Risk Factors For Adverse Pregnancy Outcomes in Systemic Lupus Erythematosus: A Meta Analysis and Systemic review

doi:10.21203/rs.3.rs-4871546/v1

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Risk Factors For Adverse Pregnancy Outcomes in Systemic Lupus Erythematosus: A Meta Analysis and Systemic review

https://doi.org/10.21203/rs.3.rs-4871546/v1

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Background: Systemic lupus erythematosus (SLE) is a prominent autoimmune disease highly linked to adverse pregnancy outcomes (APOs). Previous research on the risk factors for APOs in SLE pregnancies has been limited by regional constraints or inadequate sample sizes. There is currently a dearth of comprehensive systemic reviews on this topic. To address these research gaps, we conducted a rigorous meta-analysis and systematic review to elucidate the risk factors for APOs in SLE pregnancies.

Methods: PubMed, Embase, Web of Science, and the Cochrane Library systematically searched for articles on risk factors for APOs in SLE pregnancy from initiation to December 31, 2023. The pooled Odds Ratio (OR) was estimated using a random-effects or fixed-effects model for each investigated factor. Egger's P value was calculated to assess publication bias and heterogeneity was evaluated by the I²test.

Results: 42 unique studies were enrolled. Patients with hypertension (OR, 5.23; 95% CI, 2.76–9.91), lupus nephritis (LN) (OR, 3.02; 95% CI, 2.10–4.34), high disease activity (OR, 2.51; 95% CI, 1.39–4.50), low complements (OR, 1.94; 95% CI, 1.39–2.72), antiphospholipid syndrome (APS)/positive antiphospholipid antibody (aPL) (OR, 7.93; 95% CI, 4.35–14.44) were at higher risk for APOs. The risk factors for preterm birth included LN (OR, 3.69; 95% CI, 2.31–5.89), hypertension (OR, 4.50; 95% CI, 1.86–10.87), disease flares (OR, 4.02; 95% CI, 2.24–7.19), disease activity (OR, 3.92; 95% CI, 2.52–6.10), preeclampsia/eclampsia (OR, 8.85;95% CI, 4.72–16.58), and APS (OR, 3.95; 95% CI, 2.20–7.07). The risk factors for pregnancy loss were APS/aPL (OR, 3.46; 95% CI, 2.44–4.91), low complements (OR, 2.60; 95% CI, 1.08–6.27), disease flares (OR, 2.72; 95% CI, 1.36–5.46), LN (OR, 3.47; 95% CI, 1.74–6.89), hypertension (OR, 1.33; 95% CI, 0.71–1.94), thrombocytopenia (OR, 8.85; 95% CI, 4.72–16.58), and disease activity (OR, 9.19; 95% CI). LN also predicted intrauterine growth restriction (OR, 3.51; 95% CI, 1.30–9.51) and low birth weight (OR, 5.55; 95% CI, 1.29–23.86).

Conclusions: This study identified risk factors for APOs in SLE pregnancies, enhancing clinician awareness and enabling early intervention for high-risk patients.

Systemic lupus erythematosus

pregnancy outcome

risk factor

Systemic lupus erythematosus (SLE), commonly known as lupus, is a prevalent chronic multisystemic autoimmune disease characterized by the presence of pathogenic autoantibodies and immune complexes, contributing to tissue damage. The estimated global incidence is 5.14 (from 1.4 to 15.3) per 100,000 person-years, with a corresponding prevalence estimated at 43.7 (from 15.87 to 108.92) per 100,000 individuals [1]. The chronic disease progression and the use of immunosuppressive therapy are significant contributors to life-threatening systemic organ damage. The mortality among SLE patients remains significantly higher, with rates two to three times greater than that among the general population [2]. Certain ethnic populations, like Black, Asian, and Hispanic, exhibit a pronounced predisposition [2].

SLE presents diverse phenotypes, spanning from mild skin symptoms to severe organ failures, affecting virtually any organ in the body. It has a distinct gender bias, predominantly affecting women of reproductive age, with a female/male ratio of roughly 9:1. The average age at which SLE is diagnosed is around 35 years [3]. SLE ranks among the top causes of mortality in young females [4]. The high susceptibility of reproductive-age women to SLE raises significant concerns for clinicians regarding childbearing. Despite comparable anti-Müllerian hormone levels and fertility potential as healthy controls [5], SLE women have heightened vulnerability to adverse pregnancy outcomes (APOs) [6]. Meta-analysis revealed that SLE subgroups exhibited significantly elevated rates of spontaneous abortion, stillbirth, premature birth, "small for gestational age” (SGA) infants, and infants with low birth weight [7, 8]. SLE-associated pregnancies are deemed high-risk pregnancies. Early identification of high-risk factors for APOs is of utmost importance. The careful monitoring of predictors and effective management of pregnancies in SLE women can improve outcomes.

The risk factors for APOs in SLE pregnancies have been extensively studied. However, these reports had limitations including a small sample size and limited diversity in terms of ethnicity and geographical regions. A systemic meta-analysis on this topic is currently absent. Therefore, our study aims to conduct a systemic review and meta-analysis to identify a set of risk factors that could potentially be targeted for interventions.

Search Strategies

PubMed, Cochrane Library, Web of Science, and EMBASE were comprehensively searched for relevant articles published in English and Chinese from initiation up to December 31, 2023. The search strategies encompassed Mesh terms and free words. The detailed retrieval strategies used are displayed in Supplementary Table 1.

Study Selection

After removal of duplicates, two investigators (Sun C, Li X) independently evaluated the potentially eligible articles by skimming through titles and abstracts.

The inclusion criteria covered: (1) with SLE pregnant women as study subjects; (2) with specific diagnostic criteria for identifying APOs; (3) multivariate analysis was employed to determine risk factors; (4) cohort or case-control study.

The articles were excluded for the following criteria: (1) guidelines, reviews, editorials, case reports, abstracts, letters, meeting summaries, or recalled articles; (2) incomplete or unavailable data; (3) inconsistent definition of APOs; (4) limited to univariate analysis; (5) publications not in English or Chinese languages.

Quality evaluation

Each eligible study underwent independent evaluation by the two authors using the Newcastle-Ottawa Scale (NOS) in three domains: patient representation, exposure and outcome determination, and follow-up adequacy. A comprehensive assessment led to the overall NOS score for each study was 9, with scores of 0-5 indicating low quality, scores of 6-7 indicating moderate quality, and scores of 8-9 indicating high quality, signifying a low risk of bias.

Data Extraction

Two independent reviewers (Sun C, Li X) extracted all the data, including first author, publication year, study location, sample size, mean age of pregnancy, diagnostic criteria, and documented risk factors.

Terms Definition

APOs were defined to include at least one of the following complications:

-Pregnancy loss: abortion, stillbirth, or neonatal death.

-Preterm birth: delivery occurring before 37 weeks of gestation.

-Intrauterine growth restriction (IUGR): impaired fetal growth resulting in a smaller than expected size.

-Small for gestational age (SGA): a neonate with a birthweight below the fifth percentile for their gestational age.

-Low birth weight (LBW): infants with a birthweight below a certain threshold, typically 2500 grams.

Data Analysis

A meta-analysis was conducted to assess the connection between potential risk factors and APOs in SLE patients. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were computed by Stata 15.1 software. Forest plots were employed to present the ORs from individual studies and the pooled OR estimate.

Given the variability in baseline data across the included studies, heterogeneity was observed. To evaluate this heterogeneity, the I² test was utilized. Heterogeneity was considered statistically significant if I²≥ 50% or p-value < 0.05. Based on heterogeneity (I²), a fixed-effects (I²<50%) or random-effects (I²>50%) statistical model was employed.

The results’ robustness was appraised using sensitivity analysis, while publication bias was judged to evaluate the potential impact of selective reporting.

Article Selection

The initial research on four databases retrieved 1123 records. After the removal of duplicates, 647 records remained. After carefully reviewing the titles and abstracts, 569 articles were excluded, resulting in 78 articles for further comprehensive evaluation in full-text format. Through this rigorous selection process, 42 articles (1 in Chinese and 41 in English) were utilized for review, as depicted in Fig. 1.

Study Characteristics

Table 1 lists the key characteristics of 42 included articles, providing information on study type, geographical regions, and sample sizes. As for study types, 4 were retrospective case-control studies, 8 were retrospective cohort studies, and 30 were prospective cohort studies. The patient population was geographically diverse, spanning regions such as Asia, North America, Europe, the Middle East, and others. Overall, the analysis involved a substantial sample size of 8723 pregnancies, ensuring reliable and generalizable findings.

Table 1

Key characteristics of included articles
Study	Year	Country	Study Design	Sample Size	Mean Age of pregnancy
Andrade	2008	USA	prospective cohort	102	-
Arfaj	2010	Saudi Arabia	retrospective cohort	383	36.4 ± 7.4
Al-Riyami	2021	Oman	retrospective cohort	149	30.6 ± 5
Buyon	2015	USA	prospective cohort	385	30.93 ± 4.90
Chen	2018	China	retrospective cohort	243	28.9 ± 3.9
Chen	2021	China	retrospective cohort	85	27.4
Chen	2015	China	retrospective cohort	83
Clowse	2006	USA	prospective cohort	166	30.2 ± 4.9
Deguchi	2018	Japan	prospective cohort	56	33.9 ± 4.6
Hiramatsu	2021	Japan	retrospective case-control	108	33
Hamijoyo	2019	Indonesia	retrospective case-control	109	26 ± 6
He	2021	China	retrospective cohort	223	27.8 ± 3.9
Irino	2021	Japan	retrospective cohort	64	31.2 ± 4.9
Jiang	2021	China	retrospective cohort	513	29.7 ± 4.0
Kim	2021	Korea	retrospective case-control	163	31.9 ± 4.3
Kalok	2019	Malaysia	retrospective case-control	71	30.5 ± 3.9
Ko	2011	Korea	retrospective cohort	183	30.4 ± 3.2
Kwok	2011	Hong Kong	prospective cohort	55	30.2
Laíno-Pineiro	2023	Spain	retrospective cohort	1869	-
Larosa	2022	France	prospective cohort	238	31.6 + 4.5
Liu	2017	China	retrospective cohort	131	24.3 ± 2.8
Liu	2012	China	retrospective cohort	111	29.2 ± 4.2
Louthrenoo	2021	Thailand	retrospective cohort	90	26.94 ± 4.80
Lu	2021	China	retrospective cohort	55	-
Lv	2015	China	retrospective cohort	52	29.0 ± 3.7
Madrazo	2022	Spain	retrospective cohort	64	32.1 ± 5.04
Miranda	2021	Mexico	prospective cohort	351	28.3 ± 5.5
Mokbel	2023	Egypt	prospective cohort	201	27.16 ± 4.8
Natli	2022	Greece	prospective cohort	84	33.5 (6.8)
Oishi	2021	Japan	retrospective cohort	98	30
Palma dos Reis	2020	Portugal	retrospective cohort	157	29.6 (4.7)
Park	2014	Korea	retrospective cohort	62	-
Shaharir	2020	Malaysia	retrospective cohort	240	29.9 ± 4.8
Song	2016	China	retrospective cohort	69	26.4 ± 3.9
Sugawara	2019	Japan	retrospective cohort	57	30
Tani	2021	Germany	retrospective cohort	281	31.9 ± 4.5
Tian	2015	China	retrospective cohort	347	31.9 ± 4.5
Zamani	2020	Iran	retrospective cohort	121	33.74 ± 3.80
Zhan	2018	China	retrospective cohort	180	29.4 ± 3.5
Zhan	2017	China	retrospective cohort	263	28.6 ± 3.9
Zhang	2022	China	retrospective cohort	123	27.1 ± 4.1
Wu	2019	China	retrospective cohort	338	29.5 ± 4.0

Quality Evaluation

The risk of bias was evaluated using NOS scores, and the results are presented in Supplementary Tables 2–3. Among the 41 studies analyzed, a significant majority of 75.60% (31/41) attained 8 scores or higher, indicating high quality. Additionally, 10 studies were rated as moderate quality.

Analysis Result

Lupus Nephritis

11 studies revealed a significant association between lupus nephritis (LN) and APOs. The analysis, employing a fixed-effects model, indicated low heterogeneity (I² = 21.7, P = 0.250) and demonstrated that patients with LN exhibited a 3.02-fold higher risk of APO than those without LN (OR, 3.02; 95% CI, 2.10–4.34). P < 0.001) (Fig. 2).

In 7 studies examining the association between LN and preterm birth, a fixed-effects model was utilized, showing low heterogeneity (I² = 3.3, P = 0.401). The analysis revealed LN as a prominent high-risk factor for preterm birth, with individuals with LN having a 3.69-fold increased risk compared to those without LN (OR, 3.69; 95% CI, 2.31–5.89, P = 0.001) (Fig. 3).

In 7 studies on pregnancy loss, a random-effects model was employed, indicating moderate heterogeneity (I² = 50.1, P = 0.051). The analysis identified LN as a high-risk factor for pregnancy loss (OR, 3.47; 95% CI, 1.74–6.89, P < 0.001) (Fig. 4).

In 3 studies on IUGR, a heterogeneity test showed high heterogeneity (I² = 69.4, P = 0.038). The analysis revealed that LN was connected with a 3.51-fold elevated risk of IUGR (OR, 3.51; 95% CI, 1.30–9.51, P = 0.013) (Fig. 5).

In 3 studies on LBW, moderate heterogeneity was observed (I² = 41.8, P = 0.179). LN was significantly linked to a 5.55-fold elevated risk of LBW (OR, 5.55; 95% CI, 1.29–23.86, P = 0.021) (Fig. 6).

Hypertension

In the analysis of 6 studies, a heterogeneity test revealed moderate heterogeneity (I² = 57.4, P = 0.029). Hypertension was strongly linked to a 5.23-fold enhanced risk of APOs (OR, 5.23; 95% CI, 2.76–9.91, P < 0.001) (Fig. 7).

Similarly, in the analysis of 5 studies, moderate heterogeneity was observed (I² = 58.6, P = 0.046). Hypertension was uncovered as a high-risk factor for preterm birth, with a 4.50-fold raised risk (OR, 4.50; 95% CI, 1.86–10.87, P < 0.001) (Fig. 8).

However, the role of high blood pressure in pregnancy loss remains inconclusive (OR, 1.33; 95% CI, 0.71–1.94, P < 0.001) (Fig. 9).

Disease activity

Based on 7 studies, active lupus during pregnancy substantially increased the risk of APOs, with high heterogeneity (I² = 76.0, P < 0.000). The analysis revealed a 2.51-fold higher risk of APOs in patients with active lupus during pregnancy (OR, 2.51; 95% CI, 1.39–4.50, P = 0.002).

Furthermore, active lupus related to a 3.92-fold higher risk of preterm birth (OR, 3.92; 95% CI, 2.52–6.10, P < 0.001) and a 9.19-fold higher risk of pregnancy loss (OR, 9.19; 95% CI, 3.14–26.89, P < 0.001).

In 3 studies evaluating the impact of low disease activity state (LLDAS) during pregnancy on APOs, low heterogeneity was observed (I² = 0.00, P = 0.616). LLDAS was considered a protective factor against APOs (OR, 0.26; 95% CI, 0.12–0.57, P < 0.001).

Based on 6 studies, disease flare during pregnancy markedly enhanced the risk of preterm birth (OR, 4.02; 95% CI, 2.24–7.19, P < 0.001), with moderate heterogeneity (I² = 56.7, P = 0.042).

Additionally, in the analysis of 4 studies, disease flare was connected with a 2.72-fold raised risk of pregnancy loss (OR, 2.72; 95% CI, 1.36–5.46, P = 0.005), with moderate heterogeneity (I² = 54.2, P = 0.087) (Supplementary Figs. 1–6).

Antiphospholipid syndrome (APS)/Positive antiphospholipid antibody (aPL)

APS or positive aPL significantly elevated the risk of APOs by 4.97 times (OR, 4.97; 95% CI, 1.87–13.17, P < 0.001), based on 5 studies with high heterogeneity (I² = 71.6, P = 0.007) (Supplementary Fig. 7).

APS was also a risk factor for preterm birth, with a 3.95-fold raised risk (OR, 3.95; 95% CI, 2.20–7.07, P < 0.001), according to 5 studies with low heterogeneity (I² = 0, P = 0.457). Additionally, APS or positive aPL elevated the risk of pregnancy loss by 3.46 times (OR, 3.46; 95% CI, 2.44–4.91, P < 0.001), based on 10 articles with low heterogeneity (I² = 0, P = 0.822) (Supplementary Figs. 8–9).

Hypocomplementemia

Based on the analysis of 5 studies, there was a reported relationship between low complement levels and APOs (OR, 1.94; 95% CI, 1.39–2.72, P < 0.001), with moderate heterogeneity (I² = 45.7, P = 0.118). Additionally, low complement levels were linked to an intensified risk of pregnancy loss (OR, 2.60; 95% CI, 1.08–6.27, P = 0.033) (Supplementary Figs. 10–11).

Thrombocytopenia

Based on the analysis of 4 studies, a relationship was found between low platelet count and pregnancy loss (OR, 2.20; 95% CI, 1.00–4.81, P = 0.049), with high heterogeneity (I² = 81.8, P < 0.000), indicating significant variability in the results (Supplementary Fig. 12).

Preeclampsia/eclampsia

Based on the analysis of four studies, a relationship was found between preeclampsia/eclampsia and preterm birth (OR, 8.85; 95% CI, 4.72–16.58, P < 0.001), with low heterogeneity (I² = 0, P = 0.732), indicating consistent findings across the studies (Supplementary Fig. 13).

Publication bias

As mentioned in the previous statistical analysis, we assessed the potential publication bias. The results of Egger's tests can be found in Table 2.

Table 2

Summarized results
Adverse Pregnancy Outcomes	Risk factors	Study (n)	Heterogeneity		OR (95%CI)	P	Egger’s test
Adverse Pregnancy Outcomes	Risk factors	Study (n)	I²(%)	P	OR (95%CI)	P	Egger’s test
APO	Hypertension	6	57.4	0.029	5.23(2.76,9.91)	0.001	0.038
	Lupus nephritis	11	48.2	0.037	3.02(2.10,4.34)	0.001	0.014
	Hypocomplementemia	5	45.7	0.118	1.94(1.39,2.72)	0.001	0.219
	LLDAS	3	0.00	0.616	0.26 (0.12,0.57)	0.001	0.351
	Active disease	7	76.0	0	2.51(1.39,4.50)	0.002	0.003
	APS/aPL	5	71.6	0.007	4.97(1.87,13.17)	0.001	0.753
Preterm Birth	Lupus nephritis	7	3.3	0.401	3.69(2.31, 5.89)	0.001	0.392
	Hypertension	5	58.6	0.046	4.50(1.86,10.87)	0.001	0.093
	Preeclampsia/eclampsia	4	0.0	0.732	8.8(4.72, 16.58)	0.001	0.151
	Flare	6	56.7	0.042	4.02(2.24,7.19)	0.001	0.001
	Active disease	7	21.0	0.276	3.92(2.52, 6.10)	0.001	0.252
	APS	5	0.00	0.457	3.95(2.20, 7.07)	0.001	0.515
Pregnancy Loss	Hypocomplementemia	5	86.4	0	2.60(1.08,6.27)	0.033	0.179
	Flare	4	54.2	0.087	2.72(1.36,5.46)	0.005	0.381
	Thrombocytopenia	4	81.8	0	2.20(1.00, 4.81)	0.049	0.004
	Lupus nephritis	7	50.1	0.051	3.47(1.74,6.89)	0.001	0.660
	Hypertension	5	0.0	0.480	1.33(0.71,1.94)	0.001	0.232
	APS/aPL	10	40.9	0.085	3.46(2.44,4.91)	0.001	0.244
	Active	3	0.00	0.822	9.19(3.14,26.89)	0.001	0.182
Low Birth Weight	Lupus nephritis	3	69.4	0.038	5.55(1.29,23.86)	0.021	0.594
Intrauterine Growth Restriction	Lupus nephritis	3	41.8	0.179	3.51(1.30,9.51)	0.013	0.984

Pregnancy in SLE patients is commonly regarded as a high-risk condition due to its well-documented connection with APOs [9]. SLE pregnancies are more susceptible to pregnancy loss, preterm births, and IUGR than the general population [10, 11]. A meta-analysis of 2751 pregnancies showed a 23.4% rate of unsuccessful pregnancy and a 39.4% rate of premature birth [12]. Our meta-analysis of 41 papers investigated the risk factors for APOs.

Pregnancy and autoimmunity influence each other. The concept of Th2 phenomenon in successful pregnancy, proposed in 1993, refers to the suppression of CD4 + T helper 1 (Th1) cells and a shift towards Th2 anti-inflammatory cytokines [13]. Extensive research has revealed the dynamic balance of cytokine expression during different stages of pregnancy [14]. Proinflammatory Th17 cells are associated with APOs, while regulatory T (Treg) cells increase in healthy pregnant women and are linked to immune tolerance towards the fetus [14]. In the third trimester of SLE pregnancy, the lower-than-anticipated decrease of Th1 cytokines was detected [15]. Both the quantity and functionality of Treg cells are reduced in SLE patients, suggesting impairment in placental development and fetal tolerance [16]. They also display increased secretions of activin A, IL-6, IL-17, IL-10, and TNF-α during pregnancy, indicating a hyper-reactive immune system [17]. A 16-year cohort study by Clowse ME et al. revealed that high-activity lupus during pregnancy augmented the risk of preterm birth, decreased live births, and brought about a significant rate of fetal loss [18]. Active lupus may impact the uteroplacental unit, leading to preterm labor and membrane rupture [18]. The activity indices in SLE pregnancy can be assessed using the SLE in Pregnancy Activity Index, Modified Lupus Activity Measurement, and Lupus Activity Index in Pregnancy [19]. American College of Rheumatology’s Reproductive Health Guideline 2020 recommends SLE women to conceive during a period of clinically mild or inactive disease activity in the 6 months before pregnancy and to continue taking pregnancy-compatible lupus medications throughout pregnancy [20].

Active LN during pregnancy is linked to a high risk of fetal loss, ranging from 35–50% [21]. Smyth A et al. have confirmed LN raises the risk of preterm delivery and unsuccessful pregnancy, while IUGR incidence is estimated to be 12.7% [12], consistent with the findings of another meta-analysis [22]. Patients with class III/IV LN exhibit a lower mean birthweight [23]. In patients with renal involvement, baseline renal function, proteinuria levels, and new onset have been associated with APOs [24]. European League Against Rheumatism recommends ongoing monitoring during pregnancy, including urine protein excretion, urine sediment analysis (assessing glomerular hematuria and urinary casts), serum creatinine levels, and glomerular filtration rate [25].

SLE women have noticeably higher rates of hypertension than healthy individuals [26]. It has been firmly established that hypertension has a significant impact on pregnancy outcomes [27]. Inadequate blood pressure regulation during pregnancy is linked to decreased gestational age at delivery [28], consistent with our results. Hypertension during pregnancy can trigger an imbalance of Th cells and the release of cytokines, leading to the reactive flare of lupus [29]. Conversely, active SLE can also serve as a predictor of hypertension [29].

The meta-analysis confirmed that aPL was connected with higher rates of APOs, including elevated fetal loss risk for Antiβ2GP1 and anticardiolipin antibody (aCL), and higher risk of preterm birth for lupus anticoagulant (LAC) [30]. LAC and aCL are predictors of APOs in aPL-positive patients [30–32]. In addition to causing thrombosis in the uteroplacental vasculature, aPL directly impairs the production of chorionic gonadotropin by influencing anionic phospholipids and β2GP1 in trophoblast cells during early pregnancy [33]. Despite aspirin and low molecular weight heparin treatment, APS still results in a 20–30% rate of pregnancy loss, suggesting that hydroxychloroquine and pravastatin should be explored as potential alternative options [28].

Complement activation contributes to abnormal placental development, as evidenced by the significant association between increased Bb and sC5b-9 levels in early pregnancy and APOs [34]. Complement fragments are detected in placental samples from complicated pregnancies, and C4d emerges as the prominent biomarker for complement activation in the placenta [35]. Physiological fluctuations in complement levels during gestation can be indicative of APOs in SLE pregnancy if there is a lack of anticipated increase in C3 and C4 levels [36, 37].

Thrombocytopenia during SLE pregnancy is linked to heightened disease activity, early onset preeclampsia, and elevated rates of pregnancy loss [38]. Plateletcrit is a valuable marker for predicting the risk of stillbirth in SLE pregnancies [39]. The decrease in platelet count could potentially signify early signs of preeclampsia, microthrombosis, or lupus activity. Based on our findings, eclampsia or preeclampsia is a high-risk factor for preterm birth in SLE. SLE pregnancies carry an elevated risk of preeclampsia, which is influenced by SLE circulating immune complexes and dysregulated cytokine expression [40].

This research is constrained by several limitations, including moderate heterogeneity during subgroup analysis, differences in the definition of pregnancy outcomes and risk factors, and variations in medications used during pregnancy and treatment strategies across hospitals. These limitations should be considered when interpreting and applying the obtained findings. Further research may be necessary to address these limitations and provide more precise references.

The current systematic review and meta-analysis examined the risk factors for APOs in SLE pregnancies and identified LN, hypertension, disease activity, aPL, hypocomplementemia, thrombocytopenia, and preeclampsia/eclampsia as significant risk factors. These findings enhance comprehension regarding risk factors for APOs in SLE pregnancies and allow healthcare providers to take appropriate measures to optimize maternal and fetal health during pregnancy.

aCL

anticardiolipin antibody

APL

antiphospholipid antibody

APO

adverse pregnancy outcomes

APS

antiphospholipid syndrome

IGR

intrauterine growth restriction

LAC

lupus anticoagulant

LBW

low birth weight

lupus nephritis

NOS

Newcastle-Ottawa Scale

odds ratio

SGA

small for gestational age

SLE

systemic lupus erythematosus

Th cells

T helper cells

Treg cells

regulatory T cells

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests

The authors declare that they have no competing interests.

Funding

The authors declare that they did not receive any funding from any source.

Authors' contributions

All authors contributed to the study conception and design. Writing - original draft preparation: Sun Chen; Writing - review and editing: Sun Chen; Conceptualization: Sun Chen; Methodology: Sun Chen; Formal analysis and investigation: Sun Chen; Resources: Li Xia; Supervision: Li Xia, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

Not applicable.

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No competing interests reported.

SupplementaryMaterials.docx
Supplementary Materials Supplementary Table 1 Search strategy Supplementary Table 2 Assessment of case-control study quality-Newcastle Ottawa Scale Supplementary Table 3 Assessment of corhort study quality-Newcastle Ottawa Scale Supplementary Figure 1 OR for association between active lupus during pregnancy and APOs Supplementary Figure 2 OR for association between active lupus during pregnancy and preterm birth Supplementary Figure 3 OR for association between active lupus during pregnancy and pregnancy loss Supplementary Figure 4 OR for association between LLDAS and APOs Supplementary Figure 5 OR for association between disease flare and preterm birth Supplementary Figure 6 OR for association between disease flare and pregnancy loss Supplementary Figure 7 OR for association between APS/positive aPL and APOs Supplementary Figure 8 OR for association between APS and preterm birth Supplementary Figure 9 OR for association between APS/positive aPL and pregnancy loss Supplementary Figure 10 OR for association between hypocomplementemia and APOs Supplementary Figure 11 OR for association between hypocomplementemia and pregnancy loss Supplementary Figure 12 OR for association between low platelet count and pregnancy loss Supplementary Figure 13 OR for association between preeclampsia/eclampsia and preterm birth

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Risk Factors For Adverse Pregnancy Outcomes in Systemic Lupus Erythematosus: A Meta Analysis and Systemic review

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Version 1

Abstract

Figures

Background

Methods

Result

Article Selection

Study Characteristics

Quality Evaluation

Analysis Result

Lupus Nephritis

Hypertension

Disease activity

Antiphospholipid syndrome (APS)/Positive antiphospholipid antibody (aPL)

Hypocomplementemia

Thrombocytopenia

Preeclampsia/eclampsia

Publication bias

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1