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Gene Changes Key to Successful Pregnancy in Lupus April 29, 2019 Pregnant women with lupus are more likely to suffer complications than those who don’t. Lupus Research Alliance Scientific Advisory Board members Dr. Virginia Pascual, Professor at Weill Cornell Medicine; and Dr. Jane Salmon, Collette Kean Research Professor at Hospital for Special Surgery, and their colleagues asked if testing the blood, of pregnant women with lupus, using advanced technologies could identify, early in pregnancy, lupus patients at high risk for complications. Their new paper in the Journal of Experimental Medicine shows that during uncomplicated pregnancy in both healthy and lupus women some genes that incite the immune system become less active. These changes may make the immune system less aggressive and reduce the odds that it will attack the fetus. However, women with lupus who had pregnancy complications, including preeclampsia, did not show the desirable decrease in these immune signatures. Doctors came up with the term “lupus” because they thought the disease’s skin inflammation looked liked a wolf’s bite. The study “supports the idea that in some cases, pregnancy can ‘tame the wolf.’” Drs. Timothy Niewold and Shilpi Mehta-Lee wrote in a commentary on the paper. They note that the findings may enable doctors to identify patients with lupus who are susceptible to pregnancy complications and need careful monitoring To the immune system, a fetus developing in the womb resembles a foreign invader. Normally during pregnancy, the mother’s immune system develops what researchers call tolerance and avoids attacking the fetus. But when patients with lupus become pregnant, their immune system may be less likely to develop tolerance to the fetus, leading to complications such as preeclampsia, premature birth, and even death of the fetus. In the new study, Dr. Pascual and colleagues compared 92 pregnant women with lupus to 43 pregnant women who didn’t have the disease. The researchers obtained blood samples from the women during and shortly after their pregnancies. To detect the earliest changes associated with pregnancy onset, the scientists also analyzed blood from patients undergoing assisted reproductive technology. The researchers evaluated the patients’ immune system by measuring the activity of different genes that help determine how strongly it responds to potential threats. For a subset of these study participants, the investigators also examined the types of cells that are producing the specific immune responses. Early in pregnancy, the activity of key genes decreased in women who didn’t have lupus, probably increasing their tolerance to the developing baby. The researchers saw similar changes in women with lupus who had successful pregnancies. However, the immune system of women with lupus who went on to develop complications was not turned down. Their immune system might be more likely to attack the fetus or prevent its proper development. This inability to turn down the immune activity appears to be a risk factor for adverse pregnancy outcomes in lupus. Testing for these changes in gene activity might pinpoint patients with lupus who are more likely to develop pregnancy complications and who needs careful monitoring and specific therapeutic intervention to improve the outcome. https://www.lupusresearch.org/gene-changes-key-to-successful-pregnancy-in-lupus/

Lupus: 3 Things to Know Mark L. Fuerst Dec 3, 2018 Lupus Three new studies in systemic lupus erythematosus (SLE) reveal that a gut bacterium may be linked to autoimmune diseases, including SLE; pregnancy complications in women with lupus have decreased over the past 2 decades; and physical or emotional abuse in childhood raises the risk of lupus.1-3Scroll through the slides for the latest findings and their clinical implications. http://www.rheumatologynetwork.com/lupus/lupus-3-things-know

Women with Lupus Overwhelmingly Have Healthy Pregnancies News | June 30, 2017 | Lupus By Whitney L. Jackson In contradiction to long-standing beliefs, a healthy pregnancy is possible for women who have lupus, says Jill Buyon, M.D., a rheumatologist and lupus specialist from New York University School of Medicine. “Patients with lupus have been under the impression that pregnancy would be a very dangerous thing for them. From the mother’s perspective, the concerns are: Will the mother sustain a lupus flare? For mothers who have once had kidney involvement: How safe is it to get pregnant? Will there be adverse pregnancy outcomes? Will the baby be very small? Will the baby be born so early that it needs to be in the hospital for a long time. And, of course, the scary question is: Will my baby die? These are the outcomes we look at from the perspective of counseling and what we wanted to learn from this study,” she said. Dr. Buyon recently published research in the Annals of Internal Medicine showing that women with relatively inactive lupus without serious flares experienced a normal pregnancy with a positive outcome. Study participants were women, ages 18-to-45, enrolled in the Predictors of Pregnancy Outcome: Biomarker in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) Trial. The investigation was multi-center, multi-racial and multi-ethnic. Out of the 385 women followed during the study, 81 percent experienced no adverse events. Overall, 9 percent of pregnancies resulted in premature birth, 4 percent experienced pregnancy loss during the second or third trimester, 1 percent encountered infant death due to pregnancy complications, and 10 percent had very low birth weight. Throughout the study, investigators identified four factors that appeared to increase a woman's likelihood for a negative outcome — high blood pressure during pregnancy, more active lupus during gestation, low platelet count, and a positive lupus anticoagulant test during the first trimester. “The patients who tended to be more sick at the outset, tended to be those who might have an adverse pregnancy outcome. The highest risk factor is the presence of something called a lupus anticoagulant. The presence of this abnormal blood test is very important and one that absolutely all doctors should test for,” Dr. Buyon said. In addition, race and ethnicity — black, Hispanic and Asian — contributed to poor outcomes and was in and of itself, a risk factor. Dr. Buyon said she doubts it is due to socioeconomic factors because the patients were treated by similar doctors in tertiary care centers. She suspects it may be due to genetics, which needs to be explored. Although the findings point to the possibility of healthy pregnancies for this population, Dr. Buyon cautioned women who have high protein levels in urine due to uncontrolled kidney disease could still face significant problems with pregnancy. These women are typically advised to postpone pregnancy until their kidney disease improves. Ten to 15 percent of patients had a moderate flare requiring minimal medication changes, but less than 5 percent of patients had a flare that required high dose steroids or hospitalization. About one in five patients had a renal flare. “The other optimistic perspective was that 225 patients never had kidney disease, but many of them had anti DNA antibodies which is an antibody we worry about in developing renal disease. Only four people developed de novo renal disease. For people who had previous kidney disease ... but were in complete remission, they too had very few renal flares. I think this is very encouraging news for women with past renal disease who really are so worried that maybe they’ll never have a healthy pregnancy, that simply is not true (14:01),” Dr. Buyon said. The hope, she said, is that these findings can be used to inform discussions between doctors and their patients with lupus who are also interested in pursuing pregnancy. Dr. Buyon discusses the study, its findings and implications in the following video with Rheumatology Network. http://www.rheumatologynetwork.com/lupus/women-lupus-overwhelmingly-have-healthy-pregnancies REFERENCES Jill P. Buyon, MD; Mimi Y. Kim, ScD; Marta M. Guerra, MS, et al. "Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study," Annals of Internal Medicine, Aug. 4, 2015. DOI: 10.7326/M14-2235

Medication Use Among Pregnant Women With Systemic Lupus Erythematosus and General Population Comparators Kristin Palmsten; Julia F. Simard; Christina D. Chambers; Elizabeth V. Arkema Rheumatology. 2017;56(4):561-569. Abstract and Introduction Abstract Objective. The aim was to characterize SLE medication trends before, during and after pregnancy and to compare other commonly used medications during SLE pregnancies with non-SLE pregnancies. Methods. Women with pregnancies ending in live birth or stillbirth were identified from the Swedish Medical Birth Register (2006–12). National registers were used to identify women with prevalent SLE during pregnancy and a sample without SLE and to identify prescription medications dispensed from 3 months pre-pregnancy until 6 months postpartum. We reported the prevalence of DMARDs, systemic CSs and NSAIDs (aspirin reported separately) in SLE pregnancies. We calculated prevalence estimates of other medications that were dispensed during pregnancy to ≥ 5% of SLE pregnancies and for the same medications among non-SLE pregnancies. Results. There were 483 pregnancies among women with SLE and 5723 pregnancies among women without SLE. In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy; the prevalence was 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs and varied by pregnancy period. The prevalence of common medications among SLE pregnancies was 1.2- to 20-fold higher than among non-SLE pregnancies; for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%) and levothyroxine (15.9 vs 4.9%). Conclusion. In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Commonly used medications in SLE pregnancies had far higher prevalence estimates compared with non-SLE pregnancies. Research regarding benefits and risks of commonly used medications on SLE pregnancies, breast milk and long-term outcomes for offspring is needed. Introduction The incidence of SLE is greatest among women of reproductive ages.[1] Decisions regarding medication use during pregnancy are crucial for women with this multisystem autoimmune disease. Treatment with immunosuppressants, CSs and NSAIDs during pregnancy may be indicated to treat flares or to keep disease activity under control.[2] Other medications may also be used during pregnancy to treat co-morbidities that are more common among individuals with SLE (e.g. APS, hypertension and depression).[3,4] The most prevalent prescription medications among pregnant women in general include antibacterials and antihistamines,[5] and these may also be used commonly in SLE pregnancies. There is limited information regarding medication use among pregnant women with SLE. Most reports from the past 15 years are based on a few hundred women or less and are often from women who attended one health-care centre, which limits generalizability.[6–14] Previous reports tended to focus on medications used to treat SLE, including HCQ, AZA and CSs, and few addressed heparin or other medications.[6,8,11,13,15] There is limited information regarding the timing and trajectory of medication use before, during and, especially, after SLE pregnancies.[7,10,11,14,16] To our knowledge, no studies have compared medication use among pregnant women with SLE vs women without SLE. Besides rheumatologists, other physicians, including obstetricians and general practitioners, prescribe medications for pregnant women with SLE. The spectrum of commonly used medications among pregnant women with SLE may not be apparent to their health-care providers. A more holistic approach to studying medication use among pregnant women with SLE is needed to gain a better understanding of the medication counselling needs of women with SLE who are pregnant or are planning pregnancy. We used population-based health register data from Sweden to address the limited information on medication use among pregnant women with SLE. We identified the most prevalent medications among SLE pregnancies, characterized pre-pregnancy, pregnancy and postpartum medication prevalence, and compared medication prevalence among SLE pregnancies with non-SLE pregnancies. Methods Study Population Women With Pregnancies. Nearly all deliveries in Sweden (>98%) are captured by the Medical Birth Register (MBR), which contains standardized information on maternal health during pregnancy, delivery and neonatal outcomes.[5,17] Pregnancies with a delivery date between 5 August 2006 and 31 December 2012 were included in this study. For most of the study, the MBR captured births from 22 weeks gestation onward. However, between 2006 and 1 July 2008, stillbirths were included only if they occurred at 28 gestational weeks or later. Women could have multiple pregnancies captured during the study period. Women With SLE. To identify women with SLE, we used the MBR and the National Patient Register, which contains information from hospitalizations since 1964, with complete nationwide coverage beginning in 1987, and from hospital-based outpatient specialist visits since 2001. The first SLE diagnosis for women included in this study occurred in 1977. Women were classified as having prevalent SLE during each pregnancy if they had the following: (i) at least two discharges from either inpatient or outpatient records with diagnosis codes indicative of SLE [International Classification of Diseases (ICD), Eighth, Ninth or Tenth Revision, ICD-8 734.1, ICD-9 710.0 or ICD-10 M32], excluding drug-induced lupus, and including at least one SLE diagnosis from a department or specialist that typically diagnoses, treats or manages SLE (rheumatology, dermatology, nephrology, internal medicine and paediatrics) and at least one SLE diagnosis before the beginning of pregnancy; or (ii) at least one SLE discharge diagnosis from a department or specialist as described above and at least one self-reported diagnosis of SLE in the MBR for the current pregnancy. Using Swedish registers, it has been shown that two inpatient or outpatient SLE diagnoses, including one from a specialist, accurately identifies women with SLE.[18] Similar case definitions yielded prevalence estimates of ~100 SLE cases per 100 000 women of child-bearing age in the Swedish registers, which demonstrates face validity of the definition.[19] Women Without SLE. Women without prevalent SLE during pregnancy were identified from individuals who were sampled from the Total Population Register as previously described.[20] Women without pregnancies or women with pregnancies ending prior to 28 weeks (2006–07) or 22 weeks (2008–12) were excluded. Maternal and Pregnancy Characteristics Maternal characteristics, including age, pre-pregnancy BMI and parity, were obtained from the MBR as were multiple gestation and gestational weeks at delivery. Maternal diagnoses before or during pregnancy, including asthma, chronic hypertension, type I or type II diabetes, mood disorders and APS, were obtained from the National Patient Register any time before delivery. We used a strict definition of APS (ICD-10 code D68.6: other thrombophilia) and a broad definition of APS (ICD-10 code O99.1: Other diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism complicating pregnancy, childbirth and the puerperium). The date of the last menstrual period (LMP) was obtained from the MBR. The LMP date was most often estimated using prenatal ultrasound (89%); otherwise, maternal report of the first day of the LMP was used.[21] Medications Prescribed Drug Register. The prescribed drug register, which was established in July 2005, contains information on prescription medications dispensed outside of hospitals, including Anatomical Therapeutic Chemical (ATC) classification code and date of dispensing.[22] In Sweden, prescription drugs are provided free of charge above a specified high-cost threshold (SEK 2200 in 2014).[23] Women were linked to the prescribed drug register to identify prescription medications dispensed in the 3 months before pregnancy until 6 months after pregnancy. No information is available on i.v. infusions or medications obtained over the counter. Timing. Women could have multiple dispensings for the same medication within a pregnancy. The timing of dispensing of medication was classified relative to the estimated date of the LMP and the delivery date. We defined medication prevalence as the proportion of pregnancies with at least one dispensing date for medications of interest during each of the following periods of interest: pregnancy, LMP date until the day before the delivery date; pre-pregnancy, 94 days before LMP date until the day before the LMP date; first trimester, LMP date until 93 days after the LMP date; second trimester, 94 days after the LMP date until 187 days after the LMP date; third trimester, 188 days after the LMP date until the day before the delivery date; first postpartum, delivery date until 93 days after the delivery date; and second postpartum, 94 days after the delivery date until 187 days after the delivery date. SLE-related Medications. We reported the prevalence of medications used to treat SLE across pregnancy periods among SLE pregnancies according to medication name and class (i.e. DMARDs, systemic CSs and NSAIDs, with aspirin reported separately). In addition to more commonly prescribed DMARDs in SLE, such as AZA, MTX and HCQ, we searched for less commonly prescribed DMARDs, such as LEF and SSZ (see supplementary material Table S1 , available at Rheumatology Online, for the complete list). We stratified the four classes by term and preterm deliveries (<37 weeks gestation). The working group on anti-rheumatic drugs during pregnancy and lactation at the Fourth International Conference on Sex Hormones, Pregnancy and the Rheumatic Diseases published a recommendation in 2006 to continue HCQ during pregnancy.[24] Therefore, we conducted a secondary analysis to determine whether the prevalence of HCQ increased after the recommendation. Specifically, we stratified the prevalence of HCQ and prednisolone, separately, dispensed during pregnancy by early (2006–07) and late (2008–12) study years. Prednisolone served as a control medication, and we expected the prevalence of this medication to be similar in early and late study years. We compared prevalence estimates in early and late years using χ2 tests. Most commonly used medications among SLE pregnancies. We identified medications or vitamins/supplements that were dispensed during pregnancy to at least 5% of pregnancies with SLE using fifth level ATC classification codes; the fifth level identifies the chemical substance.[25] We calculated the prevalence of these treatments among SLE pregnancies and separately among pregnancies from the general population. Then we used generalized estimating equations to calculate prevalence ratios and 95% CIs accounting for dependence among women with more than one observed pregnancy.[26] In SLE pregnancies, we stratified prevalence estimates by pregnancy periods. Finally, we identified medication or vitamins/supplement groups that were dispensed during pregnancy to ≥5% of SLE pregnancies using the fourth level of ATC codes; the fourth level identifies the chemical/pharmacological/therapeutic subgroups.[25] We reported prevalence estimates for fourth level groups that did not have complete overlap with treatments identified from the fifth level codes. This project was approved by the Ethical Review Board of Karolinska Institute (PROTOKOLL 2011/1:7) on 20 July 2011 and declared exempt by Stanford University and the University of California, San Diego's Institutional Review Board. Results with five or fewer individuals were suppressed. Results Cohort Characteristics We identified 483 pregnancies from 391 women with prevalent SLE and 5723 pregnancies from 4322 women without SLE. There were nine women diagnosed with SLE before the age of 16 years. SLE pregnancies had shorter gestational duration on average than non-SLE pregnancies ( ). Co-morbidities, including asthma, hypertension, diabetes and mood disorders, were more common among women with SLE than without SLE. Between 5 and 15% of SLE pregnancies also had a diagnostic code related to APS. Table 1. Maternal and pregnancy characteristics in women with and without SLE Maternal and pregnancy characteristics With SLE, n = 483 Without SLE, n = 5723 Age, mean (s.d.), years 31.7 (4.7) 31.6 (4.9) BMI, mean (s.d.), kg/m2 24.2 (4.1) 24.7 (4.6) Gestational weeks at delivery, mean (s.d.) 37.8 (3.3) 39.3 (1.9) Parity, n (%) 1 226 (46.8) 2358 (41.2) 2 180 (37.3) 2178 (38.1) 3 54 (11.2) 834 (14.6) 4 or more 23 (4.8) 353 (6.2) Multiple gestation, n (%) 9 (1.9) 93 (1.6) Asthma, n (%) 25 (5.2) 193 (3.4) Hypertension, n (%) 29 (6.0) 15 (0.3) Type I or type II diabetes, n (%) 9 (1.9) 37 (0.6) Mood disorder, n (%) 38 (7.9) 325 (5.7) APS, strict definition, n (%) 25 (5.2) 0 (0) APS, broad definition, n (%) 71 (14.7) 36 (0.6) SLE-related Medications In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy, 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs. The prevalence of these medications varied by pregnancy period ( ). The highest prevalence estimates were observed in the postpartum periods with the exception of aspirin, which was highest in the first and second trimesters. HCQ was the most prevalent DMARD during pregnancy (36.4%), followed by AZA (20.7%). The prevalence estimate for HCQ was highest in the first trimester and during the second postpartum period, whereas the prevalence estimate for AZA prevalence was highest in the first and second trimesters. There were no prescribed drug register-registered biologic DMARDs dispensed during pregnancy. MTX dispensings during pregnancy were rare and occurred in five or fewer individuals. There were no dispensings for mycophenolic acid during pregnancy in this cohort. Prednisolone was the most prevalent CS during pregnancy (46.2%). The prevalence of HCQ during pregnancy in 2008–12 was higher than in 2006–07 (39.1 vs 23.8%, P < 0.01), whereas the prevalence of prednisolone was similar in both time periods (46.4 vs 45.2%, P = 0.95). Table 2. SLE-related medication dispensing prevalence by pregnancy period in women with SLE Medication group Medication name During pregnancya Pre-pregnancy Trimester 1 Trimester 2 Trimester 3 Postpartum 1 Postpartum 2 (%) (%) (%) (%) (%) (%) (%) DMARDs 49.3 35.4 38.9 36.7 28.6 37.1 40.4 HCQ 36.4 23.4 28.0 25.5 20.1 25.9 30.0 AZA 20.7 14.3 16.6 16.6 11.6 14.3 11.2 Ciclosporin 1.9 1.9 1.5 1.7 1.2 1.5 1.2 Chloroquine 1.7 2.1 NA NA NA 1.5 1.2 Other DMARDb NA 1.7 NA NA NA 1.7 4.4 CSs 48.0 29.8 31.5 35.8 32.5 40.0 34.2 Prednisolone 46.2 28.2 30.4 34.4 30.6 38.1 33.1 Betamethasone 1.7 1.5 NA NA 1.2 2.1 NA Other CSc 1.5 NA NA NA NA 1.2 NA Aspirin 40.8 6.4 28.2 32.1 17.2 8.7 6.2 Other NSAIDs 6.0 8.5 5.0 NA NA 11.0 8.1 Diclofenac 1.9 2.7 NA NA NA 6.8 2.5 Naproxen 1.7 2.1 1.7 NA 0 1.2 2.7 NSAIDs excluding aspirin, diclofenac and naproxend 2.5 4.4 2.3 NA 0 3.1 3.3 aDuring pregnancy includes trimesters 1, 2 and 3. bIncludes the following medications with n ≤ 5 during pregnancy: SSZ, mycophenolic acid, etanercept and MTX. cIncludes the following medications with n ≤ 5 during pregnancy: methylprednisolone, prednisone and dexamethasone. dIncludes the following medications with n ≤ 5 during pregnancy: ibuprofen, ketoprofen, dexibuprofen, celecoxib, etoricoxib and nabumetone. NA: there are five or fewer individuals. In SLE pregnancies, 28% had no DMARD and no CS dispensings during pregnancy. When considering the three major SLE treatments, that is, HCQ, AZA and prednisolone, 14% had dispensings for HCQ only during pregnancy, 2% had dispensings for AZA only, 17% had dispensings for prednisolone only and 32% had dispensings for at least two of these treatments. Term pregnancies had a mean gestational length of 275.8 days (s.d. 9.1) or 39 completed weeks, and preterm pregnancies had a mean gestational length of 231.5 days (s.d. 28.4) or 33 completed weeks. DMARD and CS pregnancy period-specific prevalence estimates stratified by preterm birth status are presented for SLE pregnancies in Fig. 1. Aspirin prevalence is not presented in the figure because prevalence estimates did not vary greatly between term and preterm deliveries. Other NSAID prevalence is not presented because some results had fewer than five individuals. Compared with term deliveries, DMARD prevalence was higher in the first (47.3 vs 36.9%) and second (49.5 vs 33.6%) trimesters in preterm deliveries. In the third trimester, DMARD prevalence for preterm deliveries dipped below that of term deliveries (22.6 vs 30.0%). Postpartum DMARD prevalence rebounded to ~50% for preterm deliveries. The pattern observed for CSs was similar to that for DMARDs. Figure 1. Proportion of SLE pregnancies with one or more dispensing for DMARDs or CSs, by pregnancy period Most Common Medications The prevalence of common medications among SLE pregnancies was 1.2- to 21-fold higher than among non-SLE pregnancies ( ); for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%), levothyroxine (15.9% vs 4.9%), phenoxymethylpenicillin (also known as penicillin V; 14.3 vs 11.6%), pivmecillinam (10.8 vs 4.7%) and omeprazole (10.4 vs 2.3%). Supplements dispensed at the pharmacy, including calcium, folic acid, ferrous sulphate and cyanocabalmin, were 4- to 33-fold higher than among non-SLE pregnancies. Table 3. Non SLE-related medicationsa dispensed to at least 5% of SLE pregnancies, by SLE status Medication group SLE, n = 483 Non-SLE, n = 5723 PRb (95% CIc) Medication name n (%) n (%) Supplements Calcium, combinations with vitamin D or other drugs 106 (22.0) 38 (0.66) 33.05 (22.22, 49.16) Folic acid 53 (11.0) 134 (2.3) 4.69 (3.39, 6.48) Ferrous sulphate 34 (7.0) 48 (0.84) 8.39 (5.39, 13.08) Cyanocabalamin 30 (6.2) 90 (1.6) 3.95 (2.61, 5.97) Low-molecular weight heparins Dalteparin 101 (20.9) 57 (1.0) 21.00 (14.91, 29.57) Tinzaparin 41 (8.5) 15 (0.26) 32.39 (16.73, 62.71) Antibiotics Phenoxymethylpenicillin (penicillin V) 69 (14.3) 664 (11.6) 1.23 (0.97, 1.57) Pivmecillinam 52 (10.8) 268 (4.7) 2.30 (1.70, 3.11) Nitrofurantoin 35 (7.3) 272 (4.8) 1.52 (1.08, 2.16) Nasal or cough and cold preparations Mucolytic combinations 31 (6.4) 218 (3.8) 1.68 (1.15, 2.47) Opium derivatives and expectorants 36 (7.5) 249 (4.4) 1.71 (1.21, 2.43) Phenylpropanolamine 26 (5.4) 235 (4.1) 1.31 (0.89, 1.94) Other medications Paracetamol 88 (18.2) 167 (2.9) 6.24 (4.81, 8.11) Levothyroxine sodium 77 (15.9) 282 (4.9) 3.24 (2.50, 4.19) Omeprazole 50 (10.4) 129 (2.3) 4.59 (3.27, 6.45) Codeine, combinations excluding psycholeptics 35 (7.3) 132 (2.3) 3.14 (2.18, 4.52) Promethazine 34 (7.0) 288 (5.0) 1.40 (0.97, 2.03) Clemastine 33 (6.8) 276 (4.8) 1.42 (0.98, 2.06) Carbamide 27 (5.6) 67 (1.2) 4.77 (2.97, 7.68) Prevalence ratio (PR) and 95% CI. aMost common medications are those with a prevalence ≥5% during pregnancy. bReference = SLE pregnancies. c95% CIs account for multiple pregnancies per woman. The prevalence estimates for medications dispensed to at least 15% of SLE pregnancies are plotted in Fig. 2 according to pregnancy period (see supplementary material Table S2 , available at Rheumatology Online, for all commonly used medications). Dalteparin had the greatest change; from a high of 18.0% in the second trimester to a low of 1.2% in the second postpartum period. Levothyroxine prevalence was highest in the second and third trimesters. Figure 2. Non-SLE-related medications dispensed to at least 15% of SLE patients, by pregnancy period *Calcium, combinations with vitamin D or other drugs. Groups with fourth level ATC codes that did not directly overlap with fifth level ATC codes included the following: heparin group (27.5% SLE vs 1.2% non-SLE); penicillins with extended spectrum (13.7 vs 7.1%); proton pump inhibitors (12.0 vs 2.6%); iron bivalent, oral preparations (10.4 vs 1.5%); phenothiazine derivatives (9.1 vs 7.7%), for example, promethazine; natural opium alkaloids (8.1 vs 2.4%), for example, codeine; aminoalkyl ethers (6.8 vs 4.9%), for example, clemastine; mucolytics (6.8 vs 4.1%), for example, acetylcysteine; and caries prophylactic agents (5.4 vs 1.6%), for example, sodium fluoride. Discussion This descriptive population-based study demonstrates that pregnant women with SLE are a highly medicated group. In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Compared with term SLE pregnancies, SLE pregnancies with preterm delivery had higher prevalence estimates for CSs across each pregnancy period. Postpartum CS prevalence was particularly high for pregnancies with preterm delivery in the 90 days postpartum; three out of five were dispensed a CS. Women with preterm births may have had more severe disease, and the increase in CS prevalence during the postpartum period for women with preterm births may reflect the need to treat disease flares. In two out of five SLE pregnancies, women were dispensed aspirin, primarily during the first and second trimesters. There were major differences in prevalence estimates between commonly used medications and supplements in SLE pregnancies vs non-SLE pregnancies. HCQ prevalence during pregnancy was higher in this study than in several previous reports.[8,11,13,14,27] The previous studies included several years prior to the 2006 recommendation that endorsed continuation of HCQ treatment during pregnancy and, consequently, time trends could contribute to the discrepancies. In the present study, HCQ prevalence was higher in later study years. Compared with previous studies, CS prevalence during pregnancy in Sweden was lower than reports from single hospital cohorts in Asia, Saudi Arabia and Argentina (71–89%)[6,8,12,14,27] and was similar to reports from hospital cohorts in the USA and Denmark (36–48%).[11,13] Aspirin prevalence varied greatly across previous studies of SLE pregnancies (9–60%),[6–8,11,13,14] and the estimate in this study was similar to that from the hospital-based cohort in Denmark (39%).[11] In previous studies, anti-hypertensives, as a broad therapeutic class, have been reported to have a relatively high prevalence (13–29%).[6,11,13] In this cohort of pregnancies, anti-hypertensive medications, at the fourth or fifth ATC level, had prevalence estimates of < 5% during pregnancy. MTX and mycophenolic acid are teratogenic exposures and are contraindicated during pregnancy.[28]Only rarely was a MTX dispensing during pregnancy observed in this cohort. This study provides population-based snapshots of medications dispensed across the antenatal and postpartum periods in SLE pregnancies. Pregnancies with preterm delivery had an average gestational length that was 44 days shorter than term pregnancies. The shortened opportunity to obtain prescriptions contributed to the decreased prevalence of DMARDs and CSs that was observed among preterm deliveries only in the third trimester. If the majority of individuals were given a 30 day supply for all prescriptions, we may have not observed as large a decrease in the final trimester. Overall, DMARD prevalence estimates increased from pre-pregnancy to the first trimester, decreased in the third trimester and increased postpartum, and CS prevalence estimates increased from pre-pregnancy to the first postpartum period, with the exception of a dip during the third trimester. Fifteen of the commonly dispensed medications that were identified among SLE pregnancies had prevalence estimates that were at least 50% higher among SLE pregnancies vs non-SLE pregnancies and many reflect treatment for conditions or symptoms that co-occur with SLE. Dalteparin and tinzaparin were among the most commonly dispensed medications. These low-molecular weight heparins, among others, are indicated for women with aPL and a history of obstetric complications.[29]The prevalence of levothyroxine sodium during pregnancy was 3.2-fold higher among SLE pregnancies compared with general population pregnancies, which is consistent with the higher prevalence of hypothyroidism among women with SLE.[30]Omeprazole prevalence was 4.6-fold higher during pregnancy among SLE pregnancies compared with non-SLE pregnancies, which is consistent with heartburn being a common symptom among individuals with SLE.[31] Prevalence estimates for penicillin antibiotics, that is, phenoxymethylpenicillin and pivmecillinam, and nitrofurantoin were higher among SLE pregnancies compared with pregnancies from the general population, which reflects the increased susceptibility of SLE patients to infection owing to both abnormal immunological response and immunosuppressive treatments.[32] Paracetamol prevalence was 6.2-fold higher among SLE pregnancies and codeine prevalence 3.1-fold higher among SLE pregnancies compared with non-SLE pregnancies. The prevalence estimates for several supplements (calcium combinations, folic acid, ferrous sulphate and cyanocobalamin) were much higher in the SLE population than the in non-SLE population. Women with SLE are at increased risk for osteoporosis, and calcium with vitamin D is recommended for women treated with heparin during pregnancy.[33,34]Furthermore, a high prevalence of anaemia and decreased serum B12 levels have been observed among non-pregnant individuals with SLE.[35] It is possible that women with SLE are more likely to have reached the annual high-cost threshold[23]and receive all of their prescriptions free compared with women without SLE. Women who meet the high-cost threshold have an incentive to obtain over-the-counter medications as prescriptions. Consequently, the observed imbalance in medications that are also available over the counter, for example, paracetemol and supplements, between women with SLE and women without SLE could be attributed in part to women with SLE obtaining these medications by prescription. Pharmaceutical dispensing data are useful to understand not only what physicians prescribed during pregnancy but also what prescriptions patients filled. Compared with prescribing information, dispensing information is more similar to real use. The date of dispensing does not necessarily mean that the drug was taken on the day when it was dispensed, or at all, but it can be used as a proxy for exposure. For some drugs this may be more accurate than for others. For example, one study found that agreement between self-reported and dispensed immunosuppressant therapy was high, but for CSs the agreement was low.[5]Furthermore, the data in the present study do not include infusions, such as some biological DMARDs, nor the number of days of medication supplied for each dispensing. Besides the potential for exposure misclassification, this study has some additional limitations to consider. First, there could be misclassification of SLE because of our reliance on ICD codes to identify SLE, although this is likely to be minimal considering the findings from previous studies.[18,19] Second, there may be measurement error of the pregnancy time windows because the windows are based on the estimated date of the LMP. However, for the majority of pregnancies, the date of the LMP was estimated using ultrasound. Third, medications that cause fetal harm may be underestimated because pregnancies ending in spontaneous abortions and terminations are not included. To our knowledge, this is the first population-based study to describe the prevalence of medications used to treat SLE before, during and after pregnancy. Our study is also novel because it identifies the most common medications in SLE pregnancies, not only the medications that are used to treat SLE. As such, it provides practitioners with a robust picture of medication use during pregnancy among SLE patients, beyond the medications they typically prescribe. Moreover, our study provides perspective by contrasting prevalence estimates with non-SLE pregnancies. A major strength of our study is that data were collected prospectively throughout pregnancy and avoids recall problems. We anticipate that our results are generalizable to most other populations because some medications used to manage SLE in the absence of pregnancy are contraindicated, leaving few treatment options in pregnancy. In future research, the population-based approach to study medication use among pregnant women with SLE should be implemented in other counties. Pregnant women with SLE are commonly dispensed medications. This includes not only DMARDs and CSs to treat and/or prevent flares, but numerous other medications to treat co-morbidities associated with SLE. For clinicians, it is crucial to consider the risks and benefits of all medications used in SLE pregnancies. For researchers, medications that are commonly used among women with SLE should be accounted for when studying associations between SLE-related medications and pregnancy outcomes. Research regarding the benefits and risks of these commonly used medications and their combinations on SLE pregnancies, breast milk and long-term outcomes for offspring is needed. We plan to study the associations between medication exposures and pregnancy outcomes within this cohort. Sidebar Rheumatology Key Messages Pregnant women with SLE are commonly dispensed medications. Nearly half of lupus pregnancies in Sweden used DMARDs, CSs or aspirin. Many medications besides DMARDs are used more often in SLE pregnancies than in non-SLE pregnancies. References Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum 1973;3:1–54. Clowse ME. Lupus activity in pregnancy. Rheum Dis Clin North Am 2007;33:237–52, v. Clowse ME, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127.e1–6. van Exel E, Jacobs J, Korswagen LA et al. Depression in systemic lupus erythematosus, dependent on or independent of severity of disease. Lupus 2013;22:1462–9. Stephansson O, Granath F, Svensson T et al. Drug use during pregnancy in Sweden – assessed by the Prescribed Drug Register and the Medical Birth Register. Clin Epidemiol 2011;3:43–50. Aggarwal N, Raveendran A, Suri V et al. Pregnancy outcome in systemic lupus erythematosus: Asia's largest single centre study. Arch Gynecol Obstet 2011;284:281–5. Imbasciati E, Tincani A, Gregorini G et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009;24:519–25. Cavallasca JA, Laborde HA, Ruda-Vega H, Nasswetter GG. Maternal and fetal outcomes of 72 pregnancies in Argentine patients with systemic lupus erythematosus (SLE). Clin Rheumatol 2008;27:41–6. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640–7. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA. Outcome of lupus pregnancy: a controlled study. Rheumatology 2000;39:1014–9. Jakobsen IM, Helmig RB, Stengaard-Pedersen K. Maternal and foetal outcomes in pregnant systemic lupus erythematosus patients: an incident cohort from a stable referral population followed during 1990–2010. Scand J Rheumatol 2015;44:377–84. Teh CL, Wong JS, Ngeh NK, Loh WL. Systemic lupus erythematosus pregnancies: the Sarawak experience and review of lupus pregnancies in Asia. Rheumatol Int 2011;31:1153–7. Chakravarty EF, Colón I, Langen ES et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol 2005;192:1897–904. Koh JH, Ko HS, Kwok SK, Ju JH, Park SH. Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. Lupus 2015;24:210–7. Buyon JP, Kim MY, Guerra MM et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015;163:153–63. Desai RJ, Huybrechts KF, Bateman BT et al. Brief report: Patterns and secular trends in use of immunomodulatory agents during pregnancy in women with rheumatologic conditions. Arthritis Rheumatol 2016;68:1183–9. Cnattingius S, Ericson A, Gunnarskog J, Källén B. A quality study of a medical birth registry. Scand J Soc Med 1990;18:143–8. Arkema EV, Jönsen A, Rönnblom L et al. Case definitions in Swedish register data to identify systemic lupus erythematosus. BMJ Open 2016;6:e007769. Simard JF, Sjöwall C, Rönnblom L, Jönsen A, Svenungsson E. Systemic lupus erythematosus prevalence in Sweden in 2010: what do national registers say? Arthritis Care Res 2014;66:1710–7. Arkema EV, Simard JF. Cohort profile: systemic lupus erythematosus in Sweden: the Swedish Lupus Linkage (SLINK) cohort. BMJ Open 2015;5:e008259. Høgberg U, Larsson N. Early dating by ultrasound and perinatal outcome. A cohort study. Acta Obstet Gynecol Scand 1997;76:907–12. Wettermark B, Hammar N, Fored CM et al. The new Swedish Prescribed Drug Register—opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf 2007;16:726–35. TLV. What is the high cost threshold? How it works. http://www.tlv.se/In-English/medicines-new/the-swedish-highcost-threshold/how-it-works/ (2 October 2015, date last accessed). Østensen M, Khamashta M, Lockshin M et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006;8:209. ATC Structure and principles. http://www.whocc.no/atc/structure-and-principles/. (15 September 2015, date last accessed). Zou GY, Donner A. Extension of the modified Poisson regression model to prospective studies with correlated binary data. Stat Methods Med Res 2013;22:661–70. Al Arfaj AS, Khalil N. Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. Lupus 2010;19:1665–73. Običan S, Scialli AR. Teratogenic exposures. Am J Med Genet C Semin Med Genet 2011;157C:150–69. Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv 2011;66:639–53. Antonelli A, Fallahi P, Mosca M et al. Prevalence of thyroid dysfunctions in systemic lupus erythematosus. Metabolism 2010;59:896–900. Ebert EC, Hagspiel KD. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J Clin Gastroenterol 2011;45:436–41. Sciascia S, Cuadrado MJ, Karim MY. Management of infection in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2013;27:377–89. Ruiz-Irastorza G, Khamashta MA, Hughes GR. Heparin and osteoporosis during pregnancy: 2002 update. Lupus 2002;11:680–2. Di Munno O, Mazzantini M, Delle Sedie A, Mosca M, Bombardieri S. Risk factors for osteoporosis in female patients with systemic lupus erythematosus. Lupus 2004;13:724–30. Segal R, Baumoehl Y, Elkayam O et al. Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Rheumatol Int 2004;24:14–9. Funding This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health [K01-AR06687801]. Rheumatology. 2017;56(4):561-569. © 2017 Oxford University Press http://www.medscape.com/viewarticle/880421?src=wnl_edit_tpal&uac=60604BR

Pregnancy Complications in Lupus: Can Blood Transcriptomics Predict? What mechanisms make pregnancies for women with systemic lupus erythematosus different than pregnancies in healthy women? Researchers from the Baylor Research Institute find that the neutrophil signature is a potential early biomarker of preeclampsia in women with systemic lupus erythematosus. The research, led by Seunghee Hong of Baylor, was presented on Nov. 13 at the American College of Rheumatology annual meeting held in Washington, D.C. The autoimmune disease systemic lupus erythematosus usually affects women in child-bearing years, and those pregnancies have higher rates of adverse outcomes than pregnancies in healthy women. For this study, the authors characterized the blood transcriptome to better understand the molecular mechanisms in pregnant women with systemic lupus erythematosus. For the study, researchers characterized the blood transcriptome through microarray, of 135 pregnant women (43 healthy and 92 systemic lupus erythematosus) and 54 non-pregnant women (34 healthy controls and 20 systemic lupus erythematosus) from the PROMISSE Study. They drew blood four times during the pregnancy time period, and once in the postpartum period. They classified poor pregnancy outcomes as preeclampsia, and other complications like preterm delivery, growth restriction and fetal/neonatal death. Pregnant systemic lupus erythematosus study subjects included 24 preeclampsia cases, 22 other complications and 46 with no complications. Researchers identified 9,687 transcripts expressed in healthy pregnant women, like neutrophil upregulation, myeloid inflammation and erythropoiesis signatures. They also found downregulation of immune pathways linked to lupus pathogenesis, like IFN and plasma cells. Then they compared the signatures in women with systemic lupus erythematosus/non-complicated pregnancies to those from healthy, non-pregnant women. They found that the women with systemic lupus erythematosus/non-complicated pregnancies had the same dynamic features as women with healthy pregnancies. They found a lower plasma cell signature in women with systemic lupus erythematosus non-complicated pregnancies compared to systemic lupus erythematosus non-pregnant women and healthy non-pregnant women. Also, the IFN signature was patent through pregnancy compared to the healthy non-pregnant control subjects. Systemic lupus erythematosus groups with pregnancy complications did not downregulate plasma cell signatures and IFN signatures to the same levels as their systemic lupus erythematosus counterparts who had no pregnancy complications. Systemic lupus erythematosus patients with preeclampsia showed early upregulation of neutrophil signatures, with early preeclampsia biomarkers being AZU1, CTSG and ELANE. Researchers concluded that the neutrophil signature is a potential early biomarker of preeclampsia. References Seunghee Hong. "Longitudinal Blood Transcriptomics Uncovers Immune Networks Associated with Complications in Lupus Pregnancy," Abstract number 914. 12:15 p.m., Nov. 13, 2016. ACR/ARHP 2016 Annual Meeting. http://www.rheumatologynetwork.com/ACR-RN-2016/pregnancy-complications-lupus-can-blood-transcriptomics-predict?GUID=&XGUID=&rememberme=1&ts=15112016

VIDEO: Develop plan for pregnancy in patients with lupus http://www.healio.com/rheumatology/lupus/news/online/{3b2cf651-e3c1-4231-9b7e-1fab7d5e57e3}/video-develop-plan-for-pregnancy-in-patients-with-lupus?utm_source=maestro&utm_medium=email&utm_campaign=rheumatology news CLEVELAND — At the Rheumatology Nurses Annual Conference, Monica Richey, MSN, ANP-BC/GNP, an adult rheumatology nurse practitioner at Hospital for Special Surgery, spoke about how rheumatologists and rheumatology nurses can best prepare patients with lupus for pregnancy.

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/

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.

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.

Pregnancy Outcomes Favorable in SLE Patients The majority of pregnant patients with systemic lupus erythematosus (SLE) have favorable pregnancy outcomes, with few experiencing severe flares, according to the results of the largest prospective study to date investigating pregnancy in women with SLE.“In patients with inactive disease or stable mild or moderate activity, pregnancy is safer for mother and child than it was previously believed to be, with good outcomes in 81% of patients,” write the researchers, led by Jill P. Buyon, MD, chair of the division of rheumatology at New York University/Langone Medical Center in New York. They published their results in the June 23, 2015 Annals of Internal Medicine.SLE primarily affects women of childbearing age, and it has been suggested that women with SLE end up with high rates of preterm birth, preeclampsia, and fetal loss.Previous studies have identified active disease, hypocomplementemia, presence of anti-double-stranded DNA antibodies, prior nephritis, and presence of antiphospholipid antibodies (aPLs) as risk factors for adverse pregnancy outcomes (APOs).Yet, the researchers point out that the effects of pregnancy on SLE activity and the contribution of disease activity to APOs are unclear. “Currently, patients with SLE are advised to consider pregnancy during periods of minimal and stable disease. However, data supporting this advice are based on retrospective or prospective single-center studies involving few patients, have limited generalizability to multiethnic populations, and are controversial,” they write.They identified 385 patients, half non-Hispanic white and about one-third with prior nephritis, with SLE in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) study. PROMISSE is a multicenter, prospective observational study of pregnancies in women with SLE meeting a minimum of 4 revised American College of Rheumatology criteria, women with SLE and aPLs, women with aPLs alone, and healthy women at low risk for APOs.APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational-age neonate (birthweight below the fifth percentile).Only 5% of pregnancies ended in fetal or neonatal death, and only 3% of women had severe maternal flares.“Of note, the rate of APOs was less than 8%, with fetal or neonatal deaths accounting for fewer than half of these events in non-Hispanic white women who were lupus anticoagulant-negative, had a Physician’s Global Assessment score of 1 or lower, were not treated with anti-hypertensives, and had a platelet count of at least 100 × 109 cells/L,” they write.Certain demographic and risk factors were significant. Non-Hispanic white race was protective. Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs.For women who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using anti-hypertensive medications, the APO rate was 58% and fetal or neonatal mortality was 22%.The researchers suggest that additional biomarkers should be evaluated to identify high-risk patients and define mechanisms of APOs in patients with SLE. They acknowledge that the PROMISSE study did not address first-trimester losses, and the results may not apply to women with high disease activity since they were excluded from the study.REFERENCESJane E. Salmon, Jill P. Buyon, et al. Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Annals Internal Medicine. Published online June 23, 2015 doi:10.7326/M14-2235. Abstract

SLE and Pregnancy and Prognosis? Buyon JP, Kim MY, Guerra MM, et al. Original Research: Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med. Published online 23 June 2015 doi:10.7326/M14-2235 Hahn BH. Editorial: Pregnancy in Women With Systemic Lupus Erythematosus: Messages for the Clinician. Ann Intern Med. Published online 23 June 2015 doi:10.7326/M15-1301 The good news: Among pregnant women with systemic lupus erythematosus (SLE), 81% had a good outcome. The bad news: Among Hispanic white and African-American women, only 74% had a good outcome. (“Good outcome” means not having an adverse pregnancy outcome (APO), which includes fetal or neonatal death, birth <36 weeks due to placental insufficiency, hypertension, pre-eclampsia, and <5th percentile of birth weight.) Total No APOs Non-Hispanic white 157 (85%) 27 (15%) Hispanic white 43 (74%) 15 (26%) African-American 58 (74%) 20 (26%) Other/No answer 54 (83%) 11 (17%) Total 312 (81%) 73 (19%) APO = adverse pregnancy outcome. P=0.053 That’s the result of the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody syndrome and Systemic Lupus Erythematosus(PROMISSE) study, the largest study to date, with 385 patients and 198 healthy controls. The best results (92%) were achieved by non-Hispanic white women with negative lupus anticoagulant test results, no treatment for hypertension, no or low disease activity, and platelet counts of at least 100 x 109 cells/L. Fetal or neonatal deaths occurred in only 3.9%, which is similar to healthy control participants. Among all 385 pregnancies, 5% ended in fetal or neonatal death. PROMISSE identified characteristics of US women who had good and bad outcomes. Multivariant analysis revealed several predictors of poor fetal outcomes. Being non-Hispanic white had an odds ratio of 0.45 (confidence interval 0.24-0.84) for having an APO at any time during pregnancy. Other characteristics were: -- Anti-hypertensive use at baseline -- Presence of lupus anticoagulant -- Clinical flare at any time during pregnancy -- Moderate clinical disease at baseline APOs were not associated with anti-dsDNA. In an editorial, Bevra Hahn suggests: -- Pregnancies should be planned as much as possible and timed to occur when disease activity is lowest. -- Every pregnancy during SLE is high-risk, and a high-risk obstetrician should be involved. -- SLE should be controlled as tightly as possible. Flares occur in approximately 50% of pregnant women. Nonfluorinated glucocorticoids are the mainstay of treatment, and hydroxychloroquine seems to be safe for the fetus. For the approximately 40% of patients positive for anticardiolipin, low-dose aspirin plus heparin is recommended

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.

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.

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.

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. http://www.rheumatologynetwork.com/lupus/pregnancy-sle-and-aps-new-guidelines

Women With Autoimmune Rheumatic Diseases: Considerations Before, During, and After Pregnancy Listen and learn from experts in SLE: slides and information. This presentation is meant for doctors, but gives very good information and advice from experts. http://www.peervoice.com/women-autoimmune-rheumatic-diseases-considerations-during-and-after-pregnancy?person_id=2029011#featured-presentations Presentation 1 The Impact of Pregnancy on Autoimmune Rheumatic Diseases Marta Mosca, MD, PhD Rheumatology Unit University of Pisa Pisa, Italy Presentation 2 Discussing the Implications of Pregnancy on Autoimmune Rheumatic Diseases With Your Patients Munther Khamashta, MD, PhD, FRCP Graham Hughes Lupus Research Unit Laboratory The Rayne Institute St Thomas’ Hospital London, United Kingdom Presentation 3 Clinical Approaches for Young Women With Autoimmune Rheumatic Diseases During Pregnancy Caroline Gordon , MA, MD, FRCP Rheumatology Research Group University of Birmingham Birmingham, United Kingdom Munther Khamashta, MD, PhD, FRCP Graham Hughes Lupus Research Unit Laboratory The Rayne Institute St Thomas’ Hospital London, United Kingdom Marta Mosca, MD, PhD Rheumatology Unit University of Pisa Pisa, Italy While counselling is mentioned, this is in relation to medical and not psychological aspects. Please contact me for information regarding psychological counselling. Dr. Khamashta: Many of my patients say to me, “Doctor, I have lupus. Does that mean my daughter will have lupus or my son will have lupus?”; “I have rheumatoid arthritis. Does that mean my children will have the disease?” And this is also an important part of the counseling. There is no doubt that there is a genetic component, and we tell our patients with lupus and rheumatoid arthritis that there is perhaps a 3% to 5% chance that their children will have the disease. Most patients accept that small risk.

This is to announce a separate forum for Lupus and pregnancy. We start off with an excellent presentation given by experts in this area.