Impact of Systemic Lupus Erythematosus on Conception: Insights into Infertility, Fertility Preservation, Assisted Reproductive Technology, and Pregnancy Outcomes.

ART efficacy is commonly measured by pregnancy and live birth rates, with IVF success gauged by oocyte retrieval and mature blastocyst development. While adverse events like preterm delivery or preeclampsia may signal reduced efficacy to clinicians, patients often define success as bringing home a baby, regardless of complications. The assessment of ART in SLE is complicated by small, retrospective, single-center studies that often lack controls. 117 , 120 – 122 Mao et al found that 34 SLE patients matched to controls had poorer ART outcomes, including significantly fewer embryos, good-quality blastocysts, and overall blastocyst formation. Clinical outcomes also lagged, with lower implantation and live birth rates per embryo transfer. 123 A French study revealed high pregnancy loss in SLE IVF pregnancies, with 50% ending in loss. Notably, 24% of women concealed their SLE or APS diagnoses, which was linked to worse outcomes: 75% of undisclosed cases resulted in loss compared to six of seven known cases that led to live births. 118 SLE may impair ART success through mechanisms beyond active disease. A study of 44 IVF cycles in SLE patients revealed lower AMH levels and fewer embryos than controls. Although low AMH is not directly tied to egg quality, SLE patients had poorer embryo quality and lower clinical pregnancy and live birth rates. 123 , 124 Autoantibodies like ANA, TPO, anti-Ro/SSA, anti-La/SSB, and aPLs are linked to poorer ART outcomes. However, small sample sizes and limited exploration of undiagnosed autoimmune diseases restrict the generalizability of these studies. 125 – 130 Despite these less-than-ideal outcomes, ART remains a viable option for SLE patients to meet their family-building goals. Additional counseling is warranted in regard to risks and outcomes, but ART should be offered to SLE patients. Research on specific autoimmune protocols for embryo transfer in SLE or other autoimmune diseases is lacking. Evidence for using immunosuppressive or modulatory therapies in recurrent implantation failure or pregnancy loss is also sparse. Treatments like steroids, G-CSF, intralipids, IVIG, anti-TNF-α, and calcineurin inhibitors have shown mixed results in small, nonrandomized studies. 131 – 137 A 2023 randomized placebo-controlled trial found that prednisone did not improve live birth rates in women with recurrent implantation failure and may increase the risk of preterm delivery and biochemical pregnancy. 135 Further studies are required to clarify the impact of medications on enhancing implantation and pregnancy outcomes in SLE patients undergoing ART.

There are other well-established factors associated with infertility and pregnancy loss that may be exacerbated in patients with SLE. Common causes of infertility include ovulatory dysfunction, tubal disease, and male factor infertility. Ovulatory disorders account for about 25% of infertility cases, with polycystic ovary syndrome (PCOS) affecting around 70% of these women. 17 Obesity, often linked to glucocorticoid use and reduced physical activity in SLE patients, impairs ovulation. Metabolic syndrome, characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, is also more common in SLE patients than in age-matched controls. 63 Chronic renal disease, a frequent SLE comorbidity, impacts fertility in both genders. 64 SLE patients on immunosuppressive drugs or with a history of peritoneal dialysis are at higher risk for intra-abdominal infections, which can cause fallopian tube scarring. Tubal occlusion from endometriosis, infections, or adhesions further contributes to infertility. Endometriosis, notably more common in SLE, was significantly associated with the disease in a 2023 meta-analysis. 65 Cervical and uterine factors, such as polyps and fibroids, should also be considered. 17 Despite optimizing identifiable risk factors and managing SLE disease activity, some women still face challenges in becoming pregnant, experiencing significant emotional and psychological distress. Fortunately, advancements in ART and careful risk management have helped many patients who previously struggled with infertility achieve successful pregnancies. 12

Infertility in SLE patients can result from diminished ovarian reserve (DOR), primary ovarian insufficiency (POI)/premature ovarian failure (POF), and testicular insufficiency with impaired spermatogenesis. 21 – 23 Ovarian reserve assessment commonly includes follicle-stimulating hormone (FSH), anti-Mullerian hormone (AMH), and antral follicle count (AFC) tests. Among these, AMH is frequently used as a surrogate marker, with low levels indicating reduced reserve. 19 , 24 AMH levels also predict ovarian response in ART and the onset of menopause. 24 , 25 DOR, characterized by regular menstrual cycles but abnormal ovarian reserve tests, is a normal process in the mid-40s but is considered abnormal when occurring earlier. POI and POFare often used interchangeably, though POI is preferred for describing premature ovarian aging, characterized by ≥4 months of amenorrhea and elevated FSH (>40 IU/L) in women under 40. 26 Women with SLE are more prone to developing DOR or POI/POF than the general population, 10 , 19 , 27 – 29 and Grossmann et al found that 40% of women with POI/POF had an autoimmune disease. 30 SLE’s intrinsic fertility issues, including reduced AMH levels, can occur independently of cyclophosphamide (CYC)-induced gonadotoxicity. 27 – 30 Lower AMH levels are reported in women with mild SLE compared to healthy controls. 28 Similarly, SLE negatively impacts male fertility, with findings such as reduced sperm volume, motility, and oligospermia. 14 , 31 , 32 A 2022 systematic review further identified elevated reproductive hormones (LH and FSH) and impaired semen quality in men with SLE. 32 These reproductive challenges, seen in both adult and pediatric patients, emphasize the need for thorough assessments of fertility in both sexes. 33 , 34 SLE disease activity significantly impacts fertility. Gao et al identified a negative correlation between AMH and both erythrocyte sedimentation rate (ESR) and SLE disease activity (SLEDAI). 28 Similarly, Girbash et al found lower AMH and AFC levels in SLE patients, linked to higher age, disease activity, and cumulative organ damage. 35 However, patients with mild or skin-limited lupus showed no significant differences in AMH levels compared to healthy controls. 19 , 36 Although advances in medical management may mitigate some infertility issues in SLE, ovarian aging remains irreversible. As oocytes age, their rate of aneuploidy increases. Ovarian reserve declines naturally due to biological and hormonal changes from puberty to menopause, eventually limiting both endogenous and exogenous hormonal stimulation of follicular development and ovulation. Delayed conception due to SLE, even without DOR, POI, or POF, heightens the risk of age-related oocyte aneuploidy, affecting fertility outcomes. 37

Assisted reproductive technology (ART) is increasingly used worldwide to address family-building desires ( Table 7 ). In 2023, over 40% of individuals surveyed reported using fertility treatments or knowing someone who has, a 10% increase from 5 years earlier. ART is now commonly used in the general population to address the one in eight couples who experience infertility. 104 – 106 However, current data may not accurately reflect ART utilization among rheumatology patients, especially those with SLE, who often face challenges conceiving ( Tables 1 and 2 ). Frequent discussions about pregnancy intentions are important for SLE patients due to their high risk for poor outcomes and potential infertility. Such discussions help identify patients at risk for or currently experiencing infertility who may benefit from evaluation and intervention. There is a wide gap in clinical use and research in IVF and SLE. Louise Brown, the first IVF baby born in 1978, was already in high school when the initial case reports of ART in SLE patients were published. Nearly two decades after Louise was born, ART’s safety in SLE patients remained debated, leading to caution in recommending IVF for these individuals. 107 The negative portrayal of ART in SLE patients, with concerns linking ovulation induction to SLE onset, flares, thrombosis, and even death, 108 – 110 has left a lasting impact on the medical community. Women with SLE generally have fewer children compared to those with rheumatoid arthritis, likely in part due to slower advances in SLE management, higher pregnancy risks, delayed pregnancy during peak fertility years, and propagated the myth that women with SLE “can’t” get pregnant. 11 , 98 This discrepancy has likely contributed to the widened gap in childbearing outcomes and ART utilization between these conditions. Although ART is widely used among inflammatory arthritis patients, less is known about its utilization in SLE. 111

Patients with rheumatologic conditions, particularly SLE, face several barriers to accessing ART. Key obstacles include limited knowledge about ART, concerns regarding its appropriateness and safety, disease activity, restricted access to REI specialists, financial constraints, and social or religious beliefs. 112 Mental health challenges, including depression and anxiety, are prevalent among SLE patients and can exacerbate relationship strain and discourage the pursuit of ART. Approximately 80% of individuals undergoing fertility treatments report increased stress, which is often heightened in SLE patients. 172 – 176 Additionally, IUI and IVF cycles necessitate frequent, sometimes daily, in-person appointments over 8 to 15 days. Coordinating these appointments around work, school, childcare, and other medical commitments can be challenging. Accessibility is another barrier, with one in seven women in the United States living over 60 miles from a fertility clinic. 177 The financial burden of ART is significant, with a single IVF cycle costing between $15,000 and $30,000. 178 Many patients need multiple cycles to achieve success, particularly those with DOR. Limited insurance coverage and the absence of a federal mandate for fertility coverage exacerbate this issue, especially for SLE patients relying on governmentfunded health insurance, which typically does not cover fertility evaluations or treatments. 179 Although grants exist for patients facing infertility due to cancer treatments, individuals with SLE are often excluded. 112 Fertility preservation, such as oocyte or embryo freezing, involves costs similar to a full IVF cycle, while sperm cryopreservation is less expensive but still incurs storage fees—around $1,000/year. OTC is particularly expensive due to surgical costs and the need for IVF after tissue reimplantation. Even with insurance coverage for ART, plans usually require an infertility diagnosis and do not cover fertility preservation. Racial and ethnic disparities further complicate access to ART. SLE disproportionately affects Black, Hispanic, American Indian, and Asian populations. 177 , 180 Childhood-onset SLE is often more severe, with increased renal and neuropsychiatric involvement necessitating more aggressive therapy. Patients of color are more likely to develop SLE at an early age, equating to a longer disease duration, which increases the risk of infertility. 181 , 182 Women of color are less likely to be referred to REI and, when referred, often have poorer outcomes. 183 Social determinants of health, including lower education levels, non-private insurance, proximity to REI clinics, and lower household incomes, also contribute to lower fertility treatment utilization. Men and women with SLE who already have children may be assumed to be uninterested in fertility preservation. This bias also affects unmarried, childless women of advanced maternal age. 177 , 180 , 182 , 184 – 187 To maintain favorable fertility clinic statistics, more complex SLE patients who may have medication- or disease-related DOR may be turned away or advised to use donor eggs. 188 Women with SLE often have higher BMI due to corticosteroid-induced weight gain and decreased activity from joint pain, fatigue, myositis, depression, and possibly avascular necrosis. Since body mass index is a criterion for ART procedures like egg retrieval, this introduces another bias and ethical dilemma. 189 Engaging a patient’s rheumatologist is essential, yet these specialists may lack ART expertise and hesitate to approve fertility treatments due to pregnancy risk concerns, even if recommended by REI. Although data on rheumatologists’ REI referral practices are unknown, similar hesitance is noted among other physicians. 190 Conversely, REI physicians and fertility clinic staff often lack training in evaluating SLE disease activity, leading to potential misjudgments in patient qualification, especially when relying on incomplete medical records or patient report. Additionally, uncertainty regarding medication safety during ART can result in inappropriate treatment refusals by various providers. 191

Active SLE at conception or during pregnancy is a significant risk factor for APOs, with studies showing flare rates between 25 and 68% during pregnancy and 3 months postpartum. 83 – 85 Fortunately, flares are typically mild in those with inactive or stable disease at conception. 86 Lupus nephritis flare risk also increases during pregnancy, leading to higher maternal and neonatal morbidity due to the elevated preeclampsia risk. 67 , 87 – 89 A retrospective study of 90 pregnancies found fetal loss in 35% of cases with active lupus nephritis at conception, 25% in quiescent cases, and only 9% in SLE without kidney involvement. 90 Preeclampsia is characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation and can be difficult to distinguish from a lupus nephritis flare. Severe preeclampsia/eclampsia can cause liver injury, thrombocytopenia, microangiopathic hemolytic anemia, acute kidney injury, stroke, seizures, and pulmonary edema, leading to IUGR and preterm birth. Compared to 3.4% in the general U.S. population, preeclampsia occurs in about 30% of SLE pregnancies, with preterm delivery in up to 50% of cases. Comorbidities like chronic kidney disease and hypertension increase one’s preeclampsia risk. The highest preeclampsia risk, up to 57%, is seen in women with active lupus nephritis during pregnancy. 6 , 90 – 93 Both SLE and APS individually increase the risk of preeclampsia, but the risk is highest in patients with both conditions. Notably, preeclampsia—especially early-onset— and eclampsia are included in the APS classification criteria ( Tables 3 and 4 ). 50 , 51 A 2018 prospective case–control study found 11.5% of women delivering before 36 weeks due to preeclampsia or placental insufficiency tested positive for aPLs, compared to 1.4% of controls. 94 A European registry of 1,000 obstetric APS patients reported early preeclampsia in 18% and fetal growth restriction in 16%. 75 Additionally, the presence of aPLs markedly increases the risk of thrombosis in SLE pregnancies, with a tenfold greater likelihood of DVT, PE, or stroke. 8 Ruiz-Irastorza et al found that SLE patients with APS had a significantly lower 15-year cumulative survival rate compared to those without APS. 95

Despite challenges, SLE patients can successfully use ART to achieve pregnancy and live births. IVF carries inherent risks—hypertension, gestational diabetes, prematurity, low birth weight, and preeclampsia—that are elevated in all SLE pregnancies, regardless of ART use. These risks can be mitigated with careful planning. 121 , 138 For SLE patients seeking ART, individualized reproductive endocrinology and infertility (REI) care and well-controlled disease are essential. 21 Anticoagulation is essential for managing the heightened thromboembolic risk associated with ART and SLE. This approach is supported by guidelines from the ACR and European authorities ( Table 6 ). 21 , 103 , 139 Estrogen’s procoagulant effects, combined with SLE’s increased thrombosis risk—regardless of aPL status—underscore the need for anticoagulation during IVF. Estradiol levels can soar to 1,500 to 5,000 pg/mL or higher during IVF, further elevating the risk of thrombosis. 140 The 2020 ACR Guidelines recommend anticoagulation in patients utilizing ART who are aPL-positive, and if pregnancy is achieved, adding/continuing low-dose aspirin. ACOG and the Society for Maternal-Fetal Medicine (SMFM) also recommend low-dose aspirin starting at 12 weeks of gestation for those at increased risk of preeclampsia, including SLE and APS patients. 21 , 102 , 140 – 144 Medications like clomiphene citrate or letrozole as a part of an IVF protocol can be beneficial due to their serum estrogen-lowering effects. Clomiphene binds to estrogen receptors in the brain, while letrozole inhibits aromatase, the enzyme that converts androgens to estrogen. These medications are also effective for patients with DOR, a common issue in SLE. 145 GnRH antagonist protocols can also lower estrogen and can be used in conjunction with these medications. 146 For those sensitive to hormonal fluctuations, a natural cycle IVF may be a viable option. 147 , 148 The goal is to reduce SLE flares and thrombosis risk through estrogen-lowering strategies. Ovarian hyperstimulation syndrome (OHSS) is a notable IVF complication characterized by ovarian cyst enlargement, abdominal pain, and serosal fluid accumulation, potentially causing ascites, effusions, and generalized edema. Severe cases can mimic lupus nephritis flare and lead to serious conditions like adult respiratory distress syndrome, thromboembolism, and acute renal failure. 149 Although rare in SLE patients, OHSS has been reported, including a case of lupus nephritis exacerbated by impaired renal clearance of human chorionic gonadotropin (hCG) during IVF. In such cases, GnRH agonists are preferred over hCG for oocyte maturation. 150 Infection risk is a concern for immunocompromised patients undergoing ART. Although postprocedural infections are rare (0–0.4%), data on infection rates in immunosuppressed ART patients are lacking. 151 Guidelines do not recommend antibiotics for oocyte retrieval or embryo transfers based on an immunosuppressed state. Procedures like hysteroscopy and saline infusion sonography do not require prophylactic antibiotics, except in specific cases of endometriosis, pelvic inflammatory disease, ruptured appendicitis, or multiple prior pelvic surgeries. 152 Notably, HCQ and sulfasalazine are immunomodulators rather than immunosuppressants. Consequently, patients on these medications are not immunosuppressed, and stopping or holding any rheumatology medications during ART due to infection concerns should be done only in exceptional cases and with rheumatology consultation. 21 , 153 – 157

Fertility preservation involves cryopreserving eggs, embryos, sperm, or ovarian tissue. GnRH agonists, while less reliable, can also be used to protect against age-related declines in egg quality and treatment-related impacts on oocytes. While sperm quality is less affected by age, preserving both eggs and sperm is recommended to counteract medication gonadotoxic effects and active disease. 21 , 103 Fertility preservation is increasingly common for both social and medical reasons. In the United States, oocyte freezing cycles have quadrupled over the past decade, with similar growth in sperm cryopreservation. 158 , 159 Recent improvements in oocyte cryopreservation have resulted in comparable success rates for frozen and fresh oocytes. 160 However, it remains unclear whether SLE patients have benefitted from these developments. Current calculators for estimating necessary oocyte counts for conception do not consider factors specific to SLE, DOR, or other conditions. 161 – 164 Oocyte retrieval carries similar safety concerns as previously mentioned. SLE patients not planning immediate pregnancy can continue teratogenic medications (excluding CYC) but should still aim to maintain low disease activity ( Fig. 1 ). 21 Sperm cryopreservation while on teratogens, aside from CYC, has no restrictions, similar to active attempts at conception. Table 1 reviews rheumatic medications with known impact on sperm and should be reviewed prior to cryopreservation. The optimal timing for oocyte and sperm cryopreservation is before CYC administration, though significant challenges exist. SLE patients requiring CYC are often hospitalized and have limited tolerance for ART medications. Coordinating with reproductive specialists and accessing facilities for egg retrieval and storage, as well as the trained staff needed for these delicate procedures, adds complexity while inpatient. Additionally, cost cannot be overstated as a barrier to oocyte cryopreservation. For critically ill male SLE patients needing CYC, timely sperm collection is challenging due to urgent logistics and sample processing. Ideally, sperm should be collected before CYC administration, but patients undergoing gonadotoxic treatment should not be deterred from pursuing cryopreservation at any time, supported by oncology guidelines. 165 Ovarian tissue cryopreservation (OTC) involves the lapa-roscopic removal of ovarian tissue for future reimplantation and is a viable option for pre- and postpubertal patients. 166 , 167 OTC is suitable for SLE patients who are stable for surgery but cannot delay treatment for the IVF process. 168 Although OTC is an accepted technique, its efficacy compared to other methods remains debated; however, recent studies suggest it may be on par with embryo cryopreservation. 168 Currently, no counterpart for testicular tissue is readily available. GnRH agonists should be administered to postpubertal, premenopausal SLE patients receiving CYC. These medications prevent immature ovarian follicles from maturing, reducing the pool vulnerability to gonadotoxins. They also lower estrogen levels, potentially decreasing chemotherapy delivery to the ovaries, upregulating antiapoptotic molecules, and protecting ovarian stem cells. 169 , 170 GnRH agonists have been successfully used in rheumatic diseases, particularly SLE. The ACR recommends the strategic use of GnRH agonists for SLE patients receiving CYC. 21 , 171

For some women with SLE, pregnancy is contraindicated. Those with irreversible end-organ damage such as end-stage renal disease, pulmonary hypertension, significant restrictive lung disease, severe heart failure, or inability to cease teratogenic medication(s) should be strongly discouraged from becoming pregnant due to the substantially increased morbidity and mortality risk for both mother and offspring. 69 , 96 , 97 Conditions like preeclampsia, eclampsia, or HELLP syndrome, which are more common in SLE, may further discourage subsequent pregnancies due to risk. Concerns about personal health, caregiving capacity, life expectancy, and potential child health outcomes may contribute to the gap seen between SLE patients’ desired and actual family sizes. Women with lupus often have fewer children compared to those with other autoimmune diseases, such as rheumatoid arthritis, leading to overall smaller family sizes. 11 , 13 , 19 , 98 For some, the risk to mother and/or child may prompt them to consider IVF using a gestational carrier or adoption to avoid complications, though these options come with their own challenges.

IVF with patient or donor eggs, sperm, or embryos, assisted by a gestational carrier, provides a viable pathway to parenthood for individuals with SLE. In surrogacy, a gestational carrier carries and delivers a baby for the intended parents. In the United States, surrogacy is increasingly common; approximately 5% of embryo transfer cycles in 2020 involved gestational carriers, resulting in around 4,000 births. However, data on surrogacy among SLE or autoimmune disease patients is lacking. 192 For some individuals with SLE, IVF using their own or donor gametes/embryos with a gestational carrier may be the safest option, particularly for those with significant pregnancy contraindications. Surrogacy or adoption is recommended for women with pulmonary hypertension due to high morbidity and mortality risks, even when SLE is well-controlled with pregnancy-safe medications. Significant renal, cardiac, and pulmonary diseases are relative contraindications, necessitating pregnancy avoidance and exploration of alternatives. SLE patients unable to safely discontinue teratogenic medications may also consider IVF with embryo freezing for transfer to a gestational carrier as their best option for having genetically related children. 21 Surrogacy laws vary significantly by state. Some states support and regulate surrogacy, while others do not explicitly address it. Michigan recently decriminalized surrogacy, whereas Louisiana has very restrictive laws, including prohibitions on surrogacy for same-sex or unmarried couples and limits on compensation. For an overview of surrogacy laws by state, visit https://connect.asrm.org/lpg/resources/surrogacy-by-state?ssopc=1 . 193 Internationally, surrogacy, especially compensated surrogacy, is often illegal in countries such as China, Saudi Arabia, and much of Europe, leading many to seek surrogacy services abroad. Regardless of location, surrogacy can be associated with potential exploitation and unethical practices due to insufficient regulation. 194 – 197 Surrogacy is a significant financial burden, typically costing between $100,000 and $250,000 per surrogate live birth, in addition to embryo creation costs. 178 As with ART, same-sex couples, unmarried individuals, and those seeking single parenthood often face additional barriers in surrogacy. Lastly, IVF, donor gametes, and/or surrogacy go against the beliefs of numerous religious groups, which can cause significant personal and familial strife.

Positive antinuclear antibody (ANA) status has been associated with infertility; however, these findings are confounded by the lack of evaluation for other autoantibodies, such as aPLs, anti-thyroid peroxidase (TPO), and those more specific to SLE, Sjögren’s disease, and other autoimmune conditions. 56 Thus, infertility in ANA-positive patients likely stems from an undiagnosed autoimmune disease rather than the ANA itself. 57 Thyroid dysfunction, a common and often reversible cause of ovulatory problems, is frequently seen in pregnancy. Autoimmune thyroid disease, the most prevalent autoimmune disorder during pregnancy, is linked to thyroid autoantibodies that contribute to implantation failure and spontaneous abortion. Elevated TPO and/or thyroglobulin antibodies, even in euthyroid individuals, increase risks of infertility, anemia, and preterm delivery. Notably, SLE patients have higher rates of thyroid-specific antibodies, making them more susceptible to both hypo- and hyperthyroidism. 57 – 60 Some studies suggest that specific antibodies targeting reproductive tissues are more common in women with SLE and may contribute to subfertility or infertility, although this remains controversial. 61 A 1995 study analyzed levels of gonadotropins in patients with SLE and found a high percentage of patients with organ-specific humoral immune responses against ovarian (27%) and endometrial (40%) antigens compared with controls. Pasoto et al reported that anticorpus luteum antibodies were associated with early ovarian dysfunction in SLE patients. 62 Anti-sperm antibodies have been linked to male infertility, though their role is unclear as they can also be present in healthy, fertile individuals. In infertile men who test positive for these antibodies, sperm concentration and motility are reduced. These antibodies are believed to cause sperm to clump and become immobilized, obstructing sperm–egg interaction. 14 , 31 , 32

Given the complex challenges faced by SLE patients, routine discussions about pregnancy intentions and family planning are essential across all care settings. These conversations not only identify the need for fertility preservation but also ensure pregnancy safety and address infertility challenges. While fertility preservation can be difficult, it is crucial for those at heightened risk of future infertility due to SLE and its treatments. Many SLE patients can successfully undergo follicular stimulation, IUI, and IVF, with risks comparable to the general population with acceptable efficacy. Rheumatologists play a pivotal role in recognizing fertility issues, facilitating referrals to REI and MFM specialists, and supporting ART efforts. OB/GYNs, primary care providers, and other women’s health professionals must also be proactive in identifying fertility concerns, making referrals, and counseling patients on medication-related delays in conception. Advocacy is essential to ensure that ART and fertility preservation services are accessible and affordable, especially for those considering surrogacy. By addressing the unique reproductive challenges faced by individuals with SLE, we can work toward a future where everyone, regardless of their medical condition, has the opportunity to realize their dreams of parenthood.

Although a detailed discussion of SLE management during pregnancy is beyond the scope of this review, key considerations deserve mention. Routine family planning and preconception counseling are critical for SLE patients. Optimal outcomes require planned pregnancies, SLE control with pregnancy-safe medications, careful monitoring, and a multidisciplinary care team. Preconception counseling should involve both maternal–fetal medicine (MFM) and rheumatology, with continued follow-up throughout pregnancy and postpartum. High-risk OB/MFM care is often necessary, and neonatology may need to be involved. SLE assessments, including clinical history, physical exams, and labs, should be conducted at least once per trimester. Cardiopulmonary status should also be evaluated preconception or early in pregnancy. 21 , 99 Hydroxychloroquine (HCQ) is a cornerstone of SLE management, improving disease control, survival, and pregnancy outcomes. HCQ reduces the risk of CHB in anti-Ro/SSA-positive patients and benefits APS patients due to its antiplatelet effects. 100 , 101 Pregnant patients should continue optimized dosing of HCQ, and those not on it should begin therapy unless contraindicated. Patients planning pregnancy should transition to pregnancy-compatible medications (e.g., HCQ, chloroquine, azathioprine, tacrolimus) 3 to 6 months before conception to maintain disease control. Steroids should be minimized and not started solely due to one’s pregnant state. 21 Knowledge of aPLs, anti-Ro/SSA, and anti-La/SSB status is crucial for risk stratification and management during pregnancy. Low-dose aspirin, as recommended by ACR, American College of Obstetricians and Gynecologists (ACOG), and the United States Preventive Services Task Force (USPSTF), is advised to start in the first trimester to reduce preeclampsia risk in all SLE and APS patients. The addition of anticoagulation depends on APS status and individual risk factors ( Table 6 ). 21 , 69 , 74 , 77 , 86 , 102 , 103

Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPLs), thrombosis, recurrent pregnancy loss, and obstetric complications. Up to one-third of SLE patients also have APS, which is associated with more severe disease, increased organ involvement, greater damage accrual, and higher mortality compared to those without APS. 40 – 42 Although 60 to 80% of SLE patients test positive for aPLs, many do not classify as having APS. 43 , 44 Despite not having this syndrome, they still face increased pregnancy risks linked to positive aPLs. 41 , 45 Additionally, some patients initially diagnosed with APS are later reclassified as having SLE. 46 While there are a multitude of aPLs, APS classification is based on three specific tests: (LAC is not an antibody but a functional test that demonstrates the presence of aPLs) lupus anticoagulant (LAC), anticardiolipin (aCL) IgM/IgG, and/or anti-beta-2 glycoprotein(aβ 2 GPI) IgM/IgG. 47 , 48 These tests must be positive at sufficient levels on repeat testing 12 weeks apart to meet classification criteria. In addition to pregnancy complications and thrombosis, APS can present with a wide range of clinical features, including mild thrombocytopenia, chorea, seizures, vasculitis, livedo racemosa, valvular heart disease, pulmonary hemorrhage, nephropathy, and thrombotic microangiopathy. 49 The 2006 Revised Sapporo Criteria and the 2023 ACR/EULAR APS Classification Criteria are commonly used to aid diagnosis, though these criteria were developed for research purposes ( Tables 3 and 4 ). 50 , 51 aPLs contribute to infertility and pregnancy loss by disrupting placental development through inappropriate activation of the clotting cascade, endothelial cells, platelets, complement, and neutrophils. 40 For example, β2GPI-dependent aPLs are believed to target their antigen on placental tissues, impeding the growth and differentiation of trophoblasts, ultimately leading to defective placentation. There is compelling evidence that anti-β2GPI domain I IgG antibodies play a significant role in the pathogenesis of APS. 40 , 52 Studies suggest that aPLs may also disrupt oocyte development and uterine decidualization. 53 Some early studies linked aPL positivity to decreased conception rates, though findings have been mixed. 53 Tan et al eloquently associated aPL positivity with impaired endometrial receptivity, resulting in repeated implantation failure. 54 Shoenfeld et al found a higher prevalence of aPLs, especially antiprothrombin antibodies, in infertile women compared to fertile controls. 44 A 2014 French study reported elevated aPLs, primarily anti-β2GPI IgA, in infertile women undergoing IVF, though this antibody is not part of APS criteria. 55 Data on aPLs and APS’s impact on male fertility is limited, aside from complications related to systemic disease, thrombosis, and cardiovascular risks.

CYC is a well-known cause of POI/POF, DOR, and male infertility. CYC is an alkylating chemotherapeutic agent used for those with severe SLE manifestations such as nephritis, myocarditis, or cerebritis. Its impact on the ovaries and testes is typically cumulative and irreversible. Risk factors for CYC-induced gonadal toxicity include older age at treatment, higher cumulative doses, and oral versus intravenous administration. Women receiving CYC over age 25 face a threefold increased risk of ovarian failure compared to younger women, with rates ranging from 30 to 78%. In men, CYC can cause testicular germinal aplasia, azoospermia, low sperm counts, and motility defects. About 70% of men receiving < 7.5 g/m 2 (median: 4.1 g/m 2 ) of CYC regain fertility, but only 10% recover fertility with cumulative doses exceeding 7.5 g/m 2 . 38 , 39 CYC administration for SLE differs from its oncologic use, which typically involves a single course aimed at achieving permanent remission. In SLE, a chronic condition marked by episodic flares, patients may require repeated CYC treatments over their reproductive years leading to high cumulative doses and increased gonadotoxicity. Strategies to mitigate CYC-related infertility are discussed later in the article. Other medications potentially impacting fertility can be found in Table 1 .

Newborns of mothers with SLE face significantly higher complication risks. One study found double the risk of preterm birth and SGA infants and nearly five times the risk of low birth weight. These risks increase further with the presence of APS, lupus nephritis, hypertension, preeclampsia, or active SLE. 5 The risk of fetal loss is increased in SLE. A 2020 meta-analysis highlighted significantly higher risks of overall fetal loss (RR: 7.55, 95% CI: 4.75–11.99; p < 0.00001) and stillbirth (RR: 16.49, 95% CI: 2.95–92.13; p = 0.001) compared to those without SLE. 5 Factors contributing to pregnancy loss in SLE include active disease, teratogen use, lupus nephritis, and associated proteinuria, hypocomplementemia, positive aPLs and APS, advanced maternal age, and thrombocytopenia. 69 – 71 A 2015 study identified moderate disease activity and low complement levels as risk factors for first-trimester pregnancy loss. 70 Clowse et al found that high disease activity during pregnancy significantly reduced live births, with nearly 25% of these pregnancies resulting in fetal loss. Only 26% of women with high-activity SLE reached full-term delivery, compared to 61% with no or mild activity. High-activity SLE in the first and second trimesters tripled the risk of pregnancy loss. 72 In the first trimester, proteinuria, thrombocytopenia, and hypertension independently increased the risk of pregnancy loss to 40%. 71 SLE patients with APS require special attention, as pregnancy loss and fetal death are recognized features of APS ( Tables 3 and 4 ). 50 , 51 APS is ultimately diagnosed in 15 to 20% of women with RPL, with RPL being the most common but least specific finding in obstetric APS. 73 , 74 In SLE patients with APS, pregnancy loss is three times more likely, particularly after 20 weeks of gestation ( p = 0.004). 71 In a study of 1,000 women with obstetric APS, nearly 40% experienced a miscarriage. 75 LAC strongly predicts first-trimester loss, with loss rates at 38% for positive LAC versus 9% for negative. 70 In a multicenter case–control study of 582 stillbirths and 1,547 live births, aPL antibodies (aCL or aβ2GPI) were found in 9.6% of fetal deaths beyond 20 weeks, indicating a three- to fivefold increase in the odds of stillbirth in those with positive aPLs. 76 The transplacental transfer of maternal anti-Ro/SSA, and to a lesser extent anti-La/SSB, autoantibodies can lead to neonatal lupus. These IgG autoantibodies, which target intracellular ribosomal nuclear proteins, begin crossing the placenta around 12 weeks’ gestation. Hepatic, hematological, or cutaneous abnormalities are common manifestations seen in 5 to 10% of fetuses exposed to anti-Ro/SSA antibodies in utero. These issues typically resolve after birth, as maternal autoantibodies decline in the infant’s circulation. Fetal cardiac conditions, such as atrioventricular block (congenital heart block CHB), dilated cardiomyopathy, and endocardial fibroelastosis, are associated with maternal anti-Ro/SSA antibodies and, more rarely, anti-La/SSB. These cardiac manifestations are irreversible and carry significant morbidity and mortality in the 1 to 2% of babies affected. 77 – 79 Cardiac neonatal lupus is linked to a mortality rate of approximately 15%, primarily due to hydrops, prematurity, and dilated cardiomyopathy. 77 , 80 The risk of fetal cardiac complications increases with elevated maternal anti-Ro/SSA levels and if prior affected siblings. 81 In their study, Izmirly et al reported an 86% 10-year survival probability for infants diagnosed with cardiac neonatal lupus who were born alive. However, they noted higher postnatal mortality rates among minority infants compared to white children, suggesting potential racial disparities 82 or the compounding impact of previously mentioned factors.