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Abstract
Objective To identify preconception clinical factors associated with adverse pregnancy outcomes (APO) in patients with systemic lupus erythematosus (SLE) or primary Sjögren’s syndrome (pSS).
Methods A single-centre, retrospective cohort study was conducted, which included pregnant women treated at the University Medical Center Groningen between January 2010 and August 2021 who fulfilled classification criteria for SLE or pSS. Demographic data, relevant comorbidities, disease duration, disease activity before and during pregnancy, APO, laboratory parameters and treatment regimens were recorded. Associations between the presence of APO and preconception characteristics were evaluated.
Results Our study population included 48 (70%) SLE and 21 (30%) pSS pregnancies concerning 70 fetuses (one twin). Preterm birth (n=9, 19%) was the most frequent APO in SLE pregnancies, while in pSS pregnancies this was miscarriages (n=3, 14%). There were no associations between the presence of APO in SLE pregnancies and clinical parameters, laboratory parameters or medication use prior to conception. In the pSS group, significant associations were found between the presence of APO and body mass index (p=0.010), parity (p=0.046), C4 (p=0.021) and low C4 levels (p=0.002).
Conclusions No preconception risk factors related to APO were found in SLE pregnancies, whereas preconception complement levels were associated with APO development in patients with pSS.
- Lupus Erythematosus, Systemic
- Sjogren's Syndrome
- Antiphospholipid Syndrome
Data availability statement
Data are available on reasonable request. The data that support the findings of this study are displayed in the article and in online supplemental material. Others are available on request from the corresponding author due to ethics regulations.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Patients with systemic lupus erythematosus (SLE) have an increased risk of adverse pregnancy outcomes (APO), which has not been fully described in patients with primary Sjögren’s syndrome (pSS). Preconceptional risk factor assessment is essential to guide treatment and improve outcomes during pregnancy in those patients.
WHAT THIS STUDY ADDS
A wide variety of APO was identified in patients with SLE and pSS. These diseases seem to have different APO types related to their pathophysiology. Interestingly, complement levels were related to APO in pSS pregnancies.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study identified a high risk of APO in patients with pSS. Furthermore, it suggests that preconceptional complement levels monitoring could be useful in estimating that risk.
Introduction
Systemic lupus erythematosus (SLE) mainly affects women of childbearing age, while primary Sjögren’s syndrome (pSS) is more frequent postmenopausal. Nevertheless, both SLE and pSS have been associated with adverse pregnancy outcomes (APO).1 2 A well-known APO in pregnant women with SLE or pSS is neonatal lupus, in which the transplacental passage of maternal anti-Ro/SSA antibodies to the fetus affects neonatal organs leading in some cases to myocarditis and a congenital heart block (CHB).3 While other types of APO are also relatively common in SLE and pSS pregnancies, their underlying pathophysiological mechanisms remain poorly understood. During pregnancy, the maternal immune system must tolerate a semiallogenic fetus. It has been established that this adaptation is influenced by maternal inflammatory factors, and an over-activation of maternal immune cells could explain the higher rates of APO in patients with SLE and pSS.4
SLE is a multisystemic heterogeneous autoimmune disease characterised by production of autoantibodies directed against double-stranded DNA and several other autoantigens.5 APO were identified in 19% of SLE pregnancies included in the multicentre prospective cohort study PROMISSE,6 and in 42% in a Dutch SLE cohort.7 Furthermore, a meta-analysis confirmed an increased risk of hypertension (relative risk (RR) 1.99), pre-eclampsia (RR 1.91), preterm birth (RR 3.05), fetal growth restriction (FGR) (RR 4.44) and small for gestational age (SGA) (RR 1.69) in patients with SLE.1
In addition to this, a proportion of patients with SLE develop secondary antiphospholipid syndrome (APS), an autoimmune disease characterised by thrombosis (vascular APS) and/or pregnancy morbidity (obstetric APS). APS is associated with persistent positivity of moderate or high titers of antiphospholipid antibodies (aPL).8 9 The presence of aPL is confirmed by a positive lupus anticoagulant (LA) test and/or the presence of autoantibodies against ß2-glycoprotein 1 (aß2GP1) and/or cardiolipin (aCL).8 aPL positivity increased the risk of APO also in women who did not fulfil APS diagnostic criteria, and positivity for LA and aß2GP1 IgG antibodies was identified as the highest obstetric risk aPL profile.6 10
pSS is also an autoimmune connective tissue disease that affects exocrine glands, mainly the salivary and lacrimal glands, and causes dryness (sicca) symptoms such as xerostomia and keratoconjunctivitis.11 Up to 50% of patients with pSS may additionally develop systemic manifestations. Patients with pSS have an increased risk of pre-eclampsia, premature rupture of membranes (PROM), preterm birth, FGR and miscarriages compared with the general population.2 12 13 However, there are conflicting data, as a second, small case–control study did not identify a higher risk of APO in patients with pSS.14
Together, it appears that SLE and pSS have an increased risk of APO compared with healthy women, and this could be due to the immunopathology underlying these diseases. Immune cell imbalances and proinflammatory factors present before conception and during pregnancy, may affect the maternal immune tolerance to the fetus and placental homeostasis.13 Estimating obstetric risk before pregnancy to determine and guide treatment could lead to better pregnancy outcomes in these patients.15 Therefore, we conducted a retrospective cohort study to identify preconception clinical factors associated with APO in patients with SLE or pSS in our tertiary referral centre.
Materials and methods
A single-centre, retrospective cohort study was conducted, which included pregnant women treated at the University Medical Center Groningen between January 2010 and August 2021, who fulfilled the classification criteria for SLE (≥ 4 American College of Rheumatology (ACR) criteria or ≥4 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria),16–18 or pSS (≥4 points in ACR/European League Against Rheumatism (EULAR) criteria) at the last visit between 6 months before conception and conception.19 Patients were identified via searches on treatment codes in the Department of Rheumatology and Clinical Immunology patient register. Data were extracted from the hospital electronic patient administration system, and a database was built using Research Electronic Data Capture software for analysis.20 If patients did not give birth in the study hospital, missing data were collected by contacting the caregivers responsible for the supervision of delivery and post partum. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Demographic data were obtained from patients files. The use of assisted reproductive technology (ART) and relevant comorbidities, such as diabetes mellitus, primary thrombophilia, arterial hypertension, kidney disease and previous thromboembolic events, were recorded.21 The disease duration until pregnancy was calculated as the time between date of diagnosis and first day of the last menstruation. Disease activity was assessed with the SLE Disease Activity Index (SLEDAI)22 and the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) at the last visit before conception, which was between 6 months before conception and conception.23 24
Adverse pregnancy outcomes
APO were analysed during pregnancy and postpartum (until 6 weeks after delivery). APO were defined as the presence of maternal or neonatal adverse outcomes. Maternal adverse outcomes were defined as the presence of one or more of the following: miscarriage (pregnancy loss up to 20th weeks of gestation), stillbirth (pregnancy loss at 20th weeks of gestation or later), FGR,25 PROM, preterm birth (before the 37th week of gestation), severe preterm birth (before the 34th week of gestation), pregnancy-induced hypertension, pre-eclampsia or eclampsia,26 Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome, adverse termination of pregnancy by caesarean section or fetal congenital abnormalities, thromboembolic events during pregnancy or postpartum and postpartum haemorrhage. Furthermore, neonatal adverse outcomes were defined as the presence of one or more of the following: SGA (defined as birth weight below 10th percentile according to gestational age at delivery without FGR history), Apgar score below 7 at birth, presence of CHB, neonatal hospital admission and neonatal death.
Laboratory parameters and medication use
Several laboratory parameters before pregnancy were collected if present at the last visit between 6 months before conception and conception, including C reactive protein (CRP), anti-double-stranded DNA antibodies (anti-dsDNA), aCL, aß2GP1, LA, complement 3 (C3), complement 4 (C4), anti-Ro/SSA antibodies, anti-La/SSB antibodies, immunoglobulin G levels and rheumatoid factor values. The use of oral glucocorticoids and their dose between 6 months before conception was identified. Moreover, biological drugs and treatments for comorbidities up to 12 months before pregnancy were recorded.
Statistics
According to the sample distribution, data from continuous variables are presented as mean with SD or median with interquartile range (p75–p25). More than one pregnancy per patient could be included in the analysis, and the period between the first and subsequent pregnancies was lower than 5 years for all cases. Therefore, we evaluated the association of presence of APO and baseline characteristics with generalised estimating equations (GEE) logistic binary model with an exchangeable correlation matrix. This approach allowed correct estimation for the same patient contributing more than one pregnancy in our cohort (correlated data). Due to the sample size, only univariate analysis was performed. GEE analysis was not run when any of the groups had no events in a variable of interest. Differences in baseline demographics and presence of APO during first pregnancy were evaluated with χ2 and Fisher’s exact tests for categorical variables and the independent-samples t-test or the Mann-Whitney U test for continuous variables. Statistical significance is set at a p value less than 0.05. All analyses were performed using IBM SPSS Statistics, V.28.0, IBM.
Results
Our population included 48 (70%) SLE and 21 (30%) pSS pregnancies concerning 70 fetuses (one twin) in a total number of 32 (71%) SLE and 13 (29%) pSS patients. Five patients with SLE and one patient with pSS were diagnosed during pregnancy or in the first 6 months after delivery. The mean age was 30.3 years±3.9, most patients were Caucasian (90%), and the median body mass index (BMI) was 23.6 (IQR 22–27). Kidney disease was the most frequent comorbidity (19%). ART use was reported in three (6%) SLE and three (14%) pSS pregnancies. Baseline demographics of patients with SLE and pSS per pregnancy and their association with APO are summarised in table 1. Furthermore, baseline demographics of the individual patients, using data only from the first pregnancy are described in online supplemental table 1.
Supplemental material
Baseline demographics of systemic lupus erythematosus and primary Sjögren’s syndrome pregnancies and their association with APO
APO in patients with SLE and pSS
Included pregnancies led to 37 (77%) live births in patients with SLE and 18 (86%) in patients with pSS. The median gestational age at delivery was 37.5 (IQR 27–39) and 38 (IQR 37–39) weeks in SLE and pSS groups, respectively. Preterm birth (n=9, 19%) was the most frequent APO in SLE pregnancies, while in pSS pregnancies this was miscarriages (n=3, 14%). Only two mild SLE flares (SLEDAI>6 and immunosuppressive drug increase) were identified. Two thromboembolic events during postpartum occurred in the SLE group in aPL positive patients (both LA positive, one with triple aPL positivity). Interestingly, they were not treated with prophylactic low-dose aspirin during pregnancy as it is currently recommended.27 Additionally, adverse termination of pregnancy by fetal abnormalities was reported in SLE pregnancies (n=4, 8%) but not in pSS pregnancies. Fetal abnormalities involved a molar pregnancy, two genetic conditions (trisomy 18 and congenital nephrotic syndrome due to NPHS2 gene mutation) and abnormalities associated with mycophenolate mofetil use. SGA was documented in 3 (8.1%) SLE and 1 (5.6%) pSS live births. CHB and neonatal death were not documented. Neonatal hospital admission was necessary for 6 (16%) and 2 (11%) SLE and pSS neonates, respectively. Other APO rates are described in table 2. In summary, when considering only the first pregnancy, there was a higher APO rate in SLE pregnancies (23/32) than in pSS (4/13) (p=0.011). Nevertheless, no significant differences in specific APO were identified between these groups (online supplemental table 2).
Adverse pregnancy outcomes in systemic lupus erythematosus and primary Sjögren’s syndrome
Preconception clinical factors were not related to APO in SLE pregnancies
A secondary APS and SS were reported in 9 (19%) and 2 (4%) of SLE pregnancies, respectively. The median SLE duration preconception was 5.9 years in the APO group and 7.6 years in the group without APO. The ACR and SLICC classification criteria scores were comparable between groups. Both groups had inactive or stable mild SLE prior to conception, with a median SLEDAI score of 2. Other baseline disease characteristics of SLE pregnancies are summarised in table 3.
Baseline disease characteristics of systemic lupus erythematosus pregnancies
No associations between the presence of APO and baseline BMI, gravidity, parity, systolic blood pressure or comorbidities were found in SLE pregnancies (table 1, online supplemental table 3). Furthermore, no associations were found between the presence of APO and CRP, C3, C4 or anti-dsDNA levels before conception. aPL, anti-Ro/SSA, and anti-La/SSB positivity and medication use prior to conception were not related to the presence of APO in our SLE cohort (table 3, online supplemental table 3). Preconceptionally, potential teratogenic drug use was reported in 13 (42%) and 7 (41%) SLE pregnancies with APO or without APO, respectively. However, these medications were stopped before pregnancy or when the pregnancy was established, and there was no significant association between the presence of APO and teratogenic drug use in the univariate analysis. A description of identified potential teratogenic drugs are shown in (online supplemental table 5).
Preconception clinical factors were not associated with the presence of combined maternal and neonatal APO in SLE pregnancies
Twenty-eight (58%) of SLE pregnancies had a maternal APO, of which 7 (25%) had a maternal and neonatal APO combined. Interestingly, the group with maternal and neonatal APO had a median preconception SLEDAI score of 4 (IQR 2–6), while those with only a maternal APO had a median SLEDAI score of 2 (IQR 0–4). Non-significant association was found between the presence of combined maternal and neonatal APO and C3 (median 0.91, IQR 0.7–0.92, p=0.051) or C4 (median 0.11, IQR 0.09–0.15, p=0.091) levels. Furthermore, these results were sustained when comparing the percentage of patients with low complement levels based on the clinical cut-off versus those with normal complement levels (low C3 p=0.682, low C4 p=0.297). Finally, aPL, anti-Ro/SSA, anti-La/SSB positivity and type of medication use prior to conception were not associated with the presence of combined maternal and neonatal APO (table 3).
Preconception C4 levels were associated with APO in pSS pregnancies
Concerning the pregnancies in pSS, 8 (38%) had APO, while 13 (62%) did not. The median disease duration before pregnancy was 5.9 years in the APO group and 3.8 years in the group without APO. The ACR/EULAR criteria scores were comparable between groups. Furthermore, both groups had low systemic disease activity prior to conception, with a median ESSDAI score of 4 (IQR 1–6) in the APO group and 2 (IQR 0–4) in the group without APO. Baseline disease characteristics of patients with pSS per pregnancy are summarised in table 4.
Baseline disease characteristics of primary Sjögren’s syndrome pregnancies
Significant associations between BMI (p=0.010), parity (p=0.046) and the presence of APO were found in pSS pregnancies (table 1, online supplemental table 4). Nevertheless, the BMI median was 22.1 (IQR 20.1–23.3) and 24.6 (IQR 23.4–26.6) in pSS pregnancies with and without APO, respectively, and these values are under the 25 threshold for overweight. No associations between gravidity, systolic blood pressure and the presence of APO were found (table 1, online supplemental table 4). A significant association was found between C4 levels before conception (p=0.021) and the presence of APO. Furthermore, these results were sustained when comparing the percentage of patients with C4 levels lower than the clinical cut-off (p=0.002). No associations were found between CRP, C3, immunoglobulin G and rheumatoid factor levels before conception and the presence of APO. aPL, anti-Ro/SSA and anti-La/SSB positivity and medication use prior to conception were also not related to the presence of APO in our pSS cohort (table 4, online supplemental table 4). Moreover, preconception potential teratogenic drug use was reported in 4 (50%) of pregnancies with APO and 2 (17%) without APO (online supplemental table 5). Similar to the SLE group, these medications were stopped when the pregnancy was confirmed, and there was no significant association in the univariate analysis.
Discussion
In this study, SLE and pSS were associated with a wide variety of APO but a high rate of live births as previously described.2 7 Preterm birth leads to most cases of perinatal mortality in healthy women,28 however, high preterm birth rates and live birth achievement in our SLE group are in accordance with previously published data.1 29 30 Interestingly, our SLE group had a higher preterm birth rate than the Dutch general population28 but lower than a previous Dutch cohort of SLE pregnancies.7 In our cohort, most women planned their pregnancy and conceived once their disease was in remission. Therefore, most of our patients with SLE had mild or moderate disease activity prior to conception but a higher overall rate of APO than in the PROMISSE prospective study, mainly explained by a high rate of fetal loss in our patients (16%) and the inclusion of other outcomes in our APO definition.6 Therefore, this high heterogeneity in APO definition could explain the variation in outcomes among studies. Unlike high rates of miscarriages, preterm delivery, low birth weight and birth by caesarean section reported by De Carolis et al in patients with pSS, these were not identified in our cohort.13
High rates of placenta-insufficiency-related APO, such as hypertensive disorders of pregnancy, preterm birth and FGR, were found in SLE pregnancies but not in pSS. We hypothesise that despite overlap in the immunopathology between SLE and pSS, the degree of systemic disease activity in patients with SLE leading to organ damage differs from the predominantly local lymphocytic glandular infiltration in patients with pSS with mild to moderate disease activity. Furthermore, placenta angiogenic imbalances have been described as a cause of placenta-insufficiency-related APO in patients with SLE; nonetheless, there is no evidence yet for this mechanism in patients with pSS.31 32
Risk factors associated with APO in healthy women such as advanced maternal age,33 smoking status, ethnicity and obesity were included in our analysis.28 33 34 In patients with SLE, low complement levels during the first trimester have been associated with a higher pregnancy loss rate.35 Furthermore, preconception low C3 levels and low C4 levels throughout pregnancy were identified as risk factors for preterm birth in SLE pregnancies, even in women with mild disease activity.36 37 In the PROMISSE study, pregnant patients with SLE pregnant with APO were more likely to have low C3, C4 and CH50 preconception levels than those without. Nevertheless, it was shown that complement levels as a single measure before conception were not associated with the presence of APO and a slight increase in C3 level during the second trimester predicted the presence of APO after 23 weeks of gestation, when longitudinal data were included.6 In a similar manner, we did not find associations between preconception low complement levels and the presence of APO in our patients with SLE. SLE patient complement levels interpretation before and during pregnancy could be challenging due to the interaction between higher production (increased by oestrogen) and higher use due to disease activity.38 Due to physiological rise in complement levels during pregnancy, a negative or neutral trend could be related to APO in patients with SLE, even without absolute low values.39
aPL positivity (especially LA presence) has been established as an independent risk factor for the presence of APO and thrombotic events in patients with systemic autoimmune diseases and its routine evaluation is recommended during preconception counselling.6 10 40 41 Nevertheless, despite the high rate of aPL positivity in our SLE group, no significant association with APO and no thrombotic events during pregnancy were documented. Interestingly, only two patients with a high-risk aPL profile in the SLE group had thromboembolic events postpartum and received anticoagulant treatment.
In pSS pregnancies, we found a significant association between preconception low C4 levels and the presence of APO. Lower absolute C4 levels were observed in pSS pregnancies with APO than in those without. Furthermore, we identified an association between C4 levels lower than the clinical cut-off and the presence of APO in patients with pSS. To our knowledge, there are no previous studies that assessed preconception APO risk factors in patients with pSS. Interestingly, the complement pathway seems to be related to APO in pSS pregnancies as it was described for patients with SLE and APS.42 43 Cryoglobulins and paraproteins could play a role in complement consumption in patients with SLE and pSS; however, our study did not assess it because they are not part of regular clinical follow-up.44 Regarding clinical factors, even though lower BMI was associated with the presence of APO in pSS pregnancies (p=0.010), most patients had a normal weight (BMI between 18.5 and 24.9 kg/m2). Therefore, we do not consider it a clinically relevant variable.
Approximately 1.7% of neonates from anti-Ro/SSA or anti-La/SSB positive women could develop CHB.45 Despite the high prevalence of these antibodies in our cohort, there were no CHB cases, and the rate of other severe neonatal complications was low. Interestingly, we noticed high rates of hydroxychloroquine (HCQ) use in our patients with pSS, which are known to be helpful in decreasing the risk of neonatal lupus.45 46
HCQ use is recommended preconceptionally and throughout pregnancy in patients with SLE for the prevention of disease flares and improvement of maternal and neonatal outcomes.15 Moreover, low HCQ concentrations during pregnancy were associated with a higher risk of preterm birth in treated patients with SLE.47 We reported high rates of HCQ use in SLE pregnancies; however, it was not associated with a reduction in the presence of APO. Furthermore, although HCQ may improve symptoms of pSS,48 there are no previous studies evaluating the association between HCQ use and the presence of APO in these patients. In our study, we did not find a significant association between preconception HCQ use and the presence of APO in patients with pSS; nonetheless, it must be evaluated in studies with a bigger sample size.
We acknowledge the limitations of our study, the small sample size being the most influential. Furthermore, the retrospective, single-centre design could influence the predictive value of our results. We could not perform a multivariate analysis, which impedes excluding confounding factors and detection of summative effects. Besides, cryoglobulins presence which could influence complement levels in patients with SLE and pSS was not established. Due to our sample size and study design, we encourage performing new analyses, including prospective repeated clinical markers measurements during pregnancy, as it could be helpful to discriminate between groups with and without APO and possibly guide immunomodulatory therapy before and during pregnancy.
Conclusions
In this study, we found a wide variety of APO in patients with SLE and pSS. In SLE pregnancies, no preconception risk factors related to the presence of APO were determined. However, our results suggest that preconception complement levels could be useful to estimate APO risk in patients with pSS. Further research with a multicentre and prospective design should be performed to confirm the relationship between complement levels and the presence of APO and to determine new risk factors in patients with SLE and pSS.
Data availability statement
Data are available on reasonable request. The data that support the findings of this study are displayed in the article and in online supplemental material. Others are available on request from the corresponding author due to ethics regulations.
Ethics statements
Patient consent for publication
Ethics approval
This study was conducted in accordance with the Declaration of Helsinki, the Dutch law on Medical Research in Humans and approved by the Institutional Review Board (or Ethics Committee) of the University Medical Center Groningen. Moreover, informed consent was obtained from all subjects involved in the study.
Acknowledgments
The authors thank A.M. Prosman from the University of Groningen for her contribution to data collection.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors Conceptualisation, JJF, JW and KdL; methodology, JJF and KdL; formal analysis, JJF; investigation, JJF and KdL; resources, JRP, GV, HB and JW; writing—original draft preparation, JJF; writing—review and editing, JRP, GV, HB, JW and KdL; supervision, KdL. KdL is guarantor and accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish. All authors have read and agreed to the published version of the manuscript.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: JJF is a recipient of a doctoral scholarship from Ministerio de Ciencia, Tecnología e Innovación (MinCiencias, Colombia), (906-2021). HB received support from Bristol Myers Squibb, AstraZeneca, Roche, Novartis, Medimmune, argenX and Union Chimique Belge. GV received support from argenX.
Competing interests The authors declare that there is no conflict of interest.
Provenance and peer review Not commissioned; externally peer reviewed.
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