Systemic lupus erythematosus in women: Impact on family size
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often affects women in their reproductive years. At diagnosis, these women are faced with a life-long illness that may have considerable impact not only on their physical health, but also on their existing family and/or reproductive potential. With recent advances in the management of this condition, it is hoped that good disease control can be achieved in the majority of cases, and therefore most of these women are not advised to avoid pregnancy. However, multiple disease-related factors may still affect the number of children born to women with SLE.
The influence of SLE on reproduction and family size has been investigated (1–3). A study by Hardy et al demonstrated that white women with SLE appeared less likely to have more than 2 children compared with a control group (odds ratio [OR] 0.56, 95% confidence interval [95% CI] 0.31–1.03) (1). In a population-based study of women with rheumatic diseases, a lower number of births and a reduced period of reproduction were observed in women with connective tissue diseases, including SLE, compared with healthy controls (mean, 95% CI 1.7, 1.5–1.9 versus 2.2, 2.1–2.3) (2). The interpregnancy interval was longer and the proportion of women achieving a subsequent pregnancy was reduced in women with connective tissue diseases. However, these findings may not be specific for patients with SLE.
Similar data were shown in a study of women with rheumatoid arthritis (RA) (4). Women diagnosed with RA prior to the birth of their first child had fewer pregnancies and children, and 20% reported that RA had affected their decision to have children or their decision about family size. The disease aspects most commonly reported to affect childbearing decisions were concerns about being able to care for a child, medication issues (including fear that medication would affect the fetus and concerns about stopping medication), as well as fears that their own children may eventually develop the disease.
In women with SLE, several characteristics of the disease should be considered before planning pregnancy, and these characteristics may also impact a woman's capacity and decision to have children. Although still controversial, there is a reported probable increased risk of disease flare during pregnancy and in the postpartum period. Although several small studies found no significant increase in SLE activity during pregnancy (5–8), more recent studies have found a 2- to 3-fold increase in SLE activity during pregnancy (9–12). Based on these studies, 35–70% of all pregnancies will have measurable disease activity, with most studies showing the risk to be 40–50% (7, 8, 10, 11). The risk for a moderate to severe flare is lower and ranges from 15–30% (13–15). Recent data have demonstrated the absence of fetal toxicity with the use of hydroxychloroquine (HCQ) in pregnancy (16, 17). Because HCQ discontinuation is associated with an increased risk of disease flare in pregnant and nonpregnant patients (16–18), and because HCQ is no longer contraindicated during pregnancy (19), it is likely that the risk of disease flare in pregnancy will be reduced. Nevertheless, disease exacerbation can occur at any time during pregnancy, as well as several months after delivery. Women with no or mild disease activity in the 6 months preceding pregnancy are less likely to experience disease exacerbation (20). For this reason, it is generally recommended that women have stable disease for 6 months before conceiving. This recommendation could potentially delay motherhood or increase the interval between pregnancies in some women.
Pregnant women with SLE are at increased risk of miscarriage or stillbirth. Approximately 20% of pregnancies in women with SLE will end in a miscarriage (a pregnancy loss at <20 weeks gestation), as compared with 9% in the general population (1, 21). Some studies have demonstrated that this risk was present even before SLE diagnosis, with almost a 2-fold increase compared with controls (OR 1.99, 95% CI 1.28–3.10) (1). The risk of stillbirth (a pregnancy loss at >20 weeks gestation) has also been shown to be elevated in several studies, with an ∼3-fold increase compared with the general population (9). The two most important risk factors for pregnancy loss are increased SLE activity and antiphospholipid syndrome (21). Obviously, miscarriages and stillbirths may directly contribute to a reduction in family size.
In addition, SLE is associated with an increased risk of maternal complications during pregnancy, including pregnancy-induced hypertension, preeclampsia, and thromboembolic events (20). In the general population, preeclampsia complicates 5–8% of pregnancies (20). However, the rate of preeclampsia ranges from 13–35% in women with SLE (15, 21–23). Preeclampsia can lead to significant complications, including preterm birth, stroke, and even death (20).
Furthermore, certain drugs used to treat SLE manifestations, such as methotrexate and cyclophosphamide, are contraindicated during pregnancy because of potential fetal harm (24). Recently, mycophenolate mofetil, a relatively recent addition to the treatment of SLE, has been shown to be potentially associated with a specific pattern of congenital malformations, which notably includes cleft lip and palate, microtia, micrognathia, and hypertelorism (25–28). These medications must be discontinued or switched to safer ones in prevision of conception, and this requires planning under supervision of a health care professional. Dependence on a medication in order to maintain disease control may delay pregnancy in some patients.
Moreover, future mothers might be worried that their children may be affected by SLE, even if this risk is small. There is evidence that SLE occurrence is increased in the offspring of patients with SLE, and prevalence has been estimated at ∼4% in the children of parents with SLE (29). Other studies have shown that up to 12% of SLE patients had first-degree relatives with SLE or other connective tissue diseases (30). Other autoimmune diseases, such as autoimmune thyroid disease, are also more common in first-degree relatives, including children of patients with SLE (31). There is some evidence that the disease onset may be earlier in the child than in the affected mother (31), representing a general phenomenon reported in genetically- transmitted diseases.
As a result of drug exposure, maternal disease activity, or complications, the baby may be born prematurely, have low birth weight, or intrauterine growth retardation (IUGR). Estimates of the number of pregnancies in women with SLE that end in premature delivery (delivery before 37 weeks gestation) have ranged widely, generally between 10–50% (20); higher estimates may relate to sicker patients seen in tertiary care centers. In a population-based study of 555 SLE deliveries in the US, 21% were preterm, which corresponded to an approximately 6-fold higher rate compared with healthy women (32). In general, premature babies have an increased risk of respiratory complications, infections, developmental abnormalities (especially neurologic), and death in the neonatal period (33).
On average, ∼10% of all babies born of mothers with SLE are small for their gestational age (weight below the 10th percentile for gestational age) comparable with what would be expected in the general population (20). However, some cohorts report increased rates as high as 35% (10, 15, 21); the higher figures may again relate to sicker SLE patients from tertiary care centers. In the general population, there is some evidence that low birth-weight or IUGR babies may be at risk of developing Type 1 diabetes mellitus (34, 35), early-onset hypertension (for example, in adolescence) (36), and premature coronary artery disease (37). Some studies have suggested there is an increased risk of learning disabilities (incidence of 20–30%) in children of women with SLE, particularly in boys (38–41). However, most of these studies relied on self-report, which could have biased the estimates. Only limited data are available on the long-term outcomes of children born to mothers with SLE.
Faced with the potential risks of disease flare and/or adverse maternal and fetal outcomes, and considering the additional physical, social, and emotional demands related to the management of SLE, some women may choose not to have children. In a study assessing social functioning in 114 women with SLE, 49% had children, 32% planned to have a child or another child, 18% planned no children, and 1% were undecided. SLE was viewed as a barrier to childbearing by 27% (30). Common concerns included worries that pregnancy might exacerbate the disease, that medications or the disease might harm the fetus, and that the disease might interfere with childcare. In another study addressing disease impact on family planning in 40 women having children after SLE diagnosis, 45% of women reported anxiety about pregnancy, in most cases related to the fear of transmitting the disease to their offspring (38). In addition, 23% reported that SLE interfered with their ability to attend to their family.
Personal Relationships and Sexuality
Women with SLE have impaired sexual function (42). The disease can affect sexual function in different ways. Physical problems (i.e., chronic pain and fatigue) and emotional problems (i.e., low self-esteem and depression) can decrease sexual interest and reduce intercourse frequency. Disturbances of hormonal status by corticosteroid treatment and disease activity can reduce libido and interfere with successful reproduction (43). Partnership difficulties arising from disease-related stress can also contribute to a less active sexual life (44). In a study by Boomsma et al (45), 20% of SLE patients thought that their illness had driven their family apart or worsened their relationship with their partner.
The impact of SLE on sexuality is not necessarily addressed by health care professionals, and is not part of questionnaires used routinely to assess physical function or quality of life in SLE populations (43). A recently validated disease-specific health-related quality of life instrument, the LupusQol, assessed intimate relationships, and patients who were asked for feedback thought it was an important aspect of the questionnaire (46). Patients and health care professionals may be reluctant to discuss the issue, even when there is marked impairment of sexual function (43). This miscommunication was highlighted in a study of 74 RA patients where only one patient reported being asked if the disease had caused any sexual problems (47). Most sexually active women with SLE have problems with sexual function when acutely ill (30). Disease intrusiveness on sexuality does not seem to differ between males and females in subjects with RA, but this has not been assessed in SLE patients (48). Understanding and support during SLE disease exacerbations has been cited as the most important factor leading to an adequate sexual lifestyle adjustment (30). Therefore, health care providers should be aware of how SLE can interfere with the relationships of their patients, and affect sexuality. The health care provider can also help by encouraging communication between the patient and significant others, and by providing information on how the disease and its therapy can affect a patient's sexual life. Consultation with specialists may be helpful; a gynecology opinion may be helpful for physical factors, and psychotherapy may be useful for psychological issues.
In women with SLE, fertility might be impaired due to associated autoimmune anomalies, therapies (i.e., cyclophosphamide), and hormonal dysfunction (i.e., transient amenorrhea). Antiphospholipid antibodies (aPL) are known to be associated with pregnancy losses (49). Murine studies suggest that aPL induce pregnancy loss through disruption of placental circulation and could also interfere with implantation of the embryo (50). However, the role of aPL in infertility and in vitro fertilization failure is still controversial in humans. Several retrospective studies have shown a positive association between aPL and in vitro fertilization failure, although prospective studies, the largest study assessing 793 women, have not confirmed this (51, 52). The underlying mechanisms by which aPL impair reproductive function are still obscure.
Although it is unclear if the disease itself is associated with infertility, some drugs used in its treatment might cause infertility that is either reversible (i.e., nonsteroidal antiinflammatory drugs [NSAIDs]) or potentially irreversible (i.e., cyclophosphamide) (43). Prostaglandins, inhibited by NSAIDs, are involved in ovulation and implantation. Several case reports and small series of women with rheumatic diseases have described transient infertility following treatment with NSAIDs, including indomethacin, diclofenac, and naproxen (53, 54). Animal and human studies have shown that NSAIDs can inhibit rupture of the luteinized follicle, which can cause infertility (43, 55). However, the magnitude of this adverse effect has not been established at the present time.
Premature ovarian failure has been observed after treatment with alkylating agents such as cyclophosphamide. The gonadal toxicity of cyclophosphamide is related to cumulative dose, administration route, and age at treatment onset (56). Women younger than 26 years are less likely to develop ovarian failure than those who started treatment at a later age (57). The frequency of premature ovarian failure due to cyclophosphamide varies from 11–59% (56). A recent study showed that treatment with synthetic gonadotropin-releasing hormone (GRH) while receiving cyclophosphamide significantly reduced the risk of premature ovarian failure. Only 5% of the GRH-treated group developed ovarian failure compared with 30% in the control group (58).
Moreover, menstrual irregularities and anovulatory cycles have been reported in patients with active disease and in those treated with high-dose corticosteroids (59). End-stage renal failure secondary to lupus nephritis can also result in amenorrhea (60).
Although fertility might be impaired in several ways, there is a general notion that SLE does not diminish fertility in affected women. However, this aspect of reproduction in women with SLE has never been adequately measured. Most authors cite a 1974 study by Fraga et al (3) that reported a fertility rate in women with SLE that was comparable with an age-matched control group of healthy women. However, the fertility rate was calculated using the number of pregnancies in women who had at least 1 pregnancy. This overestimated the number of pregnancies per woman with a diagnosis of SLE, because those who did not achieve any pregnancy were excluded. In this study, a total of 79 women with SLE and 80 healthy subjects with a mean (range) age of 33.1 (17–62) years were evaluated. There were a total of 183 pregnancies among 53 patients before the clinical diagnosis of SLE, which resulted in 42 spontaneous abortions and 141 live births. In the remaining 26 SLE patients, no pregnancy occurred. Forty-two pregnancies occurred in 20 patients after the onset of SLE, and 33 women did not become pregnant again. Of the 42 pregnancies, 17 ended in spontaneous abortions and 25 in live births. In 24% of the 26 women who did not have further pregnancies, the only associated factor appeared to be disease activity. In the control group, 288 pregnancies occurred in 80 women, resulting in 252 live births. In fact, these results raise the possibility that fertility rate and birth rate might be reduced in women with SLE, particularly after diagnosis.
One difficulty in assessing fertility in women with SLE is the lack of consensus on the definition and measurement of fertility. Demographic studies generally define fertility rate as the number of live births per 1,000 women of reproductive years (usually between age 15 and 44 years) in a given year (61). From this rate, a synthetic fecundity index is generally derived in demographic studies to estimate the mean number of children that a woman would have if her fertility rate during her entire life followed the same rate as reported for her population age group (61). These measures are useful for large population studies, but are difficult to apply to the study of women with SLE, in order to allow comparison with population figures.
Some refer to fertility as the absence of infertility, which itself is usually defined as the inability of a couple of reproductive age to establish a pregnancy within one year by having regular sexual intercourse (62). To date, no study has attempted to measure the prevalence of infertility in women with SLE by using this widely accepted definition. There is also no information on the time to conception in SLE. This represents an important deficiency, as these data are necessary to counsel women with SLE regarding their childbearing capacities.
Although most women with SLE would like to have children (63), some studies have shown a reduction in their family size (1, 2). Many factors, both physical and psychosocial, may influence childbearing decisions and the capacity to have children. The relative importance of these factors may vary according to disease activity, damage, and/or treatment. More studies are needed to evaluate how SLE affects reproduction, particularly the extent to which fertility is altered in women with SLE.
Dr. Vinet had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Vinet, Pineau, Gordon, Clarke, Bernatsky.
Acquisition of data. Vinet, Gordon.
Analysis and interpretation of data. Vinet, Pineau, Gordon, Clarke, Bernatsky.
Manuscript preparation. Vinet, Pineau, Gordon, Clarke, Bernatsky.