Infertility and Assisted Reproductive Technology in SLE: What Rheumatologists Should Know

Infertility is common in systemic lupus erythematosus (SLE), which mainly affects women aged between 15 and 44 years¹.

Rheumatologists play an important role in helping women with SLE understand their fertility and assisted reproductive therapy (ART) options. Effective counseling and care can help women make informed family planning decisions and achieve pregnancy, when desired.

SLE and Fertility: Current Evidence

In a recent review, Stamm et al summarized the available evidence on the link between fertility and SLE.² The researchers focused on studies that measured anti-Müllerian hormone (AMH) and antral follicle count (AFC) and noted several factors that affect fertility in women with SLE.

• Advanced Age

Fertility in women decreases gradually at approximately age 30 years and drops markedly between the mid to late 30s.³ Women diagnosed with SLE early in their reproductive years may choose to postpone pregnancy due to concerns about their personal health and the health outcomes of their child. Research suggests many women do not fully understand the effects of age on fertility and may overestimate their ability to conceive with increasing age.³

Timing pregnancy to coincide with low disease activity may lead to further delays. Studies show that active disease prior to conception increases the risk for flares during pregnancy and negative pregnancy outcomes.⁴ Disease control for at least 6 to 12 months prior to conception is recommended.⁵

• Medications

Cyclophosphamide is an immunosuppressive medication and gonadotoxic agent used to treat severe or refractory SLE. The cumulative dose of cyclophosphamide is associated with premature ovarian failure.⁶ The European Alliance of Associations for Rheumatology (EULAR) recommends adding gonadotropin releasing hormone (GnRH) analogs to cyclophosphamide to preserve fertility.⁷ Alternative immunosuppressive agents, including mycophenolate mofetil, azathioprine, and calcineurin inhibitors, do not appear to affect fertility.⁸

Other medications may lower fertility through different mechanisms. Nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit ovulation, while high-dose corticosteroids may cause menstrual disturbances.⁹

• Psychologic Factors

The psychologic aspects of SLE can also impact fertility. In a cross-sectional study of 509 men and women with SLE, the rates of depression, anxiety, and sexual dysfunction were 22%, 37.5%, and 69.9%, respectively.¹⁰ Anxiety and depression were strongly correlated with sexual dysfunction among both men and women.

Direct Impact of SLE on Fertility

Does SLE itself decrease fertility?⁷ Several studies reviewed by Stamm et al² showed reduced fertility in women with SLE, even in the absence of prior gonadotoxic therapy. Individual studies also noted inverse correlations between AMH and disease activity,¹¹ irregular bleeding,¹¹ and Black race.¹²

However, a 2016 study¹³ found no difference in serum AMH levels between patients with SLE and healthy control participants paired by contraceptive use, and no correlation between AMH and disease activity, disease duration, ethnicity, current smoking, and cyclophosphamide use.

Other disease related factors may also affect fertility.

• Menstrual disorders: Irregular periods can affect the timing and likelihood of pregnancy. Women with SLE experience more frequent menstrual irregularities, particularly amenorrhea. In a study, nearly half of patients with SLE had menstrual disturbances.¹⁴ Whether such disturbances are directly related to SLE is not clear, as severe disease typically requires treatment with cyclophosphamide and/or corticosteroids, which may also disrupt the menstrual cycle.
• Antiphospholipid syndrome (APS): APS can occur alone or with SLE. While APS is a well-known risk factor for poor pregnancy outcomes, the relationship between APS and infertility is less conclusive.¹⁵ There is some evidence that APS may affect fertilization, implantation, and overall reproductive function, and should be considered as a risk factor for infertility in women with SLE.⁹

Stamm et al² concluded, “A direct effect of SLE on fertility in women of childbearing

age is unproven; however, data do suggest that, aside from known risk factors of cytotoxic medications, advanced age and psychosocial disease effects, certain disease characteristics such as SLE activity may also impact the ability to conceive. Well-designed, large-scale studies could help confirm or refute this finding and identify the most important risk factors for infertility.”

ART in SLE

ART is an option for women with SLE with reduced fertility. The most common ART procedure is in vitro fertilization (IVF), which involves ovarian stimulation, egg retrieval, fertilization, and embryo transfer. Both eggs and fertilized embryos can be frozen for later use, giving women the flexibility for a future pregnancy.

American College of Rheumatology (ACR) Guidelines for ART in SLE

The main concerns for ART in women with SLE and APS are ovarian hyperstimulation syndrome (OHSS), disease flares, and thrombotic events. Changes in ART protocols have reduced the risk and severity of OHSS.² To reduce flares, the ACR reproductive health guidelines recommend pursuing ART only when SLE is quiescent.¹⁶ Prophylactic prednisone is also not recommended to prevent flares; physicians should monitor patients closely and treat flares if they occur.¹⁶

Physicians should measure antiphospholipid antibodies (aPL) prior to ovarian stimulation to assess the risk for thrombosis and determine the need for anticoagulation therapy (low-molecular weight heparin or unfractionated heparin).¹⁶ Positive aPL status is defined as 2 or more occasions at least 12 weeks apart of lupus anticoagulant, medium or high titer anticardiolipin antibodies (immunoglobulin [Ig]G or IgM >40 units or >99thpercentile), or anti-b₂ glycoprotein-I antibodies (IgG and/or IgM >99thpercentile).¹⁷ The ACR guidelines further categorize positive aPL status based on APS symptoms and obstetric and thrombotic history and tailor recommendations for anticoagulation therapy for each category¹⁶:

aPL Status Category	Criteria for aPL Status	ACR Recommendations for Anticoagulation Therapy
Positive aPL, no clinical APS	No symptoms or history of pregnancy complications or thrombosis.	Conditional recommendation for prophylactic anticoagulation therapy, based on discussions between patients and providers.
Obstetric APS	History of APS-related pregnancy complications (3 consecutive losses prior to 10 weeks of gestation, fetal loss at least 10 weeks after gestation, or delivery before 34 weeks due to preeclampsia, intrauterine growth restriction, or fetal distress).	Strong recommendation for prophylactic anticoagulation therapy.
Thrombotic APS	Prior thrombotic event, regardless of obstetric history.	Strong recommendation for therapeutic anticoagulation therapy.

Ovarian stimulation protocols vary, and therefore, discussions between rheumatologists and infertility specialists are important. Prophylactic anticoagulation therapy is usually 40 mg enoxaparin daily.¹⁶ The therapeutic dose of enoxaparin for thrombotic APS is 1 mg/kg subcutaneously 2 times per day. Anticoagulation therapy is started at the beginning of ovarian stimulation, suspended before oocyte retrieval, and resumed after retrieval to continue throughout pregnancy. If pregnancy is not achieved or if the embryos will be frozen, enoxaparin may be discontinued after estrogen levels drop, though the optimal duration of anticoagulation therapy has not been studied.

Patients with negative aPL may still have some level of risk. ART in these patients is not addressed by the ACR guidelines; the decision to pursue ART should be based on patient-provider discussions.¹⁶

Safety and Efficacy of ART in SLE

Published studies demonstrate the safety and efficacy of ART in SLE. In a multicenter retrospective study of 142 women with SLE, ART led to 66 intrauterine pregnancies and 60 successful deliveries (65 infants). The most common adverse pregnancy outcomes included premature delivery, gestational diabetes mellitus, disease flares, and low birthweight infants. No cases of OHSS or thrombosis were observed.¹⁸

Another study of ART in 28 women with SLE and/or APS reported 18 pregnancies (64.2%). The researchers observed disease flares in 3 cases, 1 case of OHSS, and no thrombotic events.¹⁹

Preconception Considerations for Fertility and ART

Preconception counseling is essential for women with SLE. With effective planning and care, most women can have successful pregnancies. Preconception counseling and care should consider the potential for fertility problems.

Fertility- and ART-related recommendations from the EULAR for health care providers involved in the care of women with SLE and/or APS include⁷:

• Women should be counseled about the negative effects of increasing age (especially due to delayed pregnancy) and lifestyle choices, such as tobacco and alcohol use.
• Gondatropin-releasing hormone (GnRH) analogs should be considered when administering cyclophosphamide to preserve fertility. If SLE and/or APS is not life threatening, consider less gonadotoxic treatments.
• When there are multiple risk factors for impaired fertility, ovarian reserve should be assessed at a younger age than recommended for the general population.
• ART can be safely used for women with inactive SLE and who are receiving appropriate antithrombotic treatment, if they test with antiphospholipid (aPL)-positivity.