Adverse Outcome Predictors in Pregnancies Complicated by SLE
By Ahizechukwu C. Eke, MD, PhD, MPH
Synopsis: A prior history of lupus nephritis, active systemic lupus erythematosus (SLE) at conception, secondary antiphospholipid syndrome, and chronic hypertension are critical predictors of adverse pregnancy outcomes in women with SLE.
Source: Wind M, Fierro JJ, Bloemenkamp KW, et al. Pregnancy outcome predictors in systemic lupus erythematosus: A systematic review and meta-analysis. Lancet Rheumatol. 2024;6(10):e667-e683.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multi-organ inflammation, disproportionately affecting women of reproductive age.1 In the United States, the prevalence of SLE is estimated to be approximately 20-150 cases per 100,000 individuals, with women accounting for 90% of cases.2,3 African American, Hispanic, and Asian women are particularly affected, with prevalence rates in these populations significantly exceeding those observed in non-Hispanic white women.4 For example, African American women have an estimated prevalence of 231/100,000 persons, nearly three times that of non-Hispanic white women (85/100,000).4
SLE disproportionately contributes to increased maternal morbidity and mortality, including adverse pregnancy outcomes, in pregnant and postpartum women.5 Despite advances in disease management, pregnancy in individuals with SLE remains high-risk, warranting a focused investigation into predictors of adverse pregnancy outcomes to guide clinical care.
Adverse pregnancy outcomes in women with SLE are significantly more common compared to the general population. Common adverse pregnancy outcomes include preeclampsia, intrauterine fetal growth restriction (IUGR), preterm birth, stillbirth, and neonatal death.5 Studies indicate that up to 33% of pregnancies in women with SLE result in preterm birth, compared to a baseline rate of approximately 10% in the general population.6 Similarly, preeclampsia occurs in 13% to 35% of pregnancies in women with SLE, compared to a general population rate of 5% to 8% in other affected pregnancies.6
Key predictors of these outcomes include disease activity at conception and during pregnancy, presence of antiphospholipid antibodies (aPL), lupus nephritis, and maternal comorbidities such as baseline hypertension prior to pregnancy.6 High disease activity, particularly during the first trimester, is associated with a five-fold increase in the risk of pregnancy loss.6 Moreover, women with aPL antibodies are at a two-fold higher risk for preeclampsia and placental insufficiency.7
Other factors, such as medication non-adherence and disparities in healthcare access, compound these risks, particularly in racial and ethnic minority populations.7 Identifying and understanding these predictors is critical to optimizing maternal and fetal outcomes in women with SLE.
This study by Wind et al aims to elucidate the key predictors of adverse pregnancy outcomes in women with SLE, with an emphasis on disease-related, immunological, and sociodemographic factors.8 Understanding these relationships is pivotal to developing targeted interventions to reduce the burden of adverse pregnancy outcomes in this high-risk population.
This study is a systematic review and meta-analysis of all studies involving pregnant women with SLE that reported on adverse pregnancy outcomes. Eligible studies provided original, quantitative data on preconception risk factors for at least one adverse pregnancy outcome. Exclusion criteria included sample sizes smaller than 20 patients, populations restricted to multiple pregnancies, predictors unavailable during preconception counseling (e.g., first-trimester laboratory parameters), or studies reporting only composite outcomes without individual component data.
The assessed outcomes included live birth, preeclampsia, small-for-gestational-age infants, IUGR, birthweight, preterm birth, pregnancy loss before and after 20 weeks’ gestational age, neonatal intensive care unit admission, fetal death, perinatal mortality, neonatal death, neonatal lupus, congenital heart block, antepartum or postpartum thrombosis, Apgar scores, and SLE flares. The follow-up timeframe for pregnancy outcomes extended from conception to six weeks postpartum, while SLE flares were tracked up to 12 months postpartum.
Summary estimates were calculated as odds ratios (ORs) using random-effects meta-analysis with the generic inverse variance method. The Paule-Mandel estimator determined random-effects weights. Heterogeneity among studies was assessed using the I² statistic, with values exceeding 75% indicating high heterogeneity. To assess the robustness of predictor-outcome associations, 95% prediction intervals for pooled effect sizes were calculated. The analysis was conducted using the meta package in R (version 4.2.1, R Foundation for Statistical Computing, Vienna, Austria), and results were presented as 95% confidence intervals (CIs), with statistical significance defined as P-values < 0.05.
A total of 10,355 women, including 8,065 with SLE, were enrolled across 72 studies. Prior lupus nephritis was significantly associated with poorer pregnancy outcomes, including a reduced probability of live birth (OR, 0.62; 95% CI, 0.47 to 0.81; I² = 0%), a heightened likelihood of preeclampsia (OR, 3.11; 95% CI, 2.35 to 4.12; I² = 0%), and an increased risk of preterm birth (OR, 2.00; 95% CI,1.55 to 2.57; I² = 17%).
Chronic hypertension emerged as another important risk factor, linked to higher odds of preterm birth (OR, 2.65; 95% CI,1.87 to 3.77; I² = 0%), disease flares (OR, 2.50; 95% CI, 1.74 to 3.58; I² = 0%), and preeclampsia (OR, 5.86; 95% CI, 3.41 to 10.06; I² = 33%). Similarly, SLE disease activity at conception or preconception was associated with increased risks of preeclampsia (OR, 2.32; 95% CI, 1.40 to 3.83; I² = 0%) and preterm birth (OR, 2.91; 95% CI, 1.96 to 4.33; I² = 21%).
Secondary antiphospholipid syndrome (APS) was particularly detrimental, showing strong associations with an increased risk of pregnancy loss after 20 weeks of gestation (OR, 2.77; 95% CI, 1.44 to 5.31; I² = 0%), lower likelihood of live birth (OR, 0.40; 95% CI, 0.27 to 0.58; I² = 0%), and a higher risk of preterm birth (OR, 1.65; 95% CI,1.29 to 2.11; I² = 0%).
Commentary
This meta-analysis of 72 studies, including 10,355 pregnancies in 8,065 women with SLE, provides robust evidence for the role of specific clinical predictors in adverse pregnancy outcomes. Previous lupus nephritis, chronic hypertension, active SLE at conception, and secondary APS were strongly associated with decreased live birth probabilities, increased risks of preterm birth, preeclampsia, and disease flares.
The findings underscore the significant burden of adverse pregnancy outcomes in women with SLE, highlighting the need for targeted preconception counseling and clinical management. Importantly, the study identified no significant heterogeneity (I² = 0%) for most outcomes, bolstering the reliability of the associations.
Previous lupus nephritis emerged as a strong predictor of adverse pregnancy outcomes, significantly reducing the likelihood of live birth and increasing the risk of preeclampsia.9,10 These findings align with existing literature demonstrating that lupus nephritis, even in remission, predisposes women to placental insufficiency and systemic vascular dysfunction, increasing pregnancy risks.10
Chronic hypertension similarly heightened risks, with a six-fold increase in preeclampsia risk (OR, 5.86; 95% CI, 3.41 to 10.06) and significant associations with preterm birth and disease flares. These results parallel studies from the PROMISSE cohort, where chronic hypertension (with antihypertensive use) increased the risk of adverse pregnancy outcomes by seven-fold and was a leading driver of adverse maternal outcomes.11
SLE activity at or before conception also markedly increased risks of preterm birth and preeclampsia.5,6 These findings reinforce the need for disease quiescence before conception, since high disease activity exacerbates endothelial damage and placental insufficiency.10
Secondary APS was associated with the most severe outcomes, including decreased live birth probability, increased pregnancy loss after 20 weeks, and heightened risk of preterm birth.12 This aligns with evidence linking antiphospholipid antibodies to thrombotic events and recurrent pregnancy losses.7,12 The lack of heterogeneity (I² = 0%) in these findings highlights their robustness, suggesting that APS should remain a critical focus in SLE preconception evaluations.
In conclusion, this meta-analysis underscores the critical role of prior lupus nephritis, chronic hypertension, active disease, and secondary APS in driving adverse pregnancy outcomes in women with SLE. These findings align with the American College of Obstetricians and Gynecologists guidelines, which emphasize the importance of achieving disease quiescence for at least six months before conception, managing hypertension aggressively, and screening for and treating APS with anticoagulant therapies as indicated in women with SLE.13
Comprehensive preconception counseling incorporating these risk factors can improve pregnancy planning and optimize maternal and fetal outcomes in women with SLE. Continued research into mitigating these risks and addressing study biases will further refine clinical strategies for this high-risk population.
Ahizechukwu C. Eke, MD, PhD, MPH, is Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore.
References
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8. Wind M, Fierro JJ, Bloemenkamp KWM, et al. Pregnancy outcome predictors in systemic lupus erythematosus: A systematic review and meta-analysis. Lancet Rheumatol. 2024;6(10):e667-e683.
9. Lucas A, Eudy AM, Gladman D, et al. The association of lupus nephritis with adverse pregnancy outcomes among women with lupus in North America. Lupus. 2022;31(11):1401-1407.
10. Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and managing pregnancy in patients with lupus. Autoimmune Dis. 2015;2015:943490.
11. Buyon JP, Kim MY, Guerra MM, et al. Predictors of pregnancy outcomes in patients with lupus: A cohort study. Ann Intern Med. 2015;163(3):153-163.
12. D’Ippolito S, Barbaro G, Paciullo C,. Antiphospholipid syndrome in pregnancy: New and old pathogenetic mechanisms. Int J Mol Sci. 2023;24(4):3195.
13. Committee on Practice Bulletins – Obstetrics, American College of Obstetricians and Gynecologists. Practice Bulletin No. 132: Antiphospholipid syndrome. Obstet Gynecol. 2012;120(6):1514-1521.
A prior history of lupus nephritis, active systemic lupus erythematosus (SLE) at conception, secondary antiphospholipid syndrome, and chronic hypertension are critical predictors of adverse pregnancy outcomes in women with SLE.
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