Of 475 patients recruited from May 2002 to August 2008, 369 were enrolled in the PARA study, and 245 of these were available for the present analyses (figure 1). There were no statistical differences in general characteristics between included and excluded subjects.
Flow chart showing the number of patients in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study who were available for the current analysis. ACPA, anti-citrullinated peptide antibodies; ACR, American College of Rheumatology; DAS28, 28-joint Disease Activity Score; RF, rheumatoid factor.
Study population details are shown in Table 1. During the study period, 205 women (84%) conceived, 64 of whom (31%) had a TTP longer than 12 months. These 64 women together with the 40 women who did not become pregnant during follow-up, formed the subfertile group in this cohort (subfertility 42%). In the women who got pregnant, the median TTP was 0.50 year (IQR 0.19–1.28). Pregnancy resulted in a live born baby in 178 women (87%), 26 women (13%) miscarried and there was one intra-uterine fetal death.
Thirty-five pregnant women had had fertility treatment. These women did not differ significantly from the other subjects. No data on fertility assessments were available.
Since only a few patients used cyclo-oxygenase-2 (COX-2) inhibitors, traditional NSAIDs and COX-2 inhibitors were regarded as one group for analyses.
In 61 women (25%) who were not assessed preconceptionally, only the first trimester DAS28 was available. In women who had been visited both preconceptionally and during pregnancy (n=109), a paired t test showed no significant difference between the preconception DAS28 (3.57±1.1) and the first trimester DAS28 (3.56±1.2; p=0.93). The first trimester DAS28 in these 109 women did not differ from the first trimester DAS28 in women who had not been assessed preconceptionally (3.53±1.1; p=0.86). The first trimester DAS28 was used for further analyses if the preconception DAS28 was missing.
Overall, 67% of women in the high disease activity group (DAS28>5.1), 43% of women in the intermediate disease activity group (3.2<DAS28≤5.1), 37% of women in the low disease activity group (2.6<DAS28≤3.2) and 30% of women in remission (DAS28<2.6) were subfertile (figure 2A).
Survival curves showing the time to pregnancy (TTP) in rheumatoid arthritis (RA) patients with (A) various levels of disease activity and (B) different prednisone dosages. When the TTP exceeded 1 year, patients were considered subfertile. If women had not become pregnant at the last time of contact, the TTP was considered censored at the date of the last visit. (A) Patients with high disease activity (DAS28>5.1) had a longer TTP than patients in the other groups (3.2<DAS28≤5.1, p=0.03; 2.6<DAS28≤3.2, p=0.04; DAS28<2.6, p=<0.001). Patients with intermediate disease activity (3.2<DAS28≤5.1) had a longer TTP than patients with RA in remission (DAS<2.6; p=0.008), but TTP did not differ significantly from that in patients with low disease activity (2.6<DAS28≤3.2). The TTP in patients with low disease activity did not differ significantly from that in patients in remission. (B) Patients using high prednisone dosages had a longer TTP than patients using low dosages (p=0.04), and a longer TTP than patients using no prednisone (p=0.002). The TTP between the low-dose group and the group with no prednisone did not differ significantly. DAS28, 28-joint Disease Activity Score.
In the subfertile group, age and DAS28 were significantly higher than in the fertile group (Table 2). Subfertile patients were more frequently ACPA positive and used NSAIDs and prednisone more often.
The women who did not become pregnant at all (n=40) had a significantly higher DAS28 (4.14±1.3) than those who became pregnant (3.61±1.1; p=0.008).
RF positivity was more common in women who did not conceive (90%) than in those who did (70%; p=0.01). ACPA was positive in 80% of women who did not conceive compared to 63% of women who did get pregnant (p=0.05). Disease duration did not differ significantly: it was 4.4 (1.7–7.8) years in non-pregnant women and 3.4 (1.2–8.5) years in women who did get pregnant (p=0.76).
Cox regression analysis with multiple variables showed that older age, nulliparity, higher DAS28, preconception use of NSAIDs, and preconception use of prednisone were associated with a longer TTP (Table 3). Smoking, time since RA diagnosis, RF positivity, ACPA positivity, past MTX use and preconception sulfasalazine use were not significantly associated with TTP.
When analysis was restricted to pregnancies resulting in a live birth, the same factors were identified as significantly associated with TTP (data not shown).
Because DAS28 and prednisone use may show interaction, we introduced an interaction term (DAS28 × daily prednisone dosage) into our model. This showed no significant effect (HR 1.00, 95% CI 0.99 to 1.02; p=0.41).
Prednisone. The effect of prednisone usage on subfertility was further assessed. Eighty-five patients used prednisone in dosages of 2.5–20 mg daily (median 7.5 mg). They were divided into two groups: a low-dose group (≤7.5 mg prednisone daily, n=44) and a high-dose group (>7.5 mg prednisone daily, n=41). In the high-dose group, 66% of women were subfertile compared to 43% in the low-dose group and 36% in the women who did not use prednisone. Kaplan–Meier curves showed a significantly longer TTP in prednisone users versus non-users (p=0.005), and in high-dose users versus low-dose users (p=0.045) (figure 2B). In the Cox regression with the complete variable list, a dummy variable was introduced to distinguish between low-dose prednisone and high-dose prednisone. The HR for low-dose use was not significant (0.83, 95% CI 0.57 to 1 0.21; p=0.33), but use of high-dose prednisone significantly extended the TTP, with an HR of 0.50 (0.33 to 0.76; p=0.001). The significance of other variables in the analysis did not change.
A subgroup analysis on patients with DAS28<3.2 still showed a significant association between prednisone use and a longer TTP (HR 0.21, 95% CI 0.10 to 0.45; p<0.001).
DAS28 After 1 Year
A subgroup of women who did not conceive within 12 months after the first visit, were revisited after 1 year. In the 17 patients who were still actively trying to conceive, the DAS28 for this visit did not differ from the DAS28 1 year earlier (3.96±1.6 vs 3.91±1.8; p=0.85).