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Infertility and Celiac Disease
Ralph E. Warren, MD, FRCPC, DTM&H
Member, Canadian Celiac Association Professional Advisory Board
Winter 2008
Infertility may be one of the reproductive complications of undiagnosed celiac disease, which can affect both women and men. An estimated 13%-15% of Americans of reproductive age are infertile. Ovulatory dysfunction accounts for 20% of female infertility, while tubal and pelvic abnormalities account for a further 20%. Male factor infertility accounts for 30%, combined factors account for 5% and the remaining 15% are classified as "unexplained infertility." Some studies suggest that undiagnosed celiac disease may be a factor within this group.
Celiac disease (CD) is an autoimmune disorder characterized by inflammation of the small intestine's absorption surface, induced in genetically predisposed individuals by ingestion of wheat, rye or barley. Specific peptides of these grains, collectively called gluten, elicit an inappropriate immune response that damages the surface of the small intestine, causing malabsorption of nutrients. A gluten-free diet for life is the only effective therapy in reversing the damage and complications.
CD is one of the most common inherited diseases, affecting 0.5 - 1.0% of the population of the western hemisphere. No ethnic group is known to be free of CD. European estimates suggest that the prevalence of undiagnosed CD among women with unexplained infertility is about 3%, higher than in the general population.
The most urgent problem facing infertile women with undiagnosed CD is the delay in diagnosis during their reproductive years. This delay occurs because the clinical presentation is often subtle or silent. Some effects of CD may be a gradual onset of unexplained iron deficiency (anemia), unexplained osteoporosis, irritable bowel syndrome or chronic fatigue syndrome. However, infertility may be the initial or only presentation of CD.
Unfortunately, CD is rarely considered as a possible explanation in cases of unexplained infertility. Psychological and hormonal factors receive earlier attention and greater emphasis. Some European experts refer to CD and subfertility as a "neglected association in clinical practice."
The span of time for explaining and treating unexplained infertility in CD is further compromised by two additional factors. Firstly, individuals are most often diagnosed with CD between the ages of 30 and 60, with diagnoses peaking in among people in their forties, according to the Canadian Celiac Health Survey of 2002/2003. Secondly, early menopause and recurrent miscarriages are also recognized complications of untreated CD. All of these factors increase the likelihood that this explanation of unexplained infertility will become available to women with celiac disease only retrospectively, once they are postmenopausal.
This problem could easily be solved in Canada and the USA if every fertility clinic routinely tested for CD, a service now provided by most European and South American infertility clinics. Excellent blood screening tests are available. These are the IgA tissue transglutaminase (TTG) antibody test or the IgA endomysial (EMA) antibody test. False negative results in individuals with IgA deficiency (1 in 40 celiacs) can be avoided by including a request for a serum IgA level. An over-the-counter, self-administered home screening kit for CD is now available in Canadian pharmacies, marketed under the brand name Biocard™ Celiac Test.
These blood tests do not, however, make the diagnosis of CD. They are merely for screening purposes, and may indicate the need for further testing. CD is diagnosed by microscopic analysis of tissue biopsies, taken from the upper small bowel (duodenum-jejunum), using an endoscope and sedation. Moreover, it is critical that these biopsies and screening tests be performed while the patient is continuing to ingest a standard diet. Initiating a gluten-restricted diet before biopsies are obtained is likely to invalidate the blood screening test results and render the biopsies uninterpretable. All Canadian provinces and territories except Ontario offer serological testing for CD as part of their health-covered services.
Following diagnostic biopsy confirmation of CD, a referral is made to a qualified dietitian with expertise in CD, who can guide the patient in implementing a gluten-free diet for life. Membership in the Canadian Celiac Association and involvement with its local chapter will provide valuable practical information and support.
More research regarding CD and infertility is needed. Nutritional deficiencies from malabsorption in CD may affect reproduction. Iron, folate, zinc and selenium deficiencies have been implicated. Autoimmune and hormonal factors are likely contributory, but precise mechanisms are unclear.
Less information exists about the prevalence and mechanisms of male infertility in untreated CD. Hormonal deficiencies and reduced sperm counts have been documented, along with improvement using a gluten-free diet.
Currently, the data from European studies suggest the likeliness of a connection between untreated CD and infertility in women; the evidence supporting a connection is good, but it should be more solid. Many experts are convinced of the causal connection, but pockets of controversy exist; for example, a recent, small study published by reproductive clinician-scientists at the University of California, San Francisco, did not show the same connection between CD and infertility. The Celiac Disease Center at Columbia University (New York City) is now working with infertility experts in the USA studying the prevalence of CD-related infertility. A similar study is being conducted by reproductive clinician-scientists at the University of California, San Francisco. In light of this controversy and the pending results of ongoing studies, the link between infertility and Celiac Disease may well be an excellent topic for the upcoming Canadian Consensus Conference on CD being planned by the Canadian Association of Gastroenterology for 2010.
Women of reproductive age with infertility stemming from any cause frequently undergo considerable emotional upheaval. Additional aggravating factors are the inordinate quantity of time and financial outlay necessary for diagnostic investigations, often invasive, and subjection to invasive assisted reproductive techniques that are often unsuccessful and must be repeated. Much time, cost and energy would be saved and successful pregnancies achieved if CD were diagnosed earlier in these women.
Many experts recommend that serological testing for CD be included in the protocol of all fertility clinics, and implemented by all obstetrician-gynecologists investigating infertility and recurrent miscarriages. The gluten-free diet therapy of CD is effective and is a major predictor for favourable pregnancy outcomes.
A graduate of Queen's University, Dr. Ralph E. Warren was a consulting gastroenterologist and teacher at St. Michael's Hospital and University of Toronto from 1968 to 2003. In 2003 he joined MedCan Clinic and the Toronto GI Clinic as a gastroenterology consultant. He is a specialist in celiac disease, gastrointestinal infection, tropical medicine and colonic cancer screening, and has been a member of the CCA Professional Advisory Board since 1994, and an advisor to the Toronto celiac community since 1981.
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