SLE and assisted reproductive technology
When fertility is impaired in women with SLE for any reason, ART may be necessary to achieve pregnancy. Assuring the safety of such elective procedures in patients with SLE, especially those with positive aPL or APS, is a primary concern and requires guidance from both rheumatology and reproductive endocrinology and infertility (REI) specialists.
ART procedures have significantly evolved in terms of both safety and success rates. Procedures vary, but often include ovarian stimulation, oocyte retrieval, IVF and transfer of the fertilised embryo into the uterus. Once oocytes are retrieved—usually through transvaginal puncture following ovarian stimulation—they may be frozen or fertilised through incubation with sperm or intracytoplasmic sperm injection. Following fertilisation and incubation, the embryo may be transferred into the woman’s uterus during either the cleavage stage (2–3 days postretrieval) or the blastocyst stage (5–6 days postretrieval). In recent years, blastocyst transfer has become most common; blastocysts may also be frozen and transferred later in a non-stimulated cycle.56 Protocol changes have decreased both risk and severity of ovarian hyperstimulation syndrome (OHSS), where cystic enlargement of the ovaries results in fluid shifts from the intravascular to the third space due to increased capillary permeability.57 For some patients, guidance from preimplantation genetic testing of embryos prior to transfer can improve the likelihood that the transferred euploid embryos result in successful implantation, clinical pregnancy and live birth.58
Ovarian stimulation is generally considered to be safe in patients with SLE if disease is clinically inactive and prophylactic anticoagulant medications are administered when indicated.59 The ACR reproductive health guideline details assessment and management of patients with SLE and aPL-positive patients for ART.1 All patients with SLE should be assessed for disease activity and ART deferred for those with moderate or severe disease activity. If immediate embryo transfer is planned, patients should be on pregnancy-compatible medications. Prophylactic corticosteroid to prevent flare is not generally recommended.
aPL status should be determined prior to ovarian stimulation. The ACR guideline uses APS classification criteria to define a positive aPL test: positive LAC, positive aCL (IgG or IgM >40 units) or positive anti-β2GPI (IgG or IgM >99%).48 Recommendations for low titre or ‘non-criteria’ aPL are not provided; for these patients, therapy decisions should be based on clinical and laboratory history and physician-patient discussion. For classification criteria-positive aPL patients, treatment with low molecular weight heparin (usually enoxaparin) during the stimulation cycle is recommended. For aPL-positive patients with no obstetric or thrombotic history, the recommendation for prophylactic enoxaparin 40 mg subcutaneously daily is conditional; that is, the decision to proceed is based on individualised patient-physician discussion. For aPL-positive patients meeting classification criteria for obstetric APS, prophylactic enoxaparin (40 mg subcutaneously daily) is strongly recommended; for those meeting APS classification criteria for thrombotic APS, therapeutic enoxaparin (1 mg/kg two times per day subcutaneously) is strongly recommended. Enoxaparin is generally held 24 hours prior to oocyte extraction and resumed within 12–24 hours. If pregnancy is not achieved, or if oocytes or embryos will be frozen, then enoxaparin is discontinued after 7–10 days.1
Published reports confirm the relative safety of ovarian stimulation and IVF in women with SLE and/or APS, with the lowest rates of adverse events in the most recently reported series.60 61 While there are risks, including SLE flare and thrombosis, complications are infrequent.2 IVF-induced thromboses have often occurred in the context of OHSS; however, incidence and severity of OHSS have decreased dramatically with current protocols using GnRH-a rather than human chorionic gonadotropin to trigger final oocyte maturation.62 In a single-centre review of 97 procedures in 37 women with SLE and/or APS, the overall complication rate was 8%, with 4 SLE flares and 4 thromboses; furthermore, half of the complications were in patients who prematurely discontinued medications, and no patient developed OHSS.60 Similarly, another recent multicentre study of 58 cycles in 28 women with SLE and/or APS reported only 3 lupus flares (including 1 in a woman who self-discontinued medication) and 1 case of OHSS with no thromboses.61
Successful oocyte cryopreservation is the most recent significant innovation in ART, increasingly used for both medical and social reasons. Early attempts at oocyte cryopreservation used a slow cooling procedure with limited success. Use of vitrification (a rapid freezing technique) has improved outcomes so that frozen oocytes have IVF success rates equal to those of fresh oocytes. In 2012, the Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology determined oocyte cryopreservation was no longer experimental63; since then, rates of elective oocyte freezing have increased yearly.64 Most centres recommend freezing before age 35 years when possible: the maternal age at freezing strongly affects likelihood of later successful embryo formation and successful pregnancy. However, studies suggest that women often underestimate the effect of age on future fertility.65 Social advantages of egg freezing are obvious: women may preserve their fertility to pursue career goals, achieve financial security or find a desirable partner.
Medical oocyte cryopreservation is currently offered as fertility preservation to young cancer patients facing gonadotoxic therapy.66 Patients with SLE, especially those without a long-term partner, may have both medical and social incentives to pursue oocyte cryopreservation. For many patients, cryopreserved oocytes would increase options regarding pregnancy planning with respect to disease-related activity and age-related fertility decline. A woman requiring therapy with pregnancy-incompatible medications such as MMF or methotrexate (but not CYC) may continue medication and safely undertake egg freezing without concern for teratogenic effects,1 preserving her potential for biological offspring in the future when she no longer requires these medications. Patients with SLE are counselled to pursue pregnancy during periods of quiescent disease, which may lead to deferred pregnancy plans and older age with reduced fertility when disease quiescence is finally achieved. While availability of oocyte cryopreservation is still limited in terms of access to specialists and insurance coverage, it is hoped that availability will increase in coming years particularly for medical considerations beyond cancer.
Other ART-related procedures offer additional options in family planning for some patients. While not studied specifically in patients with SLE, donor egg use is an effective fertility therapy and has been simplified by availability of oocyte cryopreservation; previously, egg donation required fresh oocytes, making timing of the procedure more complicated. Some women with POF or age-related fertility decline who are unable to successfully conceive with IVF may choose to pursue this option for a successful pregnancy. Finally, for women with disease-related damage such as pulmonary hypertension, cardiomyopathy or severe renal insufficiency that precludes pregnancy due to maternal risk, use of a gestational carrier may be an option, although potentially limited by financial, legal, cultural and other factors.