It has been known for several years that women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have fewer children than they would like to have compared to women in the normal population. A number of studies have recently addressed this issue and investigated the exact reasons for this and what options are available for patients who wish to have children.
In the case of rheumatoid arthritis, infertility is 25% (vs. 16% normal population), and subfertility, defined by a duration >1 year to a desired conception, is also twice as high at 40% vs. 20%. There are associations with the use of cortisone, NSAIDs, and especially with higher disease activity, explained Dr. Rebecca Fischer-Betz, Polyclinic for Rheumatology, Head of Pregnancy Outpatient Clinic, University Hospital Düsseldorf (D) [1]. Lupus patients, on the other hand, would not have an increased risk of infertility, but would have more frequent unsuccessful pregnancies, especially women with antiphospholipid antibodies.
A 2018 study [2] used the Norwegian Pregnancy Registry to compare pregnancy rates and time to pregnancy (TTP) in women with RA (n=180) and SLE (n=53). Age at diagnosis was lower in the lupus patients, as expected, but age at inclusion in the registry was comparable. The lupus patients were slightly more likely to have mild-active disease and they used cortisone more often, although this was not significant. However, it was found that women with lupus became pregnant significantly more often than RA patients (ratio 1.91; 95% CI 1.27-2.88; p=0.002), also they became pregnant in a significantly shorter median period (3.0 vs. 7.0 months; p=0.001).
The authors then analyzed which factors play a role: In RA, as expected, older age, regular use of NSAIDs, and poorer physical quality of life had a negative effect on pregnancy rate and TTP. SLE patients who did not achieve pregnancy had worse overall quality of life than those who did become pregnant. According to Dr. Fischer-Betz’s advice, this should be taken into account during counseling, especially with regard to an optimal medication regimen.
IL-6 associated with subfertility
A second study on fertility, originating from the Netherlands, refers in essence to the PARA* study, previously published 10 years ago, which focused on disease activity of RA in pregnancy [3]. Here there were reserve samples from some of the women. The authors wondered whether elevated levels of interleukin-6(IL-6) might have a negative effect on the onset of pregnancy. In the normal population, elevated IL-6 (and to a lesser extent TNFα) levels have been described in fertility disorders, e.g., endometriosis.
* Pregnancy-induced Amelioration of RA
In the reserve samples, cytokine levels were now examined from women with RA and childbearing potential in whom serum was available from before conception and who had eventually successfully achieved pregnancy and given birth. Sixty-one of the original 373 patients in the PARA cohort were included in this analysis. When comparing women who took <1 year to become pregnant (n=42) with those whose TTP was >1 year (n=19), there were no significant differences except for the use of cortisone, which had a negative effect on TTP here as well. Furthermore, high levels of IL-6 (but not TNFα) were associated with subfertility independent of RA activity and medication (Fig. 1) .
The authors of the study therefore conclude that possibly high IL-6 levels contribute to the fact that women with RA are more often subfertile and that this may also offer a rationale to influence this signaling pathway before conception. However, there is not much data regarding the safety of IL-6 inhibitors in pregnancy or in those of childbearing potential, which is why the authors also discuss whether TNFα blockers might be used if women do not become pregnant. Dr. Fischer-Betz referred to a small study from Japan that showed that RA patients on TNFα inhibitor therapy become pregnant slightly faster than women not taking a TNFα blocker. Because IL-6 levels are impractical to determine in routine practice, the authors suggested that elevated CRP may also be predictive of prolonged TTP.
High risk for postpartum relapses
In about 50-75% of RA patients, activity improves during pregnancy (although there are not too many prospective studies on this). However, the frequency of relapses after birth is significantly increased. In a 2019 meta-analysis [4], the authors took it upon themselves to look up which prospective studies showed disease activity in RA was declining. Studies were examined that included at least 5 patients per study and in which the authors used an objective instrument (scoring system) to measure disease activity. Only 10 studies with a total of 237 patients were included in the meta-analysis according to these criteria. Prepartum data were available for 204 of these, and postpartum disease activity data were available for 135 pregnancies.
In 60% of the women, the studies showed improvement during pregnancy on average, and postpartum worsening in 47%, although a large proportion of patients had restarted therapy after delivery. However, the results in the individual studies varied considerably in some cases, Dr. Fischer-Betz pointed out. Ultimately, this also shows how few high-quality studies exist on this topic, she concluded. Studies that take into account today’s changing therapeutic approaches would also be lacking. For example, hardly any patients would have been included who had received biologics therapy.
SpA patients less at risk
Another study looked at pregnancy complications in women with rheumatoid arthritis and spondyloarthritis (SpA) using data from a Canadian birth registry from 2005-2014 [5]. Here, pregnancy outcomes of women with RA (n=631), without inflammatory arthritis (IA, n=308 989), and SpA including PsoA (n=2461) were compared. The result: women with RA or SpA were more likely to live in rural areas at the time of delivery and were significantly more likely to have comorbidities, especially thyroid disease, hypertension, and diabetes.
Interestingly, this study showed that women with rheumatoid arthritis have a significantly increased risk for actually all pregnancy complications compared to women in the normal population, but women with spondyloarthritis do not have this increased risk (Tab.1). A clear difference was also seen with regard to therapy: Women with RA took more cortisone, NSAIDs, antimalarials, and DMARDs, as expected.
Dr. Fischer-Betz concluded by pointing out that it is not possible to read off from the registers what the effects of activity or even therapy are. “But I think the conclusion can also be drawn here that, for example, preeclampsia prophylaxis, as we recommend in lupus with aspirin, should also be considered in women with RA, certainly if these women also have other risk factors such as diabetes or hypertension.”
Take-Home Messages
- Women with lupus who want children are more likely to become successfully pregnant than women with RA. They also have a shorter time to conception.
- Higher maternal age, regular use of NSAIDs, and poorer physical quality of life prolong TTP.
- During pregnancy, more than half of the RA patients improved, but the other half of the women experienced permanent activity or even worsening, e.g., due to a reduction in therapy.
- There is a high risk of postpartum relapses.
- Women with RA, like lupus patients, also have a significantly higher risk of pregnancy complications.
Congress: Rheumatism Update 2021 (online)
Sources:
- Hot Topic: Pregnancy & Rheumatism, Rheumatism Update 2021 (online), 12.03.2021
- Göteskam Skorpen C, et al: Women with systemic lupus erythematosus get pregnant more easily than women with rheumatoid arthritis. Rheumatology (Oxford) 2018; 57(6): 1072-1079.
- Bongenaar M, et al: IL-6 but Not TNFα Levels Are Associated With Time to Pregnancy in Female Rheumatoid Arthritis Patients With a Wish to Conceive. Front Pharmacol 2020; 11: 604866.
- Jethwa H, et al: Does Rheumatoid Arthritis Really Improve During Pregnancy? A Systematic Review and Metaanalysis. J Rheumatol 2019; 46(3): 245-250.
- Keeling SO, et al: A Population-level Analysis of the Differing Effects of Rheumatoid Arthritis and Spondyloarthritis on Peripartum Outcomes. J Rheumatol. 2020; 47(2): 197-203.
InFo PAIN & GERIATRY 2021; 3(1): 16-18 (published 2/7/21, ahead of print).
