Infertility is a frequently encountered issue in medicine, seen in about 9% of men and about 11% of women of reproductive age in the U.S.1 Many rheumatologists may not be aware of the prevalence of infertility and the implications this issue may have on the care of their patients. Here, Anat Chemerinski, MD, instructor in the Division of Reproductive Endocrinology and Infertility, in the Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, N.J., sheds light on the topic.
Dr. Chemerinski completed her residency at the University of Pennsylvania, Philadelphia, and her fellowship at Rutgers New Jersey Medical School. She is a Rutgers Presidential Clinical Scientist Scholar and a Clinical Research/Reproductive Scientist Training (CREST) Program Scholar.
The Rheumatologist (TR): How common is infertility in the general population, and which rheumatic conditions or medications are associated with infertility?
AC: Infertility affects about one in eight couples trying to conceive. Several studies have reported a reduction in fertility in women diagnosed with rheumatic diseases. Whether this is related to the disease, treatment or impact on sexual function and quality of life is unclear.
Certain medications used in the treatment of rheumatic disease can be associated with infertility. High doses of cyclophosphamide, for example, can be gonadotoxic and may lead to primary ovarian insufficiency. Women should be counseled about the risk of gonadotoxicity with this medication and referral to a reproductive endocrinologist should be considered.
In patients with active vasculitis, the ACR recommends against ovarian stimulation to decrease the risk of venous thromboembolism. If disease is inactive, EULAR recommends in favor of using low-dose aspirin or low molecular weight heparin during ovarian stimulation.
Certain medications used in the treatment of rheumatic disease are teratogenic, including mycophenolate, cyclophosphamide and methotrexate, and this should be discussed with patients planning an assisted reproductive technology cycle.
Finally, it’s important to remember that NSAIDs [non-steroidal anti-inflammatory drugs] can delay or inhibit ovulation. Patients who are trying to conceive should be made aware of this information.
TR: What is your approach to family planning with patients?
AC: Family planning discussions usually include the patient’s timeline for starting a family, the number of children the patient feels would complete their family and spacing between pregnancies. It also includes a discussion about age and age-related decline in fertility for patients presenting for this type of discussion in their later reproductive years.
For patients wishing to prevent pregnancy, a discussion about contraception always includes a review of medical conditions that may preclude them from using estrogen-containing contraception, including a history of deep vein thrombosis or pulmonary embolism, lupus and antiphospholipid syndrome. I typically refer to the Centers for Disease Control and Prevention [CDC] medical eligibility criteria chart.
TR: What does it mean to ‘freeze’ eggs or embryos, and what does this process entail?
AC: Oocyte cryopreservation (i.e., egg freezing) is the process by which the ovaries are stimulated to produce multiple follicles for the purpose of harvesting the oocytes (i.e., egg retrieval) and cryopreserving them. In this way, a patient may theoretically preserve their fertility at this moment in time. That said, oocyte cryopreservation is not a guarantee of a future live birth, and patients should be counseled appropriately when they are considering this process. Some studies have found that patients must cryopreserve between 20 and 25 oocytes before the age of 35 in order to have a >90% chance of a live birth. After age 35, that number is even higher.
Oocyte cryopreservation specifically allows for independent preservation of fertility, whereas embryo banking (i.e., freezing embryos) ties fertility to another person in the form of an already formed embryo. When a patient who is about to begin treatment for a rheumatic condition inquires about fertility preservation, they need to understand this distinction.
TR: What does assisted reproductive technology (ART) refer to, and can you provide examples of these technologies?
AC: ART refers to any fertility treatment that involves the handling of oocytes or embryos. Examples of this include in vitro fertilization (IVF) and frozen embryo transfer (FET).
When a patient is referred to [my department], the first step is to evaluate for causes of infertility, including disorders in the male and female reproductive tracts. Not every patient who presents requires IVF. Some patients can conceive with oral medications and intrauterine insemination. Patients who can’t conceive in this manner may be recommended to undergo IVF.
Coverage for, and access to, these technologies varies by state. Although some states mandate coverage from private insurers, others do not. The amount of coverage may vary or be limited, as well. For example, some insurers will cover the cost of ART up to a maximum dollar amount, but others cover only diagnostic evaluation, not treatment. The average out-of-pocket cost for an IVF cycle is around $12,000, but this can vary significantly by region and by the details of the treatment.
TR: To what extent is genetic screening used?
AC: The American College of Obstetricians and Gynecologists recommends offering carrier screening to all women who are pregnant or planning pregnancy; it is best performed prior to pregnancy. This screening is now part of the preconception evaluation that is performed for women seeking care from specialists in my department.
Certain genetic conditions are sometimes found in the evaluation for infertility or recurrent pregnancy loss, including cystic fibrosis transmembrane conductance regulator (CFTR) mutations associated with congenital bilateral absence of the vas deferens, fragile X or FMR1 (fragile X messenger ribonucleoprotein 1) related primary ovarian insufficiency, and karyotype changes, as in women with Turner syndrome or Turner mosaicism or men with Klinefelter syndrome.
We now have the ability to test embryos prior to transfer. This process is called preimplantation genetic testing and can be applied to screen embryos for aneuploidy (PGT-A), structural rearrangements (PGT-SR), and single gene mutations (PGT-M). The use of PGT-A is being evaluated as a way to reduce pregnancy losses and improve live birth rates. PGT-M is allowing couples to prevent transmission of specific genetic syndromes, such as those associated with BRCA1 and BRCA2 gene mutations and FMR1 mutations that are associated with fragile X syndrome.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
Reference
- Chandra A, Copen CE, Stephen EH. Infertility and impaired fecundity in the United States, 1982–2010: Data from the national survey of family growth. Natl Health Stat Report. 2013 Aug 14;(67):1–18.