Chapter 41 Fertility in Systemic Lupus Erythematosus
Infertility, of either sex, is the inability to create an embryo. In patients with systemic lupus erythematosus (SLE), causes of infertility include severe illness, organ failure, and cytotoxic treatment. Most SLE patients are fertile. Many of those who are not avail themselves of assisted reproductive technologies (ART). Twenty-seven percent of SLE, antiphospholipid syndrome, and lupus-like disease pregnancies seen by the author in the past 2 years used ART to achieve conception.
Among SLE patients, fetal loss (inability to carry a documented fetus to viability) is more prevalent than infertility. Early fetal losses (before 10 menstrual weeks) are often unexplained or attributable to genetic fetal abnormalities. Later fetal losses are usually due to active disease or to disease-induced damage. Infertility and fetal loss together constitute pregnancy failure, a classification of which is shown in Table 41.1.
|Infertility (failure to conceive)|
|Male||Sperm count, quality|
|Fetal loss (recurrent pregnancy loss)|
|Congenital heart block|
The definition of infertility is 1 year of unprotected regular coitus without conception. (Details of frequency and timing of coitus are not considered in the definition.) Infertility affects 10 to 15% of reproductive-age couples and remains unexplained in 10 to 20% of infertile couples.3 Common causes of infertility are outlined in Table 41.2. Only drug-induced ovarian failure is an SLE-specific cause.
|Primary ovarian failure||Antiovarian antibody, cyclophosphamide|
|Endocrine abnormality||Hypothyroidism (Hashimoto)|
|Uterine anatomic abnormality||Septate uterus, myomata|
|Fallopian anatomic abnormality||Endometriosis, salpingitis|
|Parenteral chromosomal abnormality||Maternal XO|
|Fetal chromosomal abnormality||Lethal mutation|
|Male factor||Inadequate sperm number or function, infrequent intercourse|
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.
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.
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.
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).
|Drug||Impairment of Fertility|
|NSAID||Cases of inhibition of follicle rupture|
|Methotrexate||Oligospermia at high doses|
|Cyclophosphamide||In males and females|
Source: Adapted from consensus documents developed at the Fourth International Conference on Sex Hormones, Pregnancy and the Rheumatic Diseases, Stresa, Italy, September 20—22, 2004.
Recurrent losses of an established fetus occurring before 10 gestational weeks, or before identification of a fetal heartbeat, are embryonic losses; those occurring after 10 weeks or fetal heartbeat are fetal deaths. Recurrent pregnancy losses may be disease related or disease independent.
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 VLeiden, prothrombin 20210, and MTHFR mutations) may also cause fetal death, the risk imparted by these abnormalities is still debated.15,16
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.