Age-Related Infertility

Advancing maternal age is a major contributor to infertility. Thirty-three percent of normal women are infertile at age 40, and 87% at age 45,² even when menstrual cycles are still normal. In my rheumatology practice, which focuses on rheumatic disease pregnancy, 88% of patients seeking care for pregnancy-related issues are older than 30 years, 38% older than 35, and 15% older than 40. In this practice, the most common cause of infertility is advanced maternal age, followed by male factor infertility, and, uncommonly, cyclophosphamide-induced ovarian failure. No published studies have systematically analyzed causes of infertility in patients with SLE.

Disease-Related Infertility

In vitro studies demonstrate that antiphospholipid antibodies (aPLs) are toxic to trophoblast growth and function; aPLs can inhibit implantation and trophoblast invasion, events that occur within the first few weeks of fetal life.^4–6 These effects might be perceived as infertility or very early embryonic death, but because women with aPLs are generally fertile, the importance of the laboratory observations remains unclear.

Autoimmune Disease as Cause of Infertility

Diagnosable autoimmune disease is an infrequent cause of infertility in an apparently well population. One infertility clinic found only 1.5% of examined patients had SLE.⁷ Another found aPLs equally often in infertile and fertile women.⁸ A third clinic randomized antinuclear antibody-, anticardiolipin antibody-, and anti-β₂ glycoprotein I antibody—positive infertile patients to a heparin-aspirin regimen, a treatment directed against antiphospholipid syndrome, during ART attempts.⁹ The treatment was ineffective.

Treatment-Related Infertility

SLE patients treated with cyclophosphamide may develop ovarian failure. In general, the risk of ovarian failure correlates with age at first dose of (intravenous) cyclophosphamide and number of doses, and ranges from 12% for women aged under 25 years to 62% for women older than 30.^10,11 Suppression of gonadal function during cyclophosphamide treatment for the purpose of protecting ovaries or testes is often advocated. Recommendations include use of gonadotropin-releasing hormone antagonists (leuprolide) or progestin/estrogen hormone replacement (oral contraceptive pills).¹² Preliminary data support this recommendation.¹³

Methotrexate and other cytotoxic agents may also cause ovarian failure. Nonsteroidal anti-inflammatory drugs inhibit cilia motion in the fallopian tube, delaying transport of ova, and reducing chances for fertilization. The effect on fertility of most drugs used in SLE patients is unknown (Table 41.3).

TABLE 41.3 EFFECTS OF SELECTED ANTIRHEUMATIC DRUGS ON FERTILITY

Disease-Independent Recurrent Pregnancy Losses

Studies on recurrent pregnancy losses variously define “recurrent” as two or three, consecutive or not, embryonic and fetal losses, leading to some inconsistency of conclusions. In one highly rigorous study, that defined recurrence as three or more documented losses, and that used chromosomal/genetic, bacteriologic, radio-graphic, and hormonal assessments to find causes, approximately half of the women had no defined cause, 20% had maternal anatomic causes, 20% had antiphospholipid and related autoantibodies, 10% fetal structural or genetic abnormalities, and 1% infection.¹⁴ Although nonimmunologic coagulopathies (especially factor V_Leiden, prothrombin 20210, and MTHFR mutations) may also cause fetal death, the risk imparted by these abnormalities is still debated.^15,16

Lupus-Related Recurrent Pregnancy Loss

Differing referral patterns and clinical mixes of patients make it difficult to apportion disease-related causes of recurrent pregnancy loss among patients with SLE. Antiphospholipid antibody—related losses account for a large percentage in all series; severe pre-eclampsia (often associated with maternal hypertension, nephritis, and/or renal insufficiency) account for many additional losses; and active SLE, premature rupture of membranes, and maternal diabetes, the latter two related to corticosteroid therapy, are responsible for fetal death in a minority of patients. Congenital complete heart block, associated with anti-Ro/SSA and anti-La/SSB antibodies, is a rare cause of fetal death. Causes of pregnancy loss have been reviewed extensively elsewhere,¹ and in Chapter 40.