Unexplained Infertility and Celiac Disease

Recent medical literature suggests that it is reasonable for all women with unexplained infertility to be tested for Celiac Disease (CD).1 The reasons for this are threefold: First, there is a strong association of infertility in women with CD, even in those who do not exhibit the typical signs and symptoms of CD. Secondly, the cost of testing for CD is far less than the cost of an infertility workup using Assisted Reproductive Techniques (ART) such as in vitro fertilization (IVF). And thirdly, CD is not only associated with infertility but also with adverse pregnancy outcomes, therefore the condition should be ruled out.

CD is underdiagnosed largely because practitioners focus on the classic gastrointestinal manifestations of the disease such as diarrhea, weight loss, bloating and malabsorption, and not the array of non-gastrointestinal symptoms it is associated with such as unexplained infertility, thyroid disorders, anemias, menstrual irregularities and adverse pregnancy outcomes. CD can be “atypical” or “silent,” and not manifest any gastrointestinal symptoms at all.2 In fact, unexplained infertility may be the only symptom of the disease.3,4 It is also reported that the majority of patients with CD, “the great imitator,” are asymptomatic adults.5 Seemingly unrelated symptoms range from blood sugar dysregulation to thyroid, neurological, haemopoietic, and dermatological disorders or simply “feeling tired all the time.”2,5 The frequency of CD in association with unexplained infertility is 4-8%, about ten times higher than the prevalence of CD in the general population.1,3

CD screening is particularly important in women’s health as it contributes to infertility, iron deficiency anemia, menstrual irregularities and reduced bone mineral density. CD is also known to cause infertility in men by interfering with spermatogenesis.5 Therefore, if a couple is trying to get pregnant naturally, a thorough family and past medical history is crucially important. The lack of testing for CD in patients with unexplained infertility, and the strong association between the two, has led to the term in the literature: “a neglected clinical association.”6

I strongly recommend to all my fertility patients that they discuss the possibility of CD with their obstetrician or family practice physician. To my patients undergoing ART and IVF, particularly those in repeated attempts, I urge the genetic testing for CD (HLA DQ-2 or HLA DQ-8) be performed. Small bowel biopsy to verify villous damage and anti-gliadin antibody tests which rely on normal IgA levels (AGA, EMA and IgA anti-tTG antibody) are not uniformly positive in patients with celiac disease. IgA deficiencies are the most common type of immunologlobulin deficiency in the general population, and particularly prevalent in patients with CD.7 An alternative sensitive test for a patient with an IgA deficiency is to test for IgG anti-tTG antibodies.8,9

Studies show that “silent” and “atypical” CD patients often do not test positive to the gold-standard small bowel biopsy and IgA based tests mentioned above, and antibody negative CD is being recognized.2,10

While the causes of infertility are numerous, CD needs to be ruled out in cases of unexplained infertility in both men and women of childbearing years. It is reported as prevalent as 1/300, and that the majority of adult patients with CD can be asymptomatic.5 The association of CD with so many different signs and symptoms—dermatitis herpetiformis, psoriasis, arthralgias, myalgias, osteopenia, IgA deficiency, iron deficiency and folate deficiency anemias, type 1 diabetes, infertility in both men and women11,12,13, recurrent abortions, Hashimoto’s thyroiditis, depression, neuropathy, myelopathy, ataxia, epilepsy, reflux esophagitis, irritable bowel syndrome, liver diseases, ADD and ADHD in children—make CD a “great imitator” and the “diagnostic challenge” of the 21st century.2,5,11

Making the diagnosis is important because it is suggested that eliminating gluten from the diet and restoring vitamin deficiencies may restore fertility in both women and men.12

  1. Shah S. and Lefflar D. Celiac disease: an underappreciated issue in women’s health. Women’s Health (Lond Engl). 2010 September; 6(5): 753–766.
  2. Al-Salihi, B. Acupuncture and a gluten-free diet relieve urticaria and eczema in a case of undiagnosed dermatitis herpetiformis and atypical or extraintestinal celiac disease: a case report.
  3. Collin P, Vilska S, Heinonen PK, Hällström O, Pikkarainen P. Infertility and coeliac disease. Gut. 1996 Sep;39(3):382-4.
  4. Choi J, Lebwohl B, Wang J, Lee S, Murray J, Sauer M, and Green P. Increased Prevalence of Celiac Disease in Patients with Unexplained Infertility in the United States: A Prospective Study. J Reprod Med. 2011 May-Jun; 56(5-6): 199–203.
  5. Duggan JM. Coeliac disease: the great imitator. Med J Aust. 2004 May 17;180(10):524-6.
  6. Rostami K, Steegers EA, Wong WY, Braat DD, Steegers-Theunissen RP. Coeliac disease and reproductive disorders: a neglected association. Eur J Obstet Gynecol Reprod Biol. 2001 Jun;96(2):146-9.
  7. Chow MA, Lebwohl B, Reilly NR, Green PH. Immunoglobulin A Deficiency in Celiac Disease. J Clin Gastroenterol. 2012 Apr 2. [Epub ahead of print]
  8. Harrison E, Li KK, Petchey M, Nwokolo C, Loft D, Arasaradnam RP. Selective measurement of anti-tTG antibodies in coeliac disease and IgA deficiency: an alternative pathway. Postgrad Med J. 2012 Aug 7. [Epub ahead of print]
  9. Meini A, Pillan NM, Villanacci V, Monafo V, Ugazio AG, Plebani A.Prevalence and diagnosis of celiac disease in IgA-deficient children. Ann Allergy Asthma Immunol. 1996 Oct;77(4):333-6.
  10. Hopper AD, Hadjivassiliou M, Butt S, Sanders DS. Adult coeliac disease. BMJ. 2007 Sep 15;335(7619):558-62.
  11. Soni S, Badawy SZ. Celiac disease and its effect on human reproduction: a review. J Reprod Med. 2010 Jan-Feb;55(1-2):3-8.
  12. Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF. Infertility, obstetric and gynaecological problems in coeliac sprue. Dig Dis. 1994 May-Jun;12(3):186-90.
  13. Stazi AV, Trinti B. Reproduction, endocrine disorders and celiac disease: risk factors of osteoporosis. Minerva Med. 2006 Apr;97(2):191-203.
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