risk factor (OR 41.738, p = .004). However, other maternal clinical characteristics did not influence the development of fetal CHB. Conclusions In pregnancies of anti-SS-A antibody-positive women, diagnosing connective tissue disease was an independent protective factor for fetal CHB, and positive anti-SS-A antibody after conception was an independent risk factor. Anti-SS-A antibody-positive women Anti-SS-A antibodies Fetal congenital heart block Figures Figure 1 Background Anti-SS-A antibodies are autoantibodies detected in systemic lupus erythematosus and Sjögren's syndrome but may be present asymptomatically in some women. It is estimated that approximately 70% of Sjögren's syndrome patients, 50% of systemic lupus erythematosus patients, and 1% of normal population have anti-SS-A antibodies. Among the infants with neonatal lupus conditions who were born to anti-SS-A antibody-positive women, CHB is infrequent but is a major severe clinical problem. The incidence of CHB in infants born to anti-SS-A antibody-positive women is estimated to be about 1%, in which more than 60% of infants require a pacemaker, and mortality can be high to 14–34% [ 1 ]. Approximately 25% of the second children of their siblings with neonatal lupus develop the same condition. Moreover, pregnant women who have born a previous child with CHB have a 10.5% chance of having a second child with CHB [ 2 ]. Buyon et al. proposed a protocol similar to the PRIDE study [ 3 ] in which fetal echocardiography is performed weekly from 16 to 26 weeks of gestation and every two weeks after that until 34 weeks [ 4 ]. However, universal guidelines are currently unavailable for screening and treatment of CHB in fetuses born to anti-SS-A antibody-positive mothers. There are few reports on prognostic factors for fetal CHB due to the limited cases of anti-SS-A antibody-positive pregnancies. Similarly, only a few reports on maternal rheumatologic symptoms, anti-SS-A antibody titer, and neonatal prognosis were documented. Anami et al. [ 5 ] reported that an anti-SS-A antibody titer of 1:32 or higher in maternal serum by double immunodiffusion (DID) was an independent risk factor for fetal CHB. Previous studies have shown that the effectiveness of corticosteroids on the development of CHB was controversial [ 6 , 7 ]. Similarly, CHB is associated with high titers of anti-SS-B/La antibodies [ 8 ] and older maternal age [ 9 ]. An observational study suggested that intravenous administration of gamma globulin and hydroxychloroquine may reduce the risk of fetal CHB [ 10 ]. Although immunoglobulin therapy was expected to be effective in preventing the onset of neonatal lupus, a prospective study of high-risk cases in the PATCH study [ 11 ] showed no effect in preventing neonatal lupus. An ongoing multicenter clinical trial (J-PATCH) using hydroxychloroquine is expected to report its efficacy in preventing recurrence [ 12 ]. Therefore, this study investigated the prognostic factors for fetal CHB in anti-SS-A antibody-positive pregnant women. Methods Patients and data collection Of 62 anti-SS-A antibody-positive pregnant women presented at our hospital from January 2011 to November 2021, 59 cases with no missing data were included, and their medical records were retrospectively reviewed. We recorded the background characteristics of the patients, including age at delivery, the number of pregnancies, rheumatologic symptoms, dry eyes, dry mouth, erythema, purpura, Raynaud's symptoms, fever, arthralgia, lymphadenopathy, hematuria, photosensitivity, alopecia, thrombosis, diagnosing of connective tissue disease, Sjögren's syndrome, Systemic lupus erythematosus (SLE), mixed connective tissue disease, rheumatoid arthritis, antiphospholipid antibody syndrome, high titer of the anti-SS-A antibody, positive anti-SS-A antibodies after conception, immunosuppressive drugs before or after conception, antiplatelet agents or anticoagulants after conception, and corticosteroids administered before and after conception. Since anti-SS-A antibodies were measured using multiple assay methods, high titer was defined as equivalent to 32-fold or higher by the DID (double immunodiffusion) method, as described by Miyano et al [ 13 ]. Ethics This study was approved by the Ethics Committee of Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center on July 8th, 2022 (Permission number: R4-051). Statistical analysis Student t-test was used to compare the normally distributed continuous variables. Fisher’s exact test was used to compare the categorical variables. In univariate analysis, we examined the relationship between the risk of fetal CHB and clinical characteristics. Multivariate analysis was then performed using associated clinical characteristics in univariate analysis. Logistic regression analysis was performed to calculate odds ratios (OR), 95% confidence intervals, and p -values for fetal CHB. We used the JMP (JMP Statistical Discovery LLC, SAS Institute Japan) for statistical analysis. All p -values were two-tailed, and less than 0.05 was considered significant. Results Among the 59 anti-SS-A antibody-positive women undergoing perinatal care at our hospital, nine developed fetal CHB, and 50 did not. There were no significant differences in the background characteristics of the pregnant women. However, diagnosing connective tissue disease and SLE were significantly more common in without CHB group (55.6% vs. 92.0%, p = .014) and (0% vs. 42.0%, p = .020), respectively. Similarly, the use of corticosteroids before conception alone and both before and after conception were significantly more common in without CHB group (0% vs. 36.0%, p = .047) and (0% vs. 36%, p = .046), respectively. However, positive anti-SS-A antibody after conception was significantly more common in the CHB group (66.7% vs. 6.0%, p = .0001) (Table 1 ). Table 1 Comparison of clinical features of patients with and without fetal CHB. Clinical features With CHB (N = 9) Without CHB (N = 50) p value Age at delivery, mean (SD) 30 (4.7) 34 (5.1) 0.085 History of conception 1 (11.1%) 2 (4.0%) 0.631 Rheumatic symptoms 1 (11.1%) 25 (50.0%) 0.063 Dry eye 3 (33.3%) 8 (16.0%) 0.347 Dry mouth 0 (0%) 5 (10%) 1.000 Erythema 0 (0%) 9 (18%) 0.329 Purpura 0 (0%) 0 (0%) 1.000 Raynaud’s phenomenon 0 (0%) 0 (0%) 1.000 Fever 0 (0%) 5 (10%) 1.000 Arthralgia 1 (11.1%) 19 (38.0%) 0.148 Lymphadenopathy 2 (22.2%) 5 (10.0%) 0.288 Hematuria 0 (0%) 2 (4.0%) 1.000 Photosensitivity 0 (0%) 3 (6.0%) 1.000 Alopecia 0 (0%) 3 (6.0%) 1.000 Thrombosis 0 (0%) 0 (0%) 1.000 Diagnosis of connective tissue disease 5 (55.6%) 46 (92.0%) 0.014 Sjögren's syndrome 4 (44.4%) 30 (60.0%) 0.473 Systemic lupus erythematosus 0 (0%) 21 (42.0%) 0.020 Mixed connective tissue disease 0 (0%) 0 (0%) 1.000 Rheumatoid arthritis 0 (0%) 6 (12.0%) 0.577 Anti-Phospholipid antibody syndrome 0 (0%) 2 (4.0%) 1.000 High titer of anti-SS-A antibodies 7 (77.8%) 27 (54.0%) 0.278 Finding positive anti-SS-A antibodies after conception 6 (66.7%) 3 (6.0%) 0.0001 Use of corticosteroids before conception 0 (0%) 18 (36.0%) 0.047 Use of immunosuppressive drugs before conception 0 (0%) 6 (12.0%) 0.577 Use of corticosteroids after conception 5 (55.6%) 21 (42.0%) 0.489 Use of immunosuppressive drugs after conception 0 (0%) 8 (16.0%) 0.337 Use of antiplatelet agents and/or anti-coagulants after conception 0 (0%) 10 (20.0%) 0.334 Use of corticosteroids before and after conception 0 (0%) 18 (36.0%) 0.046 Use of corticosteroids (equivalent doses of PSL, at ≧ 10mg/day) before and after conception 0 (0%) 4 (8.0%) 1.000 Use of corticosteroids after conception before 16-week gestation 0 (0%) 2 (4.0%) 1.000 Use of corticosteroids (equivalent doses of PSL, at ≧ 10mg/day) after conception before 16-week gestation 0 (0%) 1 (2.0%) 1.000 CHB, congenital heart block; PSL, prednisolone. Table 2 shows the types and timing of corticosteroid administration in pregnant women. Before conception, prednisolone was administered in most cases and was not associated with the development of CHB. After conception, steroids other than prednisolone were administered, especially in the CHB group. Betamethasone administration after conception was significantly higher in the CHB group than in without CHB group ( p = .0003), suggesting that corticosteroids with higher transplacental transferability were administered in the CHB group. Table 2 Type of corticosteroids administered before and after conception. Type of corticosteroids With CHB (N = 9) Without CHB (N = 50) p value Before conception Total corticosteroids use 0 case 18 cases 0.046 PSL 0 15 0.095 mPSL 0 3 1.000 After conception Total corticosteroids use 5 cases 21 cases 0.489 PSL 0 17 0.048 mPSL 0 3 1.000 Bet 4 0 0.0003 Dex 1 0 0.153 PSL-Bet 1 1 0.284 PSL, prednisolone; mPSL, methylprednisolone; Bet, betamethasone; Dex, dexamethasone. Data are number of patients. Next, we examined the timing of CHB onset because the period from 16- to 24- week gestation has been associated with a higher risk [ 14 ]. Nine patients who developed fetal CHB in this study had onset between 16- to 31-week of gestation. The patients were classified into the following four groups according to the timing of corticosteroid administration (Fig. 1 ). Group A: consecutive administration before and after conception (n = 18); Group B: only after conception before 16 weeks of pregnancy (n = 2); Group C: only after 16 weeks of pregnancy (n = 6); Group D: No corticosteroid administration (n = 33). In this study, Groups A and B received corticosteroids before 16- week of gestation. In univariate analysis, CHB was not associated with age at delivery, history of the conception, rheumatologic symptoms, dry eyes, arthralgia, lymphadenopathy, Sjögren's syndrome, high titer of anti-SS-A antibodies, or use of corticosteroids after conception. However, there was a significant association with diagnosing connective tissue disease (OR 0.109, p = .009) and positive anti-SS-A antibodies after conception (OR 31.333, p = .0002) (Table 3 ). Table 3 Results of univariate analysis of fetal CHB. Parameters Odds ratio for fetal CHB 95% CI p value Age at delivery 0.906 0.786, 1.045 0.168 History of conception 0.577 0.277, 1.202 0.099 Rheumatologic symptoms 0.125 0.015, 1.075 0.058 Dry eye 0.381 0.079, 1.847 0.231 Dry mouth - - - Erythema - - - Purpura - - - Raynaud’s phenomenon - - - Fever - - - Arthralgia 0.204 0.024, 1.761 0.148 Lymphadenopathy 2.571 0.415, 15.917 0.310 Hematuria - - - Photosensitivity - - - Alopecia - - - Thrombosis - - - Diagnosis of connective tissue disease 0.109 0.021, 0.575 0.009 Sjogren’s syndrome 0.533 0.127, 2.232 0.389 Systemic lupus erythematosus - - - Mixed connective tissue disease - - - Rheumatoid arthritis - - - Anti-phospholipid antibody syndrome - - - High titer of anti-SS-A antibodies 2.981 0.563, 15.790 0.199 Finding positive anti-SS-A antibodies after conception 31.333 5.118, 191.823 0.0002 Corticosteroids therapy before conception - - - Use of immunosuppressants before conception - - - Use of corticosteroids after conception 1.726 0.413, 7.211 0.454 Use of immunosuppressants after conception - - - Use of anti-platelet drugs and/or anti-coagulants after conception - - - Use of corticosteroids before and after conception - - - Use of corticosteroids (equivalent doses of PSL, at ≧ 10mg/day) before and after conception - - - Use of corticosteroids after conception before 16-week gestation - - - Use of corticosteroids (equivalent doses of PSL, at ≧ 10mg/day) after conception before 16-week gestation - - - CHB, congenital heart block; PSL, prednisolone; CI, confidence interval. Multivariate analysis was performed using four possible influencing factors, including diagnosing connective tissue disease, high titer of the anti-SS-A antibody, positive anti-SS-A antibody after conception, and use of corticosteroids before conception. Diagnosing connective tissue disease was a significant protective factor (OR 0.049, p = .025), and positive anti-SS-A antibody after conception was a significant risk factor (OR = 41.738, p = .004) (Table 4 ). Table 4 Results of multivariate analysis of predictive factors for fetal CHB. Parameters Odds ratio for fetal CHB 95% CI p value Diagnosis of connective tissue disease 0.049 0.003, 0.684 0.025 High titer of anti-SS-A antibodies 6.920 0.625, 76.658 0.115 Finding positive anti-SS-A antibodies after conception 41.738 3.347, 520.550 0.004 Use of corticosteroids before conception 3.0291e-7 0, - 0.994 CHB, congenital heart block Discussion In this study, diagnosing connective tissue disease decreased the risk of developing fetal CHB. Although increased mortality was observed in infants whose mothers had an established diagnosis of SLE or Sjögren's syndrome at the time of conception [ 7 , 15 ], most of our cases with diagnosing connective tissue disease had already started appropriate treatment, and their condition had stabilized, which might influence the results of this study. The association between preconception corticosteroid administration and the development of fetal CHB was unclear. However, the type and timing of corticosteroid administration differed in characteristics between CHB and without CHB groups. Corticosteroid administration before 16-week of gestation may reduce the risk of developing fetal CHB. Previous studies have reported conflicting results on the association between corticosteroid administration and the development of fetal CHB [ 5 , 8 , 16 ], suggesting that the type and timing of administered corticosteroids may also have an effect. The association between the high titer of anti-SS-A antibodies and the development of fetal CHB was not clear. However, determining a cutoff value for a high titer is challenging. This study defined it as the 32-fold equivalent of the DID method, although it was difficult to examine the details in cases with higher titers of anti-SS-A antibodies measured using an enzyme immunoassay. Tunks et al. reported that maternal anti-La level might be a valuable predictor of fetal heart block rather than anti-Ro antibodies [ 8 ]. Moreover, Anami et al. [ 5 ] and Tsuboi et al. [ 17 ] reported that a titer of 32 or higher using the DID method was associated with the development of fetal CHB. The limitations of this study are the small number of cases and the inconsistent method of measuring antibody titers. In the future, new findings may be obtained by accumulating the number of cases with a uniform method of measuring antibody titers. Positive anti-SS-A antibody after conception was a risk factor for the development of fetal CHB. In contrast, fetal heart block findings may lead to the identification of maternal anti-SS-A antibody positivity and subsequent diagnosis of connective tissue disease [ 18 , 19 ]. Therefore, obstetricians should identify asymptomatic women with anti-SS-A antibodies to provide appropriate action for CHB during prenatal care. Conclusions In pregnancies of anti-SS-A antibody-positive women, diagnosing connective tissue disease was an independent protective factor for fetal CHB, and finding positive anti-SS-A antibodies after conception was an independent risk factor. Screening prior to pregnancy in women with symptoms suggestive of connective tissue disease and initiation of appropriate treatment depending on the diagnosis may lead to a favorable outcome. List of abbreviations CHB, congenital heart block; DID, double immunodiffusion; SLE, systemic lupus erythematosus; OR, odds ratios; PSL, prednisolone; mPSL, methylprednisolone; Bet, betamethasone; Dex, dexamethasone; CI, confidence interval. Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center on July 8th, 2022 (Permission number: R4-051) and conducted in strict accordance with the Declaration of Helsinki. We used opt-out method to obtain informed consent from all subjects or their legal guardians. Study summaries were made publicly available, and all participants were guaranteed the opportunity to refuse participation. Consent for publication The manuscript does not contain any individual person’s data in any form (including any individual details, images, or videos). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Authors’ contributions CH drafted the manuscript. CH and YA conducted the statistical analyses. CH and YA provided substantial revision. All authors have reviewed the text and approved the final manuscript. Acknowledgments The authors would like to thank Enago (www.enago.jp) for the English language review of this article. References Research Group for the Development of Pregnancy Management Guidelines for Autoantibody-Positive Women and Reduction of the Risk of Developing Neonatal Lupus, Grants-in-Aid for scientific research of Japan society the promotions of science: Guide to the Practice of pregnancy in anti-SS-A antibody-positive women. 2013. (Japanese Edition) Cimaz R, Spence DL, Hornberger L, Silverman ED. 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Vanoni F, Lava SAG, Fossali EF, Cavalli R, Simonetti GD, Bianchetti MG, et al. Neonatal Systemic Lupus Erythematosus Syndrome: a Comprehensive Review. Clin Rev Allergy Immunol. 2017;53:469-476. doi: 10.1007/s12016-017-8653-0. Press J, Uziel Y, Laxer RM, Luy L, Hamilton RM, Silverman ED. Long-term outcome of mothers of children with complete congenital heart block. Am J Med. 1996;100:328-32. doi: 10.1016/S0002-9343(97)89492-2. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2302813","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":157487903,"identity":"22541a32-118e-41a2-9a75-bbf9aa491510","order_by":0,"name":"Chiaki 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Center","correspondingAuthor":false,"prefix":"","firstName":"Tadaharu","middleName":"","lastName":"Nakasone","suffix":""},{"id":157487914,"identity":"f23ce896-21e0-4ba0-aab8-150e54c15570","order_by":8,"name":"Yuki Izumi","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Izumi","suffix":""},{"id":157487915,"identity":"a4f06a70-3b29-4f7a-ad2c-63c935bbe11e","order_by":9,"name":"Yuko Nakano","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Nakano","suffix":""},{"id":157487917,"identity":"c55e7811-3942-41ea-84ac-83693f8efe78","order_by":10,"name":"Atsuya Shimabukuro","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Atsuya","middleName":"","lastName":"Shimabukuro","suffix":""},{"id":157487919,"identity":"5c327791-4057-45cc-aba7-afedbd671b97","order_by":11,"name":"Kaoru Yamashita","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kaoru","middleName":"","lastName":"Yamashita","suffix":""},{"id":157487920,"identity":"1047ec56-1e57-4666-a9ce-b0916fb406f0","order_by":12,"name":"Sorahiro Sunagawa","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sorahiro","middleName":"","lastName":"Sunagawa","suffix":""},{"id":157487922,"identity":"c8cedf68-038f-49c9-9389-5f9919c3f0d3","order_by":13,"name":"Kaoru Sakumoto","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kaoru","middleName":"","lastName":"Sakumoto","suffix":""},{"id":157487924,"identity":"835407f8-fa60-4b9c-901e-7fcd857e7fb9","order_by":14,"name":"Yoichi Aoki","email":"","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Yoichi","middleName":"","lastName":"Aoki","suffix":""}],"badges":[],"createdAt":"2022-11-22 21:59:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2302813/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2302813/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":30018684,"identity":"84ba1cd0-b81c-4779-a8ff-de7966b45e4d","added_by":"auto","created_at":"2022-12-07 16:06:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":67974,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of the timing of corticosteroids use with the onset of fetal CHB and diagnosing of maternal connective tissue disease.\u003c/p\u003e\n\u003cp\u003eGroup A, continuous use before and after conception (n = 18); Group B, only after conception before 16-week gestation (n = 2); Group C, only after 16-week gestation (n = 6); and Group D, without the use of corticosteroids (n = 33); use of corticosteroids before conception, Group A (n = 18); use of corticosteroids after conception, Group A, B, and C (n = 26); use of corticosteroids after conception before 16-week gestation, Group A, B (n = 20); CHB, congenital heart block; CTD, connective tissue disease.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2302813/v1/bd4f342b4000cedcdc1612ea.jpg"},{"id":31284994,"identity":"43e87d95-c072-4c9c-ae85-a8eb0f010300","added_by":"auto","created_at":"2023-01-09 05:29:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":382249,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2302813/v1/bf9f64ae-a299-4371-b2ff-00d12e6b298c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictive factors of fetal congenital heart block in anti-SS-A antibody-positive pregnant women","fulltext":[{"header":"Background","content":"\u003cp\u003eAnti-SS-A antibodies are autoantibodies detected in systemic lupus erythematosus and Sj\u0026ouml;gren's syndrome but may be present asymptomatically in some women. It is estimated that approximately 70% of Sj\u0026ouml;gren's syndrome patients, 50% of systemic lupus erythematosus patients, and 1% of normal population have anti-SS-A antibodies. Among the infants with neonatal lupus conditions who were born to anti-SS-A antibody-positive women, CHB is infrequent but is a major severe clinical problem. The incidence of CHB in infants born to anti-SS-A antibody-positive women is estimated to be about 1%, in which more than 60% of infants require a pacemaker, and mortality can be high to 14\u0026ndash;34% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eApproximately 25% of the second children of their siblings with neonatal lupus develop the same condition. Moreover, pregnant women who have born a previous child with CHB have a 10.5% chance of having a second child with CHB [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBuyon et al. proposed a protocol similar to the PRIDE study [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] in which fetal echocardiography is performed weekly from 16 to 26 weeks of gestation and every two weeks after that until 34 weeks [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, universal guidelines are currently unavailable for screening and treatment of CHB in fetuses born to anti-SS-A antibody-positive mothers.\u003c/p\u003e \u003cp\u003eThere are few reports on prognostic factors for fetal CHB due to the limited cases of anti-SS-A antibody-positive pregnancies. Similarly, only a few reports on maternal rheumatologic symptoms, anti-SS-A antibody titer, and neonatal prognosis were documented.\u003c/p\u003e \u003cp\u003eAnami et al. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] reported that an anti-SS-A antibody titer of 1:32 or higher in maternal serum by double immunodiffusion (DID) was an independent risk factor for fetal CHB.\u003c/p\u003e \u003cp\u003ePrevious studies have shown that the effectiveness of corticosteroids on the development of CHB was controversial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Similarly, CHB is associated with high titers of anti-SS-B/La antibodies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and older maternal age [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. An observational study suggested that intravenous administration of gamma globulin and hydroxychloroquine may reduce the risk of fetal CHB [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although immunoglobulin therapy was expected to be effective in preventing the onset of neonatal lupus, a prospective study of high-risk cases in the PATCH study [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] showed no effect in preventing neonatal lupus. An ongoing multicenter clinical trial (J-PATCH) using hydroxychloroquine is expected to report its efficacy in preventing recurrence [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, this study investigated the prognostic factors for fetal CHB in anti-SS-A antibody-positive pregnant women.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003ePatients and data collection\u003c/h2\u003e\n\u003cp\u003eOf 62 anti-SS-A antibody-positive pregnant women presented at our hospital from January 2011 to November 2021, 59 cases with no missing data were included, and their medical records were retrospectively reviewed.\u003c/p\u003e\n\u003cp\u003eWe recorded the background characteristics of the patients, including age at delivery, the number of pregnancies, rheumatologic symptoms, dry eyes, dry mouth, erythema, purpura, Raynaud's symptoms, fever, arthralgia, lymphadenopathy, hematuria, photosensitivity, alopecia, thrombosis, diagnosing of connective tissue disease, Sj\u0026ouml;gren's syndrome, Systemic lupus erythematosus (SLE), mixed connective tissue disease, rheumatoid arthritis, antiphospholipid antibody syndrome, high titer of the anti-SS-A antibody, positive anti-SS-A antibodies after conception, immunosuppressive drugs before or after conception, antiplatelet agents or anticoagulants after conception, and corticosteroids administered before and after conception.\u003c/p\u003e\n\u003cp\u003eSince anti-SS-A antibodies were measured using multiple assay methods, high titer was defined as equivalent to 32-fold or higher by the DID (double immunodiffusion) method, as described by Miyano et al [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eEthics\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Okinawa Prefectural Nanbu Medical Center and Children\u0026rsquo;s Medical Center on July 8th, 2022 (Permission number: R4-051).\u003c/p\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eStudent t-test was used to compare the normally distributed continuous variables. Fisher\u0026rsquo;s exact test was used to compare the categorical variables. In univariate analysis, we examined the relationship between the risk of fetal CHB and clinical characteristics. Multivariate analysis was then performed using associated clinical characteristics in univariate analysis. Logistic regression analysis was performed to calculate odds ratios (OR), 95% confidence intervals, and \u003cem\u003ep\u003c/em\u003e-values for fetal CHB. We used the JMP (JMP Statistical Discovery LLC, SAS Institute Japan) for statistical analysis. All \u003cem\u003ep\u003c/em\u003e-values were two-tailed, and less than 0.05 was considered significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 59 anti-SS-A antibody-positive women undergoing perinatal care at our hospital, nine developed fetal CHB, and 50 did not. There were no significant differences in the background characteristics of the pregnant women. However, diagnosing connective tissue disease and SLE were significantly more common in without CHB group (55.6% vs. 92.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.014) and (0% vs. 42.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.020), respectively. Similarly, the use of corticosteroids before conception alone and both before and after conception were significantly more common in without CHB group (0% vs. 36.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.047) and (0% vs. 36%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.046), respectively. However, positive anti-SS-A antibody after conception was significantly more common in the CHB group (66.7% vs. 6.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.0001) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparison of clinical features of patients with and without fetal CHB.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eClinical features\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWith CHB (N\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWithout CHB (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at delivery, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (4.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (5.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.085\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistory of conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (11.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (4.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.631\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRheumatic symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (11.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (50.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.063\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDry eye\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (33.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (16.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.347\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDry mouth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (10%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eErythema\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.329\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePurpura\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRaynaud\u0026rsquo;s phenomenon\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFever\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (10%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArthralgia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (11.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (38.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.148\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymphadenopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (22.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (10.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.288\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHematuria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (4.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePhotosensitivity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (6.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlopecia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (6.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThrombosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiagnosis of connective tissue disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (55.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46 (92.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.014\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSj\u0026ouml;gren's syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (44.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (60.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.473\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSystemic lupus erythematosus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (42.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.020\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed connective tissue disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRheumatoid arthritis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (12.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.577\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnti-Phospholipid antibody syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (4.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh titer of anti-SS-A antibodies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (77.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (54.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.278\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFinding positive anti-SS-A antibodies after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (66.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (6.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids before conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (36.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.047\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of immunosuppressive drugs before conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (12.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.577\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (55.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (42.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.489\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of immunosuppressive drugs after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (16.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.337\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of antiplatelet agents and/or anti-coagulants after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (20.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.334\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids before and after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (36.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids (equivalent doses of PSL, at ≧\u0026thinsp;10mg/day) before and after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (8.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids after conception before 16-week gestation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (4.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids (equivalent doses of PSL, at ≧\u0026thinsp;10mg/day) after conception before 16-week gestation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (2.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eCHB, congenital heart block; PSL, prednisolone.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the types and timing of corticosteroid administration in pregnant women. Before conception, prednisolone was administered in most cases and was not associated with the development of CHB. After conception, steroids other than prednisolone were administered, especially in the CHB group. Betamethasone administration after conception was significantly higher in the CHB group than in without CHB group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.0003), suggesting that corticosteroids with higher transplacental transferability were administered in the CHB group.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eType of corticosteroids administered before and after conception.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eType of corticosteroids\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWith CHB (N\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWithout CHB (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eBefore conception\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal corticosteroids use\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 case\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 cases\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.046\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePSL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.095\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emPSL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eAfter conception\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal corticosteroids use\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 cases\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 cases\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.489\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePSL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.048\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emPSL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.153\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePSL-Bet\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.284\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003ePSL, prednisolone; mPSL, methylprednisolone; Bet, betamethasone; Dex, dexamethasone.\u003c/p\u003e\n\u003cp\u003eData are number of patients.\u003c/p\u003e\n\u003cp\u003eNext, we examined the timing of CHB onset because the period from 16- to 24- week gestation has been associated with a higher risk [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Nine patients who developed fetal CHB in this study had onset between 16- to 31-week of gestation. The patients were classified into the following four groups according to the timing of corticosteroid administration (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Group A: consecutive administration before and after conception (n\u0026thinsp;=\u0026thinsp;18); Group B: only after conception before 16 weeks of pregnancy (n\u0026thinsp;=\u0026thinsp;2); Group C: only after 16 weeks of pregnancy (n\u0026thinsp;=\u0026thinsp;6); Group D: No corticosteroid administration (n\u0026thinsp;=\u0026thinsp;33). In this study, Groups A and B received corticosteroids before 16- week of gestation.\u003c/p\u003e\n\u003cp\u003eIn univariate analysis, CHB was not associated with age at delivery, history of the conception, rheumatologic symptoms, dry eyes, arthralgia, lymphadenopathy, Sj\u0026ouml;gren's syndrome, high titer of anti-SS-A antibodies, or use of corticosteroids after conception. However, there was a significant association with diagnosing connective tissue disease (OR 0.109, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.009) and positive anti-SS-A antibodies after conception (OR 31.333, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.0002) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eResults of univariate analysis of fetal CHB.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameters\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOdds ratio for fetal CHB\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at delivery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.906\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.786, 1.045\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.168\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistory of conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.577\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.277, 1.202\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.099\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRheumatologic symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.125\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.015, 1.075\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.058\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDry eye\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.381\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.079, 1.847\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.231\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDry mouth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eErythema\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePurpura\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRaynaud\u0026rsquo;s phenomenon\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFever\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArthralgia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.204\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.024, 1.761\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.148\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymphadenopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.571\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.415, 15.917\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.310\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHematuria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePhotosensitivity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlopecia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThrombosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiagnosis of connective tissue disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.109\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.021, 0.575\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSjogren\u0026rsquo;s syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.533\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.127, 2.232\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.389\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSystemic lupus erythematosus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed connective tissue disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRheumatoid arthritis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnti-phospholipid antibody syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh titer of anti-SS-A antibodies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.981\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.563, 15.790\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.199\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFinding positive anti-SS-A antibodies after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.333\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.118, 191.823\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCorticosteroids therapy before conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of immunosuppressants before conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.726\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.413, 7.211\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.454\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of immunosuppressants after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of anti-platelet drugs and/or anti-coagulants after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids before and after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids (equivalent doses of PSL, at ≧\u0026thinsp;10mg/day) before and after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids after conception before 16-week gestation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids (equivalent doses of PSL, at ≧\u0026thinsp;10mg/day) after conception before 16-week gestation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eCHB, congenital heart block; PSL, prednisolone; CI, confidence interval.\u003c/p\u003e\n\u003cp\u003eMultivariate analysis was performed using four possible influencing factors, including diagnosing connective tissue disease, high titer of the anti-SS-A antibody, positive anti-SS-A antibody after conception, and use of corticosteroids before conception. Diagnosing connective tissue disease was a significant protective factor (OR 0.049, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.025), and positive anti-SS-A antibody after conception was a significant risk factor (OR\u0026thinsp;=\u0026thinsp;41.738, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.004) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eResults of multivariate analysis of predictive factors for fetal CHB.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameters\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOdds ratio for fetal CHB\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiagnosis of connective tissue disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.049\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003, 0.684\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.025\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh titer of anti-SS-A antibodies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.920\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.625, 76.658\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.115\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFinding positive anti-SS-A antibodies after conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.738\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.347, 520.550\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUse of corticosteroids before conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.0291e-7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0, -\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.994\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCHB, congenital heart block\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, diagnosing connective tissue disease decreased the risk of developing fetal CHB. Although increased mortality was observed in infants whose mothers had an established diagnosis of SLE or Sj\u0026ouml;gren's syndrome at the time of conception [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], most of our cases with diagnosing connective tissue disease had already started appropriate treatment, and their condition had stabilized, which might influence the results of this study.\u003c/p\u003e \u003cp\u003eThe association between preconception corticosteroid administration and the development of fetal CHB was unclear. However, the type and timing of corticosteroid administration differed in characteristics between CHB and without CHB groups. Corticosteroid administration before 16-week of gestation may reduce the risk of developing fetal CHB. Previous studies have reported conflicting results on the association between corticosteroid administration and the development of fetal CHB [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], suggesting that the type and timing of administered corticosteroids may also have an effect.\u003c/p\u003e \u003cp\u003eThe association between the high titer of anti-SS-A antibodies and the development of fetal CHB was not clear. However, determining a cutoff value for a high titer is challenging. This study defined it as the 32-fold equivalent of the DID method, although it was difficult to examine the details in cases with higher titers of anti-SS-A antibodies measured using an enzyme immunoassay. Tunks et al. reported that maternal anti-La level might be a valuable predictor of fetal heart block rather than anti-Ro antibodies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Moreover, Anami et al. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and Tsuboi et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] reported that a titer of 32 or higher using the DID method was associated with the development of fetal CHB. The limitations of this study are the small number of cases and the inconsistent method of measuring antibody titers. In the future, new findings may be obtained by accumulating the number of cases with a uniform method of measuring antibody titers.\u003c/p\u003e \u003cp\u003ePositive anti-SS-A antibody after conception was a risk factor for the development of fetal CHB. In contrast, fetal heart block findings may lead to the identification of maternal anti-SS-A antibody positivity and subsequent diagnosis of connective tissue disease [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, obstetricians should identify asymptomatic women with anti-SS-A antibodies to provide appropriate action for CHB during prenatal care.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn pregnancies of anti-SS-A antibody-positive women, diagnosing connective tissue disease was an independent protective factor for fetal CHB, and finding positive anti-SS-A antibodies after conception was an independent risk factor. Screening prior to pregnancy in women with symptoms suggestive of connective tissue disease and initiation of appropriate treatment depending on the diagnosis may lead to a favorable outcome.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eCHB, congenital heart block; DID, double immunodiffusion; SLE, systemic lupus erythematosus; OR, odds ratios; PSL, prednisolone; mPSL, methylprednisolone; Bet, betamethasone; Dex, dexamethasone; CI, confidence interval.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Okinawa Prefectural Nanbu Medical Center and Children\u0026rsquo;s Medical Center on July 8th, 2022 (Permission number: R4-051) and conducted in strict accordance with the Declaration of Helsinki. We used opt-out method to obtain informed consent from all subjects or their legal guardians. Study summaries were made publicly available, and all participants were guaranteed the opportunity to refuse participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe manuscript does not contain any individual person\u0026rsquo;s data in any form (including any individual details, images, or videos).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCH drafted the manuscript. CH and YA conducted the statistical analyses. CH and YA provided substantial revision. All authors have reviewed the text and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Enago (www.enago.jp) for the English language review of this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eResearch Group for the Development of Pregnancy Management Guidelines for Autoantibody-Positive Women and Reduction of the Risk of Developing Neonatal Lupus, Grants-in-Aid for scientific research of Japan society the promotions of science: Guide to the Practice of pregnancy in anti-SS-A antibody-positive women. 2013. (Japanese Edition)\u003c/li\u003e\n\u003cli\u003eCimaz R, Spence DL, Hornberger L, Silverman ED. Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr. 2003;142:678-83. doi: 10.1067/mpd.2003.233. \u003c/li\u003e\n\u003cli\u003eFriedman DM, Kim MY, Copel JA, Llanos C, Davis C, Buyon JP. Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study. Am J Cardiol. 2009;103:1102-6. doi: 10.1016/j.amjcard.2008.12.027. \u003c/li\u003e\n\u003cli\u003eBuyon JP, Clancy RM, Friedman DM. Cardiac manifestations of neonatal lupus erythematosus: guidelines to management, integrating clues from the bench and bedside. Nat Clin Pract Rheumatol. 2009;5:139-48. doi: 10.1038/ncprheum1018.\u003c/li\u003e\n\u003cli\u003eAnami A, Fukushima K, Takasaki Y, Sumida T, Waguri M, Wake N, et al. The predictive value of anti-SS-A antibodies titration in pregnant women with fetal congenital heart block. Mod Rheumatol. 2013;23:653-8. doi: 10.1007/s10165-012-0704-z. \u003c/li\u003e\n\u003cli\u003eLlanos C, Izmirly PM, Katholi M, Clancy RM, Friedman DM, Kim MY, et al. Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. Arthritis Rheum. 2009;60:3091-7. doi: 10.1002/art.24768. \u003c/li\u003e\n\u003cli\u003eIzmirly PM, Saxena A, Kim MY, Wang D, Sahl SK, Llanos C, et al. Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus. Circulation. 2011;124:1927-35. doi: 10.1161/CIRCULATIONAHA.111.033894. \u003c/li\u003e\n\u003cli\u003eTunks RD, Clowse ME, Miller SG, Brancazio LR, Barker PC. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208:64.e1-7. doi: 10.1016/j.ajog.2012.09.020.\u003c/li\u003e\n\u003cli\u003eAmbrosi A, Salomonsson S, Eliasson H, Zeffer E, Skog A, Dzikaite V, et al. Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern. Ann Rheum Dis. 2012;71:334-40. doi: 10.1136/annrheumdis-2011-200207. \u003c/li\u003e\n\u003cli\u003eGleicher N, Elkayam U. Preventing congenital neonatal heart block in offspring of mothers with anti-SSA/Ro and SSB/La antibodies: a review of published literature and registered clinical trials. Autoimmun Rev. 2013;12:1039-45. doi: 10.1016/j.autrev.2013.04.006. \u003c/li\u003e\n\u003cli\u003eIzmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, Clancy R, Copel JA, et al. Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers. J Am Coll Cardiol. 2020;76:292-302. doi: 10.1016/j.jacc.2020.05.045. \u003c/li\u003e\n\u003cli\u003eYokogawa N. Hydroxychloroquine to prevent recurrence of congenital heart block in fetuses of anti-SSA-positive mothers: an investigator-initiated, multi-center, clinical trial in Japan (J-PATCH). Precision Medicine. 2021;4:947-950. (Japanese Edition)\u003c/li\u003e\n\u003cli\u003eMiyano A, Nakayama M, Arai J, Yamaguchi K, Murashima A. Investigation of anti-SS-A/B antibody standardization using enzyme immunoassay. Clin Rheumatol. 2012;24:247-59. (Japanese Edition)\u003c/li\u003e\n\u003cli\u003eBordachar P, Whinnett Z, Ploux S, Labrousse L, Haissaguerre M, Thambo JB. Pathophysiology, clinical course, and management of congenital complete atrioventricular block. Heart Rhythm. 2013;10:760-6. doi: 10.1016/j.hrthm.2012.12.030. \u003c/li\u003e\n\u003cli\u003eBraga A, Barros T, Faria R, Marinho A, Rocha G, Farinha F, et al. Systemic Lupus Erythematosus and Pregnancy: a Portuguese Case-Control Study. Clin Rev Allergy Immunol. 2022;62:324-332. doi: 10.1007/s12016-021-08893-y.\u003c/li\u003e\n\u003cli\u003eMarder W, Littlejohn EA, Somers EC. Pregnancy and autoimmune connective tissue diseases. Best Pract Res Clin Rheumatol. 2016;30:63-80. doi: 10.1016/j.berh.2016.05.002.\u003c/li\u003e\n\u003cli\u003eTsuboi H, Sumida T, Noma H, Yamagishi K, Anami A, Fukushima K, et al. Maternal predictive factors for fetal congenital heart block in pregnant mothers positive for anti-SS-A antibodies. Mod Rheumatol. 2016;26:569-75. doi: 10.3109/14397595.2015.1106661. \u003c/li\u003e\n\u003cli\u003eVanoni F, Lava SAG, Fossali EF, Cavalli R, Simonetti GD, Bianchetti MG, et al. Neonatal Systemic Lupus Erythematosus Syndrome: a Comprehensive Review. Clin Rev Allergy Immunol. 2017;53:469-476. doi: 10.1007/s12016-017-8653-0.\u003c/li\u003e\n\u003cli\u003ePress J, Uziel Y, Laxer RM, Luy L, Hamilton RM, Silverman ED. Long-term outcome of mothers of children with complete congenital heart block. Am J Med. 1996;100:328-32. doi: 10.1016/S0002-9343(97)89492-2.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Anti-SS-A antibody-positive women, Anti-SS-A antibodies, Fetal congenital heart block","lastPublishedDoi":"10.21203/rs.3.rs-2302813/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2302813/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIdentifying predictive factors of fetal congenital heart block (CHB) in pregnant women with positive anti-SS-A antibodies is important to manage the cases properly.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively reviewed the medical records of 59 anti-SS-A antibody-positive women undergoing perinatal management at our hospital from January 2011 to November 2021. Univariate and multivariate analyses were performed to investigate predictive factors for the development of fetal CHB.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 59 women with positive anti-SS-A antibodies, 9 had fetal CHB. In univariate analysis, fetal CHB was associated with diagnosing connective tissue disease (OR 0.109, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.009) and positive anti-SS-A antibodies after conception (OR 31.333, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.0002). In multivariate analysis, diagnosing connective tissue disease was a protective factor (OR 0.049, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.025), and positive anti-SS-A antibody after conception was a risk factor (OR 41.738, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.004). However, other maternal clinical characteristics did not influence the development of fetal CHB.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn pregnancies of anti-SS-A antibody-positive women, diagnosing connective tissue disease was an independent protective factor for fetal CHB, and positive anti-SS-A antibody after conception was an independent risk factor.\u003c/p\u003e","manuscriptTitle":"Predictive factors of fetal congenital heart block in anti-SS-A antibody-positive pregnant women","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-07 16:06:38","doi":"10.21203/rs.3.rs-2302813/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"78010498-c150-42f7-baf7-4fcb485ce6cf","owner":[],"postedDate":"December 7th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-09T05:29:20+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-07 16:06:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2302813","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2302813","identity":"rs-2302813","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}