Recommended Approach for Undiagnosed Autoimmune Diseases, Unexplained Infertility, and Fertility Treatments
Hillary Klonoff-Cohen, Ph.D.
Saul J. Morse & Anne B. Morgan Professor in Applied Health Sciences, Director, MPH, MS and PhD Community Health Programs, Associate Head for Community Health, Department of Kinesiology and Community Health, University of Illinois Urbana Champaign
Acknowledgements: I would like to thank Dr. Mounika Polavarapu, MBBS, MPH, University of Illinois at Urbana-Champaign, for her expertise and scientific editing.
Although the average chance of becoming pregnant in any cycle among fertile couples is 20%, patients with unexplained infertility have only a 1-4% chance without treatment. The emotional and financial cost associated with unexplained infertility can be devastating. There are a host of auto-immunologic diseases including Celiac disease, Lupus, and hypothyroidism that could account for a portion of unexplained infertility. Consideration of these autoimmune disorders in the differential diagnosis of infertility may provide an opportunity to increase the probability of conception and uncomplicated pregnancy as well as modify appropriate medical and fertility treatments.
Background of Autoimmune Diseases Of 50 million Americans with autoimmune disease (AD), >75% of them are women (1). Autoimmune diseases have been cited in the top ten leading causes of all deaths among U.S. women age 65 and younger (1). They are also known to have a genetic basis and tend to cluster in families. It takes most autoimmune patients up to 4.6 years and nearly 5 doctors before receiving a proper diagnosis (1). Thus, autoimmune diseases remain among the most poorly understood and under-recognized of any category of illness (1).
CELIAC DISEASE Celiac disease affects 3 million Americans, 10 times more than previously estimated. This disease is three times more prevalent in women than men. Furthermore, as many as four out of five people with Celiac disease are undiagnosed. In fact, the largest Celiac study in the world, the Canadian Celiac Health Survey (n=2600), and a similar study at Columbia University (n=1600) determined a delay in celiac diagnosis of 10- 11.7 years. Celiac disease is a systemic disease with manifestations not limited to the small intestine. Symptoms include chronic diarrhea, abdominal bloating/pain, weight loss, neuropathies, seizures, edema, skin rashes, metabolic bone disease, diabetes, thyroid dysfunction, and lympho-proliferative malignancies.
CD and infertility Celiac disease (CD) may be more common in men and women with unexplained infertility. A recent meta-analysis reported that women with unexplained infertility had 6 times higher odds of having CD than controls. Delayed onset of menarche, amenorrhea, and reduced rates of pregnancy occur with Celiac disease. Furthermore, those women with undiagnosed Celiac disease who do not follow a gluten-free diet may intensify unfavorable conditions for conception and reproduction. In contrast, a gluten free diet could help restore fertility. This hypothesis has only been tested in case reports and small prospective studies but not in clinical trials. Men also suffer from infertility stemming from undiagnosed CD. Little information on male infertility and Celiac disease has appeared in the past 4 decades. However, a few studies revealed that Celiac disease results in sperm morphology and motility abnormalities, oligospermia, and reduced dihydrotestosterone. Hormones and sperm parameters improved following a gluten- free diet. Fasano studied the prevalence of undiagnosed CD in both genders combined and reported a 6.25% prevalence of CD in patients presenting with “idiopathic” infertility. In 2016, the prevalence rate of silent CD among unexplained infertile men was 7.8%. There was a significant association between autosperm antibodies as an etiological factor for infertility with silent CD. The researchers advised screening for CD as part of the work-up of unexplained infertile men.
CD and pregnancy outcomes Cumulatively, research studies provide evidence of a strong correlation between incidence of recurrent miscarriage, stillbirth, and undiagnosed Celiac disease. This disease has also been linked to premature and low-birth weight babies, shorter duration of breastfeeding, and intrauterine growth retardation.
Summary There are presently no guidelines for CD testing in patients with infertility or in women with a history of adverse pregnancy outcomes, although CD prevalence is higher in these groups than in the general population (2).
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Nearly 5 million people worldwide have been diagnosed with Lupus and 90% are women, ranging in age from 15-44 years. This disease strikes women 10-15 times more often than men, and is 2-3 times more common among African Americans, Hispanics, Asians, and Native Americans. SLE contributes to ∼1% of infertile patients. Lupus can manifest with different symptoms including sun sensitivity, joint pain, and kidney failure.
SLE and Infertility Amenorrhea results from Lupus itself or its treatment, cyclophosphamide, which causes ovarian failure. Pasoto reported that menstrual irregularity was prevalent in 53% of adult Lupus patients <40 years, and female patients with juvenile SLE (≤18 years of age) suffered from amenorrhea during high disease activity. Evidence is emerging that young women with SLE are more susceptible to sexually transmitted infections than controls, and are subsequently more likely to become infertile. Endometriosis is another recognized cause of infertility in women with SLE. In males with SLE, there is a reduction in testis volume due to damage to the seminiferous tubules. Inhibin B (secreted from the seminiferous tubules) is significantly reduced in some patients, while FSH and LH are raised. Several reports have described the presence of anti-sperm antibodies in patients with SLE, and this could explain the impairment of spermatogenesis in these patients.
Summary It is less recognized that the Lupus itself (rather than its treatment) can reduce fertility through autoimmune mechanisms, hormonal disturbances, or renal failure. Many reports indicate that women with Lupus anticoagulant have more difficulty getting pregnant and successfully carrying their pregnancies to term. Information on Lupus screening in undiagnosed infertile patients is visibly absent from the literature. There is only one study which investigated this population. A 1.5% prevalence of undiagnosed SLE was found in a cohort of 136 infertile women. (3). Given the low reported prevalence in this study, routine screening is not presently warranted.
THYROID DISEASE Thyroid autoimmunity is the most prevalent autoimmune disease that affects up to 5-20% of women during reproductive age. The most common cause of hypothyroidism is Hashimotos, which affects 14 million people. Symptoms for hypothyroidism include increased sensitivity to cold, constipation, dry skin, hoarse voice, elevated blood cholesterol, unexpected weight gain, muscle aches, and depression.
Hypothyroidism, fertility, and pregnancy outcomes Hypothyroidism may result in menstrual disturbances, infertility, increased risk of miscarriages, and possible long-term health effects in the offspring (4). Definitive data on the prevalence of hypothyroidism among infertile patients is lacking. There are no universally accepted guidelines regarding the use of thyroid hormone testing in women identified with unexplained infertility. Moreover, because fertility treatments may continue for months/years, the frequency of repeating thyroid function tests has not been adequately addressed. Endometriosis and PCOS are more frequently associated with thyroid disease. Women with hypothyroidism also carry an increased risk for miscarriage after ART. Hence, infertile women should possibly be considered for screening for thyroid peroxidase antibody (TPO), since this is the most common test for autoimmune thyroid disease. Summary High-quality, well-designed randomized clinical trials are required to clarify the causal relationship between undiagnosed thyroid disease and infertility and to evaluate whether therapeutic intervention trials using thyroid hormones could help reduce pregnancy loss. Cost-benefit As of 2017, the cost of an initial screening test for Celiac disease, (IgA and HLA-dq typing, followed by Tissue Transglutaminase antibody (tTG), endomysial antibodies and Gliadin Antibodies IgA testing) is on average $129, based on three national laboratories. A Lupus blood test (ANA) ranges in price from $59-$68. The cost for a hypothyroidism blood test consisting of TSH (on average $57), and free T4, (if TSH is not normal), is $59.
CONCLUSIONS There is a paucity of research regarding screening for undiagnosed autoimmune diseases among infertile females or males undergoing ART. IVF centers follow the Society of Assisted Reproductive Technology recommendations which require pre-requisite testing prior to initiating an IVF cycle. None of the tests are specific for autoimmune diseases (Table 1) (5). Presently, it would be beneficial to raise awareness and knowledge among reproductive endocrinologists about autoimmune diseases. Fertility specialists could decide whether selective (or at risk) screening on a case by case basis is warranted for women and men diagnosed with unexplained infertility who: 1) disclose a family history of autoimmune diseases, 2) exhibit symptoms reflective of Celiac (malabsorption, anemia), Lupus, or hypothyroidism, or 3) present with a reproductive history of difficulty conceiving, recurrent miscarriages, premature ovarian failure, delayed menarche or abnormal sperm parameters. Simple blood tests could be cost- effective in detecting autoimmune diseases in these individuals, thereby increasing their overall health and fertility. Table 1: Prerequisite Testing according to the SART in 2017. (5)
SART Prerequisite Testing Mandatory prior to IVF Female Male • HIV • Hepatitis B antigen • Hepatitis C antibody • RPR • Pap smear • Blood group, Rh and antibody screen • HIV • Hepatitis B antigen • Hepatitis C antibody • RPR • Complex semen analysis, antisperm antibodies, and strict morphology Strongly recommended prenatal tests All patients Female Male • Rubella titer • Varicella titer • Cystic fibrosis carrier screen* • Cervical swab for Gonorrhea and Chlamydia • Cystic fibrosis carrier screen* Patients of Jewish Eastern European origin Female Male • Tay’s Sachs • Canavan’s • Gaucher’s • Bloom’s • Niemann-Pick • Fanconi’s anemia • These tests are performed on the male if his partner has a positive test result Patients of French Canadian and Cajun origin Female Male • Tay Sachs (enzymatic) Patients of Mediterranean origin Female Male • Hemoglobin electrophoresis Patients of African or African American origin Female Male • Hemoglobin electrophoresis Patients of Asian origin Female Male • Hemoglobin electrophoresis Patients with family history of mental retardation Female Male • Fragile X *Test one partner first. If he or she is positive, test the other
1. American Autoimmune. Available at: https://www.aarda.org/. Retrieved April 14, 2017. 2. Shah S, Leffler D. Celiac disease: An underappreciated issue in women’s health. Womens Health (Lond Engl) 2010;6:753-766. 3. Geva E, Lerner-Geva L, Burke M, Vardinon N, Lessing JB, Amit A. Undiagnosed systemic Lupus erythematosus in a cohort of infertile women. Am J Reprod Immunol 2004;51:336-340. 4. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clinical Endocrinology [serial online]. March 2007;66(3):309-321. Accessed July 19, 2017 5. "Prerequisite Testing." SART. Society for Assisted Reproductive Technology, 2017.