Female Perspective

Several studies indicate that family size is diminished in women with RA as a result of impaired fertility, which already may be present before the diagnosis of RA is made. Women with RA experience more difficulties in conceiving, as indicated by a longer time to pregnancy (TTP). Previous studies showed that 25% to 42% of patients with RA did not conceive within 1 year. For comparison, in the general population, the median prevalence of subfertility, defined as TTP of greater than 12 months, is 9%, with a range of 3.5% to 24.2% depending on the geographic area.

Different factors might be associated with the impaired fertility. Earlier menopause has been reported in women with RA, and it has been postulated that these patients may have a smaller ovarian reserve. This could explain both impaired fertility as well as earlier menopause. In early RA, the levels of serum anti-Müllerian hormone (AMH), a reliable biomarker for ovarian reserve, did not differ from healthy controls. On the other hand, Henes and colleagues showed that AMH levels are decreased in established RA, suggesting that ovarian reserve declines secondary to the RA disease process.

Personal choices, due to RA-related concerns, have been shown to be at least partially responsible for the smaller family size, but cannot account for the observed impaired fertility. Disease activity, on the other hand, appears to contribute to impaired fertility. Brouwer and colleagues showed that 67% of women with active disease (Disease Activity Score-28 [DAS28] >5.1) had a TTP of more than 1 year compared with 30% in women in remission (DAS28 <2.6).

Antirheumatic drugs also have been associated with increased TTP, including nonsteroidal anti-inflammatory drugs (NSAIDs) and prednisone (in a dose >7.5 mg daily). NSAIDs inhibit the production of prostaglandins, which play a role in ovulation and blastocyst implantation. The effect of glucocorticoids on fertility is possibly due to (1) a transient suppression of the hypothalamic-pituitary-ovarian axis or (2) a direct effect on the ovarian function and/or endometrium. It has been postulated that previous use of methotrexate (MTX) might impair fertility. The association between MTX and impaired fertility is mainly based on studies in oncology and animal models. Recent studies, however, demonstrated that prior and short-term MTX treatment, respectively, did not affect the TTP and ovarian reserve.

Another reason for the impaired fertility in patients with RA might be a result of a lower intercourse frequency. These studies, however, were mainly conducted in postmenopausal patients with RA, and it is unclear whether this also applies to younger patients with RA with a desire to conceive.

Male Perspective

Less is known about fertility problems and pregnancy outcomes in male patients with RA, because no good studies have been performed. Lower testosterone levels have been described in men with RA, but whether this results in lower fertility is not known.

Additionally, literature about the effect of antirheumatic drugs on fertility are scarce. Sulfasalazine (SSZ) may cause oligospermia, reduce sperm motility, and increase abnormal sperm morphology. Fortunately, drug withdrawal usually results in recovery of spermatogenesis after 2 months.

The 3E (Evidence, Expertise, Exchange) initiative on the use of MTX recommends discontinuing MTX at least 3 months before a planned pregnancy, although underlying evidence for this is lacking. Recent studies showed that paternal use of low-dose MTX was not associated with an increased risk of birth defects, although an important limitation of these studies was the relatively small sample size. Although oligospermia and reversible sterility have been observed in case reports, low-dose MTX is not, in general, linked to poor semen quality and quantity. It was initially thought that tumor necrosis factor (TNF) blockers decreased sperm quality, but more recent studies show no effect and confirm that TNF blockers do not impair male fertility and/or increase the risk of adverse pregnancy outcomes. Glucocorticoids and chronic use of NSAIDs may impair male fertility, but again, clinical studies are lacking. In vitro studies suggest that chloroquine may negatively impair sperm motility, but no clinical data are available.

Disease Activity

Given that disease activity is associated with TTP as well as pregnancy outcome in patients with RA, accurately determining RA disease activity in pregnancy is important. It is noteworthy that the erythrocyte sedimentation rate (ESR) is elevated in all pregnant women, due to increased circulating fibrinogen, plasma expansion, and decreased hemoglobin concentration. In contrast, C-reactive protein (CRP) is only slightly influenced by pregnancy. Pregnancy might also influence the visual analogue scale (VAS) of global health. Therefore, disease activity indices without an ESR and VAS are preferred during pregnancy.

Disease activity improves in pregnancy, which is probably the reason why this physiologic phenomenon has been investigated so extensively. Hench was the first to describe this phenomenon in a small retrospective study in 1938. Between 1950 and 1995, multiple retrospective and a few prospective studies confirmed his initial observation and showed that 54% to 95% of pregnant patients with RA improved, with up to 39% achieving a state of remission.

In the past 2 decades, multiple larger prospective studies have been conducted, documenting less disease improvement than previously described. In the PARA study, De Man and colleagues showed that 48% of 52 patients with initial DAS28–CRP ≥3.2 improved during pregnancy. Improvement was defined as having a good and/or moderate European League Against Rheumatism (EULAR) response. In the third trimester, approximately 50% of all pregnant patients with RA, including those with remission or low disease activity at the beginning of pregnancy, had active disease (DAS28 ≥3.2), whereas 27% of patients were in remission (DAS28 <2.6).

These different improvement rates between the earlier and more recent studies are probably due to (1) the study design (ie, retrospective versus prospective); (2) patient selection, in that some of the earlier studies included only patients with active disease; and (3) the use of various definitions for improvement and remission. In addition, clinical and radiographic outcomes have improved enormously in the past 2 decades due to new therapeutic options and a treat-to-target approach, resulting in a larger proportion of patients with RA entering their pregnancy with low disease activity.

After delivery, there is an increased risk of a flare in disease activity. Postpartum exacerbations range between 62% and 90% in several retrospective studies. In the prospective PARA cohort, a flare rate after delivery was 39% despite restarting medication. Interestingly, one-third of patients experience a flare of their disease activity after miscarriage as well.

The pregnancy-associated improvement and postpartum exacerbation of RA are likely the result of multiple hormonal and immunologic changes during pregnancy followed by the gradual return of these changes to prepregnancy values after delivery. Although multiple factors have been investigated, the exact mechanisms underlying these phenomena remain unknown.

Pregnancy Outcome

Pregnancy outcome in patients with RA is slightly less favorable, especially in patients with active disease, when compared with the general population. Brouwer and colleagues showed that the risk of a miscarriage in women with RA (17%) is comparable to the general population (11%–22%). The investigators suggest that this miscarriage rate in patients with RA might be an underestimation, however, for the following reasons: (1) the investigated cohort consisted of patients with RA with a planned pregnancy and therefore did not use MTX, which is associated with an increased risk of miscarriage; and (2) there were fewer smokers and more patients with higher education levels in this cohort than in the general population.

Recently, Wallenius and colleagues confirmed concerns regarding miscarriage risk within a Norwegian birth registry, and showed a slightly increased miscarriage rate in women with RA compared with women without an inflammatory disease, with an odds ratio (95% confidence interval) of 1.32 (1.19–1.47).

Preeclampsia is a relatively uncommon pregnancy complication. Using a large population-based health care registry, Norgaard and colleagues showed that the risk of preeclampsia increased slightly from 3.4% in unaffected women to 5.0% in women with RA and a first-time singleton birth. Other studies did not confirm the previous finding, however, probably the result of a lack of power.

Pregnant patients with RA have an increased risk for a Cesarean delivery (26%–34%) when compared with the general population (16.5%–19.5%). De Man and colleagues showed that active disease was associated with an increased risk for Cesarean delivery: 22% for the active disease group (DAS28–CRP ≥3.2) versus 10% in the group with less active disease (DAS28–CRP <3.2). However, data on Cesarean delivery should be interpreted with caution, as indications to perform a Cesarean delivery may vary for different countries.

The risk of preterm delivery, defined as a birth before 37 weeks of gestation, is increased in women with RA (9.2%–15.2%) compared with healthy controls (6.2%–7.8%). Factors associated with preterm delivery are disease severity and the use of glucocorticoids.

Impact for the Child

There is no increased risk of major congenital malformations or perinatal death found in children born to women with RA. However, multiple studies report on increased risk of small-for-gestational-age (SGA) infants in women with RA (∼10%) compared with healthy controls (∼3%). De Man and colleagues demonstrated that an increase in RA disease activity during pregnancy is independently associated with lower birth weight in the offspring, although still within the normal range. In this study, the incidence of SGA infants was 3.3%.

Lower birth weight (even within the normal range) has been associated with an increased risk of cardiovascular and metabolic disease in adulthood. This effect is even more prominent if the children display rapid catch-up growth in weight during their first year of life. A recent study showed that 28% of children born to women with RA show rapid catch-up growth, and this was associated with maternal disease activity. However, when these children were reevaluated at age 7, they did not have a high-risk profile in anthropometric measures, such as an increased blood pressure or altered body composition compared with healthy controls.