Anovulation and Subfertility in Rheumatoid Arthritis

Unexplained subfertility in patients with rheumatoid arthritis may be caused by disease-related factors.

Rheumatoid arthritis (RA) factors are linked to unexplained subfertility diagnoses in women with RA, according to research published in Arthritis Care and Research.

Joop SE Laven, MD, PhD, of the Division of Reproductive Medicine, Department of Obstetrics and Gynecology at Erasmus MC, University Medical Center Rotterdam in the Netherlands, and colleagues conducted a cross-sectional study of female patients with RA who were a part of the Pregnancy-induced Amelioration of RA (PARA) cohort — a nationwide, Dutch, prospective observational cohort from 2002 to 2010 that included women with RA who were trying to conceive or who were in their first trimester of pregnancy.

High Yield Data Summary

  • The high rate of unexplained subfertility diagnosed in women with RA suggests that fertility is influenced by RA-related factors.

The final cross-sectional study included 260 women from the PARA cohort; multiple subfertility diagnoses were compared using 2 reference populations of women with subfertility.

All eligible participants received a mailed questionnaire to collect data on reproductive history, time to pregnancy, fertility assessments, and history of fertility treatments. Fertility assessment data were collected from participants’ gynecologists, and were checked for menstrual cycle length and cycle irregularities, as well as levels of estrogen and progesterone, ovulation presence, history of pelvic inflammatory disease, endometriosis, and tubal function. RA disease characteristics were drawn from the PARA study database, and included information on diagnosis date, presence of rheumatoid factor or anti-citrullinated protein antibodies, and disease activity scores (swollen joint counts in 28 joints [DAS28] and serum C-reactive protein levels [CRP]).

Of the 260 questionnaires mailed, 68% were completed and returned. Researchers found that 37% of non-participants had not achieved pregnancy compared with 17% of participants (P =.001), with non-participants more likely to be nulliparous at the conclusion of their participation in the PARA study (24% vs 9%, P =.002).

Among all women, 96% (n=170) ended their efforts to become pregnant. Reasons included a complete family (72%), advanced age (20%), an increase of RA complaints or the need for treatment with anti-rheumatic drugs that were incompatable with pregnancy (19%) or other health problems that may have complicated conception or caregiving for a child (3%); multiple answers per subject were possible. In 5% of participants (n=9), either the woman’s gynecologist advised against becoming pregnant or no further fertility treatments were available.

A total of 412 pregnancies were recorded during the study period, with a median of 2 pregnancies per woman (interquartile range [IQR]: 2 to 3; mean 2.3 ± 1); 86% of these pregnancies were conceived after the patient’s RA diagnosis. Thirty-three percent of participants had 1 or more miscarriage (IQR: 0 to 1; mean 0.42 ± 0.69) with a total of 75 miscarriages, and 334 live births were recorded (IQR: 1 to 2; mean 1.9 ± 0.78 per woman).

Of the participants, 46% (n=82, 95% confidence interval [CI], 39% to 53%) met at least 1 of the following criteria for subfertility: a time to pregnancy exceeding 12 months during at least 1 attempt to establish a pregnancy, the use of fertility treatments to get pregnant, or never having achieved a pregnancy (n=66, 41, and 6, respectively). Thirty-seven percent of women were classified with primary subfertility, whereas 9% of women had secondary subfertility.

When compared with fertile women with RA, subfertile women established significantly fewer pregnancies (IQR: 1 to 2, mean 2.1 ± 1.1 vs IRQ: 1 to 3, mean 2.5 ± 1; P =.004) and had fewer children (IQR: 1 to 2; mean 1.6 ± 0.9 vs IQR: 1 to 2; mean 2.1 ± 0.6, P <.001). Number of miscarriages per woman was not significantly different between groups (P =.33).

Data were collected on 61 of 74 subfertile women. Most commonly, subfertility was caused by unexplained subfertility (48%), anovulation (28%), or semen abnormalities (16%). In 3% of women (n=2), anovulation was due to primary ovarian insufficiency. Five percent of couples experienced both a male and female cause for subfertility, and in 8 of 61 couples no sperm analysis result was available. Among these women, diagnoses were unexplained (n=2), vaginismus (n=1), anovulation (n=4), and endometriosis (n=1). Ninety-two percent of women diagnosed by a gynecologist (vs self-reported diagnosis) had a subfertile episode during the PARA study.

Summary and Clinical Applicability

“In comparison to the general population, female [patients with RA] appear to be more often diagnosed with unexplained subfertility,” wrote Dr Laven and colleagues. “The high percentage of patients with RA diagnosed by the gynecologist with unexplained subfertility may imply that fertility in female [patients with RA] is influenced by disease related factors.”

Due to the high pregnancy rate and lower nulliparity compared with non-participants, the researchers noted that this particular PARA cohort seems overall fertile; current results may lead to an underestimation of actual incidence of total subfertility — and the impact on childbearing — in a wider population of women with RA.

Moving forward, physicians who treat patients with RA who wish to conceive should avoid NSAID use and encourage early consultation with both a rheumatologist and fertility specialist.

“Our finding that unexplained subfertility is diagnosed more often in female [patients with RA] than in the general population supports the idea that RA related factors are causally involved in subfertility in women with RA,” Dr Laven and colleagues concluded.


Dr Dolhain has received an unrestricted research grant from UCB Pharma BV.

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Brouwer J, Fleurbaaij R, Hazes JMW, Dolhain RJEM, Laven SEJ. Subfertility in rheumatoid arthritis is often unexplained or caused by anovulation. Arthrit Care Res. 2016 Oct 9. doi:10.1002/acr.23124 [Epub ahead of print]

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