after 2 years of infertility due to a severe male factor. She had a normal ovarian reserve. The last lupus flare occurred 12 months before and was managed with corticosteroids. At the time of attending the fertility unit, she was not receiving any treatment. At the age of 28, with a different partner, the woman reported a preterm birth at 32 weeks for severe preeclampsia and fetal growth restriction, delivered by cesarean section. In the postpartum period, the patient developed a deep venous thrombosis that was treated with heparin. She was then tested for thrombotic markers and was diagnosed with positive anti‐cardiolipin antibodies.
Background
SLE is a chronic multisystem autoimmune disease with a highly variable course of flares and remissions[1]. It is characterized by the generation of autoantibodies and the deposition of immune complexes in various organs, causing inflammatory responses and tissue damage [2]. SLE is more prevalent in women, with a female to male ratio of 9:1 and mainly affects young women during their childbearing years [3]. Although the etiology of the disease is not yet fully known, the high prevalence of women suffering from SLE suggests that estrogen hormones play a role in its pathogenesis. Some women with SLE experience menstrual irregularities [4]. Anticoagulant drugs or, more rarely, thrombocytopenia, can contribute to menorrhagia. A hypothalamic‐pituitary‐ovarian (HPO) axis dysfunction or lupus nephritis‐related hyperprolactinemia can lead to amenorrhea. Permanent amenorrhea can also be due to premature ovarian failure, autoimmune or drug induced. Despite these issues, reproductive function in women with mild SLE is comparable to the general healthy population [5]. The patient in the Case History presented with a normal ovarian reserve.
Treatment, which includes nonsteroidal anti‐inflammatory drugs, glucocorticoids and immunosuppressive drugs, aims to minimize or stop disease progression and organ damage. Cyclophosphamide (CTX), the agent of choice used to treat severe disease flares, may induce ovarian failure by depletion of oocytes [6]. Gonadotoxic effects of CTX are permanent and related to cumulative dose, age of exposure and treatment duration. SLE can occur in association with other autoimmune diseases, such as antiphospholipid syndrome (APS). APS is a systemic acquired thrombophilic disorder, with a prevalence of 40–50 cases per 100,000 persons [7]. It is characterized by vascular thrombosis and/or obstetric complications in the presence of antiphospholipid (aPL) antibodies (lupus anticoagulant, anticardiolipin antibodies (aCL) or antibeta2 glycoprotein I antibodies) [7]. Diagnosis consists of at least one clinical and one laboratory criteria. The presence of aPL antibodies is not a cause of reduced fertility, hence routine screening is not required in the infertile population [8]. Around 40% of SLE patients carry aPL, and aPL have been shown to be one of the strongest predictors of adverse events, vascular or obstetric. In the Case History, the patient, suffering from SLE with positive aCL antibodies, had a premature delivery <34 weeks of gestation due to severe preeclampsia and fetal growth restriction, and thrombotic complications in the postpartum period.
Management options
Accurate preconception counseling is required in SLE patients to assess disease activity and drug compatibility with pregnancy. Pregnancies should be planned during periods of disease stability, and treatment needs to be adjusted to obtain the remission of the disease or modified to avoid its potential teratogenic effects. Well‐controlled disease at conception is associated with better maternal and fetal outcomes. However, the postponement of conception, recommended in SLE patients with active disease until a period of clinical remission or disease stability of at least 6 months, may result in a decrease in the ovarian reserve associated with age [9]. In the Case History, ovarian stimulation was initiated 12 months after the last lupus flare.
Drugs commonly used in infertility treatments are not contraindicated in patients with SLE. Controlled ovarian stimulation is generally safe for infertile women diagnosed with SLE and/or APS, especially in patients with a stable disease. In the presence of active SLE, poorly controlled arterial hypertension, heart or renal disease and major prior thrombotic events, infertility treatments should be discouraged due to the high risk of maternal and fetal complications during pregnancy [10].
In aPL‐positive women undergoing ovarian stimulation, an antithrombotic treatment according to the individual risk profile is highly recommended to prevent vascular thrombosis [11]:
Women with aPL antibodies and a history of thrombosis: should receive therapeutic doses of low molecular weight heparin (LMWH) and low dose aspirin (LDA) from the beginning of COS;
Women with aPL antibodies but no history of thrombosis: should receive prophylactic LMWH starting on the day of embryo transfer, in combination with LDA [9].
In all cases, LMWH should be stopped 12–24 hours before the procedure of egg retrieval and started again 6–12 hours later if no bleeding occurs. LDA should be discontinued 5–7 days before egg retrieval and resumed the following day. According to the 2017 European League Against Rheumatism (EULAR) recommendations, LDA should be stopped only 3 days before oocyte retrieval [9]. Heparin and aspirin are to be maintained until the day of the pregnancy test and should be continued in the case of pregnancy [11].
In women with only SLE and not APS, anticoagulation is not recommended, but the use of anti‐inflammatory therapy (corticosteroids, immunosuppressants) should be considered depending on the disease activity to prevent SLE flares, especially when gonadotropins are used and serum estradiol level rises [12].
Stimulation protocols should be adapted for each patient, balancing safety and risks. Patients with SLE, especially if with concomitant aPL positivity, are at higher risk of complications linked to hormonal stimulation. The estrogenic peak reached during the ovarian stimulation increases the risk of thrombosis, ovarian hyperstimulation syndrome (OHSS) and lupus flare. The incidence of thrombotic complications is low and is often linked to a lack of adequate prophylactic anticoagulant therapy. During ovarian stimulation the predominant estrogen involved is 17 beta estradiol, which is less procoagulant than a synthetic one, and estrogens are only temporarily elevated. The risk of thrombosis during infertility treatments is lower than that observed during pregnancy where estrogens are up by 10‐fold than those obtained with fertility medications. Even if the risk of OHSS is comparable to that observed in the general population of infertile patients (3–8%) [13], SLE patients are at higher risk for OHSS‐related complications. The rate of disease exacerbations after infertility treatments in patients with a well‐controlled or quiescent disease appears to be comparable with nonstimulated women with SLE [10]. In the Case History, thrombotic complications were prevented by the administration of anticoagulants (aspirin, heparin) during and after ovarian stimulation, while lupus activity was controlled with the use of corticosteroids.
The use of oral contraceptives for cycle programming should be discouraged because of the increased risk of thrombosis, particularly in women with positive aPL[14]. A milder hormonal stimulation, a GnRH antagonist protocol, a GnRH agonist for ovulation triggering, administration of lower doses of hCG, freeze‐all approach and a single embryo transfer are some of the strategies available to prevent OHSS syndrome[11].
Progestins can be administered in patients with SLE and/or APS for luteal phase support (LPS) and during pregnancy. Depending on the individual thromboembolic risk, anticoagulant therapy may be required during progestins administration (aPL positivity) [9]. Nonoral route administration of natural progesterone (P) should be preferred to synthetic oral drugs in terms of thrombotic risk prevention [11].
Pregnancy and SLE
A strict clinical, serological and laboratory follow‐up is mandatory during pregnancy to recognize early the signs of disease flare or pregnancy complications. The evaluation should include physical examination, with particular attention to blood pressure monitoring, and regular blood tests including blood count, renal and hepatic function, urine analysis and anti‐dsDNA and complement. Furthermore, pregnant women with SLE and/or APS, in addition to routine
