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Research ArticleSystemic Lupus Erythematosus

Lupus Low Disease Activity State Achievement Is Important for Reducing Adverse Outcomes in Pregnant Patients With Systemic Lupus Erythematosus

Ji-Won Kim, Ju-Yang Jung, Hyoun-Ah Kim, Jeong I. Yang, Dong W. Kwak and Chang-Hee Suh
The Journal of Rheumatology May 2021, 48 (5) 707-716; DOI: https://doi.org/10.3899/jrheum.200802
Ji-Won Kim
1J.W. Kim, MD, J.Y. Jung, MD, PhD, H.A. Kim, MD, PhD, C.H. Suh, MD, PhD, Department of Rheumatology, Ajou University School of Medicine, Suwon;
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Ju-Yang Jung
1J.W. Kim, MD, J.Y. Jung, MD, PhD, H.A. Kim, MD, PhD, C.H. Suh, MD, PhD, Department of Rheumatology, Ajou University School of Medicine, Suwon;
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Hyoun-Ah Kim
1J.W. Kim, MD, J.Y. Jung, MD, PhD, H.A. Kim, MD, PhD, C.H. Suh, MD, PhD, Department of Rheumatology, Ajou University School of Medicine, Suwon;
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Jeong I. Yang
2J.I. Yang, MD, PhD, D.W. Kwak, MD, PhD, Department of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, Korea.
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Dong W. Kwak
2J.I. Yang, MD, PhD, D.W. Kwak, MD, PhD, Department of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, Korea.
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Chang-Hee Suh
1J.W. Kim, MD, J.Y. Jung, MD, PhD, H.A. Kim, MD, PhD, C.H. Suh, MD, PhD, Department of Rheumatology, Ajou University School of Medicine, Suwon;
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  • For correspondence: chsuh@ajou.ac.kr
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Abstract

Objective This study aimed to examine the frequency and risk factors of complications during pregnancy in women with systemic lupus erythematosus (SLE).

Methods The medical records of patients with SLE and age-matched controls at Ajou University Hospital were collected. Clinical features and pregnancy complications in women with SLE were compared to those of the controls. Multivariate logistic regression analysis was performed to determine the predictors of adverse maternal and fetal outcomes.

Results We analyzed 163 pregnancies in patients with SLE and 596 pregnancies in the general population; no significant differences regarding demographic characteristics were noted. Patients with SLE experienced a higher rate of stillbirth (OR 13.2), preeclampsia (OR 4.3), preterm delivery (OR 2.8), intrauterine growth retardation (OR 2.5), admission to neonatal intensive care unit (OR 2.2), and emergency cesarean section (OR 1.9) than the control group. Multivariate regression analysis revealed that thrombocytopenia, low complement, high proteinuria, high SLE Disease Activity Index (SLEDAI), low Lupus Low Disease Activity State (LLDAS) achievement rate, and high corticosteroid (CS) dose were associated with adverse pregnancy outcomes. In the receiver-operating characteristic curve analysis, the optimal cutoff value for the cumulative and mean CS doses were 3500 mg and 6 mg, respectively.

Conclusion Pregnant women with SLE have a higher risk of adverse pregnancy outcomes. Pregnancies are recommended to be delayed until achieving LLDAS and should be closely monitored with the lowest possible dose of CS.

Key Indexing Terms:
  • corticosteroid
  • fetal complications
  • lupus low disease activity state
  • maternal complications
  • pregnancy
  • systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with multiorgan involvement and preferentially affects women of childbearing age1. In patients who wish to carry a child, pregnancy represents a challenge because the clinical course of SLE is variable and may be characterized by acute or chronic flares in remission status. Immunological, endocrine, and environmental factors are known to develop and control SLE disease activity; however, no clear mechanism has been identified so far2,3. Given that SLE is 9 times more prevalent in women than men, it is clear that sex hormones are partially attributed to the various causes that distinguish males and females in relation to autoimmunity4. Indeed, increased estrogen levels during pregnancy influence the immune system, leading to a greater number of patients experiencing disease flares during this period. Further, studies of women with active disease at conception have reported that the flare rates during pregnancy ranged from 45% to 70%, whereas the rates of flare in a quiescent disease state at conception were < 20%5,6,7.

Although fertility is generally unimpaired by SLE, pregnancy is considered a high-risk situation; indeed, all pregnancy-related complications are higher in patients with SLE than in healthy women8,9. By using a systematic review and metaanalysis of pregnancy outcomes, patients with SLE were considered to have increased pregnancy complications including preterm labor, preeclampsia, intrauterine growth retardation (IUGR), and other problems, such as thrombosis and infection10,11. We now know that careful management of patients with SLE can lead to an improved pregnancy course; however, this does not mean that it will be uneventful12. Further, there is a lack of common treatment outcome states in SLE, such as the achievement of low disease activity (LDA) in rheumatoid arthritis using the Disease Activity Score in 28 joints13. Numerous definitions of remission have been proposed in response to this unmet need; evidence has been increasing that achieving the Lupus Low Disease Activity State (LLDAS) is a potential tool to assess control of SLE14. However, few studies have examined pregnancy outcomes in patients with SLE who have reached LLDAS, whereas adverse outcomes in SLE pregnancies have been widely reported by many previous studies.

Therefore, we designed a retrospective study to identify the outcome of pregnancy among Korean patients with SLE who reached LLDAS, from our Ajou Lupus Cohort. Moreover, we investigated the maternal and fetal outcomes between women with SLE and those without and analyzed the risk and predicting factors of such outcomes. The effect of achieving LLDAS on pregnancy outcomes was also evaluated.

MATERIALS AND METHODS

Patients. A retrospective study of all pregnancies in patients with SLE followed at Ajou University Hospital during January 1999 to June 2019 was conducted. We found 163 pregnancies in 110 women diagnosed with SLE according to the 1997 American College of Rheumatology or the 2012 Systemic Lupus International Collaboration Clinic Classification criteria15,16. Demographic, clinical, serological, and therapeutic data related to SLE and pregnancy outcomes were gathered from medical records. Disease activities were assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the attainment of LDA was assessed using LLDAS14,17. LLDAS is achieved if all of the following are met: (1) SLEDAI-2K ≤ 4, with no activity in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, and fever) and excluding hemolytic anemia or gastrointestinal activity; (2) no new features of SLE disease activity compared with the previous assessment; (3) physician global assessment ≤ 1 (scale 0–3); (4) current prednisolone-equivalent dosage ≤ 7.5 mg daily; and (5) well-tolerated standard maintenance dosages of immunosuppressive drugs and approved biologic agents14. Exclusion criteria included patients diagnosed with SLE during and after pregnancy and those who had therapeutic abortions. Control pregnancies were selected from the registry of the same hospital records with a pregnancy-related code or delivery code (International Classification of Diseases, 10th revision codes O80-84). We matched 596 control pregnancies based on maternal age and parity. Baseline demographics, clinically relevant comorbidities, and pregnancy data were recorded. This study protocol was reviewed and approved by the institutional review board of Ajou University Hospital (AJIRB-MED-MDB-19-215).

Assessment of pregnancy outcomes. We studied the association of SLE with the following pregnancy-related outcomes. Maternal outcomes consisted of (1) disease flare during pregnancy, (2) preeclampsia, and (3) emergency cesarean section. Fetal outcomes included (1) miscarriages, (2) stillbirth, (3) preterm delivery, (4) IUGR, (5) low birthweight of infants, and (6) neonatal intensive care unit (NICU) admission. All the pregnancy outcomes were investigated in the control group, except for disease flare.

The following definitions were used for the outcomes. Disease flare: new signs or worsening of SLE disease activities requiring starting or increasing corticosteroids (CS) and/or immunosuppressive agents; preeclampsia: gestational hypertension with proteinuria; emergency cesarean section: nonelective cesarean section; miscarriage: spontaneous fetal loss before 20 weeks of gestation; stillbirth: intrauterine fetal death after 20 weeks of gestation; preterm delivery: delivery before 37 weeks of gestation; IUGR: birth weight < 10th percentile for the stated gestation; and low birthweight infants: a birth weight of ≤ 2500 g.

Statistical analysis. All statistical analyses were conducted using SPSS version 25.0 software (IBM Corp). To present data, we used mean ± SD, and 2-sided P values < 0.05 were considered statistically significant. Comparisons between the SLE and controls were performed using Pearson chi-square test or independent t-test. Categorical variables were analyzed by chi-square test and continuous variables were analyzed by unpaired 2-sample t-test. Binary logistic regression was used to determine the predictors of adverse maternal and fetal outcomes. OR and 95% CI were computed after adjusting for potentially confounding factors such as age, hypertension, diabetes mellitus (DM), BMI, and thyroid disease. Receiver-operating characteristic (ROC) curves were obtained to determine the optimal cutoff values of SLEDAI-2K and CS dose for patients with SLE that would not affect pregnancy outcomes.

RESULTS

Clinical characteristics of patients with SLE. A total of 163 pregnancies in 110 women were included in this study. The demographic composition of the patients with SLE was not different from that of the controls (Table 1). However, women with SLE had lower BMI compared to controls. Comorbid conditions such as hypertension, DM, and thyroid disease were similar in both groups.

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Table 1.

General characteristics and treatments of pregnant women with and without SLE.

The mean age at diagnosis of SLE was 26.2 ± 5.7 years and the mean follow-up period was 65.8 ± 61.3 months. In patients with SLE, the main clinical symptoms during pregnancy included arthritis (20.9%), malar rash (19%), photosensitivity (12.3%), alopecia (9.2%), and oral ulcer (7.4%). A total of 29 patients (17.8%) had lupus nephritis, and 2 (1.2%) had serositis. The laboratory findings were as follows: lymphopenia (19.6%), leukopenia (14%), thrombocytopenia (11.7%), and high proteinuria (13.5%). Antinuclear antibodies were positive in all cases except for 1, anti-dsDNA antibody was positive in 56 (34.4%), anti-Sm antibody was positive in 6 (3.7%), and antiphospholipid antibodies (aPL) were positive in 30 (18.4%). More than half of the patients (53.4%) had at least 1 abnormally low complement C3 (< 90 mg/dL) or C4 (< 10 mg/dL) level. The mean baseline SLEDAI-2K and SLE Pregnancy Disease Activity Index 2000 in pregnancy were 7.20 ± 5.04 and 3.80 ± 4.57, respectively, and LLDAS was achieved by 89 (54.6%) patients.

The majority of the patients (67.5%) were taking hydroxychloroquine and 43 (26.4%) were taking nonsteroidal antiinflammatory drugs. Daily low-dose acetylsalicylic acid (ASA) was taken by 51 (31.3%) of patients with SLE, and 15 (9.2%) received daily heparin therapy. The mean cumulative CS dose before pregnancy was 7.4 ± 12.24 g prednisone-equivalent, and the mean CS dose during pregnancy was 11.2 ± 78.4 mg prednisone-equivalent. Of the patients with SLE, 45 of the pregnancies received immunosuppressive agents and some were treated with more than 1 drug before conception. A total of 22 (13.5%) received azathioprine (AZA), 14 (8.6%) received mycophenolate mofetil, 24 (14.7%) received cyclophosphamide (CYC), and 8 (4.9%) received cyclosporine.

Pregnancy outcomes in patients with SLE. The pregnancy outcomes are listed in Table 2. Out of 163 pregnancies, there were 118 live births (72.4%), which was clearly lower than that in the controls (84.2%, P < 0.001). Women with SLE had a lower gestational age (37 ± 2.7 weeks vs 37.6 ± 2.3 weeks, P = 0.004) and birth weight (2808.5 ± 0.6 g vs 3111.9 ± 0.5 g, P = 0.016) than the controls. Compared to the controls, pregnant women with SLE had a higher risk of pregnancy-related complications (55.2% vs 36.1%, P < 0.001). Further, the length of hospital stay following childbirth was longer in patients with SLE than in the controls (7.6 ± 12.8 days vs 4.5 ± 3 days, P < 0.001). In terms of maternal complications, disease flare occurred in 15 patients with SLE (8.8%). The incidence of preeclampsia was 2.9% in patients with SLE and 0.8% in controls (P = 0.027), and women with SLE had a higher rate of emergency cesarean sections (15.3% vs 8.7%, P = 0.034) than controls. There were no statistical differences in miscarriages between the 2 groups. Other adverse fetal outcomes, including stillbirths, preterm deliveries, IUGR, low birthweight infants, and NICU admission have also been reported to be high in SLE pregnancies. We observed 12 stillbirths (7.4%, P < 0.001), 28 preterm deliveries (16.4%, P < 0.001), 16 cases of IUGR (9.8%, P = 0.003), 26 low birthweight infants (16.0%, P < 0.001), and 28 infants admitted to the NICU (17.2%, P = 0.016), which were significantly increased over the controls.

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Table 2.

Pregnancy outcomes of patients with and without SLE.

The results of the multivariate analysis of pregnancy outcomes are provided in Figure 1. Women with SLE had 2.3-fold more pregnancy-related complications after adjusting for potential confounders (OR 2.32, 95% CI 1.60–3.38). When we examined the association between SLE and specific pregnancy outcomes, patients with SLE had a remarkably higher prevalence of preeclampsia (OR 4.31, 95% CI 1.20–15.48), emergency cesarean section (OR 1.86, 95% CI 1.08–3.18), stillbirth (OR 13.24, 95% CI 3.62–48.36), preterm delivery (OR 2.75, 95% CI 1.62–4.92), IUGR (OR 2.48, 95% CI 1.25–4.92), low birthweight infants (OR 2.74, 95% CI 1.57–4.76), and NICU admission (OR 2.20, 95% CI 1.32–3.68).

Figure 1.
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Figure 1.

Multivariate analysis of maternal and fetal complications in patients with SLE. OR (95% CI) of the SLE vs non-SLE population for obstetric outcomes. The OR for obstetric outcomes listed on the left are plotted as dots; lines indicate 95% CI. All values were statistically significant (P < 0.05). Adjustment was made for age, BMI, and the presence of comorbid conditions such as hypertension, diabetes mellitus, and thyroid disease. SLE: systemic lupus erythematosus.

Predictors of adverse maternal and fetal outcomes in patients with SLE. In Table 3, we compared the clinical characteristics and treatments of patients with or without maternal and fetal complications in pregnancies to analyze the risk factors of these complications. We found that the presence of thrombocytopenia, hemoglobin, complement, positivity of anti-dsDNA antibody, 24-h urine protein, SLEDAI, achievement of LLDAS, and mean CS dose during pregnancy were considerably different between SLE patients with and without complications. The frequencies of clinical features were not significantly different between both groups with the exception of arthritis. Pregnancies with maternal and fetal complications revealed a higher rate of thrombocytopenia (17.8% vs 4.1%, P = 0.005), lower hemoglobin (11.8 ± 1.7 g/dL vs 12 ± 1.3 g/dL, P = 0.034), and lower C3 and C4 levels (84.6 ± 22.7 mg/dL vs 109.2 ± 34.2 mg/dL, P = 0.019 and 17 ± 7.8 mg/dL vs 25.4 ± 11.2 mg/dL, P = 0.019, respectively). The anti-dsDNA antibody positivity rate was higher (42.2% vs 24.7%, P = 0.015) in patients with complications. Further, higher levels of 24-h urine protein excretion (1152.3 ± 3036.1 mg/d vs 70.8 ± 192 mg/d, P < 0.001), SLEDAI-2K score (5.4 ± 5.4 vs 1.9 ± 2.2, P < 0.001), and the mean dose of CS throughout pregnancy (19.4 ± 105.6 mg prednisone-equivalent vs 2 ± 4.4 mg prednisone-equivalent, P = 0.049) were observed in pregnancies with complications. The achievement of LLDAS (33.3% vs 80.8%, P < 0.001) was superior in pregnancies without complications. However, several factors were shown to only affect maternal complications. Patients who received a higher cumulative CS dose before conception and had a history of CYC treatment experienced more adverse maternal events (Table 4).

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Table 3.

Clinical characteristics and treatments of pregnancies with complications.

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Table 4.

Independent explanatory variables associated with maternal and fetal complications in patients with SLE.

ROC curve analysis was performed in order to evaluate disease activity and CS dose that increases the risk of adverse events (Supplementary Figure 1, available with the online version of this article). The area under the curve (AUC) for the SLEDAI of maternal and fetal complications was 0.71 (95% CI 0.63–0.79). The optimal cutoff value was 4.5, with a sensitivity of 92% and a specificity of 56%. The best cutoff value of cumulative CS dose before conception for maternal complications was 3.5 g prednisone-equivalent, as determined from the AUC of 0.777 (95% CI 0.68–0.87). In terms of mean CS dose during pregnancy, the AUC was 0.761 (95% CI 0.69–0.84) and a cutoff value was 6 mg/d prednisone-equivalent.

After univariate logistic regression, various factors were identified as potential explanatory factors related to adverse maternal and fetal outcomes (Table 5). Among these factors, multiple logistic regression including the risk factors for maternal complications showed that high proteinuria, LLDAS achievement, and a cumulative CS dosage of > 3.5 g prednisone-equivalent were proven to be independent risk factors. Regarding fetal complications, thrombocytopenia, low complements, a SLEDAI score > 4, and LLDAS achievement were independent risk factors by multivariate analysis. Overall, the achievement of LLDAS had the most important influence on both maternal and fetal complications.

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Table 5.

Potential risk factors of complications in pregnancies with SLE.

DISCUSSION

Over the past 40 years, improvements in disease care and regular prenatal monitoring have decreased adverse pregnancy outcomes18. Most pregnancies end in successful livebirths; nonetheless, women with SLE have more than twice the cumulative rate of pregnancy complications than the general population19,20,21. In this study, there was a noticeable difference in total pregnancy-related complications between patients with SLE and controls (55.2% vs 36.1%). Our findings were considerably higher than the rates reported in most previous studies (22.0–38.7%)22,23. One possible reason for the higher number of unsuccessful pregnancies in our data is the length of the study, in that some participants may not have received specialized close monitoring. However, the livebirth rate of patients with SLE was 72.4%, similar to rates in other studies in Korea24. Several Korean studies have reported livebirth rates ranging between 75% and 82%, which are comparable to those reported in Western countries24,25,26. Differences in the incidence of comorbidities and rates of cesarean section were not observed between women with and without SLE. These results are probably due to the need for referral of mothers without SLE having medical comorbidities to a tertiary medical center to reduce postpartum complications and mortality.

The results of our study confirm that pregnancy-related complications are significant problems in patients with SLE compared to controls. Similar to previous studies, pregnancies in SLE show high rates of miscarriage, stillbirth, IUGR, NICU admission, preeclampsia, emergency cesarean section, and preterm delivery11,27. In a subgroup analysis, we observed 2.9% cases of preeclampsia, which is similar to that of previous studies involving Japan and other cohorts in Korea26,28. However, we noticed significantly lower rates of preeclampsia in our cohorts compared to Western countries. Several studies conducted in the US and Europe reported that the preeclampsia rates range from 12% to 35%29,30. In terms of fetal complications, we found a high rate of stillbirths (7.4% vs 0.5%), preterm deliveries (16.4% vs 7.4%), IUGR (9.8% vs 4.0%), low birthweight infants (16.0% vs 6.4%), and NICU admission (17.2% vs 9.7%) in patients with SLE; this was consistent with the results of previous studies31. However, there was no statistical difference in the incidence of miscarriages among women with SLE and controls (20.2% vs 15.2%, P = 0.13). These rates were similar considering that the miscarriage rate of pregnant Korean women is 14.0–23.0%32.

We further analyzed the increased rates of adverse pregnancy outcomes after adjusting for important confounding factors. The OR for all complications proved to be higher in patients with SLE than in controls. The higher OR in our analysis was stillbirth (adjusted OR 13.2, P < 0.001) and preeclampsia (adjusted OR 4.3, P = 0.025). A previous metaanalysis by Bundhun, et al supported tendencies similar to the present study33. However, there have been no published studies comparing the frequency of pregnancy complications between SLE and the general obstetric population in Korea.

As a result of investigating pregnancy-related complications, factors affecting complications were mostly consistent with other previous analyses conducted over the years34,35. One important difference is that a positive test for aPL was not an independent risk factor for adverse pregnancy outcomes36. This might be explained by the widespread consensus on the benefit of antithrombotic prophylaxis37, as we adequately treated with ASA or low molecular weight heparin for the presence of aPL. We also found that some variables were only associated with maternal complications; these included a high cumulative CS dose during pregnancy and a history of CYC treatment. Among the various immunosuppressants, the only medication that demonstrated a meaningful relationship with adverse maternal outcomes was CYC. Despite possible teratogenic agents being discontinued in preparation for conception, ovarian failure and sustained amenorrhea might persist owing to a cumulative effect of CYC. As previously reported, the incidence of infertility by CYC was approximately 14.9–37.3%38; thus, it is recommended to limit the use of CYC in fertile women. For patients planning to continue CYC therapy, hormonal co-therapy during treatment is suggested to reduce the risk of ovarian insufficiency39.

The reduction of adverse pregnancy outcomes by achieving LLDAS has not been studied previously. Even after validation in a multivariate model, the achievement of LLDAS was the only factor that affected both maternal and fetal complications. An agreement on the principles of the definition of remission in SLE has been proposed by several research groups over the years, which includes SLEDAI, and mostly coincided with SLEDAI ≤ 440,41. In our analysis, to identify the SLEDAI that leads to better outcomes, we obtained similar results described in previous studies. However, many experts argue that the drawback of SLEDAI is that it does not reflect important systems such as hemolytic anemia or gastrointestinal activity, and treatment domains14. Indeed, currently there is a growing opinion that LLDAS has excellent validity and represents a much more attainable clinical target state42. In this regard, it is noteworthy that our study is the first study, to our knowledge, to analyze the relationship between LLDAS and pregnancy outcomes. Moreover, we investigated factors affecting LLDAS, and the results were largely consistent with factors affecting pregnancy outcomes (Supplementary Table 1, available with the online version of this article). When we compared the pregnancy-related complications between patients with SLE who achieved LLDAS and controls, there was no significant difference in the incidence of pregnancy-related complications other than stillbirth (Supplementary Table 2, available with the online version of this article). These results suggest that achieving LLDAS is important to preventing pregnancy-related complications in patients with SLE.

The areas with high disagreement on the validity of LLDAS are concerned with CS dose. The opinion that CS-related side effects generally occur at daily doses of ≥ 7.5 mg prednisone-equivalent is predominant, and this dosage is also used in the LLDAS criteria43. Contrary to the prevailing view, several studies reported that the CS dose accommodates daily doses of 10 mg prednisone-equivalent because this dosing has the benefit of rapid onset of action44. Further, CS are safe even during pregnancy; thus, this is the first-line therapy commonly used for acute flares throughout pregnancy. However, it is clear that CS are not innocuous because of the increased risk of congenital malformation and pregnancy outcomes45. The controversy over the safe maintenance CS dose of SLE pregnancies remains; thus, our available data analyzed the adequate CS doses and timing for pregnancy. Our study revealed that a mean CS dose during pregnancy of < 6 mg/day prednisone-equivalent was a reasonable value for reducing maternal and fetal risk. Cumulative CS doses exceeding 3.5 g prednisone-equivalent for women with SLE have contributed to the higher rate of adverse maternal outcomes, whereas CS doses taken 3 months before conception were not influential. Even in obstetric medicine, it is crucial to not exceed such doses while maintaining quiescent SLE. There is a general consensus that safe immunosuppressants such as AZA and tacrolimus can be administered by reducing CS to manage SLE flares in pregnant women46.

The present study is relevant for several reasons. One of the strengths of this analysis is that it is the first study conducted in Korea to compare obstetric complications in patients with SLE with the general population, to our knowledge. Second, it is the first study to reveal that achieving LLDAS plays an important role in minimizing adverse pregnancy outcomes. Third, it is meaningful that our study has tried to determine the optimal CS dose, considering that we are uncertain what CS dose is best for mothers and babies.

We encountered some limitations in our attempt. First, this is a retrospective study in a single center, with selection and information bias. Additionally, as the general population was recruited from a tertiary care center, we may have recruited relatively high-risk pregnancies. Further, our study encompasses a vast period from 1999 to 2019, and during this period many advances in diagnostic criteria and medication use have changed the outcomes of the disease.

In conclusion, this study demonstrated adverse pregnancy outcomes are still higher in pregnant women with SLE than in the general population. A comprehensive analysis of risk factors and predictors of maternal and fetal complications was provided. Minimizing the occurrence of complications during pregnancy was strongly associated with achieving LLDAS and keeping daily steroid doses of prednisone < 6 mg/day. Targeting inactive disease and preventing a disease flare is important to allow for successful outcomes. Therefore, pregnancies in SLE should receive preconception counseling with a multidisciplinary team in a specialized center and choose an optimal time for pregnancy.

ACKNOWLEDGMENT

We would like to thank Editage (www.editage.co.kr) for English language editing.

Footnotes

  • The authors declare no conflict of interest.

  • This research was supported by a grant from the Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number HI16C0992).

  • Accepted for publication September 22, 2020.
  • Copyright © 2021 by the Journal of Rheumatology

REFERENCES

  1. 1.↵
    1. Kalok A,
    2. Cader RA,
    3. Indirayani I,
    4. Karim AKA,
    5. Shah SA,
    6. Ismail NAM, et al.
    Pregnancy outcomes in systemic lupus erythematosus (SLE) women. Horm Mol Biol Clin Investig 2019;40:1868-91.
    OpenUrl
  2. 2.↵
    1. Petri M,
    2. Kallas R.
    Lupus in pregnancy. Contemp Ob Gyn 2019;64 No 03. [Internet. Accessed January 21, 2021.] Available from: www.contemporaryobgyn.net/pregnancy-and-birth/lupus-pregnancy
  3. 3.↵
    1. Ordi-Ros J,
    2. Marce CS,
    3. Cortes-Hernandez J.
    Lupus pregnancy: risk factors and management. In: Lionaki S, ed. Lupus – new advances and challenges. [Internet. Accessed February 8, 2021.] Available from: www.intechopen.com/books/lupus-new-advances-and-challenges/lupus-pregnancy-risk-factors-and-management
  4. 4.↵
    1. Chakravarty EF,
    2. Sammaritano LR.
    Pregnancy and autoimmune disease, reproductive and hormonal issues. In: Wallace D, Hahn B. Dubois’ lupus erythematosus and related syndromes 9th ed. Elsevier; 2019:499-519.
  5. 5.↵
    1. Petri M,
    2. Howard D,
    3. Repke J.
    Frequency of lupus flare in pregnancy: the Hopkins Lupus Pregnancy Center experience. Arthritis Rheum 1991;34:1538-45.
    OpenUrlPubMed
  6. 6.↵
    1. Chakravarty EF,
    2. Colón I,
    3. Langen ES,
    4. Nix DA,
    5. El-Sayed YY,
    6. Genovese MC, 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.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Buyon JP,
    2. Kim MY,
    3. Salmon JE.
    Predictors of pregnancy outcomes in patients with lupus. Ann Intern Med 2016;164:131.
    OpenUrl
  8. 8.↵
    1. Jones A,
    2. Giles I.
    Fertility and pregnancy in systemic lupus erythematosus. Indian J Rheumatol 2016;11 Suppl S2:128-34.
    OpenUrl
  9. 9.↵
    1. Wu J,
    2. Ma J,
    3. Zhang W-H,
    4. Di W.
    Management and outcomes of pregnancy with or without lupus nephritis: a systematic review and meta-analysis. Ther Clin Risk Manag 2018;14:885-901.
    OpenUrl
  10. 10.↵
    1. Moroni G,
    2. Ponticelli C.
    Pregnancy in women with systemic lupus erythematosus (SLE). Eur J Intern Med 2016;32:7-12.
    OpenUrl
  11. 11.↵
    1. Smyth A,
    2. Oliveira GHM,
    3. Lahr BD,
    4. Bailey KR,
    5. Norby SM,
    6. Garovic VD.
    A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010;5:2060-8.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Jordan N.
    Management of pregnancy in systemic lupus erythematosus: what a GP should know. Lupus 2018;27:40-3.
    OpenUrl
  13. 13.↵
    1. van Vollenhoven RF,
    2. Mosca M,
    3. Bertsias G,
    4. Isenberg D,
    5. Kuhn A,
    6. Lerstrøm K, et al.
    Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis 2014;73:958-67.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Franklyn K,
    2. Lau CS,
    3. Navarra SV,
    4. Louthrenoo W,
    5. Lateef A,
    6. Hamijoyo L, et al.
    Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis 2016;75:1615-21.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Hochberg MC.
    Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Petri M,
    2. Orbai A-M,
    3. Alarcón GS,
    4. Gordon C,
    5. Merrill JT,
    6. Fortin PR, et al.
    Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-86.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Gladman DD,
    2. Ibañez D,
    3. Urowitz MB.
    Systemic Lupus Erythematosus Disease Activity Index 2000. J Rheumatol 2002;29:288-91.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Clark CA,
    2. Spitzer KA,
    3. Laskin CA.
    Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J Rheumatol 2005;32:1709-12.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Moroni G,
    2. Doria A,
    3. Giglio E,
    4. Imbasciati E,
    5. Tani C,
    6. Zen M, et al.
    Maternal outcome in pregnant women with lupus nephritis. A prospective multicenter study. J Autoimmun 2016;74:194-200.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Moroni G,
    2. Doria A,
    3. Giglio E,
    4. Tani C,
    5. Zen M,
    6. Strigini F, et al.
    Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century. A prospective multicenter study. J Autoimmun 2016;74:6-12.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Nahal SK,
    2. Selmi C,
    3. Gershwin ME.
    Safety issues and recommendations for successful pregnancy outcome in systemic lupus erythematosus. J Autoimmun 2018;93:16-23.
    OpenUrl
  22. 22.↵
    1. Zhan Z,
    2. Yang Y,
    3. Zhan Y,
    4. Chen D,
    5. Liang L,
    6. Yang X.
    Fetal outcomes and associated factors of adverse outcomes of pregnancy in southern Chinese women with systemic lupus erythematosus. PLoS One 2017;12:e0176457.
    OpenUrl
  23. 23.↵
    1. Kim MY,
    2. Buyon JP,
    3. Guerra MM,
    4. Rana S,
    5. Zhang D,
    6. Laskin CA, et al.
    Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J Obstet Gynecol 2016;214:108.e1-108.e14.
    OpenUrlCrossRef
  24. 24.↵
    1. Shin JH,
    2. Lee EY,
    3. Lee CK,
    4. Cho YS,
    5. Kim A,
    6. Yoo B, et al.
    Fetal outcome and clinical feature during pregnancy in systemic lupus erythematosus. Korean J Med 2003;65:511-9.
    OpenUrl
  25. 25.↵
    1. Ahn HY,
    2. Kim YH,
    3. Kil KC,
    4. Park IY,
    5. Lee G,
    6. Kim SJ, et al.
    Clinical course and obstetrical outcomes of 94 pregnancies in Korean patients with systemic lupus erythematosus (SLE). Korean J Obstet Gynecol 2008;51:147-57.
    OpenUrl
  26. 26.↵
    1. Park EJ,
    2. Jung H,
    3. Hwang J,
    4. Kim H,
    5. Lee J,
    6. Ahn JK, et al.
    Pregnancy outcomes in patients with systemic lupus erythematosus: a retrospective review of 62 pregnancies at a single tertiary center in South Korea. Int J Rheum Dis 2014;17:887-97.
    OpenUrl
  27. 27.↵
    1. Ko HS,
    2. Ahn HY,
    3. Jang DG,
    4. Choi S-K,
    5. Park Y-G,
    6. Park IY, et al.
    Pregnancy outcomes and appropriate timing of pregnancy in 183 pregnancies in Korean patients with SLE. Int J Med Sci 2011; 8:577-83.
    OpenUrlPubMed
  28. 28.↵
    1. Sugawara E,
    2. Kato M,
    3. Fujieda Y,
    4. Oku K,
    5. Bohgaki T,
    6. Yasuda S, et al.
    Pregnancy outcomes in women with rheumatic diseases: a real-world observational study in Japan. Lupus 2019;28:1407-16.
    OpenUrl
  29. 29.↵
    1. Clowse ME,
    2. Jamison M,
    3. Myers E,
    4. James AH.
    A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127.e1-e6.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Chen YJ,
    2. Chang JC,
    3. Lai EL,
    4. Liao TL,
    5. Chen HH,
    6. Hung WT, et al.
    Maternal and perinatal outcomes of pregnancies in systemic lupus erythematosus: a nationwide population-based study. Semin Arthritis Rheum 2020;50:451-57.
    OpenUrl
  31. 31.↵
    1. Dhar JP,
    2. Essenmacher LM,
    3. Ager JW,
    4. Sokol RJ.
    Pregnancy outcomes before and after a diagnosis of systemic lupus erythematosus. Am J Obstet Gynecol 2005;193:1444-55.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Park C,
    2. Kang MY,
    3. Kim D,
    4. Park J,
    5. Eom H,
    6. Kim EA.
    Prevalence of abortion and adverse pregnancy outcomes among working women in Korea: a cross-sectional study. PloS One 2017;12:e0182341.
    OpenUrl
  33. 33.↵
    1. Bundhun PK,
    2. Soogund MZS,
    3. Huang F.
    Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: a meta-analysis of studies published between years 2001-2016. J Autoimmun 2017;79:17-27.
    OpenUrlCrossRef
  34. 34.↵
    1. Deguchi M,
    2. Maesawa Y,
    3. Kubota S,
    4. Morizane M,
    5. Tanimura K,
    6. Ebina Y, et al.
    Factors associated with adverse pregnancy outcomes in women with systematic lupus erythematosus. J Reprod Immunol 2018;125:39-44.
    OpenUrl
  35. 35.↵
    1. Clowse ME,
    2. Magder LS,
    3. Witter F,
    4. Petri M.
    Early risk factors for pregnancy loss in lupus. Obstet Gynecol 2006;107:293-9.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Tincani A,
    2. Bompane D,
    3. Danieli E,
    4. Doria A.
    Pregnancy, lupus and antiphospholipid syndrome (Hughes syndrome). Lupus 2006;15:156-60.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Mecacci F,
    2. Bianchi B,
    3. Pieralli A,
    4. Mangani B,
    5. Moretti A,
    6. Cioni R, et al.
    Pregnancy outcome in systemic lupus erythematosus complicated by anti-phospholipid antibodies. Rheumatology 2009;48:246-9.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Park MC,
    2. Park YB,
    3. Jung S,
    4. Chung IH,
    5. Choi KH,
    6. Lee SK.
    Risk of ovarian failure and pregnancy outcome in patients with lupus nephritis treated with intravenous cyclophosphamide pulse therapy. Lupus 2004;13:569-74.
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Sammaritano LR,
    2. Bermas BL,
    3. Chakravarty EE,
    4. Chambers C,
    5. Clowse ME,
    6. Lockshin MD, et al.
    2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 2020;72:529-56.
    OpenUrlPubMed
  40. 40.↵
    1. Gatto M,
    2. Zen M,
    3. Iaccarino L,
    4. Doria A.
    New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 2019;15:30-48.
    OpenUrlPubMed
  41. 41.↵
    1. Kwok LW,
    2. Tam LS,
    3. Zhu T,
    4. Leung YY,
    5. Li E.
    Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus 2011;20:829-36.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Petri M,
    2. Magder LS.
    Comparison of remission and lupus low disease activity state in damage prevention in a united states systemic lupus erythematosus cohort. Arthritis Rheumatol 2018;70:1790-5.
    OpenUrl
  43. 43.↵
    1. Ruiz-Irastorza G,
    2. Danza A,
    3. Khamashta M.
    Glucocorticoid use and abuse in SLE. Rheumatology 2012;51:1145-53.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Shirley E,
    2. Chakravarty EF.
    Treatment of systemic lupus erythematosus (SLE) in pregnancy. Curr Treat Options Rheum 2018;4:110-8.
    OpenUrl
  45. 45.↵
    1. Apostolopoulos D,
    2. Kandane-Rathnayake R,
    3. Louthrenoo W,
    4. Luo SF,
    5. Wu Y-J,
    6. Lateef A, et al.
    Factors associated with damage accrual in patients with systemic lupus erythematosus with no clinical or serological disease activity: a multicentre cohort study. Lancet Rheumatol 2020;2:e24-e30.
    OpenUrl
  46. 46.↵
    1. Knight CL,
    2. Nelson-Piercy C.
    Management of systemic lupus erythematosus during pregnancy: challenges and solutions. Open Access Rheumatol 2017;9:37-53.
    OpenUrl

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1 May 2021
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Lupus Low Disease Activity State Achievement Is Important for Reducing Adverse Outcomes in Pregnant Patients With Systemic Lupus Erythematosus
Ji-Won Kim, Ju-Yang Jung, Hyoun-Ah Kim, Jeong I. Yang, Dong W. Kwak, Chang-Hee Suh
The Journal of Rheumatology May 2021, 48 (5) 707-716; DOI: 10.3899/jrheum.200802

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Lupus Low Disease Activity State Achievement Is Important for Reducing Adverse Outcomes in Pregnant Patients With Systemic Lupus Erythematosus
Ji-Won Kim, Ju-Yang Jung, Hyoun-Ah Kim, Jeong I. Yang, Dong W. Kwak, Chang-Hee Suh
The Journal of Rheumatology May 2021, 48 (5) 707-716; DOI: 10.3899/jrheum.200802
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Keywords

CORTICOSTEROID
fetal complications
lupus low disease activity state
maternal complications
PREGNANCY
SYSTEMIC LUPUS ERYTHEMATOSUS

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  • systemic lupus erythematosus

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