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Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers’ pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only 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.

BackgroundAntiphospholipid antibody syndrome (APS) is an autoimmune disease that affects women in childbearing age. In recent years, great improvements were achieved in the management of pregnancies in these women. Prematurity could be an issue in these pregnancies, mainly due to the direct pathogenic effect of antiphospholipid antibodies (aPL) on the placental surface. Maternal IgG aPL can cross the placenta and theoretically interact with the growing fetus; it could reach the fetal brain because of the incompleteness of the fetal blood-brain barrier: whether this can have an effect on brain development is still debated. Neonatal thrombosis episodes have been described in children positive for aPL, not always associated with maternal antibody positivity, suggesting the hypothesis of a possible aPL de novo synthesis in fetus and neonates.MethodsA keyword-based literature search was conducted. We also described a case of neonatal catastrophic antiphospholipid syndrome (CAPS).ResultsOffspring of patients with APS are generally healthy but the occurrence of neonatal thrombosis or minor neurological disorders were reported.ConclusionsThe limited number of the available data on this sensitive issue supports the need for further studies. Clinical follow-up of children of mothers with APS seems to be important to exclude, in the neonatal period, the occurrence of aPL associated pathological events such as thrombosis, and in the long-term, impairment in learning skills or behavioral problems.

Background:In SLE pregnancies adverse pregnancy outcomes (APO) are more frequent than in general obstetric population (GOP). In clinical practice, low C3 and C4 levels are associated with active disease and, during pregnancy, complement activation products are shown to be associated with APO.Objectives:To analyse complement variations during SLE pregnancies, focusing on disease flares and APO.Methods:Data on SLE pregnancies prospectively-followed by multidisciplinary team in 2 Italian Centers from 1987 to 2018 were retrospectively analysed. C3 and C4 normal levels were calculated in general obstetric population (GOP) as previously described1, and related to maternal and fetal outcome. Non categorical variables were compared using Mann-Whitney test or Wilcoxon test when appropriate.Results:Two hundred forty-six pregnancies in 172 SLE patients were analysed (mean age at conception 31.3 ±4.9 years; mean disease duration 8.3 ±7.1). Anti-Ro antibodies were positive in 64 patients (37%) and anti-phospholipid antibodies (aPL) were positive in 84 (48%), with single positivity in 54%, double in 24% and triple in 21%; 9 patients (5%) had also a diagnosis of obstetric-antiphospholipid syndrome (APS) and 8 (4%) had thrombotic-APS. Seventy-one patients (41%) had history of Lupus Nephritis.Thirty-five flares were recorded in 30 pregnancies (12%). APO occurred in 47 pregnancies (19%) and were: 27 fetal loss (20 early miscarriage th week and 7 intrauterine fetal death), 11 severe preterm birth (th week) and 15 hypertensive disorder (11 pre-eclampsia and 5 pre-eclampsia+HELLP syndrome).In GOP, C3 progressively increased throughout pregnancy and C4 increase from the 1st trimester to the 2nd trimester, as well as in SLE pregnancies without flares and without APO, from preconception (Fig 1). In the other SLE groups, C3 and C4 showed a different trend: in pregnancies with flares, they did not increase from preconception to the 1st trimester; in fetal losses and severe pre-term births, they remained stable throughout pregnancy; in hypertensive disorders they increased only between preconception and the 1st trimester.C3 and C4 levels were higher in GOP than in all SLE pregnancies groups (including those without flares and without APO) in each trimester. SLE pregnancies without flares showed higher C3 and C4 levels than pregnancies with flares, at preconception and in each trimester. SLE pregnancies without APO had higher C3 and C4 levels than pregnancies with fetal death at 2nd trimester, higher C3 levels than severe pre-term births in each trimester and higher C4 at 3rd trimester (Fig.1).At preconception, pregnancies with flares showed a higher frequency of low C3 and of low C4 than in pregnancies without flares (76% vs 42%, p=0.01; 76% vs 26%, pst: 82% vs 48%, p=0.003; 2nd: 82% vs 64%, p=0.01; 3rd: 64% vs 30%, p=0.002). At multivariate analysis, low C4 at preconception was associated with flare (OR [95% CI]: 10.34 [2.52-42.39]; p=0.001).Figure 1.Variations of C3 and C4 median levels (mg/dL) throughout pregnancy in GOP1 and in SLE pregnancies without and with flare (a) and without and with APO (b).* p ^as compared with SLE groups: pConclusion:In SLE pregnancies, monitoring of C3 and C4 is important: its failure to increase can be useful to recognize potential risk situations which deserve particular monitoring.References:[1]Reggia R. et al. Rheumatology 2012;51:2186-2190.Disclosure of Interests:None declared

Background:In rheumatic diseases, specifically in chronic inflammatory arthritis (IA), there are no data about the effectiveness of LDA in preventing pregnancy complications.Objectives:To assess the potential benefit of LDA administration during pregnancy to prevent adverse pregnancy outcomes (APO) in IA.To compare pregnancy outcomes in IA pregnancies treated during pregnancy with LDA with those untreated.Methods:Italian P-RHEUM.it register is designed as a nationwide, web-based longitudinal observational cohort study collecting data on pregnancies in inflammatory rheumatic diseases. At baseline, socio-demographic parameters, obstetric history, comorbidities and clinical/laboratoristic characteristics are registered. During pregnancy, the course of maternal disease, medications, development of fetus and complications are collected for each trimester.Results:From May 2018 to May 2020, 349 patients were enrolled. Forty-five patients with IA had completed their pregnancy with known outcome (20 Rheumatoid Arthritis, 10 Psoriatic Arthritis, 6 Ankylosing spondylitis, 5 Juvenile Idiopathic Arthritis, 4 Undifferentiated Arthritis): 13 (28.89%) treated with LDA during pregnancy and 32 (71.11%) without LDA prophylaxis. LDA was used with a higher frequency in women with previous APO, anti-phospholipid positivity and on biological DMARDs even if it’s not statistically significant (Table 1). All the LDA-treated women had a live-birth rate of 100%, whereas among women not treated with LDA the live birth rate was of 84.4% with 27 live-birth pregnancies, 3 early miscarriages, 1 fetal loss and 1 stillbirth observed. There were no significant differences between the LDA and the not LDA groups regarding pregnancy/peripartum obstetric complications (p=0.14), although less adverse pregnancy/peripartum outcomes were registered in LDA patients’ group (Table 1).Conclusion:The preliminary data of this prospective cohort study show that LDA improve pregnancy outcome in IA even if women treated with LDA had more risk factors for APO. The extension of this cohort will allow us to further investigate these important results.References:[1]Roberge S, et al. AmJObstetGynecol.2017;216:110-120.e6.[2]Andreoli L et al. Annals of the Rheumatic Diseases 2017;76: 476–85.[3]Sammaritano L et al. Arthritis & Rheumatology 2020; 72: 529–56.Table 1.Comparison between inflammatory arthritis pregnancies treated with low-dose aspirin and those untreated.LDA (n 19)Not LDA (n 39)pMaternal age at conception, median (IQR)33 (30.5 - 36.5)33 (28.2 - 35)BMI, median (IQR)25.4 (22.9 - 28.5)22.5 (20.4 - 24.5)Smoking, n (%)3 (15.8%)4/36 (11.1%)0.68Previous APO, n (%)7/11 (63.7%)7/13 (56.1%)0.34aPL+, n (%)3 (15.8%)1/36 (2.8%)0.1CRP+, n (%)5/15 (33.3%)11/27 (40.7%)0.75GC at baseline, n (%)9 (47.4%)15/34 (44.1%)0.82cDMARDs at baseline, n (%)1 (5.3%)3/34 (8.8%)1bDMARDs at baseline, n (%)6 (31.6%)11 (28.2%)0.79Live-birth pregnancy, n (%)18 (94.7%)32 (82.1%)0.25Pregnancy loss, n (%)1 (5.3%)7 (17,9%)0.25Hypertensive disorders, n (%)2/18 (11.1%)6/38 (15,8%)1HELLP syndrome, n (%)0 (0%)0 (0%)1PROM, n (%)0 (0%)3/38 (7.9%)0.54Preterm delivery, 34-37 GW, n (%)2 (10.5%)2 (5.2%)0.59Preterm delivery, 1 (5.3%)1 (2.6%)1IUGR, n (%)0 (0%)3 (7.8%)0.54SGA, n (%)0 (0%)0 (0%)1Pregnancy/Peripartum complications, n (%)3 (15.8%)11 (28.9%)0.35Legend: aPL, Antiphospholipid syndrome; bDMARDs, biological disease-modifying antirheumatic drugs; BMI, Body mass index; cDMARDs, Conventional disease-modifying antirheumatic drugs; CRP, C-reactive protein; GC, Glucocorticoids; GW, gestational week; HELLP, haemolysis, elevated liver enzymes, and low platelets; Hypertensive disorder defined as gestational hypertension, preeclampsia and eclampsia; IQR, Interquartile range; IUGR, intrauterine growth restriction; LDA, Low-dose Aspirin; Pregnancy loss defined as early fetal-loss, miscarriage and still-birth; PROM, Premature rupture of membranes; SGA, Small for gestational age.Acknowledgements:I would like to acknowledge the Epidemiology Unit of the Italian Society for Rheumatology and the Investigators of the Italian Registry.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:The World Health Organization recommends that infants should be exclusively breastfed until the age of 6 months. The aim of this study was to assess the ratio of breastfeeding patients with Rheumatic Diseases (RD) and to identify possible causes of its discontinuation.Objectives:The aim of this study was to assess the ratio of breastfeeding patients with Rheumatic Diseases (RD) and to identify possible causes of its discontinuation.Methods:This study was embedded in the P-RHEUM.it register, as a nationwide prospective cohort study collecting data of pregnancies in inflammatory RD. Pregnancies, enrolled until the 20th week of pregnancy, are followed from pregnancy until 6 months postpartum. At baseline, sociodemographic parameters, obstetric history, comorbidities are reported. During pregnancy, the course of maternal disease, development of foetus and complications are reported. After delivery, the pregnancy outcome, data on lactation and child development are collected.Results:From May 2018 to May 2020 data of 349 patients were available. Data on lactation were available in 44 pregnancies. Two months after delivery 37 were continuing breastfeeding (n=26) or mixed feeding (n=11), while 7 were using formula feeding. Among patients using formula feeding 2 had a diagnosis of rheumatoid arthritis (RA), 1 of juvenile idiopathic arthritis, 1 of undifferentiated arthritis (UA), 1 of anti-phospholipid syndrome (APS), 1 of vasculitis and 1 of systemic lupus erythematosus. The reasons of formula feeding were the following: 2 for agalactia, 2 for personal preferences, 3 for drug-related concerns (1 for physician’s decision in a patient with APS; 2 for maternal concerns about drugs in patients with RA and UA treated respectively with Adalimumab and Tocilizumab). At 6 months 30 continued breastfeeding (n=23) or mixed feeding (n=7) and 14 formula feeding. The reasons of formula feeding were available in 9 patients: 3 for agalactia, 2 for personal preferences, 2 for physician’s decision in a patient with APS and in a patient positive for anti-phospholipid antibodies; 2 for maternal concerns about drugs.Conclusion:Preliminary data of this prospective study demonstrate a high percentage of breastfeeding/mixed feeding after delivery and after 6 months among women with RD. Drug related concerns are the main reason of discontinuation of breastfeeding, although medication results compatible with lactation. Using our results, strategies supporting patients with RD whishing to breastfeed may be developed.References:[1]Carina Gotestam Sporken et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016.[2]Sammaritano et al. 2020 American College of Rheumatology Guideline for the management of reproductive health in rheumatic and muscoloskeletal diseases, Arthritis Rheumatol. 2020.Acknowledgements:Authors would like to thank SIR study center and all patients who accepted to partecipate to our studyDisclosure of Interests:None declared