Navigating the Journey to Motherhood in SLE: A Narrative Review on the Complex Interplay of SLE and Pregnancy

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by the deposition of immune complexes and ongoing inflammation across various organ systems, including the skin, joints, kidneys, neuropsychiatric and hematologic systems [1,2]. The prevalence of SLE is higher in women compared to men, with a typical diagnosis occurring during their reproductive years [3]. The relationship between SLE and female reproductive health has been a subject of great concern, looking into the effects on reproductive health and how the disease behaves during pregnancy. While definitive evidence that SLE lowers fertility is lacking, several factors can contribute to subfertility. These include irregular menstrual cycles and ovarian failure, which might be attributed to disease activity or several SLE immunosuppressant therapies. Additional factors such as age-related declines in fertility, psychosocial influences, and the presence of secondary Antiphospholipid Syndrome (APS) can also play a role [4-6]. 

In recent years, growing knowledge has contributed to safer pregnancies in patients with SLE [7]. However, factors such as active disease at conception, lupus nephritis, hypertension, and positive antiphospholipid antibodies can negatively influence pregnancy outcomes, resulting in complications such as spontaneous abortion, stillbirth, preeclampsia, and fetal growth restriction [8]. Consequently, careful planning and management of pregnancy from the periconceptional period is crucial [7]. This narrative review aims to explore the potential impact of SLE on pregnancy and vice versa. Additionally, it will address preconception, antepartum, intrapartum, and postpartum care considerations for women with SLE, aiming to optimize the care provided to this group of patients to minimize the risks of adverse pregnancy outcomes.

A comprehensive narrative review synthesis of the literature was performed. We focused on peer-reviewed articles available in English, primarily using databases including PubMed, Google Scholar, Scopus, and ResearchGate. Relevant studies about women with SLE during their reproductive years. We paid particular attention to the necessary care for this group of patients, including preconception counseling, care throughout pregnancy, and management after delivery.

Pregnancy in women with Systemic Lupus Erythematosus (SLE) carries a 23.3% risk of disease flare, primarily due to hormonal changes [9,10]. The maternal immune system adapts to tolerate paternal antigens on fetal cells [11], with steroid hormones playing a crucial immunomodulatory role. The complex interplay between endocrine and immune mechanisms underscores pregnancy as a high-risk condition for SLE patients. Hormonal fluctuations during pregnancy influence SLE activity, given the altered levels of estrogen, androgens, prolactin, and adrenal hormones in SLE patients compared to non-SLE individuals [12-14]. 

Estrogen, which increases throughout pregnancy and peaks in the third trimester, exhibits dose-dependent immunomodulation. At lower levels, it stimulates both Th1 and Th2 responses, whereas at higher levels, it shifts immunity toward a Th2-dominant profile, potentially exacerbating SLE flares [12,15,16]. This hormonal regulation affects cytokine balance, impacting disease severity. Other hormones, including progesterone, cortisol, Dehydroepiandrosterone Sulfate (DHEA), and testosterone, also contribute to immune modulation. Progesterone promotes Th2 polarization, whereas testosterone has protective effects, correlating inversely with disease severity [12,14]. 

Estrogen Receptors (ERα and ERβ), expressed on immune cells, differentially regulate SLE. ERα activation has immune-stimulatory effects, contributing to autoantibody production and proteinuria, whereas ERβ exerts immunosuppressive effects [13,17].

• Preconception counseling 

Preconception assessment for women with SLE is vital for improving pregnancy outcomes. This counselling should emphasize the importance of controlling disease activity for at least six months before conception and assessing end-organ involvement and damage as they might have a negative impact on pregnancy and maternal and fetal outcomes [18-21]. Evaluating the compatibility of anti-rheumatic medications with pregnancy is crucial, as some of these medications could potentially be teratogenic, and their safety during pregnancy may not be fully known [22,23]. 

Testing for anti-Ro, anti-La antibodies, and antiphospholipid antibody (APLA) status is crucial due to their potential impact on pregnancy outcomes [8,18,23]. Additionally, discussing the safest contraception options for those advised to delay or avoid pregnancy due to disease activity, complications, or medication incompatibility is essential [7,23]. 

• Contraception 

For women with SLE, several contraindications to pregnancy exist. Relative contraindications include active disease in the six months prior to conception, including active lupus nephritis, being on teratogenic therapy, and a history of stroke or major thrombotic events in the past six months. On the other hand, absolute contraindications encompass severe pulmonary hypertension, severe restrictive lung disease, severe renal insufficiency (eGFR < 30 mL/min/1.73 m²), advanced heart failure, and a history of pre-eclampsia or HELLP syndrome despite appropriate treatment [7,24]. 

In these circumstances, it's essential to discuss contraception options with the SLE patient to ensure the selection of a safe method. In 2020, the American College of Rheumatology (ACR) issued guidelines for selecting safe contraception for women with SLE. For those with a positive antiphospholipid (aPL) test, Intrauterine Devices (IUDs) or progestin-only pills are preferred, while combined estrogen-based contraceptives should be avoided. For women with a negative aPL test and SLE with low disease activity, similar contraceptive options are recommended, with estrogen patches to be avoided. In cases of negative aPL test and SLE with moderate to high disease activity, the preference is for IUDs or progestin implants, avoiding estrogen patches and combined methods unless necessary. Additionally, if taking mycophenolate medications, patients should use an IUD or combine two other forms of contraception because Mycophenolate Mofetil (MMF) may reduce the efficacy of oral contraceptives [23].

Monitoring during pregnancy 

The prognosis of pregnancy in SLE is variable, as it depends on organ involvement and the overall disease activity. Ideally, as highlighted earlier, patients should be in clinical remission for at least 6 months at conception and have no evidence of active renal disease. This reduces the risk of adverse pregnancy outcomes [8,11]. Patients should be seen regularly, at least once a trimester, to assess lupus disease activity and evaluate for potential complications. Laboratory assessment should include a Complete Blood Cell count (CBC) with differentials, creatinine clearance, anti-double-stranded DNA (anti-dsDNA), complement levels (C3 and C4), Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), urinalysis with microscopy, and a Urine Protein-to-Creatinine Ratio (UPCR) [25-27]. Assessing disease activity during pregnancy may be challenging, as the physiological changes in pregnancy may mimic SLE flares [28]. Common pregnancy-related changes that can overlap with SLE manifestations include facial rashes and mild arthralgia [7], as well as hematological changes such as hemodilution, leading to mild anemia and mild thrombocytopenia, and an elevation in inflammatory markers like ESR. Pregnancy also causes an increase in Glomerular Filtration Rate (GFR) and renal filtration, leading to increased urinary protein excretion, and gestational proteinuria is considered normal until it exceeds 300 mg/24 h [29]. 

During active SLE, complement levels are usually consumed, while pregnancy is associated with increased complement levels, especially C3, stimulated by estrogen. Nonetheless, monitoring C3 and C4 during pregnancy is essential, as failure to increase can indicate SLE flare and has also been associated with adverse pregnancy outcomes [12,30]. 

SLE and renal monitoring during pregnancy 

Routine assessments for SLE pregnant women are required, including regular blood pressure monitoring and serum creatinine every 4-6 weeks, as well as urinalysis and urinary protein quantification every 2-4 weeks [24,31]. 

• Lupus Nephritis (LN) during pregnancy 

Pregnancy in the context of Lupus Nephritis (LN) is considered high risk, necessitating careful planning and management. Renal involvement at conception is associated with an increased risk of maternal flares and adverse pregnancy outcomes, including preterm birth, pregnancy loss and hypertensive disorders such as pre-eclampsia [32-35]. For example, a retrospective study conducted by Attia et al., indicated that renal flares occurred in over 50% of pregnancies with pre-existing LN, showing the need for vigilant monitoring and management [36,37]. However, overall pregnancy outcomes may not significantly differ between LN and non-LN pregnancies with appropriate care [32]. On the other hand, long-term renal outcomes following pregnancy-related flares can be poor, with chronic kidney disease developing in 21.4% of cases [37]. Achieving remission before pregnancy and promptly reducing proteinuria during flares are crucial for optimal outcomes [37]. 

• Distinguishing proteinuria from preeclampsia 

Proteinuria, a hallmark of both Lupus Nephritis (LN) and preeclampsia, presents diagnostic challenges during pregnancy, especially since the management strategies for these conditions differ (Table 1) [7,38-43]. Studies suggest a higher prevalence of preeclampsia in women with LN, although findings vary due to differences in study design and populations [11,44,45]. This highlights the importance of a multidisciplinary approach including nephrologists, obstetricians, and other specialists to guide therapy for these conditions [38-40].

Table 1: Differentiating lupus nephritis from preeclampsia.

• Risk of de novo LN in pregnancy and biopsy considerations 

Pregnancy can also trigger de novo LN, particularly in women with undiagnosed SLE [40]. Kidney biopsy is a valuable diagnostic tool for pregnant lupus patients who experience a sudden decrease in Glomerular Filtration Rate (GFR) or present with active urinary sediment and proteinuria exceeding 500 mg per day, especially when less invasive diagnostic tests fail to clarify the disease etiology. This is crucial, as it can be challenging to clinically differentiate between active lupus nephritis, chronic kidney disease, and preeclampsia [46-48]. Some studies suggest that performing a kidney biopsy during pregnancy is generally safe when indicated [39,49]. However, it is recommended that biopsies should not be carried out beyond 28 weeks of gestation to minimize procedural risks, such as perinephric hematomas, placental abruption, and preterm labor [47].

SLE medications use during pregnancy 

Low-dose corticosteroids are generally safe, when indicated, and effective for maintaining disease control during pregnancy, though high doses may increase maternal and fetal risks, necessitating careful dose management [7,23,50]. Hydroxychloroquine (HCQ) remains a cornerstone of SLE treatment, offering multiple benefits such as reducing the risk of disease flares, thrombosis, and neonatal lupus while also lowering the chances of recurrent miscarriage, preeclampsia, pregnancy-related hypertension, intrauterine growth restriction, and prematurity. Additionally, HCQ may improve insulin sensitivity, suggesting a potential anti-diabetic effect. Patients should be counseled on its safety and benefits during pregnancy [21-23,51]. 

Among immunosuppressive agents, azathioprine and calcineurin inhibitors (tacrolimus, cyclosporine) can be used safely during pregnancy with appropriate monitoring, particularly for those on calcineurin inhibitors for blood pressure [21-23,52]. In contrast, several medications are contraindicated. Methotrexate (MTX) and thalidomide should be discontinued 1-3 months before conception due to teratogenic effects, while Leflunomide (LEF) requires a cholestyramine washout until levels are undetectable. Mycophenolate Mofetil (MMF) and mycophenolic acid should be stopped at least six weeks before conception, and cyclophosphamide should ideally be discontinued three months prior, though it may be conditionally used in severe cases during the second or third trimester [22,23]. 

Regarding biologic therapies, rituximab (RTX) is generally discontinued at conception but may be used later in pregnancy for severe disease [22,23]. Belimumab is also recommended to be stopped at conception due to limited safety data, though emerging evidence suggests its continuation may help maintain disease control and improve pregnancy outcomes without significantly increasing congenital risks. However, individualized decision-making is essential, and larger studies are needed for conclusive recommendations [53-55]. There is insufficient data on the safety of anifrolumab during pregnancy [56], while voclosporin should be avoided due to its alcohol content and a lack of data on pregnancy-related risks [57]. Intravenous Immunoglobulin (IVIG), however, is considered safe throughout pregnancy when indicated [21,50].

Other medications to be used during SLE pregnancy

• Aspirin 

Women with SLE have a 9-23% increased risk of preeclampsia during pregnancy compared to healthy women, regardless of their antiphospholipid antibodies or the presence of secondary antiphospholipid syndrome [58]. Therefore, aspirin is indicated for SLE during pregnancy to help reduce this risk. The dosage of aspirin to decrease the risk of preeclampsia has been established by many international societies (Table 2) [23,59].

Table 2: Summary of the international recommendations for the use of aspirin to decrease the risk of preeclampsia.

ACR, American College of Rheumatology; ACOG, American College of Obstetricians and Gynecologists; WHO, World Health Organization; NICE, National Institute of Health and Care Excellence; RCOG, Royal College of Obstetricians.

• Special considerations while following SLE during pregnancy
• Assessing anti-Ro and anti-La antibodies

  The presence of maternal anti-Ro/SSA or anti-La/SSB antibodies poses additional risks during pregnancy, as these autoantibodies can cross the maternal-fetal barrier. Approximately 1-2% of pregnancies in women with these antibodies are affected by Congenital Heart Block (CHB), while up to 5% of offspring may develop neonatal lupus syndrome [60-62]. Neonatal lupus manifestations include cardiac complications such as CHB, cutaneous lupus, hepatobiliary dysfunction, and hematological abnormalities [63]. The risk of CHB increases significantly in subsequent pregnancies for mothers with a history of bearing a child affected by complete CHB. In such cases, the likelihood of CHB rises from 2% to 18% [64]. To mitigate these risks, screening with fetal echocardiography between 16 and 26 weeks of gestation is crucial, alongside adherence to hydroxychloroquine, which has been shown to reduce the risk of CHB [23]. Such careful preparation reduces the likelihood of complications and optimizes fetal outcomes.

• Assessing anti-phospholipid (aPL) antibodies

  Assessing anti-phospholipid (aPL) antibodies is crucial, as they are present in 20-35% of women with SLE of childbearing age [65,66]. Women with SLE and secondary Antiphospholipid Syndrome (APS) have an increased risk of complications, including recurrent miscarriages, gestational hypertensive disorders such as preeclampsia and HELLP syndrome, venous and arterial thrombosis, and pregnancy loss. Fetal complications associated with aPL antibodies include preterm birth, fetal growth restriction, stillbirth, neonatal lupus, and neonatal death [61]. aPL antibodies significantly impact fertility and pregnancy outcomes. The ACR 2020 guidelines recommend specific strategies to optimize pregnancy outcomes based on a patient’s aPL status. For those with positive aPL antibodies but without APS, low-dose aspirin is advised. In obstetric APS cases, adding prophylactic heparin alongside aspirin is recommended to mitigate pregnancy risks. For thrombotic APS, a combination of therapeutic heparin and aspirin is suggested to manage the heightened risk of thrombosis [23].

• Delivery plan considerations 

  Delivery for pregnant women with SLE is generally scheduled between 39 and 40 weeks of gestation, although earlier delivery may be indicated in cases of Fetal Growth Restriction (FGR) or other comorbidities [67]. Ideally, women with lupus who have uncomplicated pregnancies can opt for a standard vaginal delivery. While the indications for cesarean section (C-section) in lupus pregnancies are similar to those in the general population, the increased risk of complications, such as preeclampsia and fetal distress, results in C-sections being performed in about 33% of these cases [7]. 

  In general, a key component to improving pregnancy outcomes for patients with SLE is the collaborative care provided by a multidisciplinary team. This team typically includes rheumatologists, obstetricians/gynecologists, maternal-fetal medicine specialists, and other healthcare providers involved in managing SLE manifestations. By working together, these professionals can ensure comprehensive monitoring and management, addressing the unique challenges that SLE patients face during pregnancy and ultimately enhancing maternal and fetal health [68].

• SLE flare prevention and early detection 

Patients with SLE require close monitoring in the postpartum period, typically in the six months postpartum, by both the obstetrician and the rheumatologist to ensure their disease is stable, especially since the flares in women with SLE during the postpartum period range between 35-70% [69,70]. Fortunately, most postpartum flares comprise serologic or cutaneous manifestations that are mild and do not usually require the escalation of immunosuppressive therapy. Each visit should include a thorough clinical evaluation and labs, including CBC, a metabolic profile, liver function tests, kidney function, urinalysis, and UPCR in addition to disease activity markers, i.e. ESR, CRP, anti dsDNA and C3 and C4 levels. 

• Breastfeeding and antirheumatic medications 

Breastfeeding offers numerous benefits for the mother and the infant. The American Academy of Pediatrics (AAP) and the World Health Organization (WHO) recommend exclusive breastfeeding for approximately 6 months after birth [71,72]. Therefore, it is essential to address and encourage breastfeeding for women. One study found that women with SLE had similar breastfeeding initiation rates compared to the general population; however, they experienced a higher prevalence of early discontinuation in the first three months. Factors contributing to early interruption include smoking, elevated body mass index, and joint involvement. The use of hydroxychloroquine and a longer disease duration (with a median of six years) were associated with a longer breastfeeding duration [73]. Moreover, other reports showed that mothers with SLE had lower rates of breastfeeding and a shorter duration in comparison with non-SLE mothers [74,75]. Hanssen et al., found that the majority of mothers with SLE (78%) breastfed six weeks postpartum. However, rates dropped to 54% and 30% at 6 and 12 months postpartum, respectively [76]. Therefore, following up with women regarding breastfeeding is essential. 

Some patients discontinue their medications for fear of a possible negative impact of their anti-rheumatic medication on their babies; therefore, it is essential to address drug compatibility and breastfeeding during the postpartum period (Table 3). 

Drugs used during pregnancy are usually compatible with breastfeeding. Prednisolone is compatible with lactation, and whenever possible, the dose should be < 20 mg a day [23]. If the dosage is above 20 mg a day is indicated, it is recommended that women delay breastfeeding for 4 hours following prednisolone administration [23]. HCQ, azathioprine, tacrolimus, cyclosporine, RTX, and IVIG are considered compatible with lactation [22,23]. In contrast, MTX, LEF, MMF, mycophenolic acid, thalidomide, and cyclophosphamide are not recommended for use during breastfeeding [22,23]. There is insufficient data regarding the safety of belimumab, anifrolumab, and voclosporin while breastfeeding [22,23,57].

Table 3: Compatibility of SLE anti-rheumatic medications with pregnancy and breastfeeding.

• Postpartum psychological impact 

Perinatal mental illnesses include anxiety, depression, and psychotic disorders. Antenatal and postpartum depression affects up to 20 percent of women [77-79]. One study found that the prevalence of postpartum depression is estimated at around 10 percent [78]; therefore, addressing and discussing these possible conditions during the postpartum period is essential. Moreover, previous reports found an association between patients with autoimmune diseases, including SLE and perinatal depression [80]. Another study found that 27 percent of patients with SLE developed postpartum depression [81]. In conclusion, it seems that SLE may increase the risk of developing postpartum mental illness, which means that providing psychological support to these patients is crucial during this period. 

• Infant vaccination 

The American College of Rheumatology (ACR) conditionally recommends that live vaccinations, including the rotavirus vaccine, be postponed for over 6 months in neonates or infants who have been exposed to rituximab during the second and/or third trimester of pregnancy. In contrast, there is no requirement to delay non-live vaccinations, and no other FDA-approved SLE biologics are mentioned in their recommendations [82].

Pregnancy with SLE can be challenging. However, with careful planning, many women can experience successful pregnancies. This review highlights the importance of personalized preconception counseling, which allows healthcare providers to understand the patient’s specific needs and assess their disease activity and medication options effectively. Regular monitoring during pregnancy is key to identifying and managing potential complications early. It’s also important to focus on postpartum care, as mothers with SLE may be at a higher risk for emotional struggles and flare-ups. By creating a caring and collaborative environment, healthcare professionals can help women with SLE navigate their pregnancy journeys with confidence. With ongoing research and a commitment to patient education, we can continue improving outcomes and fostering healthier futures for both mothers and their children.

Authors declare no conflict of interest.

None.

All authors contributed equally to the literature review and the preparation of this manuscript.

Ethical approval was not required, as this is a narrative review article.

The authors declared no potential conflicts of interest with respect to the narrative review, authorship, and/or publication of this article.

The authors received no financial support for the narrative review, authorship, and/or publication of this article.

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