Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE), characterized by inflammation and kidney damage. Prevalence rates in SLE patients range from 20% to 65%, with LN associated with higher mortality compared to the general population (1–3). It predominantly affects women in their reproductive years, presenting unique challenges during pregnancy (4). Pregnant women with LN are at increased risk for complications like pre-eclampsia, intrauterine growth restriction, stillbirth, and preterm delivery (5). The risk is further amplified by factors such as lupus activity, the presence of specific antibodies (like Antiphospholipid antibody (APA), anti-SSA/Ro, and anti-SSB/La), and pre-existing conditions like hypertension (6). The differentiation between an LN flare and pregnancy-induced hypertension or proteinuria can be challenging but is crucial for appropriate management.

Lupus nephritis involves the deposition of immune complexes in the kidneys, triggering a cascade of inflammatory responses, including local complement activation, leukocyte recruitment, and cytokine signaling, leading to glomerular and tubulointerstitial injury. This inflammatory process leads to kidney damage presenting as proteinuria, acute kidney injury, chronic kidney disease (CKD), and eventually, in some cases, end-stage kidney disease (ESKD).

The progression of LN to ESKD is influenced by various factors, including the initial nephron number (determined at birth), episodes of nephron loss (during LN flare), and the rate of nephron loss beyond physiological aging (ongoing inflammation due to LN) or in some cases concomitant uncontrolled diabetes mellitus, and/or hypertension (6). Flares of LN are episodes of acute kidney injury that result in irreversible nephron loss, shortening the kidney lifespan. Persistent or smoldering LN, even with induction therapy, accelerates the annual rate of nephron loss, hastening the onset of ESKD (7, 8).

Effective management of LN during pregnancy is pivotal to minimizing maternal and fetal risks. Tailoring treatment strategies that balance disease control and fetal safety is imperative. Pre-conception counseling and multidisciplinary care involving rheumatologists, nephrologists, and obstetricians are vital to optimize outcomes. Monitoring and managing blood pressure, kidney function, and lupus activity throughout pregnancy and postpartum safeguard maternal and fetal health ( Table 1 ). The management strategy should also consider the potential impact of medications on the fetus and adjust them accordingly to ensure safety while maintaining disease control.

This review aims to comprehensively explore the complex interplay between pregnancy and LN, shedding light on the increased risks and challenges encountered by pregnant women with LN.

Before conception, a thorough evaluation of disease activity and organ involvement is imperative. This involves:

Identifying and discussing potential risks and complications during pregnancy is crucial. This includes:

Lupus nephritis management involves various medications to control disease activity and protect kidney function. Pregnancy necessitates a careful review of medications due to potential risks to the fetus. Medications should be adjusted to those that are safe during pregnancy while still effectively managing LN. Adjustments to medication regimens should be individualized, considering both the mother’s health and fetal safety. Active disease management during pregnancy might require modifying treatment plans while minimizing risks. A brief overview of the medications commonly utilized in the treatment of SLE and LN is provided in the following sections ( Figure 1 ).

The care of pregnant individuals with LN necessitates a coordinated effort among a rheumatologist, nephrologist, and an obstetrician well-versed in managing high-risk pregnancies. A comprehensive strategy for overseeing pregnant women with LN, along with addressing active LN flare-ups during pregnancy, is outlined in the subsequent sections.

Maternal-fetal monitoring strategies during pregnancy lack a universally optimal schedule. Increased monitoring frequency is warranted for women with SLE in conjunction with routine prenatal care; the monitoring protocol includes:

The diagnosis of lupus nephritis flare during pregnancy necessitates the initiation of therapy (86). A severe lupus nephritis flare, particularly in a young woman early in her pregnancy, should catalyze deliberations regarding therapeutic abortion. Although medical termination of pregnancy might be the safest option to manage lupus optimally, many women, particularly later in gestation or when it may represent their sole opportunity for pregnancy, opt against abortion. Treating LN flare as soon as possible becomes the sensible pathway (84, 87).

A first-line strategy typically involves steroids. Lupus nephritis usually warrants the addition of immunosuppressive treatment to steroids. A conventional approach is starting azathioprine up to 2mg/kg/day. The utility of calcineurin agent tacrolimus is beneficial due to its steroid-sparing capacity, rapid reduction of proteinuria due to off-target effects on podocyte stabilization, and favorable tolerability. Treatments involving tacrolimus have reported favorable pregnancy outcomes (84, 88).

Furthermore, women with nephrotic range proteinuria should be prescribed prophylactic low-molecular-weight heparin to mitigate venous thromboembolism risk. Tight monitoring in the first six months after giving birth is crucial due to the elevated risk of an LN flare-up (88).

During the later stages of pregnancy, cyclophosphamide could potentially be used to treat severe cases of lupus or LN (89). Nevertheless, the decision to use this treatment involves careful consideration of the risks associated with premature delivery and the subsequent separate management of the health of both mother and baby.

Enhanced monitoring is essential for these patients, especially when symptoms such as hypertension, proteinuria, or end-organ dysfunction emerge after the 20th week of pregnancy, signaling the possible onset of preeclampsia. The occurrence of severe, early-onset fetal growth restriction further signifies an increased risk of developing preeclampsia (90). Although preeclampsia that arises later in pregnancy can typically be managed with a watchful waiting approach, early detection during pre- and peri-viable stages is critical to facilitate prompt delivery and prevent complications in the mother.

The likelihood of developing preeclampsia in individuals with SLE varies from 16 to 30 percent. Low-dose aspirin therapy between the 12th and 16th weeks of pregnancy can decrease the absolute risk of preeclampsia by about 10 percent for those at higher risk, including all patients with SLE (33).

Pre-eclampsia is a severe multisystem disorder of pregnancy characterized by high blood pressure after 20 weeks of gestation, accompanied by signs like proteinuria and maternal or fetal complications (91). Although numerous risk factors for pre-eclampsia have been identified, their ability to predict the condition is generally limited, even when combined. Lupus, especially in its active form with lupus nephritis, significantly increases the risk of pre-eclampsia (92, 93).

Flares of lupus nephritis, while potentially being the initial presentation of lupus, remain relatively rare, particularly in those devoid of prior or inactive nephritis at pregnancy onset. Distinguishing preeclampsia from lupus nephritis or a lupus flare poses a considerable challenge ( Table 3 ). During pregnancy, flares of lupus nephritis may resemble preeclampsia, showcasing heightened proteinuria, hypertension, thrombocytopenia, and declining renal function (94). Simultaneous occurrences of active lupus nephritis and preeclampsia are also plausible. If a woman shows signs of increasing proteinuria, hypertension, and deteriorating kidney function early in pregnancy, especially if she has a history of lupus nephritis, this strongly indicates the likelihood of a lupus nephritis flare-up (84, 94).

The task of differentiating lupus nephritis from preeclampsia, especially from the late second trimester, becomes markedly complex, as both can manifest with proteinuria, hypertension, generalized symptoms, thrombocytopenia, and kidney impairment. Diagnostic confirmation often leans heavily on historical data and is augmented by suitable investigations. Complement levels should typically be normal or elevated, given the pregnancy’s state of acute phase response. A decrement, even within the normal range, alongside elevating dsDNA antibody levels, should raise alarms regarding lupus activity. A higher soluble fms-like tyrosine kinase-1 (sFLT-1) to placental growth factor (PIGF) ratio in the third trimester was particularly noted in women with preeclampsia compared to those with chronic kidney disease (97). This indicates the possible clinical benefit of assessing the sFlt-1/PIGF ratio in cases of new-onset lupus nephritis and other forms of glomerulonephritis that are associated with hypertension. However, it is essential to note that this diagnostic modality is not yet widely available for routine clinical use.

If there is a notable and unexpected increase in proteinuria that could potentially impact immunosuppressive management, and the woman is in the early or middle stages of the second trimester, a kidney biopsy might be performed, bearing in mind that pregnancy does not increase biopsy risks.

However, consideration must be given to the potential post-biopsy bleeding and the permissible duration for delaying anticoagulation in a pregnant woman with substantial proteinuria and possibly anti-phospholipid antibodies, thus increasing the risk for venous thromboembolism. If thromboembolism risks exceed the diagnostic benefits, biopsy should be forsaken. A biopsy is unnecessary if serology aligns with an LN flare and previous nephritis is documented.

For patients with lupus nephritis, it is crucial to provide advice regarding the likelihood of delivery before 37 weeks and the increased risk of operative delivery if it is very early. The delivery timing should be meticulously determined based on a thorough maternal and fetal well-being evaluation. It is imperative to note that a nephritis flare is not an indication to proceed with delivery.

Postpartum monitoring is imperative, recognizing that many disease flares and thromboembolic events manifest within the initial six months post-delivery (98). Breastfeeding is encouraged; however, a personalized discussion regarding the safety of medications during lactation is crucial. Individual risk assessments are necessary, particularly for premature or ill infants who may face heightened vulnerability to certain medications. Hydroxychloroquine (HCQ), cyclosporine, tacrolimus, prednisone, and azathioprine are considered safe for use during breastfeeding. On the other hand, mycophenolate mofetil, leflunomide methotrexate, and cyclophosphamide are deemed unsafe for breastfeeding mothers. Biologics, except for NFα inhibitors, seem to be safe and effective without a significant maternal or fetal risk and are not recommended during pregnancy and breastfeeding due to insufficient data (99, 100).

Pregnancy in women with LN who have undergone a kidney transplant is a feasible option despite presenting specific challenges that necessitate careful preparation. These women can achieve pregnancies that do not jeopardize their transplant’s health, though they do face a higher likelihood of experiencing preeclampsia and miscarriages (101). However, with diligent care and oversight, the health outcomes for both the mother and child can match those of transplant recipients without LN (102). It’s essential to begin preparing for pregnancy between one and two years after the transplant to ensure the kidney is functioning stably without major issues like significant proteinuria, recurrence of LN, uncontrolled hypertension, episodes of rejection, or other graft complications (103). A crucial part of this preparation involves adjusting immunosuppressive treatment, notably discontinuing mycophenolate mofetil before conception to mitigate its risks and potentially switching to azathioprine, a less risky antimetabolite, when necessary (103).

Although the risk of cardiovascular complications in patients with lupus nephritis during pregnancy has been less studied, recent research indicates that pregnant patients with SLE face increased risks of acute cardiovascular complications, including peripartum cardiomyopathy, heart failure, arrhythmias, stroke, and venous thromboembolism, during delivery hospitalization (104).

Additionally, these patients are at a higher risk of developing hypertension later and are nearly four times more likely to encounter subclinical cardiovascular diseases in the future, particularly those who have had adverse pregnancy outcomes like pre-eclampsia (105).

Given these risks, it is crucial for women with SLE and lupus nephritis to receive thorough counseling about the potential for acute cardiovascular complications during their delivery hospital stay. This counseling should address not only common comorbidities such as hypertension, diabetes, obesity, and dyslipidemia but also the systemic inflammatory state typical of SLE. Implementing this comprehensive approach is essential to effectively mitigate both immediate and long-term cardiovascular risks for pregnant patients with lupus nephritis.

In the management of pregnant women with lupus nephritis and significant renal impairment undergoing renal replacement therapy, several critical interventions are essential to ensure both maternal and fetal well-being. To improve clearance and reduce volume fluctuations, it is recommended that hemodialysis sessions be increased in frequency and intensity, with five to seven sessions per week and a minimum of 24 hours per week (106). This approach has been shown to improve outcomes significantly, reducing pre-dialysis urea levels to below 20 mmol/L, thus mitigating the risk of uremic complications that could affect both mother and child (106, 107).

Ensuring adequate erythropoiesis and managing anemia are equally crucial; increased doses of erythropoiesis-stimulating agents may be required to maintain hemoglobin levels within the desired range, thereby supporting proper fetal growth and reducing risks associated with anemia, such as low birth weight and premature birth (108).

Nutritional management tailored to the needs of renal impairment also plays a pivotal role. High-protein diets are necessary to meet the increased metabolic demands during pregnancy, and adjustments in vitamin and mineral intake, such as calcium and phosphate, are vital (106, 109). Careful selection of phosphate binders like calcium carbonate, which is deemed safe during pregnancy, helps manage serum phosphate levels without exposing the fetus to potential harm (106).

Additionally, daily monitoring and adjustments of fluid balance, electrolytes, and dialysis parameters are necessary to address the physiological changes during pregnancy (106, 107). These measures help prevent complications such as hypercalcemia or metabolic alkalosis, which could otherwise lead to significant maternal and fetal health issues. Thus, a multidisciplinary approach involving nephrologists, obstetricians, and dieticians is imperative to optimize outcomes for both the mother and the developing fetus.

Pregnancy-induced changes hold the potential to trigger LN flares, impacting maternal health. To optimize pregnancy outcomes for patients with SLE and lupus nephritis, it is crucial to plan conception during periods of disease stability and to ensure the use of medications that are safe during pregnancy. This scenario poses a significant challenge for nephrologists and rheumatologists due to the heightened risk of adverse perinatal outcomes and complications related to pregnancy-induced hypertension. Future efforts in the management of lupus nephritis during pregnancy should emphasize the development of personalized management strategies, underscoring the pressing need for more clinical trials to better understand the safety and efficacy of current SLE treatments during this critical period.

ZG: Conceptualization, Data curation, Validation, Writing – original draft, Writing – review & editing. TS: Supervision, Validation, Writing – original draft, Writing – review & editing. KJ: Validation, Writing – original draft, Writing – review & editing. SS: Validation, Writing – original draft, Writing – review & editing. EL: Validation, Writing – original draft, Writing – review & editing. AA: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. SN: Conceptualization, Supervision, Validation, Writing – original draft, Writing – review & editing.