BACKGROUND:To enhance patient-tailored preconception risk assessment for women with systemic lupus erythematosus (SLE), knowledge on risk factors associated with adverse pregnancy outcomes is required. Therefore, we did a systematic review and meta-analysis to identify and provide unambiguous effect sizes of preconception predictors of pregnancy outcomes in women with SLE. METHODS:In this systematic review and meta-analysis, we searched PubMed and Embase for studies reporting preconception predictors of pregnancy outcomes in women with SLE, from database inception to Aug 22, 2023. Studies were included if they presented original, quantitative data on pregnant women with SLE and reported on preconception risk factors on at least one of the outcomes as defined in the protocol. Studies were excluded if they had a sample size of less than 20 patients, were restricted to multiple pregnancies, had unclear timing of prognostication, or exclusively reported a composite outcome. Literature screening, data extraction, and risk-of-bias assessment (quality in prognostic studies tool) were done by two reviewers independently, in a blinded, standardised manner. The reported outcomes included livebirth, pre-eclampsia, small for gestational age, preterm birth, pregnancy loss before and after 20 weeks of gestation, and SLE flares. We computed pooled univariate odds ratios (ORs) and 95% CIs using a random effects model. We assessed heterogeneity using the I statistic and prediction intervals. This study is registered with PROSPERO, CRD42022344732. FINDINGS:Of the 6705 unique articles identified, 72 (1·1%) were included in the meta-analysis, comprising 10 355 pregnancies in 8065 women with SLE. One potentially eligible study was retracted and therefore removed from our analysis. Previous lupus nephritis was associated with decreased livebirth probability (OR 0·62 [95% CI 0·47-0·81]; I=0%), increased risk of preterm birth (2·00 [1·55-2·57]; I=17%), and increased risk of pre-eclampsia (3·11 [2·35-4·12]; I=0%). Chronic hypertension was associated with increased risk of disease flare (2·50 [1·74-3·58]; I=0%), preterm birth (2·65 [1·87-3·77]; I=0%), and pre-eclampsia (5·86 [3·41-10·06]; I=33%). SLE disease activity at conception or preconception was associated with increased risk of preterm birth (2·91 [1·96-4·33]; I=21%) and pre-eclampsia (2·32 [1·40-3·83]; I=0%). Secondary antiphospholipid syndrome was associated with decreased livebirth probability (0·40 [0·27-0·58]; I=0%), increased risk of pregnancy loss after 20 weeks of gestation (2·77 [1·44-5·31]; I=0%), and increased risk of preterm birth (1·65 [1·29-2·11]; I=0%). Across studies, risk-of-bias assessment suggested considerable bias in study attrition and confounding. INTERPRETATION:We identified previous lupus nephritis, chronic hypertension, SLE disease activity before and at conception, and secondary antiphospholipid syndrome as predictors of adverse pregnancy outcomes in women with SLE. These findings contribute to an optimal patient-tailored risk assessment in preconception counselling. FUNDING:None.

OBJECTIVE:Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab. METHODS:Data collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively. RESULTS:Among 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data. CONCLUSIONS:Observations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

BACKGROUND:The prevalence of autoimmune conditions is two-fold higher in women than in men, especially during the reproductive years. Autoimmune conditions have been associated with a greater risk of adverse pregnancy outcomes, and some conditions have been studied more than others with inconsistent findings. The objective of this umbrella review was to identify, appraise, synthesise, and consolidate findings from published systematic reviews of autoimmune conditions and adverse pregnancy outcomes. METHODS:In this umbrella review, we searched Medline, Embase, and Cochrane databases for systematic reviews from inception to Sept 30, 2022, without language restrictions. We used the Medical Subject Headings and free text search for autoimmune conditions and pregnancy outcomes. Screening, data extraction, and quality appraisal (AMSTAR 2) were done by two independent reviewers. Data was extracted using a standardised form, which was piloted before use. Data were synthesised narratively and quantitatively. Odds ratios (ORs) with 95% CIs were reported. The protocol has been registered to PROSPERO (CRD42022334992). FINDINGS:We selected 33 reviews, which included 709 primary studies. Pregnant women with autoimmune conditions were at high risk of both adverse maternal and fetal outcomes. The risk of miscarriage was increased in pregnant women with Sjögren's syndrome (relative risk [RR] 8·85, 95% CI 3·10-25·26), systemic lupus erythematosus (SLE; OR 4·90, 95% CI 3·10-7·69), thyroid autoimmunity (OR 2·77, 2·10-3·65), systemic sclerosis (OR 1·60, 1·29-2·22), and coeliac disease (OR 1·38, 1·12-1·69). The risk of pre-eclampsia was increased in pregnant women with type 1 diabetes (T1DM; OR 4·19, 3·08-5·71) and SLE (OR 3·20, 2·54 - 4·20). The risk of gestational diabetes was increased in pregnant women with inflammatory bowel disease (IBD; OR 2·96, 1·47-5·98) and thyroid autoimmunity (OR 1·49, 1·07-2·07). The risk of intrauterine growth restriction (IUGR) was increased in pregnant women with systemic sclerosis (OR 3·20, 2·21-4·53) and coeliac disease (OR 1·71, 1·36-2·14). The risk of delivering a small-for-gestational age baby was increased in pregnant women with SLE (OR 2·49, 1·88-3·31) and rheumatoid arthritis (OR 1·49, 1·22-1·82). The risks of other fetal outcomes such as stillbirth, preterm birth, and low birthweight were also increased in pregnant women with autoimmune disorders. T1DM in women was associated with lower odds of small-for-gestational-age outcome (OR 0·68, 0·56-0·83). INTERPRETATION:Pregnant women with autoimmune conditions are at greater risk of developing adverse pregnancy outcomes. Further research is required to develop better preconception to post-natal care for women with autoimmune conditions. FUNDING:Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR).

OBJECTIVE:Systemic lupus erythematosus (SLE) disproportionately affects women during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of pregnancies in lupus patients, although reports vary by parity and multifetal gestation. We investigated whether taking HCQ early in pregnancy may reduce the risk of preeclampsia. METHODS:We studied 1,068 live birth singleton pregnancies among 1,020 privately insured patients with SLE (2007-2016). HCQ treatment was defined as three months preconception through the first trimester, and prescription fills were a proxy for taking HCQ. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (CIs), stratified by parity. Propensity scores accounted for confounders, and stratified analyses examined effect modification. RESULTS:Approximately 15% of pregnant patients were diagnosed with preeclampsia. In 52% of pregnancies, patients had one or more HCQ fills. Pregnant patients exposed to HCQ had more comorbidities, SLE activity, and azathioprine treatment. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR 1.26 [95% CI 0.82-1.93]) and multiparous pregnancies (RR 1.20 [95% CI 0.80-1.70]). Additional controls for confounding decreased the RRs toward the null (nulliparous pregnancy, propensity score-adjusted [PS-adj] RR 1.09 [95% CI 0.68-1.76]; multiparous pregnancy, PS-adj RR 1.01 [95% CI 0.66-1.53]). CONCLUSION:Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ treatment in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in pregnant patients with SLE and among persons at greater risk of hypertensive disorders of pregnancy.

Importance:Individuals with systemic lupus erythematosus (SLE) have an increased risk of pregnancy-related complications. However, data on acute cardiovascular complications during delivery admissions remain limited. Objective:To investigate whether SLE is associated with an increased risk of acute peripartum cardiovascular complications during delivery hospitalization among individuals giving birth. Design, Setting, and Participants:This population-based cross-sectional study was conducted with data from the National Inpatient Sample (2004-2019) by using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM) codes to identify delivery hospitalizations among birthing individuals with a diagnosis of SLE. A multivariable logistic regression model was developed to report an adjusted odds ratio (OR) for the association between SLE and acute peripartum cardiovascular complications. Data were analyzed from May 1 through September 1, 2022. Exposure:Diagnosed SLE. Main Outcomes and Measures:Primary study end points were preeclampsia, peripartum cardiomyopathy, and heart failure. Secondary end points included ischemic and hemorrhagic stroke, pulmonary edema, cardiac arrhythmias, acute kidney injury (AKI), venous thromboembolism (VTE), length of stay, and cost of hospitalization. Results:A total of 63 115 002 weighted delivery hospitalizations (median [IQR] age, 28 [24-32] years; all were female patients) were identified, of which 77 560 hospitalizations (0.1%) were among individuals with SLE and 63 037 442 hospitalizations (99.9%) were among those without SLE. After adjustment for age, race and ethnicity, comorbidities, insurance, and income level, SLE remained an independent risk factor associated with peripartum cardiovascular complications, including preeclampsia (adjusted OR [aOR], 2.12; 95% CI, 2.07-2.17), peripartum cardiomyopathy (aOR, 4.42; 95% CI, 3.79-5.13), heart failure (aOR, 4.06; 95% CI, 3.61-4.57), cardiac arrhythmias (aOR, 2.06; 95% CI, 1.94-2.21), AKI (aOR, 7.66; 95% CI, 7.06-8.32), stroke (aOR, 4.83; 95% CI, 4.18-5.57), and VTE (aOR, 6.90; 95% CI, 6.11-7.80). For resource use, median (IQR) length of stay (3 [2-4] days vs 2 [2-3] days; P < .001) and cost of hospitalization ($4953 [$3305-$7517] vs $3722 [$2606-$5400]; P < .001) were higher for deliveries among individuals with SLE. Conclusions and Relevance:This study found that SLE was associated with increased risk of complications, including preeclampsia, peripartum cardiomyopathy, heart failure, arrhythmias, AKI, stroke, and VTE during delivery hospitalization and an increased length and cost of hospitalization.

Systemic lupus erythematosus (SLE), a multiorgan systemic inflammatory disorder, predominantly affects women during their reproductive years. In this review, we summarize the state of knowledge about preconception planning and management of SLE during pregnancy. Achieving remission or low disease activity for several months on medications compatible with pregnancy prior to conception is essential to decreasing the risk of disease flare and improving pregnancy outcomes, including pre-eclampsia, preterm birth, and intrauterine growth restriction. With close management and well-controlled disease before and during pregnancy, <10% of patients flare. All patients with SLE should remain on hydroxychloroquine unless contraindicated. Expectant mothers with a history of antiphospholipid syndrome should be treated with anticoagulant therapy during pregnancy. Women with anti-Ro/SSA or anti-La/SSB antibodies require additional monitoring because their offspring are at increased risk for congenital heart block. Patients with SLE should be offered low-dose aspirin starting at the end of the first trimester to reduce the risk of pre-eclampsia. Flares of SLE during pregnancy require escalation of therapy. The immunosuppressives azathioprine, tacrolimus, and cyclosporine are compatible with pregnancy, and biologic agents can also be considered. Glucocorticoid use in pregnancy should be limited to the lowest effective dose. Mycophenolate mofetil/mycophenolic acid, methotrexate, leflunomide, and cyclophosphamide are known to be teratogenic and are contraindicated in pregnancy. Distinguishing a flare of lupus nephritis during pregnancy from pre-eclampsia can be particularly challenging. Overall, outcomes in pregnancy for women with lupus are improving, but gaps in knowledge about optimal management strategies persist.

To evaluate the utility of neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic immune-response index (SIRI) in the prediction of adverse pregnancy outcomes in pregnant women with systemic lupus erythematosus (SLE). This retrospective case-control study was conducted in Ankara City Hospital perinatology clinic between 2019 and 2023. First-trimester NLR, SII (NLR X platelet count), and SIRI (NLR X monocyte count) values were compared between pregnant women with SLE (n = 29) and low-risk controls (n = 110). Afterward, pregnant women with SLE were divided into two groups: 1) SLE with perinatal complications (n = 15) and 2) SLE without perinatal complications (n = 14). NLR, SII, and SIRI values were compared between the two subgroups. Finally, a ROC analysis was performed to determine optimal cut-off values for NLR, SII, and SIRI in the prediction of composite adverse pregnancy outcomes. The study group had significantly higher first-trimester NLR, SII, and SIRI values compared to the controls. The SLE with perinatal complications group had significantly higher NLR, SII, and SIRI values than the SLE group without perinatal complications (p < 0.05). Optimal cut-off values were 6.5 (66.7% sensitivity,71.4% specificity), 1612.6 (73.3% sensitivity, 71.4% specificity), and, 4.7 (73.3% sensitivity, 77.6% specificity) for NLR, SII, and SIRI, respectively. SII, SIRI, and NLR may be used to predict adverse pregnancy outcomes in pregnant women with SLE.