Risk of gestational diabetes mellitus in systemic lupus erythematosus pregnancy: a systematic review and meta-analysis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease predominantly affecting women of reproductive ages, characterized by loss of self-tolerance, production of autoantibodies and deposition of antigen-antibody complexes. SLE usually involved multiple organs, like skin, joints, kidneys and nervous system. SLE is reported to involve multiple organs like skin, joints, kidneys and nervous system. Besides, pregnancy is also dangerous for women with SLE. Recently, more studies focus on the higher risks of pregnancy complications in SLE patients, especially in patients with the existence of autoantibody positive, antiphospholipid syndrome (APS), nephritis or pulmonary hypertension, and patients with immunosuppressive therapies [1]. Although the fertility rate of SLE women is normal, SLE pregnancy was reported to significant increased risk of adverse maternal and fetal adverse outcome [2]. Increasing numbers of studies reported that autoimmune diseases including SLE could affect the process of pregnancy and induce adverse pregnancy outcomes (APOs), such as gestational hypertension, pre-eclampsia and lupus flares [3‐6]. Gestational diabetes mellitus (GDM) is the most common autoimmune endocrine complication of pregnancy. However, the relationship between GDM and SLE has not been well illustrated yet.

GDM is a common pregnancy complication, defined as impaired glucose tolerance first detected during pregnancy, and is associated with adverse maternal and fetal outcomes, including hyperinsulinemia, hypocalcemia, hyperbilirubinemia, preeclampsia, and macrosomia [7, 8]. The risk of dystocia, usually caused by macrosomia, cesarean section and even stillbirth are also increased in pregnancy women with GDM [9, 10]. For the long-dated consequences, GDM is related to markedly increased risk of post-partum diabetes and cardiovascular diseases [7, 11]. Although the exact pathological mechanism underlying GDM is still obscure, exacerbated insulin resistance is reported to play a pivotal role in GDM. SLE is also reported to associate with increased risk of insulin resistance and diabetes mellitus. Besides, studies also indicated that abnormal insulin secretion may be caused by autoimmune damage [12], and autoimmune response may impair the function of pancreatic beta cell [13]. Patients with SLE are accompanied with autoimmune microenvironment during pregnancy, which may relate to GDM incidence. Present studies indicated that SLE pregnancy is associated with elevated risk of GDM [10]. However, studies also reported that the GDM risk of SLE patients was not significant increased [9, 14, 15]. Besides, whether there are specific risk factors influencing GDM incidence in SLE patients is also doubtful. In light of these facts, we performed this study to comprehensively review and meta-analyze the relationship between SLE and GDM.

This study was performed was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [16] (see Additional file 1: Table S1) .

Women with SLE are receiving better multidisciplinary antenatal care ensuring better pregnancy outcome with the development of medicine. Nevertheless, current studies [5, 23‐25] also reported that SLE was associated with APOs including pre-eclampsia, pregnancy-induced hypertension, spontaneous abortion. The present study have synthesized current published studies regarding GDM and SLE, and the results indicated that SLE with not associated with GDM. The potential reasons for previous inconsistent results are listed as following.

With abnormal insulin resistance playing an irreplaceable role, GDM was reported to associate with clinical factors in SLE patients. A previous meta-analysis [24] regarding the risk of maternal and fetal outcomes in SLE pregnancy identified that several factors included lupus nephritis [26, 27], aPL positive and APS [28] were responsible for the higher risk of APOs following pregnancy. We also conducted meta-regression analysis on corresponding factors to assess their impact on GDM risk. As previous studies reported that diabetes mellitus was developed around 12% of SLE patients due to high-dose glucocorticoid therapy (prednisolone use ≥1 mg/kg/day) [29, 30]. Our study also identified that glucocorticoid use during pregnancy was positively associated GDM risk in SLE patients. Consistent with our results, studies also reported that women with higher dose of steroid during pregnancy have an increased risk of diabetes, and steroid exposure should be restricted to a minimum during pregnancy [4, 31]. Glucocorticoid was known to necessary for the control of SLE disease activity during pregnancy. One original study reported that the higher risk of GDM in SLE patients compared with controls may due to high rate of glucocorticoids use of SLE patients during pregnancy [10]. Our results also demonstrated that hydroxychloroquine use and the number of cases were borderline significant factors positively associated with the GDM risk. However, hydroxychloroquine use may reduce glucocorticoid doses during pregnancy, consequently reducing the risk of GDM development. Studies also reported that hydroxychloroquine is safe enough to continue throughout the whole pregnancy process by all pregnant women with SLE [24, 32]. Simultaneously, epidemiologic studies have demonstrated that hydroxychloroquine could significantly reduce diabetes mellitus risk of SLE patients in a dose-dependent manner [33, 34]. So we hypothesized that the increased risk of GDM by hydroxychloroquine use was a false positive result. Hydroxychloroquine use during SLE pregnancy could be recommended for reducing glucocorticoid doses. The potential reason may be that medication use demands of SLE patients were differential across studies populations depending on disease activity. The hydroxychloroquine use rate was associated with glucocorticoids use rate in some extent. Besides, the glucocorticoids use rate of SLE patients during pregnancy was extremely high. The false positive result may due to the confounding of glucocorticoids. We also found that SLE patients with anti-ds-DNA were associated with higher risk of GDM. Whether it is the consequences of autoimmune dysfunction contributing to autoimmune GDM is still obscure. In words, we hypothesized that the use of glucocorticoids may increase the risk of GDM and the autoimmune dysfunction of SLE may related to autoimmune GDM.

Another reason accounting for the inconsistent results of original studies may be related to the inconsistent diagnosis criteria of GDM. As the most common metabolic disturbance among pregnant women, GDM has a series of diagnosis criteria [32, 33]. A recent meta-analysis by Behboudi-Gandevani S and colleagues reported that the worldwide prevalence of GDM was 4.4%, regardless of type of screening threshold categories. According to seven different diagnosis criteria, subgroup analysis of the study indicated that the prevalence of GDM was ranged from 2.2 to 10.6% [29]. The diagnosis criteria of GDM in original studies were different, because of the lack of international consistently diagnosis criteria for GDM. GDM risk of SLE patients is not the primary outcome of most included studies, so the screening methods of GDM have not been exactly reported. In our included studies, only two studies reported that GDM was defined as any degree of glucose intolerance with onset or first recognition during pregnancy [9, 10]. It is hard for us to evaluate the impact of criteria on GDM risk with the present available data. The inconsistent diagnosis criteria of GDM in original studies have indeed made some certain effects on the final diagnosis of GDM, which may partly account to the significant heterogeneity of our study.

Autoimmune GDM is a subset of GDM with the representation of various autoimmune antibodies (GADA, IA2-A, IAA, ZnT8-A), and account for about 10% of all GDM [13]. Autoimmune GDM was also reported to associate with higher risk of type 1 diabetes or latent autoimmune diabetes in adult. Therefore patients with autoimmune GDM was worthy of studying for the prevention of type 1 diabetes in pregnancy or afterwards [30]. SLE is an autoimmune dysfunction disease and characterizing with the presence of various antibodies, likely to associate with autoimmune GDM. Regrettably, of studies, none of the present studies, researching the relationship between SLE and GDM, reported the results of autoimmune GDM or related antibodies. Further studies focus on the relationship between autoimmune GDM and SLE are also necessary.

The major strength of this present study is that we have integrated existing research using systematic quantitative methods, minimizing the selection and reporting biases. There are also some limitations existing. First, the small sample sizes of our included studies may limit the power to find positive association between SLE and GDM. Second, data about demographic characteristics (as body mass index and dietary characteristics) and clinical manifestations (as disease activity and drug usage), associated with GDM risk, was absent in our included studies, and differences of these characteristics across our original studies may account for the significant heterogeneity. Also, screening methods of GDM in our original studies were obscure, which may cause the results varying. Lastly, the significant heterogeneity may limit the generalizability of the pooled results.

In summary, this meta-analysis suggested SLE is not associated with the risk of GDM and glucocorticoids therapy is associated with the increased risk of GDM in SLE patients. A right time for pregnancy (remission or inactive disease status) and detailed preconception counselling are pivotal for a successful pregnancy. Furthermore, further elaborate prospective cohort studies and immunologic researches are needed to reveal the mechanism underlying GDM and glucocorticoids use.