Reproductive Health in Rheumatoid Arthritis

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

The presence of an underlying rheumatic disease clearly affects an individual's reproductive health, with concerns about pregnancy, contraception, and medication safety looming large.

"In general, in all of our patients with rheumatic diseases the disorder has an impact on their reproductive life," said Lisa R. Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery in New York City. Nonetheless, with greater understanding and experience, current approaches to these issues have significantly improved outcomes.

"The risks are more pronounced for some patients, such as those with lupus and antiphospholipid syndrome, where there is a higher risk of pregnancy loss and elevated estrogen levels that can significantly increase the risk of blood clots, but for women with rheumatoid arthritis [RA], there are still risks we should be cognizant of," said Sammaritano, who was the lead author of the 2020 American College of Rheumatology (ACR) Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases.

Pregnancy

Of utmost importance for patients who wish to become pregnant is that their RA be well controlled. The 2020 guideline states that "we strongly suggest counseling women with RMD [rheumatic and musculoskeletal diseases] who are considering pregnancy regarding the improved maternal and fetal outcomes (based on many studies) associated with entering pregnancy with quiescent/low activity disease."

The guideline also notes that experts in obstetrics-gynecology or maternal-fetal medicine are central to the care of pregnant women with RMD, but that "an understanding of basic pregnancy physiology is helpful for rheumatologists to identify and treat active disease during pregnancy and coordinate care with obstetric providers."

Particular concerns include the intravascular volume increases seen in pregnancy, which can have adverse effects in patients who already have compromised heart or renal function, and that certain symptoms of normal pregnancy such as arthralgias may mimic active RA.

Drug Safety in Pregnancy

Drug safety is another important focus. "Fortunately for our patients with RA, today many are on tumor necrosis factor [TNF] inhibitors, which are considered low risk to continue throughout pregnancy and breastfeeding. That gives us an option that we really didn't have years ago," Sammaritano noted.

In contrast to the TNF inhibitors, methotrexate -- long considered a cornerstone drug for RA -- is a known teratogen and must be stopped 1-3 months before attempting pregnancy because of risks of miscarriage and fetal abnormalities. Prednisone should be tapered to a dosage below 20 mg/day both preconception and during pregnancy, because certain risks during pregnancy are elevated with high-dose steroids, such as gestational diabetes and hypertension.

Few data are available regarding the safety of the newer biologics and oral medications in pregnancy. "Pregnant women of course are not included in efficacy studies, so we only have safety data after the drug is approved and patients are inadvertently exposed. But I think the landscape of treatment options will broaden in the coming years," Sammaritano predicted.

The good news for patients with RA is that about half actually go into remission while pregnant, and many can stop their medications altogether. "I have a number of patients who tell me they feel like they never had RA while they were pregnant," Sammaritano said.

As to why this occurs, she noted that there have been a number of suggestions over the years, such as that an HLA mismatch between the mother and fetus or maternal seronegativity might be associated with remission.

"However, the immunology of pregnancy is complicated and not completely understood," she explained. "Why a woman can carry a fetus for 9 months that has antigens foreign to her body, with 50% coming from the father, requires a lot of tolerance on the part of the maternal immune system. But the bottom line is that we don't fully understand it. In time, hopefully we'll have a better understanding and perhaps the ability to predict for an individual whether remission is likely to happen."

An additional concern in pregnancy is the presence of autoantibodies such as anti-Ro and anti-La, which are detected in a majority of patients with primary Sjogren's syndrome and in approximately one-third of patients with lupus. They also are present in a significant proportion of patients with RA; this has been estimated at 15%. "These antibodies can lead to the development of inflammation in the fetus that, at its most severe, can lead to complete congenital heart block, which necessitates placement of a pacemaker in the infant after birth."

"This is a very rare complication, occurring in only about 2% of offspring of women with these antibodies, but obviously it's a very serious complication," Sammaritano cautioned. Accordingly, in RA patients with anti-Ro/La antibodies, serial fetal echocardiograms are recommended between weeks 16 and 26.

In addition, patients should be given hydroxychloroquine (if they are not already on the drug), because studies of patients with lupus have indicated that treatment with this antimalarial during pregnancy reduces the risk of complete congenital heart block by more than 50%, she noted.

In general, despite the myriad challenges in reproductive health having a rheumatic disease places on an individual woman, "the likelihood today of a safe and successful pregnancy in patients with rheumatoid arthritis is high," said Sammaritano.

Contraception

In discussing contraception, the ACR guideline states: "RMD patients typically underutilize contraception. The most important reason for effective contraception in women with RMD is to avoid risks of unplanned pregnancy, which include worsening disease activity that may threaten maternal organ function or life, adverse pregnancy outcomes (pregnancy loss, severe prematurity, and growth restriction), and teratogenesis."

"We do not want them to accidentally become pregnant while taking a teratogenic medication," Sammaritano emphasized. "One of the big pushes in the rheumatology field in the past few years has been to address this issue with patients from the get-go, to address contraception and family planning with young women of reproductive age at an early point so that we don't have any surprises."

The guideline classifies copper and progestin IUDs and progestin implants as highly effective, with failure rates below 1% per year, and progestin-only daily pills as effective, with failure rates of 5-8%. Other effective methods include combined estrogen-progestin contraceptives and depot medroxyprogesterone acetate injections, but these cannot be used for patients with positive antiphospholipid antibodies.

Less effective methods include diaphragms and condoms, with failure rates of 12-18%. The guideline authors "strongly recommend" the use of effective or highly effective methods of contraception.

Difficulties have arisen in the past because rheumatologists are not experts in contraception, nor are ob-gyns experts in rheumatology, said Sammaritano. "I had a patient with RA where I recommended an IUD but her ob-gyn didn't want to place it because she thought that having an autoimmune disease meant her body would reject it. That is not based on any kind of data but is typical of the kind of lack of knowledge that exists on both sides."

"What we've been trying to do is educate rheumatologists so that they communicate with their patients and encourage collaboration with ob-gyns," she said.

Infertility

In general, women with RA typically have fewer children than age-matched women in the overall population, with potential contributing factors including having active disease, exposure to teratogenic medications, and psychosocial concerns, as well as fears that offspring might themselves develop RA.

But the most important obstacle to fertility is age, as in the general population. Patients may have spent time trying to bring their disease under control and dealing with medications, and may be older when they begin considering pregnancy. Cryopreservation is now an option for preserving fertility among women who may wish to have a biological child in the future, Sammaritano said. "There are many technologies that can help if women with RA experience infertility, and they are perfectly capable of undergoing these assisted reproductive technologies."

Read previous installments in this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Part 4: Case Study: Patient With RA Develops Dangerous Symptoms

Part 5: Second-Line Treatment of Rheumatoid Arthritis: What Are the Options?

Part 6: Managing Rheumatoid Arthritis in the Time of COVID