2021 recommendations of the Brazilian Society of Rheumatology for the gynecological and obstetric care of patients with Sjogren’s syndrome

Fabiola Reis Oliveira Valeria Valim Sandra Gofinet Pasoto Marilena Leal Mesquita Silvestre Fernandes Maria Lucia Lemos Lopes Sonia Cristina de Magalhães Souza Fialho Aysa César Pinheiro Laura Caldas dos Santos Simone Appenzeller Tania Fidelix Sandra Lucia Euzébio Ribeiro Danielle Christinne Soares Egypto de Brito Tatiana Libório Maria Carmen Lopes Ferreira Silva Santos Leandro Tanure Juliana DAgostino Gennari Vinicius Tassoni Civile Ana Carolina Pereira Nunes Pinto César Ramos Rocha Filho Samira Tatiyama Miyamoto Lissiane Karine Noronha Guedes Alisson Pugliesi Virginia Fernandes Moça Trevisani About the authors

Abstract

Sjogren’s syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs. Women with SS often experience gynecological symptoms due to the disease and need extra care regarding their sexual activity, reproductive health and during pregnancy, conditions that are not properly conducted in the clinical practice. To cover this gap, a panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis on the identification of symptoms, diagnosis, monitoring, prognosis, and treatment of these manifestations. A Focus Group meeting was held and included experts in the field and methodologists, based on a previously developed script, with themes related to the objective of the study. The most important topics were summarized and 11 recommendations were provided.

Background

Sjogren’s syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs [11. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017;69(2326–5205 (Electronic)):35–45.]. The disease may occur in isolation, when it is called primary Sjogren’s syndrome (pSS), or in conjunction with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or another rheumatic disease, when it is called secondary Sjogren’s syndrome [22. Patel R, Shahane A. The epidemiology of Sjogren’s syndrome. Clin Epidemiol. 2014;30(1179–1349 (Print)):247–55.]. pSS is a common disease that affects 0.04–0.08% of people worldwide and has a female to male ratio of 9–14 to 1 [33. Qin B, Wang J, Yang Z, Yang M, Ma N, Huang F, et al. Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(11):1983. https://doi.org/10.1136/annrheumdis-2014-205375.
https://doi.org/10.1136/annrheumdis-2014...
]. As the process leads to progressively reduced or absent glandular secretion along with mucosal dryness, SS is characterized by symptoms ranging from xerophthalmia, xerostomia, fatigue, myalgia, and arthralgia to severe systemic symptoms with cutaneous, vascular, renal, pulmonary, or neurological involvement [22. Patel R, Shahane A. The epidemiology of Sjogren’s syndrome. Clin Epidemiol. 2014;30(1179–1349 (Print)):247–55.]. Besides these well-known symptoms, women with SS often experience vaginal dryness and dyspareunia, which result in a substantial disease burden as well as reduced quality of life [44. Fox RI. Sjögren’s syndrome. Lancet. 2005;366(9482):321–31. https://doi.org/10.1016/S0140-6736(05)66990-5.
https://doi.org/10.1016/S0140-6736(05)66...
]. Despite this, little attention has been given to gynecological and obstetric variables in women with SS [55. van Nimwegen JF, Arends S, van Zuiden GS, Vissink A, Kroese FG, Bootsma H. The impact of primary Sjögren’s syndrome on female sexual function. Rheumatology (Oxford). 2015;54(7):1286–93. https://doi.org/10.1093/rheumatology/keu522.
https://doi.org/10.1093/rheumatology/keu...
]. Knowledge of the main gynecological and obstetric characteristics is required for early diagnosis, careful monitoring, and multidisciplinary programs.

To address these gaps, the Sjögren’s syndrome Committee of the Brazilian Society of Rheumatology conducted a broad systematic review of the literature on population-based studies investigating gynecological symptoms and obstetric morbidities in Sjogren’s patients. The Brazilian Society of Rheumatology gathered the experts in the field and developed recommendations for the screening and management of women with these manifestations. Therefore, the current study represents an effort by this committee with the objective of retrieving the best available evidence and providing guidance for the identification of symptoms, diagnosis, monitoring, prognosis, and treatment of gynecological and obstetric manifestations in women with SS.

Methods

A systematic literature review was conducted of papers on the identification of symptoms, diagnosis, monitoring, prognosis, and treatment of gynecological and obstetric manifestations in women with Sjogren’s syndrome. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS, and Trip Database for studies published up to January 7th, 2021 (Fig. 1). A search strategy was designed for MEDLINE (Additional file 1: Appendix 1) and adapted for the main electronic databases. The search was conducted without language, date, or any other type of restriction. The methodological quality of studies reporting prevalence data was evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. We pooled clinical data by extracting the number of events and total patients to perform proportion meta-analysis. For studies that presented continuous data as medians and inter-quartile ranges, or as medians and ranges, we estimated means and standard deviations following the method described by Wan et al. [66. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. https://doi.org/10.1186/1471-2288-14-135.
https://doi.org/10.1186/1471-2288-14-135...
]. To present pooled results with their respective 95% confidence intervals (CI), we used the “meta” and “metafor” packages from R software (version 3.6.1). We used a generalized linear mixed model (GLMM) method with a random-effects model for pooling the results. To calculate an overall proportion, we used logit transformation. For continuous data, we pooled results of means with their respective 95% CI by the inverse variance method with a random-effects model. A panel composed by specialists in SS and members of the Sjögren’s syndrome Committee of Brazilian Society of Rheumatology elaborated question and recommendations. Agreement between the recommendations was achieved in a Focus Group meeting occurred on March 10th, 2020.

Fig. 1
Study flow diagram

Important points—gynecological care

  • Women with SS experience more genital discomfort related to dryness of the mucosa, which can be the cause of dyspareunia and decreased satisfaction with sexual activity. There is a prevailing association between these complaints and indices of poor quality of life.

  • The coincidence between age of onset and onset of climacteric symptoms in Sjogren’s Syndrome can worsen the framework.

  • These women are also more predisposed to reproductive disorders that harm fertility, although reduced gonadal reserve and premature ovarian failure are unusual.

  • The impact on fertility can be evidenced by oocyte quality and quantity rates, reduced serum levels of anti-mullerian hormone, and increased Luteinizing Hormone (LH) levels. Long menstrual cycles (> 35 days) may be associated with infertility.

Gynecological recommendations

  1. Active inquiry regarding genital and sexual complaints is recommended, since they are not spontaneously reported to the rheumatologist. (Hundred percent agreement).

  2. Patients should be referred for follow-up with the gynecologist. (Hundred percent agreement).

Gynecological involvement

Vaginal dryness, dyspareunia, genital infections

Women with SS experience vaginal discomfort related to mucosal dryness, which can be the cause of higher rates of dyspareunia and decreased satisfaction with sexual activity in this population [77. Lehrer S, Bogursky E, Yemini M, Kase NG, Birkenfeld A. Gynecologic mani-festations of Sjögren’s syndrome. Am J Obstet Gynecol. 1994;170(3):835– 7. https://doi.org/10.1016/s0002-9378(94)70294-2.
https://doi.org/10.1016/s0002-9378(94)70...
1010. Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjogren’s Syndrome. A clinical, pathological, and serological study of sixty-two cases. Medicine (Baltimore). 1965;44:187–231.]. The complaints become more relevant in the climacteric period, adding vaginal atrophy related to hypoestrogenism to the preexisting dryness [1111. Marchesoni D, Mozzanega B, De Sandre P, Romagnolo C, Gambari PF, Maggino T. Gynaecological aspects of primary Sjogren’s syndrome. Eur J Obstet Gynecol Reprod Biol. 1995;63(1):49–53. https://doi.org/10.1016/0301-2115(95)02224-u.
https://doi.org/10.1016/0301-2115(95)022...
]. The most common manifestations were vaginal dryness (prevalence of 64%) and dyspareunia (62%) (Figs. 2, 3; Table 1 on Additional file 1).

Fig. 2
Meta-analysis of the prevalence of vaginal dryness in women with Sjogren’s syndrome
Fig. 3
Meta-analysis of the prevalence of dyspareunia in women with Sjogren’s syndrome
Table 1
Brazilian recommendations for the gynecological and obstetric care of women of Sjogren Syndrome

Despite the changes occurring in the genital mucosa as a result of local dryness and the increased use of lubricant, there seems to be no high risk of vaginal infections in these cases [1212. van der Meulen TA, van Nimwegen JF, Harmsen HJM, Liefers SC, van der Tuuk K, Kroese FGM, et al. Normal vaginal microbiome in women with primary Sjögren’s syndrome-associated vaginal dryness. Ann Rheum Dis. 2019;78(5):707–9. https://doi.org/10.1136/annrheumdis-2018-214404.
https://doi.org/10.1136/annrheumdis-2018...
]. Previous data show that premenopausal SS women are not more exposed to vaginal infections than healthy women of the same age, although according to some authors they exhibit more inflammation and vaginal atrophy [1212. van der Meulen TA, van Nimwegen JF, Harmsen HJM, Liefers SC, van der Tuuk K, Kroese FGM, et al. Normal vaginal microbiome in women with primary Sjögren’s syndrome-associated vaginal dryness. Ann Rheum Dis. 2019;78(5):707–9. https://doi.org/10.1136/annrheumdis-2018-214404.
https://doi.org/10.1136/annrheumdis-2018...
, 1313. Capriello P, Barale E, Cappelli N, Lupo S, Teti G. Sjögren’s syndrome: clinical, cytological, histological and colposcopic aspects in women. Clin Exp Obstet Gynecol. 1988;15(1–2):9–12.]. Some studies indicate that the pH and composition of the vaginal microbiota are similar between reproductive-age SS patients and healthy controls and the most prevalent genera in this flora (Lactobacillus, Gardnerella, and Streptococcus) are equally found in both cases [1414. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci. 2011;108(Supplement 1):4680–7. https://doi.org/10.1073/pnas.1002611107.
https://doi.org/10.1073/pnas.1002611107...
]. In contrast, the changes in vaginal microbiota that occur postmenopause can be explained by hypoestrogenism and worsened by sicca due to SS. Lactobacilli use the breakdown products of glycogen to produce lactic acid, which contributes to low vaginal pH and thereby inhibits the growth of other bacteria. This phenomenon occurs through the influence of estrogen (premenopausal) and makes the health of this epithelium less dependent on dryness [1515. Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa R, et al. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate to severe dryness. PLoS ONE. 2011;6(11): e26602. https://doi.org/10.1371/journal.pone.0026602.
https://doi.org/10.1371/journal.pone.002...
, 1616. van Nimwegen JF, van der Tuuk K, Liefers SC, Verstappen GM, Visser A, Wijnsma RF, Vissink A, Hollema H, et al. Vaginal dryness in primary Sjögren’s syndrome: a histopathological case–control study. Rheumatology. 2020;59(10):2806–15. https://doi.org/10.1093/rheumatology/keaa017.
https://doi.org/10.1093/rheumatology/kea...
]. Contradictorily, the oral dryness leads to proliferation of Lactobacillus in the oral mucosa, which contributes to increased dental caries and Candida infection rates [1717. van der Meulen TA, Harmsen HJM, Bootsma H, Liefers SC, Vich Vila A, Zhernakova A, et al. Dysbiosis of the buccal mucosa microbiome in primary Sjögren’s syndrome patients. Rheumatology (Oxford). 2018;57(12):2225–34. https://doi.org/10.1093/rheumatology/key215.
https://doi.org/10.1093/rheumatology/key...
]. Despite this, additional genital infections can be expected in SS patients considering the set of dryness, hypoestrogenism, therapeutic regimens, and degree of immunosuppression to which they are submitted.

Sexual dysfunction

Sexual dysfunction refers to a multifactorial etiology of symptoms that compromise the quality of general and sexual lives of several individuals, including rheumatic patients, proportionally related to the chronicity of the disease [1818. Ferreira C, da Mota LM, Oliveira AC, de Carvalho JF, Lima RA, Simaan CK, et al. Frequency of sexual dysfunction in women with rheumatic diseases. Rev Bras Reumatol. 2013;53(1):35–46. https://doi.org/10.1016/s22555021(13)70004-x.
https://doi.org/10.1016/s22555021(13)700...
]. The evaluation of sexual dysfunction is heterogeneous in different societies, arising from cultural and religious influences. The female sexual function index (FSFI), in Rosen et al. [1919. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000;26(2):191–208. https://doi.org/10.1080/009262300278597.
https://doi.org/10.1080/009262300278597...
], is a female inventory of symptoms that takes into account six main domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. The lower the score achieved, the worse the quality of sexual life reported by the individuals [1919. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000;26(2):191–208. https://doi.org/10.1080/009262300278597.
https://doi.org/10.1080/009262300278597...
]. Pooled results from studies evaluating sexual dysfunction in women with Sjogren’s syndrome are displayed in Fig. 4.

Fig. 4
Meta-analysis of the female sexual function index (FSFI) in women with Sjogren’s syndrome

Studies on sexual dysfunction conducted in patients with SS and controlled by healthy women in the same age group using this specific instrument demonstrate significant impairment in the sexual life of SS patients. The results show lower means of total score, a lower frequency of sexual intercourse, and a worse index in the domains of lubrication and dyspareunia [55. van Nimwegen JF, Arends S, van Zuiden GS, Vissink A, Kroese FG, Bootsma H. The impact of primary Sjögren’s syndrome on female sexual function. Rheumatology (Oxford). 2015;54(7):1286–93. https://doi.org/10.1093/rheumatology/keu522.
https://doi.org/10.1093/rheumatology/keu...
, 2020. Yildiz Ç, Karakuş S, Bozoklu Akkar Ö, Şahin A, Bozkurt B, Yanik A. Primary Sjögren’s syndrome adversely affects the female sexual function assessed by the female sexual function index: a case–control study. Arch Rheumatol. 2017;32(2):1238. https://doi.org/10.5606/ArchRheumatol.2017.6066.
https://doi.org/10.5606/ArchRheumatol.20...
2222. Priori R, Minniti A, Derme M, Antonazzo B, Brancatisano F, Ghirini S, et al. Quality of sexual life in women with primary Sjögren syndrome. J Rheumatol. 2015;42(8):1427–31. https://doi.org/10.3899/jrheum.141475.
https://doi.org/10.3899/jrheum.141475...
].

There is a clear relationship of greater sexual dysfunction with age, with the degree of vaginal dryness, and with the physical impact of the disease (intensity of pain and fatigue measured by ESSPRI) in SS patients. The use of vaginal lubricants, apparently, improves sexual satisfaction in these cases [2121. Isik H, Isik M, Aynioglu O, Karcaaltincaba D, Sahbaz A, Beyazcicek T, et al. Are the women with Sjögren’s Syndrome satisfied with their sexual activity? Rev Bras Reumatol. 2017;57:210–6.].

A considerable proportion of patients do not raise complaints of a gynecological or sexual nature in rheu-matological appointments, since they do not associate them with the underlying disease or because of embarrassment [2121. Isik H, Isik M, Aynioglu O, Karcaaltincaba D, Sahbaz A, Beyazcicek T, et al. Are the women with Sjögren’s Syndrome satisfied with their sexual activity? Rev Bras Reumatol. 2017;57:210–6., 2323. Maddali Bongi S, Del Rosso A, Orlandi M, Matucci-Cerinic M. Gynaecological symptoms and sexual disability in women with primary Sjögren’s syndrome and sicca syndrome. Clin Exp Rheumatol. 2013;31(5):683–90.].

Fertility

Sjogren’s syndrome preferably affects women of nearmenopausal age and sometimes women of reproductive age. As in other autoimmune diseases (systemic lupus erythematosus, Hashimoto’s thyroiditis, etc.), reproductive dysfunctions like reduced gonadal reserve and early ovarian failure may occur [77. Lehrer S, Bogursky E, Yemini M, Kase NG, Birkenfeld A. Gynecologic mani-festations of Sjögren’s syndrome. Am J Obstet Gynecol. 1994;170(3):835– 7. https://doi.org/10.1016/s0002-9378(94)70294-2.
https://doi.org/10.1016/s0002-9378(94)70...
, 88. Skopouli FN, Papanikolaou S, Malamou-Mitsi V, Papanikolaou N, Moutsopoulos HM. Obstetric and gynaecological profile in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 1994;53(9):569–73. https://doi.org/10.1136/ard.53.9.569.
https://doi.org/10.1136/ard.53.9.569...
]. Two studies assessing reproductive dysfunction in women with Sjogren’s syndrome were pooled and the results are shown in Additional file 1: Appendix 2 (Fig. 5).

Fig. 5
Meta-analysis of the prevalence of reproductive dysfunction in women with Sjogren’s syndrome

Nevertheless, Lehrer et al. [77. Lehrer S, Bogursky E, Yemini M, Kase NG, Birkenfeld A. Gynecologic mani-festations of Sjögren’s syndrome. Am J Obstet Gynecol. 1994;170(3):835– 7. https://doi.org/10.1016/s0002-9378(94)70294-2.
https://doi.org/10.1016/s0002-9378(94)70...
], applied questionnaires on gynecological symptoms to 539 patients and the resulting data did not show statistical differences between Sjogren’s syndrome females and the healthy American population with respect to fertility rate (10% vs. 10–15%), miscarriage (17% vs. 12–16%), or premature ovarian failure [77. Lehrer S, Bogursky E, Yemini M, Kase NG, Birkenfeld A. Gynecologic mani-festations of Sjögren’s syndrome. Am J Obstet Gynecol. 1994;170(3):835– 7. https://doi.org/10.1016/s0002-9378(94)70294-2.
https://doi.org/10.1016/s0002-9378(94)70...
]. Skopouli et al., in a Greek cohort study from the same year, supported these findings of no impact on fertility, parity, or age at onset of menopause [88. Skopouli FN, Papanikolaou S, Malamou-Mitsi V, Papanikolaou N, Moutsopoulos HM. Obstetric and gynaecological profile in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 1994;53(9):569–73. https://doi.org/10.1136/ard.53.9.569.
https://doi.org/10.1136/ard.53.9.569...
].

Currently, the reduction in fertility can be measured by several parameters. The decrease in serum anti-mullerian hormone, rise in LH serum levels, and reduced amount in quantity and quality of oocytes are some of the methods employed. However, there is no consensus that patients with SS might submit the complete investigation routinely [2424. Karakus S, Sahin A, Durmaz Y, Aydin H, Yildiz C, Akkar O, et al. Evaluation of ovarian reserve using anti-müllerian hormone and antral follicle count in Sjögren’s syndrome: preliminary study. J Obstet Gynaecol Res. 2017;43(2):303–7. https://doi.org/10.1111/jog.13216.
https://doi.org/10.1111/jog.13216...
]. Prolactin levels may be higher in primary SS patients but it is unclear if there is any association to clinical, hormonal or immunological outcomes [2525. El Miedany YM, Ahmed I, Moustafa H, El Baddini M. Hyperprolactinemia in Sjogren’s syndrome: a patient subset or a disease manifestation? Joint Bone Spine. 2004;71(3):203–8. https://doi.org/10.1016/S1297-319X(03)00151-9.
https://doi.org/10.1016/S1297-319X(03)00...
2727. Gutiérrez MA, Anaya JM, Scopelitis E, Citera G, Silveira L, Espinoza LR. Hyperprolactinaemia in primary Sjögren’s syndrome. Ann Rheum Dis. 1994;53(6):425. https://doi.org/10.1136/ard.53.6.425-a. PMID: 80375 02; PMCID: PMC1005360.
https://doi.org/10.1136/ard.53.6.425-a...
]. Long menstrual cycles lasting more than 35 days seem to have some relationship with infertility in SS [77. Lehrer S, Bogursky E, Yemini M, Kase NG, Birkenfeld A. Gynecologic mani-festations of Sjögren’s syndrome. Am J Obstet Gynecol. 1994;170(3):835– 7. https://doi.org/10.1016/s0002-9378(94)70294-2.
https://doi.org/10.1016/s0002-9378(94)70...
].

Endometriosis

Endometriosis is an estrogen-dependent inflammatory disease caused by the implantation of endometrial tissue outside the uterus. It affects 2 to 10% of women of childbearing age and can cause pelvic pain, dysmenorrhea, and infertility [2828. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79. https://doi.org/10.1056/NEJMra0804690.
https://doi.org/10.1056/NEJMra0804690...
, 2929. Shigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, et al. The association between endometriosis and autoimmune diseases: a systematic review and metaanalysis. Hum Reprod Update. 2019;25(4):486–503. https://doi.org/10.1093/humupd/dmz014.
https://doi.org/10.1093/humupd/dmz014...
]. The gold standard of diagnosis is laparoscopy, only indicated in women with relevant symptoms. The phenomenon may occur through a combination of retrograde menstruation and disturbances in immune surveillance. A number of immunological changes have been described in endometriosis since the 80s, leading to the proposal of possible associations with cases of fibromyalgia, thyroiditis, multiple sclerosis, and arthritis. Apparently, SLE and SS are diseases with a higher risk ratio [3030. Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715–24. https://doi.org/10.1093/humrep/17.10.2715.
https://doi.org/10.1093/humrep/17.10.271...
].

It remains poorly defined, however, if the immunological alterations described, such as the circulating immunoglobulin surge, detection of anti-endometrial antibodies, and changes in the chemokine profile, could be inducing endometriosis or are simply a consequence of its presence.

It is not possible to stipulate the frequency of the association of endometriosis and SS, due both to different protocols used for diagnosing the first and to the lack of data in SS cohorts.

The majority of registry studies with analysis of a large number of patients with endometriosis in Spain, Denmark, and Israel [3131. Matorras R, Ocerin I, Unamuno M, Nieto A, Peiró E, Burgos J, et al. Prevalence of endometriosis in women with systemic lupus erythematosus and Sjögren’s syndrome. Lupus. 2007;16(9):736–40. https://doi.org/10.1177/0961203307081339.
https://doi.org/10.1177/0961203307081339...
3333. Greenbaum H, Weil C, Chodick G, Shalev V, Eisenberg VH. Evidence for an association between endometriosis, fibromyalgia, and autoimmune diseases. Am J Reprod Immunol. 2019;81(4): e13095. https://doi.org/10.1111/aji.13095.
https://doi.org/10.1111/aji.13095...
] failed to demonstrate an unequivocal association.

Contraception and hormonal replacement therapy

The use of contraceptive methods sometimes includes potential interactions among hormonal contraceptives and other medications, increase in infection risk with intrauterine devices and thrombosis [3434. Ammaritano LR. Therapy insight: guidelines for selection of contraception in women with rheumatic diseases. Nat Clin Pract Rheumatol. 2007;3(5):273–81. https://doi.org/10.1038/ncprheum0484 (quiz 305-6).
https://doi.org/10.1038/ncprheum0484...
] Menopausal hormone therapy (HT) has not been studied in SS patients. Decisions about which contraceptive methods and about the risks and benefits of HT use should be individualized and take into consideration patient's medical status, tobacco use, family history of hormonal-dependent cancers, laboratory features such as antiphospholipid antibody, and stage of reproductive live [3434. Ammaritano LR. Therapy insight: guidelines for selection of contraception in women with rheumatic diseases. Nat Clin Pract Rheumatol. 2007;3(5):273–81. https://doi.org/10.1038/ncprheum0484 (quiz 305-6).
https://doi.org/10.1038/ncprheum0484...
].

Important points—obstetric care

  • Neonatal lupus syndrome (NLS) results from the trans placental passage of maternal anti-SSA/ Ro antibodies around the eleventh week of pregnancy. The most severe manifestation is congenital heart block (CHB) which may require cardiac pacemaker implantation.

  • In addition to cardiac conduction system injuries in the newborn, fetal hydrops, liver dysfunctions, cytopenias, and transient skin lesions may also occur.

Obstetric recommendations

  1. 3.

    All pregnant women with SS should be assisted by a multidisciplinary team in a high-risk prenatal care center, regardless of the controversy in literature data on gestational outcomes such as spontaneous abortion rates, fetal growth restriction, or prematurity. (Hundred percent agreement).

  2. 4.

    It is recommended that the disease be well controlled in the 6 months before pregnancy and that the profile of antiphospholipid and anti-SSA/Ro antibodies be updated. (Hundred percent agreement).

  3. 5.

    Adjustment of pregnancy compatible drugs and specific vitamin supplements for pregnant women are recommended. The use of hydroxychloroquine should be encouraged in positive anti-SSA/Ro pregnant women and it is mandatory in pregnant women with a previous history of fetal heart block or other forms of neonatal lupus. (Hundred percent agreement).

Obstetric recommendations in the presence of Neonatal Lupus Syndrome risk

  1. 6.

    Prenatal care and delivery should be accomplished in a referral Hospital. (Hundred percent agreement).

  2. 7.

    Hydroxychloroquine (5 mg/kg/d) should be prescribed for all positive anti-SSA/Ro pregnant women because of its impact on reducing the recurrence of NLS (which can reach 20%) in subsequent pregnancies, compared to patients who do not use the drug. (Hundred percent agreement).

  3. 8.

    In these pregnant women, the effectiveness of treatment with corticosteroids, human immunoglobulin, β-sympathomimetics, or plasmapheresis is controversial. Dexamethasone may be useful in reversing carditis and incomplete blocks in addition to improving the hemodynamic conditions of the fetus. It is recommended that the decision for treatment be shared and adjusted considering each case. (Hundred percent agreement).

  4. 9.

    Electrocardiogram and weekly fetal echocardiography are recommended in the interval of greatest risk for the onset of heart block (CHB) and in the newborn (12–22 weeks). (Hundred percent agreement).

  5. 10.

    All newborns should also be evaluated with a blood count and liver assessment. The risk of these children developing an autoimmune disease in the future is not increased. (Hundred percent agreement).

  6. 11.

    Breastfeeding should be encouraged. (Hundred percent agreement).

Obstetric and fetal manifestations

Obstetric

Although fertility disorders are rare, the likelihood that women with autoimmune inflammatory diseases will have complicated pregnancies is much more significant. Forest plots for the incidence of obstetric and fetal outcomes in patients with Sjogren’s syndrome or rheumatic diseases with reactive anti-SSA/Ro antibodies are presented in Figs. 5, 6, 7, 8 and 9. The effects of underlying disease on pregnancy and of pregnancy on maternal health differ depending on the disease, pre-existing systemic damage, profile of autoantibodies, and type of prescription regime [3535. Carvalheiras G, Faria R, Braga J, Vasconcelos C. Fetal outcome in autoimmune diseases. Autoimmun Rev. 2012;11(6–7):A520–30. https://doi.org/10.1016/j.autrev.2011.12.002.
https://doi.org/10.1016/j.autrev.2011.12...
]. Data on pregnancies in primary Sjogren’s syndrome are scarce [55. van Nimwegen JF, Arends S, van Zuiden GS, Vissink A, Kroese FG, Bootsma H. The impact of primary Sjögren’s syndrome on female sexual function. Rheumatology (Oxford). 2015;54(7):1286–93. https://doi.org/10.1093/rheumatology/keu522.
https://doi.org/10.1093/rheumatology/keu...
]. In preliminary studies, with retrospective data collection, anti-SSA/Ro antibodies appear as a possible factor causing pregnancy loss [3636. Watson RM, Braunstein BL, Watson AJ, Hochberg MC, Provost TT. Fetal wastage in women with anti-Ro(SSA) antibody. J Rheumatol. 1986;13(1):90–4., 3737. Hull R, Harris E, Morgan S, Hughes G. Anti-Ro antibodies and abortions in women with SLE. Lancet. 1983;2:1138.]. Considering the high frequency of these antibodies in SS patients (60– 90%) compared to other rheumatic diseases such as SLE (30–50%) and RA (11%), we could assume higher rates of spontaneous abortions in pSS and in pregnant women with anti-SSA/Ro [3838. Routsias JG, Tzioufas AG. Sjögren’s syndrome-study of autoantigens and autoantibodies. Clin Rev Allergy Immunol. 2007;32:238–51. https://doi.org/10.1007/s12016-0078003-8.
https://doi.org/10.1007/s12016-0078003-8...
4040. Satoh M, Chan EK, Ho LA, Rose KM, Parks CG, Cohn RD, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum. 2012;64(7):2319–27. https://doi.org/10.1002/art.34380.
https://doi.org/10.1002/art.34380...
]. However, the literature does not show clinical or statistical differences between the outcomes of pregnancy in seropositive or seronegative patients [3838. Routsias JG, Tzioufas AG. Sjögren’s syndrome-study of autoantigens and autoantibodies. Clin Rev Allergy Immunol. 2007;32:238–51. https://doi.org/10.1007/s12016-0078003-8.
https://doi.org/10.1007/s12016-0078003-8...
4242. Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40(1):27–41. https://doi.org/10.1007/s12016-009-8190-6.
https://doi.org/10.1007/s12016-009-8190-...
].

Fig. 6
Meta-analysis of the incidence of spontaneous abortion in women with Sjogren’s syndrome or rheumatic diseases with reactive anti-SSA/Ro antibodies during pregnancy
Fig. 7
Meta-analysis of the incidence of intrauterine growth retardation in fetuses of women with Sjogren’s syndrome or rheumatic diseases with reactive anti-SSA/Ro antibodies
Fig. 8
Meta-analysis of the incidence of premature delivery in pregnant women with Sjogren’s syndrome or rheumatic diseases with reactive anti-SSA/Ro antibodies
Fig. 9
Meta-analysis of the incidence of congenital autoimmune heart block in fetuses of women with Sjogren’s syndrome or rheumatic diseases with reactive anti-SSA/Ro antibodies

Likewise, for some authors there is a higher rate of premature births and a lower neonatal average weight, explained by pathological restriction on intrauterine growth in SSA-positive pregnant women [4343. Priori R, Gattamelata A, Modesti M, Colafrancesco S, Frisenda S, Minniti A, et al. Outcome of pregnancy in Italian patients with primary Sjögren syndrome. J Rheumatol. 2013;40(7):1143–7. https://doi.org/10.3899/jrheum.121518.
https://doi.org/10.3899/jrheum.121518...
, 4444. Hussein SZ, Jacobsson LT, Lindquist PG, Theander E. Pregnancy and fetal outcome in women with primary Sjogren’s syndrome compared with women in the general population: a nested case-control study. Rheumatology (Oxford). 2011;50(9):1612–7. https://doi.org/10.1093/rheumatology/ker077.
https://doi.org/10.1093/rheumatology/ker...
]. Contradictorily, other studies do not show increased rates of prematurity or fetal growth restriction [88. Skopouli FN, Papanikolaou S, Malamou-Mitsi V, Papanikolaou N, Moutsopoulos HM. Obstetric and gynaecological profile in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 1994;53(9):569–73. https://doi.org/10.1136/ard.53.9.569.
https://doi.org/10.1136/ard.53.9.569...
, 4242. Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40(1):27–41. https://doi.org/10.1007/s12016-009-8190-6.
https://doi.org/10.1007/s12016-009-8190-...
, 4545. Martínez-Sánchez N, Pérez-Pinto S, Robles-Marhuenda Á, Arnalich-Fernández F, Martín Cameán M, Hueso Zalvide E, et al. Obstetric and perinatal outcome in anti Ro/SSA-positive pregnant women: a prospective cohort study. Immunol Res. 2017;65(2):487–94. https://doi.org/10.1007/s12026-016-8888-5.
https://doi.org/10.1007/s12026-016-8888-...
]. Even if the literature data are controversial regarding gestational outcomes, all pregnant women should be assisted in a high-risk prenatal care centre [4646. Gupta S, Gupta N. Sjögren Syndrome And Pregnancy: a literature review. Perm J. 2017;21:16–047. https://doi.org/10.7812/TPP/16-047.
https://doi.org/10.7812/TPP/16-047...
].

Furthermore, several authors agree that there is a higher rate of cesarean sections in Sjogren’s syndrome (see Additional file 1: Table 2).

For a safe pregnancy, SS patients must be well controlled for at least 6 months [4646. Gupta S, Gupta N. Sjögren Syndrome And Pregnancy: a literature review. Perm J. 2017;21:16–047. https://doi.org/10.7812/TPP/16-047.
https://doi.org/10.7812/TPP/16-047...
]. Adjustments for tapering and discontinuing some medications that require washout periods should be provided [4747. Korpen CG, Hoeltzenbein M, Tincani A, Fischer-betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheumatic Dis. 2016. https://doi.org/10.1136/annrheumdis-2015-208840.
https://doi.org/10.1136/annrheumdis-2015...
]. Mycophenolate mofetil, leflunomide, cyclophosphamide, methotrexate, and biologic disease modifying anti-rheumatic drugs like rituximab, belimumab and tocilizumab are the main drugs to be avoided [4747. Korpen CG, Hoeltzenbein M, Tincani A, Fischer-betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheumatic Dis. 2016. https://doi.org/10.1136/annrheumdis-2015-208840.
https://doi.org/10.1136/annrheumdis-2015...
4949. Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford). 2016. https://doi.org/10.1093/rheumatology/kev405.
https://doi.org/10.1093/rheumatology/kev...
]. Dietary supplementation with vitamins, minerals and folic acid should be indicated according to the specifics of each patient, by the gynecologist, in prenatal care. The use of hydroxychoroquine should be encouraged in positive anti-SSA/Ro pregnant women and it is mandatory in pregnant women with a previous history of fetal heart block or other forms of neonatal lupus [5050. Tunks RD, Clowse MEB, Miller SG, Brancazio LR, Barker PCA. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208(1):64.e1-7. https://doi.org/10.1016/j.ajog.2012.09.020.
https://doi.org/10.1016/j.ajog.2012.09.0...
] It's also recommended to update the profile of antiphospholipid, anti-SSB/La and anti-SSA/Ro antibodies at this time [4646. Gupta S, Gupta N. Sjögren Syndrome And Pregnancy: a literature review. Perm J. 2017;21:16–047. https://doi.org/10.7812/TPP/16-047.
https://doi.org/10.7812/TPP/16-047...
, 5050. Tunks RD, Clowse MEB, Miller SG, Brancazio LR, Barker PCA. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208(1):64.e1-7. https://doi.org/10.1016/j.ajog.2012.09.020.
https://doi.org/10.1016/j.ajog.2012.09.0...
].

Neonatal lupus syndrome (NLS)

One of the most feared gestational complications in patients with SS is neonatal lupus syndrome, especially congenital heart block (CHB) [4242. Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40(1):27–41. https://doi.org/10.1007/s12016-009-8190-6.
https://doi.org/10.1007/s12016-009-8190-...
].

NLS occurs as a result of passive transplacental passage of maternal anti-SSA and/or anti-SSB antibodies at the beginning of pregnancy (∼ 11 weeks) [4242. Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40(1):27–41. https://doi.org/10.1007/s12016-009-8190-6.
https://doi.org/10.1007/s12016-009-8190-...
]. It affects similarly male and female fetuses and can cause cardiac disease [4242. Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40(1):27–41. https://doi.org/10.1007/s12016-009-8190-6.
https://doi.org/10.1007/s12016-009-8190-...
4545. Martínez-Sánchez N, Pérez-Pinto S, Robles-Marhuenda Á, Arnalich-Fernández F, Martín Cameán M, Hueso Zalvide E, et al. Obstetric and perinatal outcome in anti Ro/SSA-positive pregnant women: a prospective cohort study. Immunol Res. 2017;65(2):487–94. https://doi.org/10.1007/s12026-016-8888-5.
https://doi.org/10.1007/s12026-016-8888-...
], skin lesions, cytopenias, neurological and hepatobiliary manifestations in the newborn [5151. Zuppa AA, Riccardi R, Frezza S, Gallini F, Luciano RM, Alighieri G, Romagnoli C, De Carolis S. Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Rev. 2017;16(4):427– 32. https://doi.org/10.1016/j.autrev.2017.02.010.
https://doi.org/10.1016/j.autrev.2017.02...
5454. Boros CA, Spence D, Blaser S, Silverman ED. Hydrocephalus and macrocephaly: new manifestations of neonatal lupus erythematosus. Arthritis Rheum. 2007;57(2):261–6. https://doi.org/10.1002/art.22543.
https://doi.org/10.1002/art.22543...
]. All the extracardiac injuries, usually mild and self-limited, may be present at birth or develop during the first months of life [5151. Zuppa AA, Riccardi R, Frezza S, Gallini F, Luciano RM, Alighieri G, Romagnoli C, De Carolis S. Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Rev. 2017;16(4):427– 32. https://doi.org/10.1016/j.autrev.2017.02.010.
https://doi.org/10.1016/j.autrev.2017.02...
, 5555. Julkunen H, Kaaja R, Kurki P, Palosuo T, Friman C. Fetal outcome in women with primary Sjögren’s syndrome. A retrospective case-control study. Clin Exp Rheumatol. 1995;13(1):65–71.]. Laboratory abnormalities in asymptomatic babies can be identified in up to one third of cases [5151. Zuppa AA, Riccardi R, Frezza S, Gallini F, Luciano RM, Alighieri G, Romagnoli C, De Carolis S. Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Rev. 2017;16(4):427– 32. https://doi.org/10.1016/j.autrev.2017.02.010.
https://doi.org/10.1016/j.autrev.2017.02...
, 5252. Cimaz 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(6):678– 83. https://doi.org/10.1067/mpd.2003.233.
https://doi.org/10.1067/mpd.2003.233...
, 5454. Boros CA, Spence D, Blaser S, Silverman ED. Hydrocephalus and macrocephaly: new manifestations of neonatal lupus erythematosus. Arthritis Rheum. 2007;57(2):261–6. https://doi.org/10.1002/art.22543.
https://doi.org/10.1002/art.22543...
].

Among the most significant cardiac injuries are arrhythmogenic damage to the conduction system, such as congenital autoimmune heart block (AVBc), endocardial fibroelastosis, and myocarditis, which can progress to dilated cardiomyopathy [5555. Julkunen H, Kaaja R, Kurki P, Palosuo T, Friman C. Fetal outcome in women with primary Sjögren’s syndrome. A retrospective case-control study. Clin Exp Rheumatol. 1995;13(1):65–71.6363. Askanase AD, Friedman DM, Copel J, Dische MR, Dubin A, Starc TJ, et al. Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro anti-SSB/La antibodies. Lupus. 2002;11(3):145– 51. https://doi.org/10.1191/0961203302lu173oa.
https://doi.org/10.1191/0961203302lu173o...
]. The increased risk period for the development of fetal heart injury is between 16 and 26 weeks of pregnancy and it can be detected by fetal echocardiography [4242. Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40(1):27–41. https://doi.org/10.1007/s12016-009-8190-6.
https://doi.org/10.1007/s12016-009-8190-...
, 5858. Brucato A, Frassi M, Franceschini F, Cimaz R, Faden D, Pisoni MP, et al. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum. 2001;44(8):1832–5. https://doi.org/10.1002/1529-0131(200108)44:8%3c1832::Aidart320%3e3.0.Co;2-c.
https://doi.org/10.1002/1529-0131(200108...
, 6464. Altman CA, Sheth SS. Could timing be everything for antibody-mediated congenital heart? J Am Coll Cardiol. 2018;72(16):1952–4. https://doi.org/10.1016/j.jacc.2018.08.1039.
https://doi.org/10.1016/j.jacc.2018.08.1...
6666. Friedman D, Buyon J, Kim M, Glickstein JS. Fetal cardiac function assessed by Doppler myocardial performance index (Tei index). Ultrasound Obstet Gynecol. 2003;21:33–6.]. In some studies, the prevalence of congenital autoimmune heart block (defined as atrioventricular block diagnosed in utero, at birth, or in the neonatal period) reaches 1–2% [4646. Gupta S, Gupta N. Sjögren Syndrome And Pregnancy: a literature review. Perm J. 2017;21:16–047. https://doi.org/10.7812/TPP/16-047.
https://doi.org/10.7812/TPP/16-047...
, 5555. Julkunen H, Kaaja R, Kurki P, Palosuo T, Friman C. Fetal outcome in women with primary Sjögren’s syndrome. A retrospective case-control study. Clin Exp Rheumatol. 1995;13(1):65–71., 5656. Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, Huong DL, Denjoy I, Vauthier D, et al. Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on electro-cardiographic variations in the children and comparison with a control group. Arthritis Rheum. 2004;50(10):3187–94. https://doi.org/10.1002/art.20554.
https://doi.org/10.1002/art.20554...
].

Irreversible third degree CBH is the most serious manifestation of NLS, requiring cardiac pacemaker implantation and beings associated with higher rates of intrauterine and perinatal mortality [5757. Gerosa M, Cimaz R, Stramba-Badiale M, Goulene K, Meregalli E, Trespidi L, et al. Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases—a multicentre prospective study. Rheumatology. 2007;46(8):1285–9. https://doi.org/10.1093/rheumatology/kem073.
https://doi.org/10.1093/rheumatology/kem...
, 6767. Buyon JP, Hiebert R, Copel J, et al. Autoimmune-associated congenital heart block: mortality, morbidity, and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998;31:1658–66.]. Electric conduction blocks, regardless of degree, can be detected by prenatal ultrasound between 18 and 24 weeks of gestation [6868. Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation. 2008;117(4):485–93. https://doi.org/10.1161/circulationaha.107.707661.
https://doi.org/10.1161/circulationaha.1...
]. Fetal bradycardia is the main finding, often the only one. Due to the existence of the gap between the transfer of maternal antibodies and development of the electric fetal conduction system (∼ 12 weeks) and the late clinical observation of CHB (∼ 20 weeks), without other structural fetal abnormalities, it becomes very difficult to fix any effective therapeutic intervention [6868. Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation. 2008;117(4):485–93. https://doi.org/10.1161/circulationaha.107.707661.
https://doi.org/10.1161/circulationaha.1...
].

Sinus bradycardia, atrioventricular nodal dysfunction, and increased QT interval are also included electrocardiographic disorders [5757. Gerosa M, Cimaz R, Stramba-Badiale M, Goulene K, Meregalli E, Trespidi L, et al. Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases—a multicentre prospective study. Rheumatology. 2007;46(8):1285–9. https://doi.org/10.1093/rheumatology/kem073.
https://doi.org/10.1093/rheumatology/kem...
, 5858. Brucato A, Frassi M, Franceschini F, Cimaz R, Faden D, Pisoni MP, et al. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum. 2001;44(8):1832–5. https://doi.org/10.1002/1529-0131(200108)44:8%3c1832::Aidart320%3e3.0.Co;2-c.
https://doi.org/10.1002/1529-0131(200108...
, 6868. Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation. 2008;117(4):485–93. https://doi.org/10.1161/circulationaha.107.707661.
https://doi.org/10.1161/circulationaha.1...
].

Some fetuses (6% of all cases of AVBc) may develop dilated cardiomyopathy and die from congestive heart failure or still require a heart transplant. Valve malformations, pulmonary artery stenosis, and atrial or ventricular septal defects have been reported occasionally [5959. Eronen M, Sirèn MK, Ekblad H, Tikanoja T, Julkunen H, Paavilainen T. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics. 2000;106(1 Pt 1):86–91. https://doi.org/10.1542/peds.106.1.86.
https://doi.org/10.1542/peds.106.1.86...
6262. Ho SY, Esscher E, Anderson RH, Michaëlsson M. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol. 1986;58(3):291–4. https://doi.org/10.1016/0002-9149(86)90064-0.
https://doi.org/10.1016/0002-9149(86)900...
]. Fetal necropsy findings also reveal unsuspected fibrotic lesions of the sinoatrial node [6262. Ho SY, Esscher E, Anderson RH, Michaëlsson M. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol. 1986;58(3):291–4. https://doi.org/10.1016/0002-9149(86)90064-0.
https://doi.org/10.1016/0002-9149(86)900...
].

Interestingly, asymptomatic fetuses and newborn infants with incomplete AV changes can evolve with a variable spectrum of cardiac injuries, even later and in the absence of circulating maternal antibodies, suggesting that an intrinsic factor (the fetal itself or the intrauterine environment) might be relevant in the progression of lesions [6363. Askanase AD, Friedman DM, Copel J, Dische MR, Dubin A, Starc TJ, et al. Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro anti-SSB/La antibodies. Lupus. 2002;11(3):145– 51. https://doi.org/10.1191/0961203302lu173oa.
https://doi.org/10.1191/0961203302lu173o...
].

A cardiac pacemaker is implanted in most of these fetuses in the neonatal period. Even asymptomatic patients with AVBc have an indication for prophylactic pacemaker implantation, due to the unpredictable risk of Stokes-Adams attacks [6363. Askanase AD, Friedman DM, Copel J, Dische MR, Dubin A, Starc TJ, et al. Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro anti-SSB/La antibodies. Lupus. 2002;11(3):145– 51. https://doi.org/10.1191/0961203302lu173oa.
https://doi.org/10.1191/0961203302lu173o...
, 6464. Altman CA, Sheth SS. Could timing be everything for antibody-mediated congenital heart? J Am Coll Cardiol. 2018;72(16):1952–4. https://doi.org/10.1016/j.jacc.2018.08.1039.
https://doi.org/10.1016/j.jacc.2018.08.1...
]. Intrauterine and neonatal mortality due to AVBc affects up to 30% of cases when associated with fetal hydrops and prematurity, even with advanced intensive care support [6464. Altman CA, Sheth SS. Could timing be everything for antibody-mediated congenital heart? J Am Coll Cardiol. 2018;72(16):1952–4. https://doi.org/10.1016/j.jacc.2018.08.1039.
https://doi.org/10.1016/j.jacc.2018.08.1...
].

The literature is controversial regarding the effectiveness of pharmacological therapy, be it the use of fluorinated corticosteroids that are resistant to the placental enzyme action or IVIG for the prevention or treatment of CHB. The rationale for this type of management in an attempt to obtain better outcomes for the fetus would be to: 1—reduce circulating maternal antibodies and placental transfer; 2—reduce cardiac tissue inflammation before fibrosis and irreversible AVBc [6969. Rosenthal D, Druzin M, Chin C, Dubin A. A new therapeutic approach to the fetus with congenital complete heart block: preemptive, targeted therapy with dexamethasone. Obstet Gynecol. 1998;92(4 Pt 2):689–91. https://doi.org/10.1016/s00297844(98)00149-5.
https://doi.org/10.1016/s00297844(98)001...
7373. Kaaja R, Julkunen H. Prevention of recurrence of congenital heart block with intravenous immunoglobulin and corticosteroid therapy. Arthritis Rheum. 2003;48(1):280–1.]. However, there is not enough evidence that this actually occurs or that the therapy can prevent AVBc, and safety of some regimes remains a concern [7474. Izmirly PM, Saxena A, Sahl SK, Shah U, Friedman DM, Kim MY, et al. Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis. 2016;75(6):11615. https://doi.org/10.1136/annrheumdis-2015-208311.
https://doi.org/10.1136/annrheumdis-2015...
7676. Levesque K, Morel N, Maltret A, Baron G, Masseau A, Orquevaux P, et al. Description of 214 cases of autoimmune congenital heart block: results of the French neonatal lupus syndrome. Autoimmun Rev. 2015;14(12):1154–60. https://doi.org/10.1016/j.autrev.2015.08.005.
https://doi.org/10.1016/j.autrev.2015.08...
]. In selected cases, studies support the idea that dexamethasone (but not prednisone) can reverse carditis and incomplete blocks in addition to improving the hemodynamic conditions of the fetus [7171. Copel JA, Buyon JP, Kleinman CS. Successful in utero therapy of fetal heart block. Am J Obstet Gynecol. 1995;173(5):1384–90. https://doi.org/10.1016/0002-9378(95)906215.
https://doi.org/10.1016/0002-9378(95)906...
7474. Izmirly PM, Saxena A, Sahl SK, Shah U, Friedman DM, Kim MY, et al. Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis. 2016;75(6):11615. https://doi.org/10.1136/annrheumdis-2015-208311.
https://doi.org/10.1136/annrheumdis-2015...
, 7777. Buyon JP, Clancy RM. Neonatal lupus: review of proposed pathogenesis and clinical data from the US-based Research Registry for Neonatal Lupus. Autoimmunity. 2003;36(1):41–50. https://doi.org/10.1080/0891693031000067340.
https://doi.org/10.1080/0891693031000067...
, 7878. Buyon JP, Hiebert R, Copel J, Craft J, Friedman D, Katholi M, et al. Autoimmune associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998;31(7):1658–66. https://doi.org/10.1016/s0735-1097(98)00161-2.
https://doi.org/10.1016/s0735-1097(98)00...
]. Sympathomimetic agent improves bradycardia but does not influence the prognosis [6868. Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation. 2008;117(4):485–93. https://doi.org/10.1161/circulationaha.107.707661.
https://doi.org/10.1161/circulationaha.1...
, 7979. Miyoshi T, Maeno Y, Sago H, Inamura N, Yasukohchi S, Kawataki M, et al. Evaluation of transplacental treatment for fetal congenital bradyarrhythmia: nationwide survey in Japan. Circ J. 2012;76:469–76.]. Plasmapheresis has been reported as a therapeutic option in a few case reports [8080. Barclay CS, French MA, Ross LD, Sokol RJ. Successful pregnancy following steroid therapy and plasma exchange in a woman with anti-Ro (SS-A) antibodies. Case report Br J Obstet Gynaecol. 1987;94(4):369–71. https://doi.org/10.1111/j.14710528.1987.tb03107.x.
https://doi.org/10.1111/j.14710528.1987....
].

The multicenter study by Cuneo et al. [8181. Cuneo BF, Sonesson SE, Levasseur S, Moon-Grady AJ, Krishnan A, Donofrio MT, et al. Home monitoring for fetal heart rhythm during anti-Ro pregnancies. J Am Coll Cardiol. 2018;72(16):1940–51. https://doi.org/10.1016/j.jacc.2018.07.076.
https://doi.org/10.1016/j.jacc.2018.07.0...
], followed 315 pregnant women with anti SSA/Ro antibodies through home monitoring, using a device for measuring the fetal heart rate and rhythm twice a day, and showed that the window of opportunity for therapeutic intervention is very slight [8181. Cuneo BF, Sonesson SE, Levasseur S, Moon-Grady AJ, Krishnan A, Donofrio MT, et al. Home monitoring for fetal heart rhythm during anti-Ro pregnancies. J Am Coll Cardiol. 2018;72(16):1940–51. https://doi.org/10.1016/j.jacc.2018.07.076.
https://doi.org/10.1016/j.jacc.2018.07.0...
].

The recurrence of AVBc in a subsequent pregnancy is approximately 10 times greater [7878. Buyon JP, Hiebert R, Copel J, Craft J, Friedman D, Katholi M, et al. Autoimmune associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998;31(7):1658–66. https://doi.org/10.1016/s0735-1097(98)00161-2.
https://doi.org/10.1016/s0735-1097(98)00...
, 8282. Julkunen H, Eronen M. The rate of recurrence of isolated congenital heart block: a population-based study. Arthritis Rheum. 2001;44(2):487–8. https://doi.org/10.1002/1529-0131(200102)44:2%3c487::Aidanr70%3e3.0.Co;2-d.
https://doi.org/10.1002/1529-0131(200102...
] and the rate of NLS reaches 20% [6868. Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation. 2008;117(4):485–93. https://doi.org/10.1161/circulationaha.107.707661.
https://doi.org/10.1161/circulationaha.1...
, 8383. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus. 2001;10(6):401–4. https://doi.org/10.1191/096120301678646137.
https://doi.org/10.1191/0961203016786461...
]. Hydroxychloroquine (HCQ) impacts on reducing these outcomes and it has not been related to fetal malformations or hearing and visual risks evaluated in the first year of life [7474. Izmirly PM, Saxena A, Sahl SK, Shah U, Friedman DM, Kim MY, et al. Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis. 2016;75(6):11615. https://doi.org/10.1136/annrheumdis-2015-208311.
https://doi.org/10.1136/annrheumdis-2015...
, 7575. Costedoat-Chalumeau N, Amoura Z, Le Thi HD, Wechsler B, Vauthier D, Ghillani P, et al. Questions about dexamethasone use for the prevention of anti-SSA related congenital heart block. Ann Rheum Dis. 2003;62(10):1010–2. https://doi.org/10.1136/ard.62.10.1010.
https://doi.org/10.1136/ard.62.10.1010...
, 8383. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus. 2001;10(6):401–4. https://doi.org/10.1191/096120301678646137.
https://doi.org/10.1191/0961203016786461...
, 8484. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126(1):76–82. https://doi.org/10.1161/circulationaha.111.089268.
https://doi.org/10.1161/circulationaha.1...
]. Several retrospective studies suggest that women taking hydroxychloroquine are less likely to have a fetus with second- or third-degree heart block [5050. Tunks RD, Clowse MEB, Miller SG, Brancazio LR, Barker PCA. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208(1):64.e1-7. https://doi.org/10.1016/j.ajog.2012.09.020.
https://doi.org/10.1016/j.ajog.2012.09.0...
, 8484. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126(1):76–82. https://doi.org/10.1161/circulationaha.111.089268.
https://doi.org/10.1161/circulationaha.1...
]. Most authors recommend the administration of HCQ before conception and another part as soon as the patient with positive anti-SSA becomes pregnant [5050. Tunks RD, Clowse MEB, Miller SG, Brancazio LR, Barker PCA. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208(1):64.e1-7. https://doi.org/10.1016/j.ajog.2012.09.020.
https://doi.org/10.1016/j.ajog.2012.09.0...
, 8383. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus. 2001;10(6):401–4. https://doi.org/10.1191/096120301678646137.
https://doi.org/10.1191/0961203016786461...
, 8484. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126(1):76–82. https://doi.org/10.1161/circulationaha.111.089268.
https://doi.org/10.1161/circulationaha.1...
].

Management of the newborn with NLS

Specific procedures are adopted according to the manifestation presented by each child [8585. Vanoni F, Lava SA, Fossali EF, Cavalli R, Simonetti GD, Bianchetti MG, et al. Neonatal systemic lupus erythematosus syndrome: a comprehensive review. Clin Rev Allergy Immunol. 2017;53(3):469–76. https://doi.org/10.1007/s12016-017-8653-0.
https://doi.org/10.1007/s12016-017-8653-...
].

Skin lesion

A transient, erythematous-desquamative or erythematous-annular and photosensitive skin rash similar to that found in SLE can appear at birth (20%) and up to 2–3 months later (80%). The lesions last for the period of clearance of the circulating maternal antibodies and usually resolve spontaneously without leaving scars, and therefore do not require drug treatment [8686. Lee LA, Weston WL. Cutaneous lupus erythematosus during the neonatal and childhood periods. Lupus. 1997;6(2):132–8. https://doi.org/10.1177/096120339700600208.
https://doi.org/10.1177/0961203397006002...
, 8787. Neiman AR, Lee LA, Weston WL, Buyon JP. Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J Pediatr. 2000;137(5):674–80. https://doi.org/10.1067/mpd.2000.109108.
https://doi.org/10.1067/mpd.2000.109108...
]. Histological and immunofluorescence findings are similar to subacute cutaneous lupus. Newborns with skin lesions should be protected from sun exposure until complete regression [8585. Vanoni F, Lava SA, Fossali EF, Cavalli R, Simonetti GD, Bianchetti MG, et al. Neonatal systemic lupus erythematosus syndrome: a comprehensive review. Clin Rev Allergy Immunol. 2017;53(3):469–76. https://doi.org/10.1007/s12016-017-8653-0.
https://doi.org/10.1007/s12016-017-8653-...
, 8888. Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: issues in diagnosis and treatment. Am J Clin Dermatol. 2009;10:365–81.].

Cytopenias:

Thrombocytopenia, anemia, and neutropenia are described in NLS. According to Cimaz et al., [5252. Cimaz 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(6):678– 83. https://doi.org/10.1067/mpd.2003.233.
https://doi.org/10.1067/mpd.2003.233...
], inconspicuous hematological variations can occur in up to 27% of those born to positive anti-SSA mothers and revert spontaneously. Cases of anemia or severe thrombocytopenia may require blood transfusions, the use of corticosteroids, and intravenous human immunoglobulin in their treatment [5252. Cimaz 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(6):678– 83. https://doi.org/10.1067/mpd.2003.233.
https://doi.org/10.1067/mpd.2003.233...
, 8989. Watson R, Kang JE, May M, Hudak M, Kickler T, Provost TT. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol. 1988;124(4):560–3., 9090. Kanagasegar S, Cimaz R, Kurien BT, Brucato A, Scofield RH. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions. J Rheumatol. 2002;29(1):187–91.].

Hepatic

Liver disorders range from a slight increase in serum transaminases to severe cholestatic syndrome, hepatomegaly and, rarely, splenomegaly [5252. Cimaz 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(6):678– 83. https://doi.org/10.1067/mpd.2003.233.
https://doi.org/10.1067/mpd.2003.233...
, 5353. Motta M, Rodriguez-Perez C, Tincani A, Lojacono A, Chirico G. Outcome of infants from mothers with anti-SSA/Ro antibodies. J Perinatol. 2007;27(5):278–83. https://doi.org/10.1038/sj.jp.7211688.
https://doi.org/10.1038/sj.jp.7211688...
, 9191. Laxer RM, Roberts EA, Gross KR, Britton JR, Cutz E, Dimmick J, et al. Liver disease in neonatal lupus erythematosus. J Pediatr. 1990;116(2):238–42. https://doi.org/10.1016/s0022-3476(05)82880-x.
https://doi.org/10.1016/s0022-3476(05)82...
].

Neurological

Non-specific CNS anomalies on cerebral image, in absent of clinical neurological findings, are reported in newborns with NLS [5151. Zuppa AA, Riccardi R, Frezza S, Gallini F, Luciano RM, Alighieri G, Romagnoli C, De Carolis S. Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Rev. 2017;16(4):427– 32. https://doi.org/10.1016/j.autrev.2017.02.010.
https://doi.org/10.1016/j.autrev.2017.02...
, 5454. Boros CA, Spence D, Blaser S, Silverman ED. Hydrocephalus and macrocephaly: new manifestations of neonatal lupus erythematosus. Arthritis Rheum. 2007;57(2):261–6. https://doi.org/10.1002/art.22543.
https://doi.org/10.1002/art.22543...
]. The anomalies resolve during follow-up and do not present any clinical correlate.

Cardiac

The most common involvement is AVBc of the first, second, and third degrees usually without structural cardiac lesions. The treatment of intrauterine fetal atrioventricular block is often disappointing and more than 90% of affected newborns undergo definitive pacemaker implantation. Fortunately, these children can lead practically normal lives if there is no associated cardiomyopathy [9292. Martin V, Lee LA, Askanase AD, Katholi M, Buyon JP. Long-term followup of children with neonatal lupus and their unaffected siblings. Arthritis Rheum. 2002;46(9):2377–83. https://doi.org/10.1002/art.10638.
https://doi.org/10.1002/art.10638...
].

After birth, a progressive reduction of anti SSA/Ro blood titers occurs over 6 months.

A clinical and laboratorial follow-up should be performed in all infants, until the first year of life [5151. Zuppa AA, Riccardi R, Frezza S, Gallini F, Luciano RM, Alighieri G, Romagnoli C, De Carolis S. Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Rev. 2017;16(4):427– 32. https://doi.org/10.1016/j.autrev.2017.02.010.
https://doi.org/10.1016/j.autrev.2017.02...
]. The risk of children with NLS developing autoimmune diseases in the future is not superior than the risk of asymptomatic children born to mothers with autoimmune diseases. There is no contraindication to breastfeeding [5252. Cimaz 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(6):678– 83. https://doi.org/10.1067/mpd.2003.233.
https://doi.org/10.1067/mpd.2003.233...
, 9292. Martin V, Lee LA, Askanase AD, Katholi M, Buyon JP. Long-term followup of children with neonatal lupus and their unaffected siblings. Arthritis Rheum. 2002;46(9):2377–83. https://doi.org/10.1002/art.10638.
https://doi.org/10.1002/art.10638...
, 9393. Cimaz R. Any increased risk of autoimmune disease? Lupus. 2004;13(9):736–9. https://doi.org/10.1191/0961203303lu1093oa.
https://doi.org/10.1191/0961203303lu1093...
].

The topic of neonatal lupus syndrome is vast, especially in the field of fetal heart block, and goes beyond Sjogren's syndrome. We do not intend to exhaust all the content in this approach (Table 1).

Conclusions

Despite its importance, the gynecological and obstetric care of patients with SS are not as properly incorporated in the clinical practice, as sicca symptoms or extra glandular manifestations are. A significative prevalence of gynecological symptoms and obstetric care needs were identified in this systematic review and meta-analysis as well a high morbidity associated with them. To attend these demands and improve pSS women's health care, our panel of specialists developed eleven recommendations, all of them with high agreement between the members. A limitation of our guideline was the absence of a patient representative or a gynecologist/obstetric in the voting panel, a strategy that will be used in future guidelines.

  • Funding
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  • Availability of data and materials
    All data generated or analyzed during this study are included in this published article (and its Additional file 1).
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  • Ethics approval and consent to participate
    Not applicable.
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Acknowledgements

Not applicable.

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Additional file 1.

Table 1: Gynecological symptoms in Sjogren's syndrome patients.

Table 2: Gestational outcomes in patients with Sjogren’s syndrome or rheumatic diseases with reactive anti-SSA / Ro antibodies.

Publication Dates

  • Publication in this collection
    27 Sept 2021
  • Date of issue
    2021

History

  • Received
    01 June 2021
  • Accepted
    03 Aug 2021
  • Published
    03 Sept 2021
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