Should infertility patients be screened for celiac disease?

Celiac disease occurs in roughly 1% of all humans. It is an autoimmune condition initially caused by hypersensitivity and hyperimmunity to a class of proteins, called gliadins, which are found in the outer husk of common grains such as wheat, barley, rye and oats. Because the small intestine becomes chronically inflamed by chronic immune attack, celiac disease is also referred to as ‘immune enteropathy’.

Having a damaged and inflamed gastrointestinal mucosa leads to malabsorption and nutritional deficiencies that may be accompanied by weight loss, diarrhoea or post-prandiol pain that may last for days after exposure to an offending food antigen. Once elicited by exposure to an external antigen, the antibodies become autoantibodies and also react against mucosal proteins in the gut, particularly tissue transglutaminase and endomysium, and interfere with nutrient absorption. Once the process gets incited, attack antibodies and secondary immune enteropathy can be directed against a range of other food proteins. Persistent gut damage may lead to loss of gut enzymes responsible for digestion, including lactase, and the individual may report lactose intolerance. It is felt that celiac disease has become increasingly more common because gliadins are ubiquitously used as food stabilisers during the manufacture of processed foods and are found in what would otherwise seem to be ‘wheat-free’ foods, such as butter, milk, ice cream, carbonated beverages, corn chips, condiments and sandwich meats. Many medications, including over-the-counter remedies, contain gluten because it is a chemical stabiliser and helps ingredients stick together.

Until the development of sensitive and specific screening tests, the diagnosis of celiac disease was based on symptoms and clinicians having a high index of suspicion. Indeed, celiac disease was once considered to be limited to a disease of childhood. The most common childhood presentation was persistent, non-infectious diarrhoea. The presentation in adults is highly variable and includes osteoporosis, intestinal lymphoma, weight loss, joint pain or chronic fatigue. Indeed, chronic diarrhoea is not the most common presentation in adults. Concomitant nutritional deficiencies include folate, iron, vitamin D, all of which are critical for adult health. Genetic predisposition also plays a role in addition to exposure to gluten. In one study, the concordance in monozygotic twins was 83% versus 17% in monozygotic twins [1].

Why should the infertility specialist know and care about celiac disease? In reproductive age women, celiac disease is as common as diabetes and autoimmune thyroiditis. Common reproductive presentations in adult women include infertility, menstrual irregularity, recurrent miscarriage and intrauterine growth restriction if pregnancy is achieved either spontaneously or via medical intervention. Celiac disease is much more common in women with infertility due to oligomenorrhoea associated with weight loss and those with known autoimmune conditions, the most common of which is autoimmune thyroiditis. Gluten enteropathy may be mistaken for stress-induced anovulation. Celiac disease is associated with a relative risk of 9 for intrauterine growth restriction.

Why is celiac disease associated with a relative risk of 9 for intrauterine growth restriction? Recently, it was reported that maternal autoantibodies bind to placental tissue transglutaminase (tTG) and interfere with nutrient transport to the foetus [2]. Monoclonal anti-tTG strongly stained the syncytial microvillus membrane as well as the cytotrophoblast and stromal and vascular elements. The microvillus is critical to nutrient transport and placental tTG, a kinase involved in apoptosis, and plays a fundamental role in regulating placental viability. Although it is easier said than done, adherence to a gluten-free diet reduces both circulating autoantibodies and the risk of foetal growth restriction during pregnancy [3].

Given the population prevalence, occult adult presentation, deleterious reproductive and non-reproductive consequences of chronic immune enteropathy and widespread availability of a sensitive, specific and affordable screening test for anti-tTG autoantibodies, it makes sense to screen for celiac disease in women with infertility. It would be especially important to assess nutritional status before conception, particularly folate levels, because a damaged intestine will not be able to absorb critical nutrients from vitamin supplements. The clinician should keep in mind that many vitamin pills, including the prenatal variety, contain gluten and may be poorly tolerated by those women who would otherwise stand to benefit the most from taking them. If universal screening is not deemed worthwhile, then index screening should include all women with a personal history of unexplained weight loss, with or without recognised menstrual irregularities and those with mild gastrointestinal complaints. Additionally, those with a personal or family history of autoimmune thyroiditis, juvenile diabetes and other autoimmune conditions should be screened.