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Background:Congenital heart block (CHB) is due to placental transfer of maternal anti-Ro/SSA autoantibodies to the fetus. The prevalence of CHB has been estimated as 1-2% in anti-Ro/SSA women while the recurrence rate is 16-19% (1). This condition is associated with a high rate of fetal/neonatal mortality and most of the cases requires pacemaker (PM) pacing. Given the rarity of CHB, limited data are available regarding the long-term follow-up of the offspring other than the cardiovascular complications.Objectives:The results of the Italian Registry of the autoimmune congenital heart block were recently described (2). A peculiarity of this cohort was that most of the mothers had an established diagnosis of systemic autoimmune disease at CHB detection, in contrast with other registries where CHB was mostly incidentally detected in healthy women. Here we report an update, with the preliminary data regarding the long-term outcome of patients with CHB, their unaffected siblings and health controls born from mothers positive for Ro/SSA.Methods:Data regarding demography, treatment, maternal, neonatal outcome, and follow-up were collected through an online electronic datasheet. A dedicated questionnaire was created with the aim to investigate general health, cardiovascular follow-up, and frequency of autoimmune diseases.Results:One-hundred and five cases of CHB in 99 patients were included from 1969 to December 2020. CHB was mostly detected in utero (97 cases, 92.3%) with 8 neonatal cases. Third degree CHB occurred in 71 cases (67.6%). Child mortality was observed in 29 (27.6%) cases: 20 in utero, 7 during neonatal period and 2 during childhood. Overall, a PM was implanted in 54 out of the 85 live births (63.5%). Then, our cohort was divided into 2 subgroups: pregnancy that occurred before (N=61) and after 2010 (N=44) with the aim to evaluate possible differences among the subgroups. Whereas mortality, PM, CHB degree were similar, CHB more frequently occurred in the last 10 years among Ro/SSA asymptomatic carriers than in the group of pregnancies before 2010 (53.6% vs 32.8%, p=0.038). Questionnaires from 14 surviving CHB cases, 8 unaffected siblings 12 controls born from mothers Ro/SSA positive were collected. Among CHB cases, 6 were males and 8 females, median age 12 years (range 6-28). All presented a third degree CHB, 10 required a neonatal PM pacing and one had an implantable ECG recorder. PM was substituted at least once in 9 patients, the oldest patient had to change it four times. No dilated cardiomyopathy occurred and most of the patients maintain an annual follow-up. Two cases of autoimmune diseases were registered among CHB cases, one idiopathic juvenile arthritis and one Cogan’s vasculitis, both born from mothers with Sjogren Syndrome. Four cases of neurodevelopmental disorders occurred: three cases of learning disabilities (one in each group) and one case of speech disorder in the sibling group. In addition, a CHB case presented a stress disorder linked to frequent hospitalizations.Conclusion:This registry is an ongoing project aiming at collecting all Italian CHB. Moreover, here we reported the preliminary data concerning the evaluation of long-term follow-up of CHB patients. Our data, even if need to be confirmed in larger cohort, seems reassuring: no differences were reported comparing CHB patients with unaffected siblings or controls.References:[1]Brito-Zéron et al. Nat Rev Rheumatol 2015;11:301-312.[2]Fredi M et al. Front Cardiovasc Med. 2019 Feb 28;6:11.Disclosure of Interests:None declared

Background:The role of complement in the antiphospholipid (aPL) related pathology has been widely studied in animal models. Antiphospholipid antibodies can induce fetal loss in experimental animals but mice deficient in specific complement components (C4, C3, C5) appear somehow protected. In addition, in pregnant mice injected with aPL, antibody deposition has been found at decidual level causing focal necrosis, apoptosis and neutrophil infiltrates and supporting aPL pathogenetic potential. On the other hand, human studies did find hypocomplementemia associated to pregnancy complications in patients with obstetric antiphospholipid syndrome (APS). These results, however, are not unanimously confirmed and, in addition, some studies only show increased levels of complement activation products (i.e. Bb) and not decreased levels of C3 and/or C4. A recently study focusing on complement level in early pregnancy and before pregnancy showed a significant correlation with pregnancy complications and loss in a large cohort of primary APS.Objectives:To investigate if the simple detection of low C3 and/or C4 could be considered a risk factor for adverse pregnancy outcome in APS and aPL carriers pregnancies.Methods:We performed a multicentric study including patients from 10 Italian and 1 Russian Centers. Data on pregnancies in women with primary APS (n=434) and asymptomatic carriers with persistently positive aPL but not fulfilling clinical criteria for APS (n=218) were retrospectively collected. Serum C3 and C4 levels were evaluated by nephelometry; hypocomplementemia was defined by local laboratory reference values. Statistical analysis was performed using GraphPad.Results:Preconceptional complement levels and gestational outcome were available for 107 (25%) pregnancies in APS out of 434 and for 196 (90%) pregnancies in aPL carriers women out of 218. In pregnancies with low preconceptional C3 and/or C4, a significantly higher prevalence of pregnancy losses was observed (p=0.019). A subgroup analysis focusing on triple aPL positive patients was also performed. Preconceptional low C3 and/or C4 levels were found to be associated with an increased rate of pregnancy loss (p = 0.027) in this subgroup also. Otherwise, adverse pregnancy outcomes in single or double aPL positive women were not related to preconception complement levels (p = 0.44) (Table 1). Of note, all the pregnancy losses in the triple positive group occurred in patients treated with low dose aspirin and low molecular weight heparin from the time of positive pregnancy test.Conclusion:Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of adverse outcome. This has been seen only in in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss. test positivity.References:[1]De Carolis S, et al. Complementemia and obstetric outcome in pregnancy with antiphospholipid syndrome. Lupus (2012) 21:776–8.[2]Kim MY, et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis (2018) 77:549–55.[3]Fredi M, et al. Risk Factors for Adverse Maternal and Fetal Outcomes in Women With Confirmed aPL Positivity: Results From a Multicenter Study of 283 Pregnancies. Front Immunol. 2018 May 7;9:864.Triple aPL positivitySingle or double aPL positivityGestational outcomeLow C3/C4 (n=49)Normal C3/C4(n=17)pLow C3/C4 (n=57)Normal C3/C4(n=165)pTerm live birth (>37w)15 (31%)6 (35%)ns34 (60%)110 (67%)nsPreterm live birth (≤37w)22 (45%)11 (65%)ns15 (26%)38 (23%)nsPregnancy losses (abortion and miscarriages)12 (24%)0 (0%)0.0278 (14%) 17 (10%)nsDisclosure of Interests:None declared

Background:Antiphospholipid (aPL) antibodies are considered in obstetric morbidity even when Sydney criteria for OAPS are not met. Classification and treatment of NC-OAPS patients and aPL carriers during pregnancy are still debated.Objectives:To increase knowledge, we evaluated and compared aPL serum profiles, exposure to antithrombotic therapies and pregnancy outcomes in OAPS, NC-OAPS and aPL carrier patients, accessing to our centre.Methods:A retrospective observational study was conducted on pregnant outpatients from January 2003 to April 2020. According to Sydney revised classification criteria, we considered lupus anticoagulant (LA), IgM and IgG anti-cardiolipin antibodies (aCL), IgM and IgG antibeta2 glycoprotein I antibodies (aβ2-GPI), to stratify aPL risk profiles [Ref]. In each pregnancy, after case stratification into high (≥ 2 aPL or LA serum positivity) versus low (single aPL positivity) risk profile, we evaluated antithrombotic treatment strategy and subsequent pregnancy outcomes as live-births, spontaneous abortions (SA) or foetal losses.Results:A total of 78 pregnancies were followed: 17 in OAPS, 9 in NC-OAPS and 52 in aPL carrier patients. Rheumatic diseases (RD) coexisted predominately in carriers (73.1%), mainly systemic lupus erythematosus (57.9%). As presented in Table 1, in OAPS and aPL plus RD carrier groups the association of acetyl-salicylic acid (ASA - mean dose 100 mg q.d.) and low-molecular weight heparin (LMWH - mean dose 4000 UI q.d.) showed a better rate of positive outcomes (97.8% of pregnancies) in high aPL risk profile, compared to monotherapy, especially with LA or triple aPL positivity. Conversely, negative outcomes occurred mostly with triple aPL positivity in the first group and double aPL in the second, despite therapy approaches. No significant data were obtained in NC-OAPS group, due to its paucity, though adverse outcomes were observed with monotherapy both in high and low risk profiles. Except aPL carriers with RD, in all other low risk subgroups, a prevalence of negative outcomes occurred using ASA alone, without statistical significance (OR 0; p= 0.45). Similarly, considering the whole population, the use of a mono or a combination therapy in high risk subgroups had not a significant correlation with pregnancy outcomes (OR 1.79; 95%CI 0.31-10.15; p= 0.50).Conclusion:In our study, negative pregnancy outcomes were sporadic, occurring mostly with ≥ 2 aPL positivity. Combination treatment showed better results overall in high aPL risk profile patients, both in OAPS and NC-OAPS or aPL carriers. Though no significant correlation between outcomes and treatments were found, we hinted how aPL-based risk stratification may be useful in adopting personalised therapies to prevent obstetric failures.Reference:[1]Miyakis S, et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 4:295–306.Table 1.Population groups, aPL risk profiles, antithrombotic therapies and pregnancy outcomes.Population groupaPL risk profileType/n° of aPLTherapy (n° of pregnancies)Pregnancy outcomesOAPSHighLAASA (1)ASA + LMWH (1)1 live-birth1 live-birth2 aPLASA + LMWH (3)3 live-births3 aPLASA + LMWH (9)7 live-births 2 foetal lossesLow1 aPLASA (2)ASA + LMWH (1)1 live-birth1 foetal loss1 live-birthNC-OAPSHighLA--2 aPLASA (1)LMWH (1)1 live-birth1 SA3 aPL--Low1 aPLASA (6)ASA + LMWH (1)5 live-births1 SA1 live-birthaPL carriers without RDHighLAASA (1)LMWH (1)1 live-birth1 live-birth2 aPLASA (1)LMWH (2)1 live-birth2 live-births3 aPLASA (1)ASA + LMWH (3)1 live-birth3 live-birthsLow1 aPLASA (5)4 live-births1 foetal lossaPL carriers with RDHighLAASA (4)ASA + LMWH (7)3 live-birth1 foetal loss6 live-births1 SA2 aPLASA (6)ASA + LMWH (4)6 live-births2 live-births1 SA1 foetal loss3 aPLLMWH (2)ASA + LMWH (5)2 live-births5 live-birthsLow1 aPLASA (8)ASA + LMWH (3)8 live-births3 live-birthsDisclosure of Interests:None declared