Knowledge is power: regarding SMFM Consult Series #64: Systemic lupus erythematosus in pregnancy.

The premise of the recommendations listed in the Society for Maternal-Fetal Medicine (SMFM) Consensus Statement #641 regarding the risk of fetal atrioventricular block (AVB) owing to maternal anti-Ro/SSA (anti–Sjögren-syndrome related antigen A) antibodies is that surveillance by echocardiography is unwarranted and unnecessary because treatment is futile. The authors contend that treatment of incomplete (1° and 2°) AVB does not prevent its progression and treatment of complete (3°) AVB does not improve outcomes. Such negative recommendations warrant balance, especially because they represent an oversimplification of an extremely complex topic. Moreover, the SMFM recommendations omit discussion of recent peer-reviewed publications presenting data at variance with the older literature referenced by the authors. Surveillance of anti-Ro/SSA exposed fetuses should represent a shared decision-making process with the patient, their rheumatologists and pediatric cardiologists, and the review of all available supporting evidence. We understand that this is a consensus statement—that is, a generally agreed upon statement by a group of experts. This is in contrast with a clinical practice guideline, where methodological requirements include a multidisciplinary panel, full systematic review, and GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) analysis, with formal voting for direction and strength of recommendations (strong or conditional). It is notable that the American College of Rheumatology (ACR) Reproductive Health Guideline (1A) conditionally recommends fetal echocardiograms and corticosteroid therapy, recognizing that this area is controversial, and that risks and benefits should be discussed with the patient in a shared decision-making process. The European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism [EULAR]) recommendations for pregnant subjects with anti-Ro/SSA antibodies and Sjogren syndrome also supports monitoring with echocardiography and the consideration of home Doppler monitoring, and steroid treatment for 2° AVB and 3° AVB with extranodal fetal cardiac disease.2Ramos-Casals M. Brito-Zerón P. Bombardieri S. et al.EULAR recommendations for the management of Sjogren’s syndrome with topical and systemic therapies.Ann Rheum Dis. 2020; 79: 3-18Crossref PubMed Scopus (264) Google Scholar In contrast, the suggested SMFM recommendation for fetal echocardiography and treatment are as strong (1B and 1C), but lacking in scientific rigor and at odds with the ACR and EULAR clinical practice guidelines. The stark differences between the society statements will result in more confusion for the clinician trying to do the right thing. It is understandable that prenatal treatment with fluorinated steroids (dexamethasone, betamethasone) and intravenous immunoglobulins (IVIG) is controversial because the treatment will not reverse isolated 3°AVB permanently, there are potential adverse effects on the developing fetus and the mother, and because survival is often attained without prenatal intervention. However, to limit amelioration of anti-Ro/SSA mediated cardiac disease to conduction system disease, and to judge the effect of treatment-only on the success of reversing AVB, is shortsighted. The rationale for treatment extends beyond restoring sinus rhythm and includes: 1) improved fetal and postnatal survival3Mawad W. Hornberger L. Cuneo B. et al.Outcome of antibody-mediated fetal heart disease with standardized anti-inflammatory transplacental treatment.J Am Heart Assoc. 2022; 11e023000Crossref Scopus (10) Google Scholar,4Sunderji S. Peyvandi S. Jaeggi E. et al.NAFTNet retrospective report on the treatment of anti-Ro/SSA mediated fetal heart block with dexamethasone.J Matern Fetal Neonatal Med. 2022; 35: 9263-9270Crossref PubMed Scopus (4) Google Scholar; 2) histologic evidence on autopsy that cardiac inflammation and fibrosis often extends beyond what echocardiography can detect5Levesque K. Morel N. Maltret A. et al.Description of 214 cases of autoimmune congenital heart block: results of the French neonatal lupus syndrome.Autoimmun Rev. 2015; 14: 1154-1160Crossref PubMed Scopus (104) Google Scholar; and 3) the ≥30% risk of dilated cardiomyopathy after birth, with heart failure, cardiac transplantation and/or premature death.6Llanos C. Friedman D.M. Saxena A. et al.Anatomical and pathological findings in hearts from fetuses and infants with cardiac manifestations of neonatal lupus.Rheumatol (Oxf Engl). 2012; 51: 1086-1092Crossref PubMed Scopus (86) Google Scholar,7Moak J.P. Barron K.S. Hougen T.J. et al.Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela.J Am Coll Cardiol. 2001; 37: 238-242Crossref PubMed Scopus (333) Google Scholar Treatment of 1° and 2° AVB has prevented the progression to 3° AVB and restored sinus rhythm in some cases.8Cuneo B.F. Sonesson S.E. Levasseur S. et al.Home monitoring for fetal heart rhythm during anti-Ro pregnancies.J Am Coll Cardiol. 2018; 72: 1940-1951Crossref PubMed Scopus (53) Google Scholar,9Cuneo B.F. Ambrose S.E. Tworetzky W. Detection and successful treatment of emergent anti-SSA-mediated fetal atrioventricular block.Am J Obstet Gynecol. 2016; 215: 527-528Abstract Full Text Full Text PDF PubMed Google Scholar Treatment of 1° and 2° AVB also decreases the outcome of dilated cardiomyopathy from 7% to 3%.3Mawad W. Hornberger L. Cuneo B. et al.Outcome of antibody-mediated fetal heart disease with standardized anti-inflammatory transplacental treatment.J Am Heart Assoc. 2022; 11e023000Crossref Scopus (10) Google Scholar Even acknowledging that treatment may not provide benefit in fetuses with isolated 3°AVB10Rivera T.L. Izmirly P.M. Birnbaum B.K. et al.Disease progression in mothers of children enrolled at the research registry for neonatal lupus.Ann Rheum Dis. 2009; 68: 828-835Crossref PubMed Scopus (95) Google Scholar should not be interpreted as a reason to eliminate surveillance because the purpose of surveillance is to avoid 3° AVB. Others have reported that treatment of fetuses with 3°AVB can increase fetal, neonatal and 1-year survival to 95%, 93%, and 89% respectively,3Mawad W. Hornberger L. Cuneo B. et al.Outcome of antibody-mediated fetal heart disease with standardized anti-inflammatory transplacental treatment.J Am Heart Assoc. 2022; 11e023000Crossref Scopus (10) Google Scholar a significant improvement compared with other contemporary studies that included untreated fetuses. The authors of the SMFM statement did not base their recommendations on any of the recent publications cited above; in fact, the dates of their references were from 1995 to 2016, with most having been published >10 years ago. From the literature cited, not all of the conclusions reached by Silver et al1Society for Maternal-Fetal Medicine (SMFM). Electronic address: [email protected], Silver R, Craigo S, et al. Society for Maternal-Fetal Medicine Consult Series #64: Systemic lupus erythematosus in pregnancy. Am J Obstet Gynecol 2023;228:B41–60.Google Scholar are accurate. Most fetuses with AVB are not born to mothers with systemic lupus erythematosus, as stated in the review, but to those who are completely asymptomatic or those with an undifferentiated autoimmune syndrome.10Rivera T.L. Izmirly P.M. Birnbaum B.K. et al.Disease progression in mothers of children enrolled at the research registry for neonatal lupus.Ann Rheum Dis. 2009; 68: 828-835Crossref PubMed Scopus (95) Google Scholar The results of the systematic review11Ciardulli A. D’Antonio F. Magro-Malosso E.R. et al.Maternal steroid therapy for fetuses with second-degree immune-mediated congenital atrioventricular block: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2018; 97: 787-794Crossref PubMed Scopus (32) Google Scholar were inconclusive regarding fetal monitoring and treatment benefit, and thus, should not necessarily be interpreted as negative. The cited prospective study regarding treatment was in fact a study of AV block prevention, with replacement dose (400 mg/kg) IVIG showing no benefit.12Friedman D.M. Llanos C. Izmirly P.M. et al.Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: results of a multicenter, prospective, open-label clinical trial.Arthritis Rheum. 2010; 62: 1138-1146Crossref PubMed Scopus (181) Google Scholar Higher anti-inflammatory doses of IVIG (1 g/kg, up to 70 g) have not been investigated for treatment in a randomized clinical trial. But a multicenter study (not included in the SMFM statement) showed that before IVIG was the standard of care, 85% of fetuses and infants died or received cardiac transplantation; and after it was routinely given, 80% of fetuses and infants were alive and without transplant for 1.1 to 9.8 years after birth.13Trucco S.M. Jaeggi E. Cuneo B. et al.Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibody-mediated cardiomyopathy.J Am Coll Cardiol. 2011; 57: 715-723Crossref PubMed Scopus (95) Google Scholar Regarding the prospective echocardiographic monitoring reported in PRIDE (PR Interval and Dexamethasone Evaluation) study,14Friedman D.M. Kim M.Y. Copel J.A. 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: 485-493Crossref PubMed Scopus (257) Google Scholar noncompliance of some affected pregnancies limited firm conclusions. Lastly, we agree that opinions vary on optimal surveillance and treatment for this disease. But a consensus statement on a topic with no consensus requires the equipoise of rheumatologists, pediatric cardiologists, and MFM specialists with experience and expertise in caring for these patients. Presently, the scientific rigor of the data is insufficient for a consensus statement, rendering the current statement premature at best. It is anticipated that the medical community and our patients would be better served by waiting for the outcomes of 2 studies that will lead to the necessary evidence-based guidelines. The first is the ongoing prospective AVB study STOP BLOQ (Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly; ClinicalTrials.gov identifier: NCT04474223) and the second is the Slow Heart Registry of Fetal Immune-mediated High Degree Heart Block (ClinicalTrials.gov identifier: NCT04559425). The STOP BLOQ study risk-stratifies pregnancies by anti-Ro/SSA antibody titer, employs thrice-daily home Doppler monitoring in high-titer pregnancies, and investigates the efficacy of rapid initiation of steroid and IVIG treatment on fetal 2° AVB, to restore normal rhythm or to prevent progression to 3°AVB or extranodal disease. The Slow Heart Registry prospectively compares morbidity and mortality between treated and untreated fetuses through the first 2 years of life. We fear that the current SMFM statement will negatively impact recruitment for these clinical trials that aim to provide the evidence that is so critically needed. In fact, some MFM specialists at STOP BLOQ sites are questioning referrals to the trial because of the consensus statement. Although consensus statements are not meant to be rigid directives for all patients, they do serve to guide clinical practice and consequently, the current statement may deter surveillance and treatment that has the potential to be lifesaving. Knowledge should be considered power until unambiguously proven otherwise. Society for Maternal-Fetal Medicine response to Cuneo et alAmerican Journal of Obstetrics & GynecologyVol. 229Issue 4PreviewWe thank Cuneo et al for their detailed response to the article entitled “Society for Maternal-Fetal Medicine Consult Series #64: Systemic Lupus Erythematosus in Pregnancy”1 and the concerns they raise about screening and management of patients with anti–Sjögren-syndrome related antigen A or B (anti-SSA/SSB) antibodies in pregnancy. We are encouraged by the many points of agreement we have. For example, we could not agree more that we must determine the care that optimizes outcomes for patients with these antibodies and their fetuses or infants. Full-Text PDF