As treatment options continue to evolve and rheumatoid arthritis (RA) becomes less disabling, more women with the disease may choose to pursue pregnancy. However, meeting the family planning needs of these patients requires frank discussion and careful coordination.

For as many as 42% of female patients with RA diagnosed with the disease before family completion, the time to pregnancy exceeds 12 months, as compared with only 10% to 17% of the general population.1 Because antirheumatic treatment has to be adjusted for most women with RA before they start trying to conceive, a longer time to pregnancy can mean prolonged periods with less adequate RA control and an increased risk for permanent joint damage.1 Understanding the underlying mechanisms of subfertility in patients with RA and treating those mechanisms whenever possible is an important step forward in the care of patients with RA who are planning to grow their families.

Related Articles

“Women with RA who wish to become pregnant may be reassured that many women with RA have successful pregnancies, particularly when their diseases are well controlled at the time of conception,” says Nicole Hunt of the Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh.2

Reasons for Reduced Family Size With RA

Research has shown that for more than 60 years women with RA have had smaller families and higher rates of nulliparity than women without the disease.2 In a Dutch study of 245 women with RA, 42% reported a delay of more than 12 months to conception.3

Reasons that women with RA have trouble growing their families include2,3:

  • higher rates of miscarriage;
  • physical disability that limits sexual activity;
  • maternal age;
  • menstrual irregularity;
  • disease activity;
  • reduced levels of anti-Mullerian hormone, which is an indicator for ovarian reserve in women;
  • daily dose of prednisolone higher than 7.5 mg.
  • use of non-steroidal anti-inflammatory drugs (NSAIDs);
  • ovulatory dysfunction; and
  • endometriosis.

High disease activity may contribute to a smaller family size and a higher incidence of infertility in patients with RA, as severe illness has been found to reduce sexual function due to pain and immobility.3 Another theory is that women with an RA diagnosis may have concerns about their abilities to care for children due to their level of fatigue and physical limitations. Fears about whether medications might affect a developing fetus or if the disease may be passed on to their children may also play a role.2 For many women with RA, however, the reasons for infertility are unexplained.2

“The high percentage of RA patients diagnosed by the gynecologist with unexplained subfertility may imply that fertility in female RA patients is influenced by disease-related factors,” said Jenny Brouwer, MD, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

A Dutch study found a significant association of periconceptional NSAID use with unexplained subfertility.1 Researchers found that NSAIDs may interrupt the ovulatory process, possibly leading to luteinized unruptured follicle (LUF) syndrome.1 In LUF syndrome, although ovulation is inhibited, menstrual cycle length and regularity is unaffected, meaning patients with LUF would probably be classified as ovulatory during examination.1

Men, RA, and Infertility

Although RA is 3 times more common among women, men still develop the disease.2

RA has not been definitively linked to infertility in men, but some RA medications prescribed to men have been linked to subfertility.2 Men with RA who experience infertility may require semen analysis testing for further diagnosis.2

Regarding men with RA, NSAIDs, hydroxychloroquine, and TNF-α inhibitors don’t seem to increase the risk for adverse outcomes in paternally exposed children, although data on NSAID and hydroxychloroquine exposure are scant.2 Sulfasalazine has been associated with lack of sperm and decreased sperm motility, but these effects may be reversible.2 Earlier research suggested that methotrexate be discontinued by fathers before attempting to conceive, but recent studies conclude that methotrexate-exposed fathers do not have higher rates of major birth defects, growth restriction, or preterm birth.2

Prescriber Beware

Health care providers may need to adjust treatment plans for women with RA who are planning to conceive. As previously stated, NSAIDs should be prescribed with caution. By preventing the rupture of the luteinized follicle, NSAIDs may impair ovulation and lengthen time to pregnancy.3 NSAIDs also have been linked to an increased risk for miscarriage, although these data have been somewhat unclear.2 Women with RA should discontinue taking methotrexate at least 3 months prior to becoming pregnant because it is an abortifacient and may cause birth defects.2 Other drugs that could contribute to the subfertility in patients with RA include potentially teratogenic disease-modifying antirheumatic drugs (DMARDs).3

“The use of various DMARDs reduces the disease activity, but the reproductive health of women, who are the ones predominantly affected by RA, should also be taken into consideration when formulating a treatment plan,” said Richard Oluyinka Akintayo, Department of Rheumatology, Lagos State University Teaching Hospital, Ikeja, Nigeria.3

Assisted Reproductive Technology and Family Planning

The number of women with RA during the fertile years is increasing.4 In the Dutch study, the percentage of participants who were subfertile and received fertility treatments was almost 50% higher than in the general population.1

Assisted reproductive technology (ART) has helped women all over the world to conceive, however a Danish study conducted over 23.5 years found that this infertility treatment was less successful for women with RA. Specifically, the study found that ART treatments in women with RA provided a significantly decreased chance of live birth per embryo transfer compared with ART treatments in women without RA.4 Researchers believe this is due to challenges with embryo implantation.4 However, the study also found that women with RA who had a corticosteroid prescribed before embryo transfer may have an improved chance of a live birth compared with women with RA who did not take a corticosteroid before embryo transfer, although the findings were not definitive.4

Applying the Research to Your Practice

Although research suggests that some women with RA may experience subfertility, it’s recommended that health care providers avoid assuming that women with RA are infertile, subfertile, or uninterested in pursuing pregnancy.

Women with rheumatic diseases should receive risk counseling from their health care providers if they are considering pregnancy.2 Specifically, the patient’s RA should be well controlled on safe, anti-rheumatic drugs for at least 3 to 6 months before she gets pregnant to provide the best chance for a successful outcome.2 And though it may seem counterintuitive, contraception may offer unique benefits to women with RA. For example, contraception can help delay a desired pregnancy until an optimal time when the patient is using pregnancy-compatible medications and her disease is well controlled, thereby bolstering maternal, fetal, and pregnancy outcomes.2

Researchers recommend that health care providers initiate a conversation about family planning with all patients of reproductive age at the time they are diagnosed with RA and before starting or changing medications with fetotoxic potential.

“In daily practice, when an RA patient wishes to conceive, NSAIDs should be avoided, and early consultation with an expert rheumatologist and a fertility specialist should be considered to optimize the patient’s chance of a complete family,” said Brouwer.1

References

1. Brouwer J, Fleurbaaij R, Hazes JMW, Dolhain RJEM, Laven JSE. Subfertility in women with rheumatoid arthritis and the outcome of fertility assessments. Arthritis Care Res. 2017; 69(8):1142-1149.

2. Hunt N, Talabi MB. Family planning and rheumatoid arthritis [published online March 6, 2019]. Curr Rheumatol Rep. doi: 10.1007/s11926-019-0816-y

3. Akintayo RO, Aworinde OO, Ojo O, et al. Is rheumatoid arthritis an innocent bystander in female reproductive problems? A comparative study of fertility in Nigerian women with and without rheumatoid arthritis. Eur J Rheumatol. 2018; 5(3):179-183.

4. Nørgård BM, Larsen MD, Friedman S, Knudsen T, Fedder J. Decreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study. Ann Rheum Dis. 2019; 78(3):328-334.