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    Reproductive effects of celiac disease

    There is an established relationship between overt celiac disease and adverse reproductive consequences, including infertility. Celiac disease also has been suggested as a contributor to recurrent pregnancy loss.

    Awareness of celiac disease (CD) has increased dramatically during the past 10 years in both the medical community and the general public. This is reflected by an increase in the number of patients diagnosed, an appreciation of the broader spectrum of clinical presentation, and an expanding array of gluten-free dietary alternatives and support resources for affected patients. Ob/gyns are most likely to encounter women with CD presenting with abdominal and pelvic pain. Irritable bowel syndrome and endometriosis are commonly part of the differential diagnosis.

    Incidence and prevalence

    Celiac disease is an inherited autoimmune chronic inflammatory intestinal disease that, uniquely, has a known inciting agent—gluten. People with other autoimmune diagnoses or genetic conditions such as Down syndrome, Turner syndrome, and Ehlers-Danlos syndrome have genetic susceptibility or predisposition loci and an increased incidence of CD. The risk of CD for a first-degree relative of a person with CD is 10% to 15%. It is 1.5 times to 2 times more common in women than men.1

    Genetic susceptibility and exposure to gluten protein are necessary but not sufficient to cause loss of enteric function and CD. Celiac disease may resemble tropical sprue, a long-recognized malabsorption syndrome endemic to tropical locales, and was initially referred to as “celiac sprue.” Common symptoms include diarrhea; abdominal pain; malabsorption, with vitamin deficiencies; weight loss; hepatobiliary dysfunction; and fatigue. It is now recognized as a much more common malady than previously appreciated.

    Different populations have substantial differences in prevalence of CD. It is more common in Scandinavian countries, southern Italy, North Africa, and the Mideast, and is relatively rare in Asia.1 One in 250 to 1 in 300 people are affected, with a spectrum of presentations including iron- and folate-deficient anemias, depression, herpetiformis dermatitis, and decreased bone mineral density.2-4 Rarer complications include refractory sprue, small intestinal adenocarcinoma, and enteropathy-associated T-cell lymphoma.

     

     

    Presentation

    Patients presenting with silent CD, without gastrointestinal (GI) symptoms, may have short stature or neurologic symptoms and possible reproductive disorders, including delayed menarche, menstrual disturbances, infertility, and recurrent miscarriage.1,4,5 Patients with obvious or clinically relevant disease may also have these findings. Risk factors include family history, type 1 diabetes mellitus, autoimmune thyroid disease, Down syndrome, and Turner syndrome (Table 1).1,2 Celiac disease has also been associated with chronic pelvic pain, including dysmenorrhea and deep dyspareunia.6

    Individuals with gluten intolerance may have CD, a wheat allergy, or gluten sensitivity. All involve a gastrointestinal or dermatologic reaction to the gluten protein found in wheat, rye, and barley. The clinical presentation may be identical, but wheat allergy typically has a more abrupt onset. Only CD is associated with enteropathy; wheat allergy and gluten sensitivity are not associated with coexisting conditions. 

    Pathophysiology

    The underlying injury involves an inflammatory reaction, primarily in the duodenum and jejunum, mediated by gliadin reactive CD4+ T cells in the lamina propria. These cells bind to gliadin, a primary wheat protein, and produce inflammatory cytokines, especially interferon-γ.7 The immunogenicity of gliadin is enhanced by the enzyme tissue transglutaminase, which dimidiates the gliadin peptides and serves as a marker for CD. The ensuing cascade of events involves release of several toxic mediators, including metalloproteinases, which ultimately produce hyperplasia of the crypts and injury of the villi. As the damage progresses, the enterocytes are lethally injured, and absorption is impaired.

    The mechanisms by which CD affects reproduction are unknown, and indeed, not all studies examining the relationship have consistently found adverse effects. Nutritional and other factors have been suggested but do not appear to be involved in patients with silent CD.

     

     

    Reproductive effects

    There is an established relationship between overt CD and adverse reproductive consequences, including infertility. The relationship between silent CD and infertility has been more controversial.

    Studies evaluating the relationship between CD and adverse reproductive experiences—including infertility, recurrent pregnancy loss, and poor obstetric outcome—have a number of limitations, including inconsistent and incomplete criteria for the diagnosis of CD and infertility. They have often involved small and underpowered sample sizes and have combined patients who presented with typical gastrointestinal symptoms and those with silent disease. Several reports have had inappropriate control groups or no control groups at all.

    Several studies primarily involving Europe and the Mideast have suggested that CD is associated with infertility in 4% to 8% of cases, compared with a background incidence in those populations of approximately 1%.8-10 A cohort study involving Northern California women with unexplained infertility screened with serologic markers reported that fewer than 1% were affected.11 A more recent series of 191 patients with unexplained infertility screened in New York found a 6% prevalence  of histologically confirmed cases of previously undiagnosed CD.12

    The contradictory conclusions may be because of differences in the ethnicity of the study populations. A Swedish nationwide population-based study that evaluated the fertility experience of patients with known histologically confirmed CD concluded that women with CD overall had normal fertility but did have decreased fecundity in the 2 years before their diagnosis.13

    More compelling evidence of a role for CD in unexplained infertility may be suggested by a positive response to therapy in those with yet-untreated disease. There are several reports of successful pregnancy after adoption of a gluten-free diet, but the number of CD cases detected by screening has been too small and the concomitant use of other effective interventions limits conclusions about causality.14 To date, efficacy of a gluten-free diet as part of an infertility treatment regimen has not been tested in a systematic manner.

    Celiac disease also has been suggested as a contributor to recurrent pregnancy loss. In a small series, 8% of affected patients had positive serology and the diagnosis of CD was confirmed by biopsy in 88%.15 Benefit of treatment was not determined. A large Italian population-based study of patients with serologically detected but not histologically confirmed CD found a higher incidence of anemia but not of spontaneous abortion, premature delivery, low birth weight, or intrauterine growth restriction (IUGR) in affected patients.16 In the absence of maternal symptoms, screening for occult CD is not currently recommended in the workup of recurrent spontaneous abortion.

    The benefit of a gluten-free diet is more conclusively proven to improve birth outcomes in women previously diagnosed with CD. A large Danish cohort study noted that before institution of a gluten-free diet, mean birth weight of newborns of mothers with CD was 8.39 oz less than controls, and they had a 3-fold greater risk of IUGR, but these differences disappeared in subsequent pregnancies with treatment.17 These findings have been confirmed with expanded follow-up studies and in other populations, and reduction in risk of preterm delivery has been confirmed as well.18,19

     

     

    Diagnosis

    The diagnosis of CD rests on histologic confirmation with duodenal biopsy and a positive response to a gluten-free diet.2 Serologic tests are critical for CD screening and should be considered for first-degree relatives of patients with a CD diagnosis. Typical findings include crypt hyperplasia, intraepithelial lymphocytosis, and villous atrophy. These findings are characteristic of CD, but not specific or diagnostic. Ultimate confirmation is provided by clinical improvement on a gluten-free diet.

    Before undergoing endoscopy with biopsy, most patients will have serologic testing as a screen. Immunoglobulin A (IgA) antibodies offer the most sensitive testing, and endomysial serology offers the greatest specificity, with near 100% accuracy.2 Tissue transglutaminase is the auto-enzyme that produces endomysial antibodies, and currently available enzyme-linked immunoassays offer a rapid, less-expensive quantitative alternative to endomysial antibody testing. Both tests have greater than 90% sensitivity, are considered optimal for screening for CD, and correlate with the extent of mucosal injury. Antigliadin antibody testing, once recommended for screening, lacks the sensitivity and specificity for use as a screening test in reproductive-aged patients.

    Selective IgA deficiency is 10 times more common in patients with CD, and affected patients may not have abnormal antibody testing.2 For this reason, some investigators have recommended that anti-tissue transglutaminase antibodies be used as the sole screening test and, if not elevated and CD is strongly suspected, total IgA levels should be obtained to exclude the diagnosis of selective IgA deficiency.2,20 IgG antibodies to tissue transglutaminase are often elevated in this setting.

    Testing of serum IgA anti-tissue transglutaminase antibodies is recommended initially in those without IgA deficiency, because it is highly sensitive and specific.1 IgA anti-endomysial antibodies are nearly 100% specific but may only be used to confirm diagnosis, because they may be seen in other autoimmune disorders.

    Ninety percent to 95% of patients with CD carry the HLA-DQ2 allele and almost all the additional patients have HLA-DQ8.2 Approximately 30% to 40% of the population carries these genes, so testing for them offers poor predictive value. Their absence makes the diagnosis highly unlikely, and they may be occasionally useful as a negative screening test in people who are at risk. 

     

     

    Treatment

    The lifelong elimination of wheat, rye, and barley from the diet is the only therapy proven to be effective for treating CD.2 The gluten threshold for causing intestinal mucosal damage is estimated to be 10 mg to 50 mg, or approximately 1/150 to 1/30 of a slice of bread.1,21 Initiation of a gluten-free diet results in the reduction of serologic markers and resolution of the abnormal GI histology.2 Adherence to a gluten-free diet is difficult, and patients with CD are at risk of frequent inadvertent exposure to gluten as a contaminant of other commonly used substitutes, such as oats. Additional gluten-containing grains that should be avoided include semolina, kamut, spelt, triticale, and malt. Patients are advised to use alternative grains and starches (Table 2).

    Most alternative grains are not fortified with B vitamins, and testing for folic acid; vitamins B6, B12, A, D, E, and K; and iron and calcium should be performed.2 Any deficiencies should be corrected. Up to 30% of patients will fail to experience clinical or histologic improvement on a gluten-free diet.22 Most often, these patients have been unable to adhere to the diet because of known or inadvertent exposure. If dietary noncompliance is excluded, the confidence of the original diagnosis should be reassessed. There are other causes of villous atrophy, and intercurrent illnesses can occur.

    There is also interest in developing treatment involving nondietary alternatives, such as recombinant enzymes that could digest gliadin in the stomach or proximal small intestine.23 These therapies are not yet available, but patients may be interested in information about them (Table 3).

     

     

     

    Clinical management

    There are no interventions known to prevent development of CD, although breastfeeding is associated with a 50% reduction in risk when gluten is introduced before the infant is weaned.1,24 Patients presenting with typical symptoms of CD including diarrhea, abdominal pain, and malabsorption should have serologic screening with anti-tissue transglutaminase IgA and/or endomysial antibodies. Testing should be completed before starting therapy. Patients with atypical pelvic pain, particularly with GI components, may also benefit from screening. The current literature does not consistently support silent CD as a cause of unexplained infertility or recurrent pregnancy loss, and routine screening is not recommended. Patients at risk for CD may have HLA-DQ2 and HLA-DQ8 testing.

    Patients with negative serology should also be tested for total IgA levels to exclude an isolated IgA deficiency (Figure). After positive serologic screening, endoscopy with upper GI biopsies should be recommended to establish the diagnosis. If confirmatory, a gluten-free diet should be advised.

    Because adherence to a gluten-free diet is difficult and requires a lifelong commitment, both patient and physician should have clear expectations for potential benefit at the outset. Pregnant patients and those planning to conceive in the near future can expect to reduce the risks of preterm delivery, low-birth-weight infants, and IUGR associated with overt CD. Patients known to have CD should expect to have near-normal fertility potential with appropriate diet, but the benefits of adopting a gluten-free diet in patients with silent CD are unproven. 

     

     

     

     

     

     

     

     

     

     

     

    References

    1. Fasano A, Catassi C. Celiac disease. N Engl J Med. 2012;367(25):1419-1426.

    2. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357(17):1731-1743.

    3. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362(9381):383-391.

    4. Eliakim R, Sherer DM. Celiac disease: fertility and pregnancy. Gynecol Obstet Invest. 2001;51(1):3-7.

    5. Kolho KL, Tiitinen A, Tulppala M, Unkila-Kallio L, Savilahti E. Screening for coeliac disease in women with a history of recurrent miscarriage or infertility. Br J Obstet Gynaecol. 1999;106(2):171-173.

    6. Porpora MG, Picarelli A, Prosperi Porta R, Di Tola M, D’Elia C, Cosmi EV. Celiac disease as a cause of chronic pelvic pain, dysmenorrhea, and deep dyspareunia. Obstet Gynecol. 2002;99(5 pt 2):937-939. 

    7. Nilsen EM, Jahnsen FL, Lundin KE, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998;115(3):551-563.

    8. Meloni GF, Dessole S, Vargiu N, Tomasi PA, Musumeci S. The prevalence of coeliac disease in infertility. Hum Reprod. 1999;14(11):2759–2761.

    9. Collin P, Vilska S, Heinonen PK, Hällström O, Pikkarainen P. Infertility and coeliac disease. Gut. 1996;39(3):382-384.

    10. Bradley RJ, Rosen MP. Subfertility and gastrointestinal disease: ‘unexplained’ is often undiagnosed. Obstet Gynecol Surv. 2004;59(2):108-117.

    11. Jackson JE, Rosen M, McLean T, Moro J, Croughan M, Cedars MI. Prevalence of celiac disease in a cohort of women with unexplained infertility. Fertil Steril. 2008;89(4):1002-1004.

    12. Choi JM, Lebwohl B, Wang J, et al. Increased prevalence of celiac disease in patients with unexplained infertility in the United States. J Reprod Med. 2011;56(5-6):199-203.

    13. Zugna D, Richiardi L, Akre O, Stephansson O, Ludvigsson JF. A nationwide population-based study to determine whether coeliac disease is associated with infertility. Gut. 2010;59(11):1471-1475.

    14. Nenna R, Mennini M, Petrarca L, Bonamico M. Immediate effect on fertility of a gluten-free diet in women with untreated coeliac disease. Gut. 2011;60(7):1023-1024. 

    15. Gasbarrini A, Torre ES, Trivellini C, De Carolis S, Caruso A, Gasbarrini G. Recurrent spontaneous abortion and intrauterine fetal growth retardation as symptoms of coeliac disease. Lancet. 2000;356(9227):399-400.

    16. Greco L, Veneziano A, Di Donato L, et al. Undiagnosed coeliac disease does not appear to be associated with unfavourable outcome of pregnancy. Gut. 2004;53(1):149-151.

    17. Norgård B, Fonager K, Sorensen HT, Olsen J. Birth outcomes of women with celiac disease: a nationwide historical cohort study. Am J Gastroenterol. 1999;94(9):2435-2440. 

    18. Khashan AS, Henriksen TB, Mortensen PB, et al. The impact of maternal celiac disease on birthweight and preterm birth: a Danish population-based cohort study. Hum Reprod. 2010;25(2):528-534.

    19. Ludvigsson JF, Montgomery SM, Ekbom A. Celiac disease and risk of adverse fetal outcome: a population-based cohort study. Gastroenterology. 2005;129(2):454-463.

    20. Rostom A, Dubé C, Cranney A, et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology. 2005;128(4 suppl 1):S38-S46.

    21. Catassi C, Fabiani E, Iacono G, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007;85(1):160-166.

    22. O’Mahony S, Howdle PD, Losowsky MS. Review article: management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther. 1996;10(5):671-680.

    23. Stepniak D, Spaenij-Dekking L, Mitea C, et al. Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease. Am J Physiol Gastrointest Liver Physiol. 2006;291(4):G621-G629.

    24. Szajewska H, Chmielewska A, Piéscik-Lech M, et al; PREVENTCD Study Group. Systematic review: early infant feeding and the prevention of coeliac disease. Aliment Pharmacol Ther. 2012;36(7):607-618.

    Steven J. Ory, MD
    Dr. Ory is a professor of obstetrics and gynecology, Florida International University College of Medicine, Miami, and a partner at IVF ...
    Daniel R. Christie, MD
    Dr. Christie is a partner at IVF Florida Reproductive Associates, Margate.

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