Fertility and pregnancy in systemic lupus erythematosus

Etiology of infertility in subsets of SLE patients

Causes of decreased fertility in some SLE patients include advanced maternal age, active disease or disease-related damage, and medication effects. Many SLE patients are older when they attempt to conceive as they may have been counseled to avoid pregnancy if their disease has not been quiescent, and thus, they may encounter difficulties related to an age-associated loss of ovarian reserve and oocyte quality.

Premature ovarian failure, defined as persistent amenorrhea with elevated FSH prior to age 40 years, is sometimes due to autoimmune etiologies but it is rare for these patients to have coexisting systemic autoimmune disease. However, SLE patients may have menstrual disturbances or amenorrhea related to active disease. Anti-Mullerian hormone (AMH) serum level, a marker of ovarian reserve, has been reported to be lower in a group of non-cyclophosphamide-treated SLE patients than in age-matched healthy controls, although use of oral contraceptives and other medications differed between the two groups. Lupus patients with renal insufficiency or failure may develop hypofertility or infertility through a disruption of the hypothalamic–pituitary axis that can reverse with renal transplantation. While early reports proposed an association among anti-phospholipid antibodies (aPL), infertility, and poor in vitro fertilization (IVF) outcome, recent controlled studies do not support this association and so treatment of aPL for infertility in the absence of antiphospholipid syndrome with obstetrical complications is not recommended.

Cyclophosphamide (CYC), used for severe lupus manifestations including nephritis and central nervous system disease, accounts for the majority of fertility issues in SLE patients. Patients administered CYC are more likely to maintain fertility if they are younger than 30 years old, the total number of monthly intravenous pulses is six or less, the cumulative dose is less than 7 g, and if there is no amenorrhea before or during administration.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for control of mild SLE symptoms. Despite experimental and anecdotal data suggesting that these drugs have the potential to interfere with normal follicular rupture and ovulation, systematic clinical data are lacking. High-dose corticosteroids may also affect the menstrual cycle, but it is difficult to distinguish effects of disease activity from those of the corticosteroid itself.

Preservation of fertility

Counseling and frank discussion regarding risk and benefit of both the CYC therapy and any suggested fertility prevention must be done with each individual patient. The dose of CYC should be minimized especially in older patients. The use of the Euro-Lupus CYC regimen, mycophenolate mofetil, or other non-CYC combination therapies may be helpful in this regard.

Treatment to provide ovarian protection from CYC effects with gonadotrophic hormone receptor (GnRH) agonists has become common practice, although the benefit of this therapy is still somewhat controversial. Administration of the GnRH agonist leuprolide at 10–14 days prior to CYC pulse therapy was shown to be protective against development of persistent amenorrhea in one large series, and a recent meta-analysis calculated a 68% increase in rate of preserved ovarian function in treated versus untreated women. GnRH-agonist therapy should not be administered immediately before CYC: if given in the follicular part of the cycle, it can stimulate the ovaries (potentially worsening ovarian damage) and increase estrogen levels. ^. As a result, patients are rarely treated with GnRH agonists before their first CYC infusion, but can be treated at monthly intervals mid-cycle thereafter. In the past, the traditional measure of infertility after CYC has been the development of amenorrhea; newer objective measures such as AMH level may provide a better assessment of ovarian reserve in the future

Long-term preservation of fertility through cryopreservation techniques, while appealing in theory, presents a challenge when administration of CYC is deemed urgent (as is often the case for severe disease). Cryopreservation of oocytes or embryos requires ovarian hyperstimulation, a procedure that involves a time delay in lupus treatment of at least 2 weeks as well as elevated levels of estrogen, both usually contraindicated in the setting of lupus flare. Although patient's psychosocial issues and beliefs and financial constraints may limit use of these techniques, increasing numbers of women in their early to mid-thirties in the general population are pursuing oocyte or freezing for fertility preservation in anticipation of IVF in future years. This fertility-preservation technique can be considered for SLE patients with stable inactive disease who are faced with age-related fertility concerns (discussed later).

Cryopreservation of ovarian tissue is an emerging technique in which ovarian tissue is removed through laparoscopic oophorectomy, without the need for ovarian stimulation or significant time delay. Oocytes from the retrieved tissue may be matured in vitro and then frozen, or the ovarian tissue itself may be frozen in thin strips for later in vitro oocyte maturation or autotransplantation. When fertility is not or cannot be preserved with available methods, IVF utilizing a donor oocyte and partner's sperm provides an alternative option for pregnancy during a period of quiescent disease.

Assisted reproductive techniques

Ovulation induction (OI) and the controlled ovarian hyperstimulation necessary for IVF may increase risk of flare and/or thrombosis in patients with SLE. Risk appears to be related to degree of elevation in 17β-estradiol levels. While individual case reports describe OI- and IVF-related flare and thrombosis in SLE and antiphospholipid syndrome (APS) patients, two large series report overall positive outcomes in a combined total of 177 OI and IVF cycles in patients with SLE and/or APS. Flare occurred in 21%–42% of SLE patients but was generally mild and responsive to therapy. Risk of both flare and thrombosis was greater if the diagnosis of SLE was not known at the start of the cycle. Flare risk was higher with use of gonadotrophins than with the estrogen antagonist clomiphene, but pregnancy rates for clomiphene were significantly lower. Thrombosis was rare, although almost all patients with positive aPL or APS were treated throughout the cycle with some form of anticoagulation (aspirin and/or heparin). While one group has reported the absence of thrombotic complications in 17 aPL-positive patients undergoing ovulation induction without use of any prophylactic anticoagulation, no controlled studies have been performed. Thrombosis risk is higher with IVF protocols than with OI due to the higher estrogen levels generated, with thrombosis risk most closely associated with the complication of ovarian hyperstimulation syndrome, a capillary-leak syndrome resulting in hemoconcentration.

Options to minimize overall IVF risk for patients with SLE and aPL generally involve modulating the IVF process to avoid very high estrogen levels. Prophylactic heparin therapy for patients with positive aPL is usually recommended, given the likely increase in thrombosis risk and the absence of data-derived guidelines. We recommend that patients with APS on warfarin switch to therapeutic heparin or low molecular weight heparin prior to the start of the cycle and to hold it 12–24 h before oocyte retrieval with resumption 12 h later.

There are no data to support prophylactic low-dose corticosteroid to reduce risk of lupus flare through IVF cycles; however, patients should be closely observed for evidence of flare and treated promptly when flare occurs. Importantly, assisted-reproductive techniques should only be performed in lupus patients who have stable inactive disease on pregnancy-compatible medications, that is, those who would otherwise be considered safe to undertake pregnancy. Occasionally, a patient may be considered suitable for IVF but not pregnancy, for example, those with significant renal insufficiency or pulmonary hypertension. Such patients may tolerate ovarian stimulation but not the hemodynamic stress of pregnancy; in this situation, IVF followed by embryo transfer to a gestational carrier can result in a biological child. For every patient, and whatever the specific procedure planned, collaboration among the reproductive medicine specialist, high-risk obstetrician, and rheumatologist is critical for maximizing the potential for a successful outcome while minimizing maternal risk.