Relationship of lupus nephritis and pregnancy: A narrative review

Abstract

Pregnancy in women with lupus, particularly those with lupus nephritis (LN), carries an increased risk of adverse outcomes. Women with active LN at the time of conception are at a high risk of poor maternal and fetal outcomes. Recent studies indicate that even in the presence of quiescent disease, factors such as hypertension and positive lupus anticoagulant are predictors of worse pregnancy outcomes. Consequently, pre-conception evaluation is essential to ensure that pursuing pregnancy is safe and timely, and to facilitate proper planning for optimizing medical regimens, discontinuing teratogenic agents, and treating active disease. Additionally, pre-existing LN is associated with higher rates of preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Women with lupus and prior LN can have successful pregnancies, but a multidisciplinary approach with close monitoring is essential for optimal outcomes. By systematically reviewing the available evidence, this narrative review aims to provide a comprehensive update on the complex interaction between LN and pregnancy, offering insights to guide clinical practice and future research in this field.

Key Words: Lupus nephritis; Pregnancy; Systemic lupus erythematosus; Fetal development; Maternal complications

Core Tip: Pregnancy in women with lupus, particularly lupus nephritis (LN), carries an increased risk of adverse outcomes. Women with active LN at conception are at a high risk of poor maternal and fetal outcomes. Pre-conception evaluation is essential to ensure proper planning for optimizing medical regimens, discontinuing teratogenic agents, and treating active disease. Women with prior LN can have successful pregnancies, but a multidisciplinary approach with close monitoring is essential. This narrative review aims to provide a comprehensive update on the complex interaction between LN and pregnancy, offering insights to guide clinical practice and future research in this field.

INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune multisystem connective tissue disorder primarily affecting women of childbearing age. Approximately 60% of patients with SLE develop lupus nephritis (LN)[1,2]. It is well-established that SLE adversely affects pregnancy, posing higher maternal and fetal risks compared to pregnancies in healthy women[3,4]. Other autoimmune conditions can also adversely affect pregnancy[5-7]. Women with lupus are at a higher risk of experiencing complications such as pregnancy loss, preeclampsia, preterm delivery, and fetal growth restriction. The risk of preterm delivery is notably higher, often due to the need to manage severe maternal complications like preeclampsia or eclampsia, which can endanger both the mother and the fetus. Conversely, lupus can also exacerbate during pregnancy, leading to flares that can affect both maternal and fetal health. These flares can manifest as exacerbations of symptoms such as joint pain, rashes, and fatigue, potentially leading to more severe complications like organ involvement. The hormonal changes and immune system modulation during pregnancy can trigger these flares, making close monitoring and management essential. Progressive renal disease and maternal thromboembolism are also significant concerns for pregnant women with lupus. Notably, lupus increases the risk of maternal thromboembolism, including deep vein thrombosis and pulmonary embolism, due to hypercoagulable states often seen in lupus patients. Antiphospholipid syndrome (APS), often associated with lupus, further elevates this risk, necessitating anticoagulation therapy and vigilant monitoring to ensure the safety of both mother and child. Autoantibodies present in lupus patients, such as anti-Ro/SSA and anti-La/SSB, can cross the placenta and lead to neonatal lupus (NL), which may cause congenital heart block (CHB) and other neonatal issues. Women with LN often grapple with intense emotional stress and challenging decisions about family planning. The fear of disease flares, potential complications such as preeclampsia, and the need to balance treatment safety with fetal health can be overwhelming.

Highlighting their journeys not only adds a human touch to medical care but also underscores the importance of a supportive, holistic approach to their treatment and well-being.

Hence, pregnant women with lupus must work closely with a multidisciplinary team, including rheumatologists and obstetricians specializing in high-risk pregnancies, to ensure optimal outcomes[8]. LN in pregnancy requires careful management to prevent severe kidney damage and associated complications like hypertension and proteinuria, which can adversely affect both maternal and fetal health. The relationship between lupus and pregnancy outcomes is complex (Table 1). There is insufficient evidence in the literature regarding the specific effects of LN on pregnancy and vice versa[8,9].

Table 1 The relationship between lupus nephritis and pregnancy.

Risk of lupus to pregnancy	Risk of pregnancy to lupus
Pregnancy loss	Lupus flares
Pre-term delivery	Progressive renal disease
Eclampsia	Maternal thromboembolism
Neonatal lupus due to Ro and La antibodies

Over recent decades, the long-term prognosis of LN has improved due to more effective therapeutic strategies and enhanced patient surveillance[10]. Whether these advancements have led to more favorable pregnancy outcomes and reduced risks for mothers is not well-established, especially in developing countries where data is sparse. Evidence from two systematic reviews and meta-analyses indicates that active LN is associated with poor pregnancy outcomes for both mothers and their children[11,12]. A recent study by Elahi et al[13] from Pakistan also demonstrated adverse maternal and fetal outcomes in patients with pre-existing active LN.

This review addresses the importance of pre-pregnancy evaluation in patients with pre-existing LN and suggests an approach for management during conception, pregnancy, and the postpartum period.

LITERATURE SEARCH

A comprehensive literature search was conducted using electronic databases, including PubMed, MEDLINE, Scopus, and Web of Science. The search covered articles published from January 2000 to June 2024 to ensure the inclusion of recent studies. The following keywords and MeSH terms were used to identify relevant studies: " LN", " SLE", "pregnancy", "pregnancy outcomes", "perinatal outcomes", "renal functions", "hypertension", "spontaneous abortion", "preeclampsia", "intrauterine growth retardation (IUGR)", and "stillbirth". Boolean operators (AND, OR) were employed to refine the search results. Additionally, reference lists of selected articles were manually screened to identify any additional pertinent studies.

MANAGEMENT OF LN IN PREGNANCY

Effective management of LN during pregnancy involves pre-conception counseling, careful planning, and the use of medications that are safe for both the mother and the developing fetus. Disease activity should ideally be well-controlled for at least six months before conception. Medications like hydroxychloroquine (HCQ) are commonly used as they are considered safe during pregnancy and help in maintaining disease control. Close monitoring through regular check-ups and ultrasound examinations is essential to detect any early signs of complications, including preeclampsia and fetal growth issues. Despite the increased risk of pregnancy loss and other complications, with proper medical care and vigilant monitoring, many women with LN can have successful pregnancies and deliver healthy babies.

Pre-conception planning

Women with LN are strongly encouraged to undergo comprehensive pre-pregnancy planning to ensure disease remission and a safe and successful pregnancy[14].

Pre-pregnancy evaluation

Pre-pregnancy evaluation requires a multidisciplinary approach through shared decision-making. Renal involvement, either as active LN at the time of conception or a new onset or flare of LN during pregnancy, is associated with worse maternal and fetal outcomes[15]. Patients with LN can be stratified into three groups.

LN with severe impairment of organ function and/or pre-existing severe organ damage

Pregnancy should be discouraged due to the risks for disease progression that could lead to end-stage kidney disease and pregnancy-related adverse outcomes[16]. This is confirmed by findings published by Andrade et al[17], showing that pregnancy outcomes depend on the summation of contributing factors rather than a single element, including pre-existing maternal comorbidities and disease activity at conception and during pregnancy. Tedeschi et al[18] also showed that the organ system active in the disease process six months before conception predicted the organ system involved in a pregnancy disease flare.

Active LN

Pursuing pregnancy with active disease is strongly correlated with adverse outcomes. Several studies have shown that active disease at conception correlates with disease flares during pregnancy[18,19]. Conversely, Buyon et al[20] in their prospective study, PROMISSE, reported that less than 10% of patients with mild to moderate disease during the first trimester had mild flares, and only 3% had severe flares. Therefore, all patients are advised to wait at least six months after LN is inactive before considering pregnancy to minimize adverse outcomes.

Quiescent or inactive LN for at least six months

These patients are allowed to conceive[16].

RISK STRATIFICATION

Despite inactive disease for at least six months, women with prior obstetric-related complications should be evaluated by both a gynecologist and a nephrologist. Pregnancy may cause LN flares with progressive kidney disease. A recent systematic review and meta-analysis of 16 studies comprising 1760 pregnancies evaluated outcomes in patients with LN over the last two decades. Major obstetrical outcomes observed included gestational hypertension, pre-eclampsia, SLE flare, LN flare, and proteinuria. In terms of fetal outcomes, pregnant patients with LN showed a significant decrease in live births and a significant increase in preterm births and IUGR[12]. An assessment using clinical, laboratory, and histological parameters (e.g., kidney biopsy) is made before conception. All patients are strongly recommended to screen for APS antibodies[21] and antibodies to Ro/La before pregnancy, as these antibodies may predispose to NL[22]. Disease activity should be continuously monitored throughout pregnancy. Recommendations adapted from the Italian Study Group on Kidney Disease and Pregnancy suggest regular blood tests, including full blood count, kidney function, and electrolytes every 6-8 weeks, while urinalysis and urine protein quantification should be monitored every 2-4 weeks based on the level of proteinuria (Table 2)[23].

Table 2 Lupus nephritis in pregnancy: Evaluation and monitoring.

Before pregnancy	Every 6-8 weeks (adjustable)1
Complete metabolic panel	Complete metabolic panel
Prothrombin time/partial thromboplastin time
24-h urinary protein and creatinine clearance2
sPCR	sPCR
Anti-dsDNA	Anti-dsDNA
Anti-Ro/SS-A and anti-La/SS-B antibodies
Lupus anticoagulant3
Anticardiolipin IgG, IgM, IgA3
Anti-β2 glycoprotein I IgG, IgM, IgA3
Complement levels (C3, C4)	Complement levels (C3, C4)
Uric acid	Uric acid
Urine detailed report with microscopy	Urine detailed report with microscopy

¹Adjust monitoring intervals based on the clinical situation.

²For patients with proteinuria, consider repeating the 24-hour urine test each trimester.

³If the test is positive for the first time, repeat it after 12 weeks.

Anti-dsDNA: anti-double stranded DNA; sPCR: Spot protein/creatinine ratio.

Fertility and assisted reproductive techniques

Fertility in patients with SLE does not appear to be altered by the disease itself; however, a decrease in ovarian reserve can occur in women exposed to cyclophosphamide (CYC)[24]. With the availability of mycophenolate mofetil (MMF), CYC is less commonly used for LN than in the past. The risk of premature ovarian failure has been reduced with the concurrent use of gonadotropin-releasing hormone (GnRH) analog therapy, mostly leuprolide[25]. Patients stable enough to safely undergo ovarian hyperstimulation can consider embryo and oocyte cryopreservation to preserve fertility. They may undergo assisted reproduction techniques, including in vitro fertilization (IVF), with a rare complication being ovarian hyperstimulation syndrome. The risk of flare and thrombosis increases with elevated estrogen levels[26]. IVF-induced flares generally have good outcomes. Data do not support antiphospholipid (aPL) antibodies as a cause of failed IVF or infertility, and anticoagulation is not indicated for this condition[27].

Contraception

Contraception methods should be advised to those with active disease or receiving teratogenic medications to prevent unplanned pregnancies. Options include intrauterine devices and progestin-only contraception in the form of pills, intramuscular depot injections, or subdermal implants[21]. The choice depends on the patient’s preference and thrombotic risk profile. Barrier methods, pericoital methods, and withdrawal are generally avoided due to high failure rates[21].

Medications before conception

Medications must be reviewed and adjusted before conception to maintain disease control with medications that have the best safety profile during pregnancy. Although some medications used to treat LN are potentially harmful or contraindicated during pregnancy, many are safe. Unfortunately, concerns over presumed toxicity often lead to discontinuation of necessary therapy, resulting in increased disease activity and worsening outcomes. The aim is to maintain patients in remission. Just before or after conception is not the right time to wean women off maintenance medications such as low-dose prednisolone and azathioprine. If patients are on low-dose aspirin, they should remain on it, and if not, they should plan to start it once pregnant to reduce the risk for preeclampsia. HCQ reduces the incidence of flares, infections, and thrombosis and is associated with better long-term renal survival[28-30].

Current therapeutic options for LN during pregnancy and lactation are given in Table 3.

Table 3 Medication compatibility with pregnancy and lactation.

Medications	Before conception	During pregnancy	Lactation
Stop at conception
Abatacept	Stop with the positive pregnancy test		+
Belimumab	Stop with the positive pregnancy test		+
Rituximab	Stop with the positive pregnancy test		+
Compatible drugs
Hydroxychloroquine	+	+	+
Azathioprine	+	+	+
Cyclosporine	+	+	+
Tacrolimus	+	+	+
Sulfasalazine	+	+	+
Prednisone	Dose < 20 mg/day	Dose < 20 mg/day	Dose < 20 mg/day
NSAIDs	Discontinue w/difficulty conceiving	Stop at week 20	+
Non-compatible drugs
Cyclophosphamide	Stop 3 months before conception	x	x
MMF/mycophenolic acid	Stop 6 weeks before conception	x	x
Methotrexate	Stop 1-3 months before conception	x	x low transfer into breast milk

NSAIDs: Non-steroidal anti-inflammatory drugs; MMF: Mycophenolate mofetil.

HCQ

This medication is generally considered safe and is recommended to be continued throughout pregnancy and breastfeeding, as it helps control lupus activity without posing significant risks to the fetus.

Azathioprine

This immunosuppressant is also compatible with pregnancy and lactation in usual doses. It can be used prior to and throughout pregnancy to manage LN but doses should not exceed 2 mg/kg/day.

Calcineurin inhibitors

Medications like tacrolimus and cyclosporine are generally compatible with pregnancy and lactation. They are used to manage LN and maintain disease control.

Low-dose corticosteroids

Prednisone, when used at the lowest effective dose, can be safe during pregnancy. It helps manage inflammation and lupus flares while minimizing potential side effects.

Low-dose aspirin

Low-dose aspirin (75-100 mg/day) is often recommended during pregnancy in women with LN, particularly those at risk of preeclampsia. Aspirin can help reduce the risk of placental insufficiency and improve overall pregnancy outcomes. It is generally initiated early in the second trimester. Low-dose aspirin is considered safe during breastfeeding, though high doses should be avoided due to the potential risk of Reye’s syndrome in infants.

Avoiding teratogenic medications

It is crucial to discontinue medications known to be teratogenic, such as methotrexate, MMF, and CYC, before conception and during pregnancy.

Antihypertensive medications

The most commonly used antihypertensives in pregnancy are methyldopa, labetalol, nifedipine, and hydralazine. Conversely, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are contraindicated during pregnancy due to associated fetal risks. Diuretics can be used with caution. Nitroprusside is considered the last resort for urgent management of refractory severe hypertension and should be used only for a short duration in emergencies.

Selective use with caution during pregnancy for biologic medications

The data on the use of biologic medications, like the B cell depleting antibody, rituximab, or the B-cell-activating factor (BAFF) inhibitor, belimumab, during pregnancy, is limited. Because IgG does not cross the placenta significantly until around week 15 of gestation, we continue these medications through conception (i.e., the first missed menstrual period in a woman with regular cycles). It is recommended to wait one year after rituximab before conception or use rituximab only when no other options are available to control the disease effectively, preferably not after the first trimester[31].

PREGNANCY COMPLICATIONS

Disease flare during pregnancy

In the past, patients with LN were routinely counseled against becoming pregnant due to the increased risk of flares. Modern management strategies suggest that the majority of women with LN can anticipate a successful pregnancy[20], although the flare rate varies. Active disease pre-conception increases flare risk to 60%, while quiescent disease pre-conception reduces flare risk to as low as 10%[11,22,29,32,33]. Differentiating between disease flare and pregnancy-related changes is challenging. Factors increasing flare risk during pregnancy include active disease during the six months before conception, number of flares before conception, discontinuation of HCQ or other medication, primigravidas compared to subsequent pregnancies, low C4 levels, and previous disease involvement patterns[29,34,35].

Pre-eclampsia during pregnancy

20% of lupus pregnancies are complicated by pre-eclampsia[19,36,37]. Differentiation between pre-eclampsia and LN flares remains a challenge. Certain features can help distinguish between the two conditions (Table 4)[38,39]. This discrimination is vital as the therapeutic approaches differ drastically. Immediate delivery treats pre-eclampsia, while lupus flare requires immunosuppression.

Table 4 Features important in differentiating lupus nephritis from pre-eclampsia.

Features	Lupus nephritis	Pre-eclampsia
Timing	Any time during pregnancy	After 20 weeks of gestation
Hypertension	Can be present or absent	Always present
Other organ involvement	Present (e.g., skin, joints)	Absent
Complement levels (C3, C4)	Decreased or normal	Normal
Anti-dsDNA	Positive	Negative
Lupus serology	Active disease markers present	Usually absent
Active urinary sediment Urinary calcium Response to steroids	Present	Absent
	> 195 mg/d	< 195 mg/d
	Generally responsive	No response
Platelet count	Usually normal or mildly low	Often low (thrombocytopenia)
Liver enzymes	Usually normal	Elevated (HELLP syndrome)

HELLP: Hemolysis, elevated liver enzymes, and low platelets.

Role and timing of kidney biopsy during pregnancy

Kidney biopsy plays a critical role in the management of LN during pregnancy by providing diagnostic, therapeutic, and prognostic information. The timing of the biopsy should be carefully considered with a focus on balancing the risks and benefits for both the mother and the fetus. A kidney biopsy should be performed when there is progressive kidney function impairment and/or severe proteinuria[40]. It is usually performed before 25 weeks gestation to reduce bleeding risk[41].

Complications associated with antiphospholipid antibody

aPL antibodies during pregnancy are a major risk factor for pregnancy loss and other adverse outcomes. The clinical criteria for APS include pregnancy loss, unexplained venous or arterial thrombotic events, and persistent medium-to-high titre aPL on at least two tests 12 weeks apart[42,43]. Maternal complications include pre-eclampsia, placental insufficiency, IUGR, preterm delivery, and hemolysis, elevated liver enzymes, and low platelet syndrome. The PROMISSE study found lupus anticoagulant to be more specific in predicting adverse outcomes[20]. Pregnancy outcomes in aPL-exposed patients have improved, with live birth rates over 80%[44].

FETAL AND NEONATAL COMPLICATIONS

LN directly impacts fetal and neonatal outcomes, increasing risks of preeclampsia, preterm birth, fetal loss, IUGR, and NL syndromes (NLS). Active disease exacerbates these risks. Maternal autoantibodies like aPL and anti-Ro/SS-A and anti-La/SS-B further increase risks[29,45].

NLS

NLS is a form of passively acquired fetal autoimmunity from maternal antibodies anti-Ro and anti-La[46]. These antibodies confer a risk for CHB and other complications. Fetal echocardiography is recommended for at-risk pregnancies. CHB leads to high fetal mortality; most survivors require pacemakers[47,48].

Neonatal antiphospholipid antibody complications

Patients without a history of thrombotic manifestations in previous pregnancies may have more favorable neonatal outcomes. Prematurity and IUGR are common aPL-related complications[49]. Predictors for poor neonatal outcomes are similar to those for adverse pregnancy outcomes. Transplacental passage of anticardiolipin antibodies rarely causes thrombosis in the fetus or neonate[50].

MEDICATION MANAGEMENT

The selection and effect of different therapeutic strategies on pregnancy and fertility are major concerns in real-life practice. This involves careful consideration of the risk-to-benefit ratio of various approaches in various settings (Table 3).

Treatment of a LN flare

Immediate therapy is essential. In early pregnancy, severe flares may lead to a discussion about therapeutic abortion. In later pregnancy, treatment must be balanced with pregnancy continuation. First-line therapy includes high-dose methylprednisolone (MP) pulses followed by oral prednisolone[21]. Adding or increasing azathioprine and using tacrolimus may be necessary[51]. MMF or CYC can be used in later pregnancy if needed. Rituximab is not recommended during pregnancy due to fetal exposure. Safe breastfeeding drugs include AZA, HCQ, cyclosporine, and tacrolimus (Table 3).

Treatment of aPL/APS

The management strategies differ, based on the risk profile of each pregnancy[52]. The presence of persistent aPL antibodies without a history of obstetric complications or thrombosis does not warrant treatment, as no data support the treatment of this group. However, for women with high-risk aPL profiles or the presence of additional risk factors such as concomitant LN, hypertension, or renal insufficiency, low-dose aspirin is often used empirically[53,54]. Combining low-dose aspirin with low-dose heparin, either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH), remains standard prophylactic therapy for obstetric APS (OB-APS)[55]. Meta-analyses of treatment trials confirm the benefit of combination therapy; however, controversy continues regarding efficacy. One combined analysis of 334 primary APS patients calculated success rates of 75% with combination therapy vs 56% with low-dose aspirin alone[56]. Another meta-analysis found that aspirin plus heparin was effective for recurrent early but not late losses and that UFH but not LMWH improved outcome[57]. LMWH must be transitioned to UFH before delivery. Patients with prior systemic thrombosis should receive full therapeutic doses of heparin throughout pregnancy with a change from warfarin either preconception or before six weeks gestation. Postpartum anticoagulation should be continued for 6-12 weeks[58].

Some patients continue to have recurrent pregnancy losses because they are refractory to the aspirin and heparin treatment. In such difficult situations, the management strategy requires an individualized approach after having a complete discussion with the couple. Second-line therapy for treatment failure usually involves the addition of steroids, intravenous immunoglobulin (IVIg), and plasmapheresis. Steroids have been reported to improve outcomes[59], while randomized treatment trials do not support the benefit of IVIg[52]. Recommendations for long-term thrombosis prophylaxis in patients with OB-APS without a history of thrombosis are lacking, although one large observational cohort study reported an increased risk for subsequent deep-vein thrombosis and stroke in these women[60].

Breastfeeding

Breastfeeding is encouraged for most women with LN. After reviewing specific risks, the safety of medications in lactation should be discussed on an individual basis. Premature or ill infants may be at increased risk of some medication exposures (Table 3)[28].

EMERGING RESEARCH AND TECHNOLOGIES IN LN DURING PREGNANCY

Recent advancements in the field of LN have introduced promising diagnostic tools and biomarkers. Researchers have identified novel urinary proteins, such as L-selectin, urine Angptl4, and TGFβ1, which show potential in tracking disease activity and predicting flares. These biomarkers could provide clinicians with more precise tools for monitoring LN during pregnancy[61].

In terms of therapies, new biological and targeted treatments are being explored, especially with the release of the 2024 KDIGO guidelines[62,63]. These guidelines present several important updates and recommendations aimed at enhancing patient outcomes. They emphasize the safety of certain immunosuppressive medications during pregnancy, while advising against the use of newer agents like belimumab and voclosporin due to insufficient evidence regarding their safety for pregnant and lactating women[64,65]. The guidelines recommend the continued use of HCQ and the initiation of low-dose aspirin before 16 weeks of gestation to reduce pregnancy complications and control disease activity. These updates reflect a comprehensive approach to managing LN in pregnancy, highlighting the importance of individualized treatment plans based on the latest evidence and patient-specific factors. The primary focus is on minimizing the cumulative dose of glucocorticoids and improving long-term outcomes with less toxic regimens[62,63]. Ongoing research aims to explore new therapeutic options and optimize existing treatments further.

FUTURE PERSPECTIVES

The future perspectives of managing pregnancy in women with LN look promising, with ongoing advancements in targeted therapies[66,67], personalized medicine, enhanced monitoring technologies, and comprehensive care models. Addressing racial disparities, expanding education programs, and conducting innovative research will further improve outcomes for these patients. Continued collaboration among healthcare providers, researchers, and patient communities is essential to realize these goals.

CONCLUSION

Women with lupus and prior LN can have safe, successful pregnancies with close monitoring and a collaborative framework. Careful preconception planning, high-risk pregnancy management, and vigilant maternal and fetal monitoring are crucial for positive outcomes. Multidisciplinary care between obstetricians, nephrologists, rheumatologists, and other specialists is essential for successful outcomes.