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  1. An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus Y K Onno Teng Edwin O W Bredewold Ton J Rabelink Tom W J HuizingaH C Jeroen Eikenboom Maarten Limper Ruth D E Fritsch-StorkKitty W M Bloemenkamp Marieke Sueters Rheumatology, kex374, https://doi.org/10.1093/rheumatology/kex374 Published: 20 November 2017 Abstract Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients. https://academic.oup.com/rheumatology/advance-article-abstract/doi/10.1093/rheumatology/kex374/4641853?redirectedFrom=fulltext
  2. Lupus anticoagulant, disease activity and low complement in the first trimester are predictive of pregnancy loss 1Division of Rheumatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA 2Division of Rheumatology and Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 3Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, USA Correspondence to Dr Michelle Petri; mpetri{at}jhmi.edu Abstract Introduction Multiple factors, including proteinuria, antiphospholipid syndrome, thrombocytopenia and hypertension, are predictive of pregnancy loss in systemic lupus erythematosus (SLE). In the PROMISSE study of predictors of pregnancy loss, only a battery of lupus anticoagulant tests was predictive of a composite of adverse pregnancy outcomes. We examined the predictive value of one baseline lupus anticoagulant test (dilute Russell viper venom time) with pregnancy loss in women with SLE. Methods From the Hopkins Lupus Cohort, there were 202 pregnancies from 175 different women after excluding twin pregnancies and pregnancies for which we did not have a first trimester assessment of lupus anticoagulant. We determined the percentage of women who had a pregnancy loss in groups defined by potential risk factors. The lupus anticoagulant was determined by dilute Russell viper venom time with appropriate mixing and confirmatory testing. Generalised estimating equations were used to calculate p values, accounting for repeated pregnancies in the same woman. Results The age at pregnancy was <20 years (2%), 20–29 (53%), 30–39 (41%) and >40 (3%). 55% were Caucasian and 34% African-American. Among those with lupus anticoagulant during the first trimester, 6/16 (38%) experienced a pregnancy loss compared with only 16/186 (9%) of other pregnancies (p=0.003). In addition, those with low complement or higher disease activity had a higher rate of pregnancy loss than those without (p=0.049 and 0.005, respectively). In contrast, there was no association between elevated anticardiolipin in the first trimester and pregnancy loss. Conclusions The strongest predictor of pregnancy loss in SLE in the first trimester is the lupus anticoagulant. In addition, moderate disease activity by the physician global assessment and low complement measured in the first trimester were predictive of pregnancy loss. These data suggest that treatment of the lupus anticoagulant could be considered, even in the absence of history of pregnancy loss. Key messages A positive Lupus anticoagulant in the first trimester, rather than a previous positive result, is predictive of pregnancy loss. High disease activity as well as low complement levels during the first trimester is also predictive of pregnancy loss. Introduction Rates of pregnancy loss in systemic lupus erythematosus (SLE) have improved over the decades. Clark et al1 found a decrease in fetal loss rates from 40% to 17% based on a literature review from 1960 to 2000. More recent cohort studies have reported pregnancy loss rates in the range of 10–25%.2–10 Genetic anomalies, chromosomal abnormalities, anatomical defects and hormonal dysfunction all contribute to first trimester fetal loss in patients with SLE just as they do in the general population.11–14 In SLE, however, other risk factors for poor fetal outcomes from the first trimester to the neonatal period play a major role. We previously reported four factors at the first pregnancy visit to predict pregnancy loss: proteinuria (>500 mg in a 24 h urine collection or urine protein-to-creatinine ratio >0.5), thrombocytopenia (platelet count <150 000) and antiphospholipid syndrome and hypertension (blood pressure >140/90 mm Hg).9 We have also found high lupus activity as defined by the physician global assessment score >2, on a 0–3 visual analogue scale, a risk factor for fetal loss.10 Additional risk factors reported in the literature have included positive anti-dsDNA at any time during pregnancy and low complement levels in the second trimester.2 Clowse et al,9 in a previous study of the Hopkins Lupus Cohort in 2006, found that patients with SLE with antiphospholipid antibodies, but without secondary antiphospholipid syndrome, had the same miscarriage rate as those patients without antiphospholipid antibodies (12% vs 15%). Mecacci et al,5 in a study of 58 lupus pregnancies divided into three groups (antiphospholipid syndrome, antiphospholipid antibody positive and antiphospholipid antibody negative), found no differences in the live birth rate. In a prospective study by Lima et al15in 1995 of 108 pregnancies in patients with SLE, lupus anticoagulant did not predict fetal loss (p=0.056). In 1994, Derksen et al16 described 35 pregnancies in 25 patients with SLE and found that there was no difference in the live birth rate between those patients with antiphospholipid antibodies and those without. In contrast to the previous findings, two studies have found increased rates of fetal loss in patients with antiphospholipid antibodies. In 2002, Moroni et al17studied 70 pregnancies in 48 patients with lupus nephritis. In both univariate and multivariate analyses, the presence of antiphospholipid antibodies was significantly associated with increased fetal loss. There was, however, no differentiation between the presence of lupus anticoagulant and anticardiolipin antibodies. In the PROMISSE study, Lockshin et al3 studied pregnancies in SLE or in antiphospholipid-positive women versus control pregnancies. Adverse pregnancy outcome was defined as fetal demise after 12 weeks, neonatal death prior to discharge, preterm delivery prior to 34 weeks and small for gestational age. In the PROMISSE study, lupus anticoagulant was considered positive if it was identified by any of three tests: dilute Russell viper venom time (dRVVT), a lupus anticoagulant-sensitive partial thromboplastin time or the dilute prothrombin time.21 It was found that the lupus anticoagulant predicted adverse pregnancy outcome (p<0.0001). In multivariate analysis, but not in bivariate analysis, the presence of SLE conferred a relative risk of 2.16 (p=0.005). In this paper, we report on an updated set of pregnancies from the Hopkins Lupus Cohort. Our goal was to assess the association of lupus anticoagulant detected by the dRVVT in the first trimester with the risk of pregnancy loss in patients with SLE. Patients and methods Cohort We performed an analysis of pregnancies among patients in the Hopkins Lupus Cohort for which there was a measure of lupus anticoagulant during the first trimester. The Hopkins Lupus Cohort consists of consecutively enrolled patients with SLE who have been followed by one rheumatologist (MP) from 1987 to 2012 at the Hopkins Lupus Center. Patients were seen at 4-week to 6-week intervals during their pregnancy until delivery. Pregnancy was confirmed by urine and serum beta human chorionic gonadotrophin tests and fetal ultrasound. Pregnancy losses were defined as any fetal death in utero. Pregnancy outcomes were obtained from obstetric records. Cohort pregnancies were excluded from the analysis if they were not singleton, if there was uncertainty about the outcome or if the patient was not assessed for lupus anticoagulant in the first trimester. The physician global assessment score was obtained at each visit. This validated visual analogue scale assesses lupus activity (0, no activity; 1, mild lupus activity; 2, moderate lupus activity; 3, severe lupus activity).18 Lupus anticoagulant was screened by the dRVVT and then confirmed by mixing studies and confirmatory tests.19 Anticardiolipin was determined by ELISA (Inova). Statistical analysis We identified subgroups of pregnancies based on their characteristics during the first trimester and compared them with respect to pregnancy loss rates. Subgroups were defined by age, ethnicity, year of conception, disease activity and serological activity. The statistical significance of each observed difference was determined using a generalised estimating equation approach to adjust for the fact that some women contributed more than one pregnancy. We performed a sensitivity analysis using only the first pregnancy for each woman and compared rates using Fisher's exact test. Analyses were performed using SAS V.9.2. Results This analysis is based on the 202 pregnancies for which there was a first trimester assessment of lupus anticoagulant. These 202 pregnancies were from 175 women. In total, 154 women had one pregnancy, 17 had two pregnancies, 3 had three pregnancies and 1 had five pregnancies. Fifty-three per cent of pregnancies occurred in women between the ages of 20 and 29; 41% occurred in women between the ages of 30 and 39; 3% in women over >40 and 2% in women younger than 20 years of age (table 1). The ethnic composition of our sample consisted of 55% Caucasian, 34% African-American and 11% other ethnicity. Table 1 Characteristics of singleton pregnancies in the Hopkins Lupus Cohort There were 22 pregnancy losses out of the 202 pregnancies (11%). Of these, 12 (55%) occurred within the first trimester, 9 (40%) occurred during the second trimester and 1 (5%) occurred during the third trimester. There were no statistically significant differences in frequency of pregnancy losses by age group, ethnicity or year of conception (table 2), although 3/6 pregnancies (50%) among those 40 years of age or older resulted in a pregnancy loss. Table 2 Pregnancy loss rates by characteristics of the patients First trimester lupus anticoagulant was significantly associated with an increased pregnancy loss rate (p=0.0035, table 2). In 186 pregnancies with a negative first trimester lupus anticoagulant, the pregnancy loss rate was 9%. In the 16 pregnancies with a positive lupus anticoagulant in the first trimester, there were 6 pregnancy losses (36%). Also, 4 of the 16 pregnancies with first trimester-positive lupus anticoagulant had a history of previous thrombosis; 2 of the 6 pregnancies with pregnancy loss and 2 of the 10 without. A history of lupus anticoagulant prior to pregnancy was not predictive of pregnancy loss (table 2). In fact, of the 25 patients with a history of lupus anticoagulant who did not have lupus anticoagulant during the first trimester, none had a pregnancy loss. A score of ≥2 on the physician global assessment (on a 0–3 visual analogue scale) during the first trimester was statistically associated with increased risk of pregnancy loss (29% vs 8%, p=0.005). Although the numbers in some of the subgroups were not large enough to perform a complex multivariable analysis, an analysis of the association between lupus anticoagulant in the first trimester, scores of disease activity and pregnancy loss was performed. Of the 11 patients with lupus anticoagulant but without high disease activity during the first trimester, 3 (27%) experienced a pregnancy loss. Of the three with both lupus anticoagulant and high disease activity during the first trimester, two experienced a pregnancy loss. Statistically, the association between lupus anticoagulant and pregnancy loss persisted after adjustment for high physician global assessment (p=0.013). Anticardiolipin IgG levels were measured at the first pregnancy visit in 115 pregnancies. Among the seven patients with high IgG titres, none had a miscarriage. Sixty-three per cent of pregnancies had a history of positive anticardiolipin antibodies. There was no significant difference in the pregnancy loss rate between those pregnancies with or without a history of anticardiolipin IgG antibodies (12% vs 9%, p=0.66). Low complement levels occurred in the first trimester in 83 pregnancies (41%). The pregnancy loss rate in this group was 16%. When compared with the 118 pregnancies with normal complement levels in the first trimester, the loss rate was 7% (p=0.049). A positive anti-dsDNA was not significantly associated with increased risk of pregnancy loss (15% vs 9%, p=0.19). A prednisone dose >10 mg/day at the first pregnancy visit was more frequent in those with pregnancy loss (16% vs 8%, p=0.09). Rates of pregnancy loss were somewhat elevated among those with a history of thrombosis or prior miscarriage; however, these differences were not statistically significant in this small sample. As a sensitivity analysis, we performed the same analyses using only the first pregnancy for each woman. This analysis was based on 175 women. In this analysis, we found that there was still a significant association between pregnancy loss and lupus anticoagulant in the first trimester: pregnancy losses were 5/13 (38%) vs 20/162 (6%) for those with and without lupus anticoagulant (p=0.0020). A positive association between pregnancy loss and both high disease activity and low complement was also seen in this smaller sample (p=0.016 and 0.068, respectively). Discussion Our results demonstrate an increased risk of pregnancy loss associated with the presence of lupus anticoagulant by the dRVVT at the first trimester visit; however, a history of positive lupus anticoagulant was not associated. We also found that lupus activity defined by the physician global assessment in the first trimester was significantly associated with increased risk of pregnancy loss. Other variables including age, ethnicity, high titres of anticardiolipin antibody, use of prednisone dose as a surrogate for lupus activity and the presence of anti-dsDNA were not significantly associated with increased risk of pregnancy loss. Lupus anticoagulant remained statistically significant in multiple variable models that included disease activity and low complement. The impact of antiphospholipid antibodies on pregnancy loss has previously been reported in this cohort.9 Clowse et al found an increased risk of total pregnancy loss in patients with SLE with antiphospholipid syndrome. The presence of either lupus anticoagulant or anticardiolipin antibody, but without the clinical criteria for classification of antiphospholipid syndrome, did not increase the risk of miscarriage. In this study, we looked separately at the contribution of lupus anticoagulant and anticardiolipin antibody to the risk of pregnancy loss. While lupus anticoagulant was strongly associated with increased pregnancy loss risk, anticardiolipin antibody was not associated with increased risk. Our current results differ from our past report in that we have now looked at each antiphospholipid antibody separately. Our study looked at the utility of one single lupus anticoagulant test, the dRVVT, at the first pregnancy visit with one outcome (pregnancy loss). Thus, we confirm the PROMISSE finding that only the lupus anticoagulant ‘matters’ but extend the PROMISSE finding to the most important of the adverse pregnancy outcomes, namely pregnancy loss. Our study differed from PROMISSE in that dRVVT was done as the lupus anticoagulant assay; only first trimester results were used; we excluded PROMISSE patients and a different outcome measure (pregnancy loss) was used. The PROMISSE study could not evaluate the contribution of high disease activity, as such patients were excluded. High disease activity assessed by physician global assessment score of ≥2 in our study was significantly associated with an increased risk of pregnancy loss. Prednisone dose as a surrogate for disease activity was higher as well, but did not meet statistical significance. Clowse et al,10 in a previous analysis of our cohort in 2004, demonstrated a significant decrease in the live birth rate (84% vs 57%, p=0.04) in pregnancies with high versus low lupus activity in the first trimester defined by the physician global assessment. Chakravarty et al22 defined active disease at conception as the use of 10 mg of prednisone daily. With only six pregnancy losses in the first trimester and none in the second or third trimester, they were unable to demonstrate an increased risk of pregnancy loss. We have extended our previous work to show the independent effect of disease activity in multiple variable models. Our study found that low complement during the first trimester was associated with an increased risk of pregnancy loss. Between 1992 and 2003, Ramos-Casalset al23 routinely measured complement levels in 530 female patients with SLE. They found similar rates of pregnancy loss in those patients with low complement (14%) compared with those patients with normal complement. This is in contrast to the data published by Cortes-Hernandez et al24 in 2002, in which low complement levels detected at the first visit or at 3-month intervals were significantly associated with a combination of miscarriage and stillbirth. Clowse et al2 previously compared low or normal complement levels and the presence or absence of anti-dsDNA in the Hopkins Lupus Cohort. Neither first trimester hypocomplementemia (18% vs 15%, p=0.55) nor the presence of anti-dsDNA (20% vs 13%, p=0.29) significantly increased the rate of pregnancy loss. However, low complement levels in the second trimester were associated with a significantly increased risk of fetal loss. The larger number of pregnancies in our updated analysis has allowed us to show the effect of low complement in the first trimester. Multicentre studies such as PROMISSE are ideal, but our study fills in three important gaps. First, one lupus anticoagulant assay, the dRVVT, with confirmatory testing, is predictive of pregnancy loss. Only the presence of the lupus anticoagulant during the pregnancy matters, as a history of lupus anticoagulant is not predictive. Thus, in clinical practice, a large battery of tests is unnecessary. Prophylactic treatment could be considered in these pregnancies. Second, high disease activity (omitted from PROMISSE) is a risk factor and control of disease activity before conception is essential to successful pregnancy outcome. Third, low complement in the first trimester is also a risk factor. In the non-pregnant patient with SLE, low complement in the absence of disease activity (serologically active, clinically quiescent) is not treated.25Although we cannot address treatment, our study indicates the value of low complement for the prediction of pregnancy outcome. Footnotes Contributors AM contributed to writing and editing the manuscript. MP contributed to writing and editing the manuscript. LSM provided statistical analysis and editing of the manuscript. Funding The Hopkins Lupus Cohort is supported by National Institute of Health grant AR-43727. Competing interests None declared. Patient consent Obtained. Ethics approval This cohort has been approved on a yearly basis by the Johns Hopkins Institutional Review Board. Provenance and peer review Not commissioned; externally peer reviewed. Data sharing statement No additional data are available. Received April 10, 2015. Accepted August 5, 2015. Published 9 December 2015 http://lupus.bmj.com/content/2/1/e000095.full This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/ References ↵ Clark , Spitzer , Laskin . Decrease in pregnancy loss rate in patients with systemic lupus erythematosus over a 40 year period. J Rheumatol ;:–. [AbstractFull text] ↵ Clowse , Magder , Petri . The clinical utility of measuring complement and anti-dsDNA antibodies during pregnancy in patients with systemic lupus erythematosus. J Rheumatol ;:–. doi:10.3899/jrheum.100746 [AbstractFull text] ↵ Lockshin , Laskin , . Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum ;:–. doi:10.1002/art.34402 ↵ Krizova , Ouimet , . Pregnancy outcome in systemic lupus erythematosus is improving: Results from a case control study and literature review. Open Rheumatol J ;:–.doi:10.2174/1874312900802010089 [Medline] ↵ Mecacci , Bianchi , Pieralli , . Pregnancy outcome in systemic lupus erythematosus complicated by antiphospholipid antibodies. Rheumatology (Oxford) ;:–.doi:10.1093/rheumatology/ken458 [AbstractFull text] ↵ Brucato , Doria , Frassi , . Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus ;:–.doi:10.1191/0961203302lu252oa [AbstractFull text] ↵ . Outcome of pregnancy in patients with systemic lupus erythematosus.Taiwan J Obstet Gynecol ;:–. doi:10.1016/S1028-4559(09)60208-4 [Medline] ↵ Andrade , Sanchez , Alarcon , . Adverse pregnancy outcomes in women with systemic lupus erythematosus from a multiethnic US cohort: LUMINA (LVI). Clin Exp Rheumatol ;:–. ↵ Clowse , Magder , Witter , . Early risk factors for pregnancy loss in lupus. Obstet Gynecol ;:–.doi:10.1097/01.AOG.0000194205.95870.86 ↵ Clowse , Magder , Witter , . The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum ;:–. doi:10.1002/art.20864 ↵ Lathi , Gray Hazard , Heerema-McKenney , . First trimester miscarriage evaluation. Semin Reprod Med ;:–.doi:10.1055/s-0031-1293200 ↵ Suzumori , Sugiura-Ogasawara . Genetic factors as a cause of miscarriage. Curr Med Chem ;:–.doi:10.2174/092986710793176302 ↵ Lebedev . Mosaic aneuploidy in early fetal losses. Cytogenet Genome Res ;:–.doi:10.1159/000324120 ↵ Porter , Scott . Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol ;:–. doi:10.1016/j.bpobgyn.2004.11.005 ↵ Buchanan , Khamashta , . Obstetric outcomes in systemic lupus erythematosus. Semin Arthritis Rheum ;:–. doi:10.1016/S0049-0172(95)80030-1 ↵ Derksen , Bruinse , de Groot , . Pregnancy in systemic lupus erythematosus: a prospective study. Lupus ;:–.doi:10.1177/096120339400300304 [AbstractFull text] ↵ Moroni , Quaglini , Banfi , . Pregnancy in lupus nephritis. Am J Kidney Dis ;:–.doi:10.1053/ajkd.2002.35678 ↵ Petri , Genovese , Engle , . Definition, incidence and clinical description of flare in systemic lupus erythematosus. Arthritis Rheum ;:–. doi:10.1002/art.1780340802 ↵ Petri , Nelson , Weimer , . The automated modified Russell viper venom time test for the lupus anticoagulant. J Rheumatol ;:–. Pengo , Tripodi , Reber , . Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost ;:–. doi:10.1111/j.1538-7836.2009.03555.x ↵ Chakravarty , Colón , Langen , . Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obs Gynecol ;:–.doi:10.1016/j.ajog.2005.02.063 ↵ Ramos-Casals , Campoamor , Chamorro , . Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients. Lupus ;:–. doi:10.1191/0961203304lu1080oa [AbstractFull text] ↵ Cortés-Hernández , Ordi-Ros , Paredes , . Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) ;:–. doi:10.1093/rheumatology/41.6.643 [AbstractFull text] ↵ Steiman , Gladman , Ibañez , . Outcomes in patients with systemic lupus erythematosus with and without a prolonged serologically active clinically quiescent period. Arthritis Care Res (Hoboken) ;:–. doi:10.1002/acr.21568 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
  3. Pregnant women with aPL antibodies may benefit from hydroxychloroquine Sciascia S, et al. Am J Ob Gyn.2015;doi:10.1016/J.ajog.2015.09.078. October 15, 2015Women with antiphospholipid syndrome or positive antiphospholipid antibodies who became pregnant while receiving hydroxychloroquine for at least 6 months were more likely to have positive pregnancy outcomes compared with patients who did not receive hydroxychloroquine, according to analysis of recently published data. An observational, retrospective, single-center study of 170 pregnancies in 96 women with antiphospholipid antibodies (aPL) was conducted at a tertiary referral center. All women had positive aPL levels conformed at least 12 weeks apart prior to the index pregnancy. Investigators collected clinical and serological data, including demographics, disease and pregnancy characteristics, the presence of systemic lupus erythematosus (SLE) or other comorbidities, risk factors for cardiovascular disease and autoantibody status. They also noted all medications, including aspirin and low-molecular-weight heparin (LMWH). From January 2008 to July 2015, 31 women who received hydroxychloroquine for at least 6 months (group A) experienced 51 pregnancies. Of these women, 64.5% had SLE and 32.2% had primary antiphospholipid syndrome (APS). In 26 pregnancies, women received 200 mg hydroxychloroquine twice a day. In 25 pregnancies, mothers took 200 mg hydroxychloroquine once a day. Hydroxychloroquine was the only treatment aside from aspirin or LMWH received by 30 patients. Seven women were primigravida and 24 were multiparous. A second group of 65 patients with aPL experienced 119 pregnancies and did not receive hydroxychloroquine (group B). In this group, 7.7% of patients had SLE, 69.2% of patients had primary APS and 23.1% had a positive aPL status with no prior disease events or indications to receive hydroxychloroquine. Analysis showed pregnancy complications related to aPL status were reduced, and the number of live births were higher in patients who received hydroxychloroquine. Independent factors related to poor pregnancy outcomes included previous pregnancy morbidity (odds ratio of 12.1) and triple aPL positivity (odd ratio of 2.6). Pre-eclampsia, abruption placenta and intrauterine growth restriction was more common in group B (10.9%) compared with patients in group A (2%). The frequency of vaginal births was 37.3% in patients in group A compared with 14.3% of patients in group B. No thrombotic events occurred during the study period. – by Shirley Pulawski Disclosure s : The researchers report no relevant financial disclosures.
  4. Pregnancy, SLE, and APS: New Guidelines Pregnancy can pose unique complications for women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), including preeclampsia and preterm birth. New guidelines issued at the 2015 annual meeting of the European League Against Rheumatism (EULAR) outline ways to reduce those risks in the context of disease activity and the impact of medications. At the same time, a large population study from Sweden presented at the EULAR meeting offers some reassurance that, for women who’ve previously had children, pregnancy does not cause an accelerated risk of cardiovascular complications. However, they urged that women with SLE must be watched carefully for disease-related effects, such as maternal-placental insufficiency-- especially those who’ve never been pregnant. The EULAR recommendations for women’s health and pregnancy include ways to deal with reduced fertility in SLE, use of birth control, assisted reproductive technology, and hormone therapy during menopause. Since SLE and APS often strike during a woman’s reproductive years, often before a woman has started or completed a family, “physicians must ensure that optimal management includes best-practice measures to reduce these risks from the onset of disease and throughout pregnancy,” stresses the lead author of the guidelines, Laura Andreoli, MD, of the Rheumatology and Clinical Immunology Unit at the University of Brescia, Italy. Recommendations include preservation of fertility with gonadotropin-releasing hormone (GnRH) analogues before women are treated with certain medications, including alkylating agents like cyclophosphamide (Cytoxan). Also included in the guidelines: Human papilloma virus (HPV) immunization should be considered for women with stable disease.Clotting risk in APS and disease activity in SLE should be taken into account when oral contraceptives and other birth control measures are being used or considered.Assisted reproduction can be considered in women with stable or inactive disease, with provisions to limit the risk of flare.Disease activity, serological markers, and renal function should be closely monitored to guard against adverse pregnancy outcomes (such as preeclampsia and preterm birth) as well as disease flares.Fetal monitoring, including ultrasound, should be done during high risk pregnancy--especially after 24-28 weeks of pregnancy to screen for placental insufficiency and other problems.Fetal echocardiography is indicated for suspected fetal dysrhythmia, especially in patients with positive anti-Ro and/or anti-La.Hydrochloroquine, glucocorticoids, azathioprine, cyclosporine-A, tacrolimus, and intravenous immunoglobulin can be used to prevent or manage SLE flares during pregnancy.For menopausal women with stable disease and no antiphospholipid antibodies, hormonal therapy can be used for severe vasomotor symptoms.Cancer screening, especially for pre-malignant cervical lesions, is needed in women taking certain immunosuppressive drugs.As for cardiovascular risks, the retrospective Swedish study of 3,232 women with SLE (72% of whom had undergone childbirth), found that incidence of cardiovascular events was highest among women who had never had children. The researchers conclude that pregnancy and its complications do not accelerate cardiovascular events to the same extent as SLE-related conditions. In fact, they suggest, for some women with lupus an uncomplicated pregnancy may be a positive sign of later cardiovascular health.
  5. HCQ may improve pregnancy outcomes for women with antiphospholipid syndrome July 2, 2015Treatment with hydroxychloroquine may reduce pregnancy risks and increase gestational duration in women with antiphospholipid syndrome, according to data presented at the European League Against Rheumatism Annual European Congress of Rheumatology. Researchers conducted an observational study of 170 pregnancies in 96 women with antiphospholipid syndrome (aPL). Of the patients, 31 women treated with hydroxychloroquine (HCQ) for at least 6 months prior to conception underwent 65 pregnancies. In 65 women, 119 pregnancies occurred during the study period. A significantly higher rate of live births was observed in the patients who received HCQ (66.7%) compared with patients who did not receive HCQ (57.1%). Pregnancy morbidity was lower (47.1%) in the group treated with HCQ compared with untreated women (63%), and pregnancy duration was longer in the treatment group (27.6 weeks vs. 21.5 weeks). Vaginal labor was more prevalent in patients treated with HCQ (37.3% vs. 14.3%), and fetal death after 10 weeks of gestation were more infrequent in treated women (2% vs. 10.9%), according to the researchers. A lower frequency of placental complications, including pre-eclampsia, abruption placenta and intrauterine growth restriction, was observed in HCQ-treated women (2% vs. 10.9%). Additionally, the odds ratio for the absence ofpregnancy complications was 2.2 for women who received HCQ before and during pregnancy. – by Shirley Pulawski Reference: Sciascia S, et al. Paper #OP0188. Presented at: European League Against Rheumatism Annual European Congress of Rheumatology; June 10-13, 2015; Rome. Disclosure: The researchers report no relevant financial disclosures.
  6. Certain biomarkers may predict pregnancy complications in women with SLE Kim MY, et al. Am J Obstet Gynecol. 2015;doi:10.1016/j.ajog.2015.09.066. September 30, 2015Women with systemic lupus erythematosus and certain serum biomarkers during pregnancy may be more likely to have adverse pregnancy outcomes, according to recently published research. Researchers studied 492 pregnant women with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) enrolled at 12 weeks gestation in a prospective, multicenter study between September 2003 and August 2013 in the U.S. and Canada. The study included 335 women with SLE without antiphospholipid (APL) antibodies, 59 women with SLE and APL, and 98 women with only APL. Serum was monitored monthly for soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PIGF) and soluble endoglandin (sEng) and for pregnancy complications. A healthy control group of 197 pregnant women was recruited with similar ethnicity to patients and low risk for adverse pregnancy outcomes. Patients were excluded in the presence of 20 mg or higher daily prednisone use, urine protein to creatinine ratio greater than 1,000, urinary erythrocyte casts, serum creatinine greater than 1.2 mg/dL, type 1 or 2 diabetes or blood pressure above 140/90 mm Hg at the time of screening. Fifty-nine (12%) severe and 49 (10%) moderate adverse pregnancy outcomes occurred within the cohort of patients. At 12 to 15 weeks of gestation, women who had adverse pregnancy outcomes had significantly raised sFlt1, sEng and a high sFlt1 to PIGF ratio, which increased over the duration of the pregnancy. Small but consistent levels and increases of sFlt1, sEng and a high sFlt1 to PIGF ratio were also observed in patients with SLE or APS who did not have adverse outcomes compared to 197 healthy participants who did not have adverse outcomes. “Given that over 20% of pregnant women with lupus APL experience adverse pregnancy outcomes, the ability to identify patients early in pregnancy, who are destined for poor outcomes, would significantly impact care of this high-risk population,” investigator Jane E. Salmon, MD, of the Division of Rheumatology, Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY, said in a press release. The presence of lupus anticoagulant, a history of high blood pressure or thrombosis, diastolic blood pressure over 80 mm Hg and high BMI were baseline clinical variables associated with a higher risk for adverse pregnancy outcomes. The use of aspirin appeared to be protective, according to the researchers. – by Shirley Pulawski Disclosure: Kim reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures. Large proportion of pregnancies in women with SLE are uncomplicated Buyon J, et al. Annals Int Med. 2015;doi:10.7326/M14-2235. June 22, 2015A large proportion of childbirths to patients with systemic lupus erythematosus occurred without complications, and outcomes were not related to anti-dsDNA antibodies, according to research published in The Annals of Internal Medicine. “For those patients who had a poor outcome, we were able to identify specific risk factors,” lead study author Jill P. Buyon, MD, director of the division of rheumatology and director of the lupus center at New York University Langone, told Healio.com/Rheumatology in an interview. “Happily, most of the women did do very well with their pregnancies.” Buyon and colleagues studied the outcomes of 385 pregnant women with systemic lupus erythematosus (SLE) between September 2003 and December 2012 at eight locations in the U.S. and one in Canada. Consecutive pregnant women with up to 12 weeks of gestation were recruited into the PROMISSE study. Eligibility criteria included age between 18 years and 45 years; presence of a single, intrauterine pregnancy; and hematocrit levels above 26%. Exclusion criteria were use of prednisone at doses greater than 20 mg daily, a ratio of protein to creatinine greater than 1,000 mg/g, presence of urine erythrocyte casts, diabetes, serum creatinine above 1.2 mg/dL and blood pressure above 140/90 mm Hg. Patients underwent a physical examination that included a complete blood count; comprehensive metabolic panel; urinalysis; detection of antibodies including anti-dsDNA, anti-Ro, anti-La, antiphospholipid (aPL) anti-beta-2-glycoprotein I and anticardiolipin; lupus anticoagulant; and C3 and C4 levels. Disease activity was measured at baseline and follow-up using the Systemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI), and a flare composite was derived from the composite used in the SELENA (Safety of Estrogens in Lupus Erythematosus, National Assessment) trial. Adverse pregnancy outcomes (APOs) were defined as fetal death after 12 weeks of gestation (not attributable to anatomic malformation, chromosomal abnormalities or congenital infection) or as neonatal death prior to hospital discharge related to prematurity, placental insufficiency or both. Other APOs included preterm delivery before 36 weeks caused by gestational hypertension, placental insufficiency or preeclampsia, or an outcome of small-for-gestational-age neonate (low birthweight). One or more APOs were observed in 19% of the participants, with fetal death in 4% of the cohort. Neonatal death occurred in 1% of patients, preterm delivery occurred in 9% of patients, low birthweight was present in 10% of the children, and 17 patients had more than one APO. Preeclampsia was observed in 2% of patients after 36 weeks. Severe flares were observed in 2.5% of patients in the second trimester and in 3% of patients in the third trimester. In patients without aPL antibodies, rates of APOs were 15.4% compared with 43.8% in patients with aPLs and 3% in patients without SLE. Other risk factors included non-white race, hypertension and low platelet counts, according to the researchers. “Going into pregnancy counseling, the physician can use these parameters to discuss the risks with the patient,” Buyon said. “Helping patients manage their expectations is important. If a patient knows she may have a small baby or a premature baby, she can seek out appropriate care, such as a high-risk obstetrician or a hospital with a center dedicated to premature babies.” For some patients, finding appropriate care may involve travel and additional research to find appropriate specialists, but Buyon said these steps could mitigate some of the risk, and that future research is needed to understand and mitigate the risk factors identified. Buyon said that in the past, because of the role estrogen has been believed to play in SLE, many women were advised to avoid pregnancy; however, most of the women in her study had good outcomes. This study builds on some of her earlier work focused on estrogens and birth control medications in women with SLE, she said. Regarding the role of estrogen, Buyon said there is much to learn. “Things are more complicated than we have thought,” Buyon said. “As in life, biology is more complex than we can predict.” – by Shirley Pulawski Disclosures: Buyon reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
  7. Certain biomarkers may predict pregnancy complications in women with SLE Kim MY, et al. Am J Obstet Gynecol. 2015;doi:10.1016/j.ajog.2015.09.066. September 30, 2015Women with systemic lupus erythematosus and certain serum biomarkers during pregnancy may be more likely to have adverse pregnancy outcomes, according to recently published research. Researchers studied 492 pregnant women with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) enrolled at 12 weeks gestation in a prospective, multicenter study between September 2003 and August 2013 in the U.S. and Canada. The study included 335 women with SLE without antiphospholipid (APL) antibodies, 59 women with SLE and APL, and 98 women with only APL. Serum was monitored monthly for soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PIGF) and soluble endoglandin (sEng) and for pregnancy complications. A healthy control group of 197 pregnant women was recruited with similar ethnicity to patients and low risk for adverse pregnancy outcomes. Patients were excluded in the presence of 20 mg or higher daily prednisone use, urine protein to creatinine ratio greater than 1,000, urinary erythrocyte casts, serum creatinine greater than 1.2 mg/dL, type 1 or 2 diabetes or blood pressure above 140/90 mm Hg at the time of screening. Fifty-nine (12%) severe and 49 (10%) moderate adverse pregnancy outcomes occurred within the cohort of patients. At 12 to 15 weeks of gestation, women who had adverse pregnancy outcomes had significantly raised sFlt1, sEng and a high sFlt1 to PIGF ratio, which increased over the duration of the pregnancy. Small but consistent levels and increases of sFlt1, sEng and a high sFlt1 to PIGF ratio were also observed in patients with SLE or APS who did not have adverse outcomes compared to 197 healthy participants who did not have adverse outcomes. “Given that over 20% of pregnant women with lupus APL experience adverse pregnancy outcomes, the ability to identify patients early in pregnancy, who are destined for poor outcomes, would significantly impact care of this high-risk population,” investigator Jane E. Salmon, MD, of the Division of Rheumatology, Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY, said in a press release. The presence of lupus anticoagulant, a history of high blood pressure or thrombosis, diastolic blood pressure over 80 mm Hg and high BMI were baseline clinical variables associated with a higher risk for adverse pregnancy outcomes. The use of aspirin appeared to be protective, according to the researchers. – by Shirley Pulawski Disclosure: Kim reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
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