DR. SEUNGDAMRONG is a Senior Reproductive Endocrinology and Infertility Fellow, Department of Obstetrics, Gynecology, and Women's Health, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, N.J.

Aimee Seungdamrong, MD

Subfertility. Miscarriage. Low-birthweight babies. Just three reasons why you should be on the alert for detecting celiac disease in your patients-especially if they have gastrointestinal symptoms. This insidious autoimmune disorder can fool you. You may be aware that people who have it must avoid eating wheat, barley, and rye. Or that it's characterized by an inflammatory injury of the small intestinal mucosa inflicted by dietary glutens-which results in malabsorption and nutritional deficiencies.

 But you might be surprised to learn that half of adults with this incurable disorder, which occurs in the genetically predisposed, have none of its classic GI symptoms. Instead, their manifestations may include osteoporosis and infertility.

 Moreover, it's a lot more common than once thought.

Glutens, and their breakdown products, gliadins, are proteins found in wheat, barley, and rye that contain a high percentage of proline and glutamine amino acid residues. When presented to small intestinal mucosal T-cells, these amino acid components make glutens highly recognizable to HLA-DQ2 and HLA-DQ8 molecules and trick them into inappropriately producing cytokines. Tissue damage results. The inappropriate immune response doesn't stop there. It also prods plasma cells to produce antibodies to the wheat proteins, which have been implicated in the disease's manifestations outside the intestines. (In contrast, the proteins in other cereals such as rice and oats consist of different amino acids, which are much less reactive and don't cause the same inflammation.) The inflammatory response causes the villi in the small bowel to atrophy and inflammatory cells to infiltrate the lamina propria; it also produces intestinal crypt hyperplasia (Figure 1).

The disease presents in a variety of ways. Although once thought to be rare, there's growing evidence that it's more common and often undiagnosed. In a 2003 study of more than 3,600 asymptomatic Scandinavian schoolchildren screened for celiac disease, the prevalence ratio was 1:99 children (95% CI; 1 in 146 to 1 in 75), based on biopsy. [Other studies show the rate as 1:300 in the general population.] The classic form presents as chronic diarrhea-with or without the malabsorptive symptoms of bloating, abdominal pain, excess fat in the stools, weight loss, flatulence, and nutritional deficiencies. Not surprisingly, patients are frequently misdiagnosed as having inflammatory bowel disease. The classic form can present in childhood or in adulthood and [only 50% of adults with celiac disease have GI symptoms. However, the diagnosis is often elusive as the GI symptoms can be vague and nonspecific.] The other half of adults with celiac disease lack GI symptoms and present with a wide spectrum of manifestations such as insulin-dependent diabetes, osteoporosis, iron, folate, and vitamin B

deficiency, dermatitis herpetiformis, and infertility.

 Our goal here is to explore the damage to extraintestinal systems that could affect fertility and pregnancy.

Two things cause the iron deficiency anemia in celiac disease: the malabsorption of dietary iron from the small intestine and occult blood loss from the GI tract. The good news is that the standard treatment for celiac disease-a gluten-free diet-resolves the anemia in 94% of cases.

Celiac disease also causes folate and vitamin B

 to be poorly absorbed from the GI tract. We know that women with folate deficiency are at increased risk of giving birth to infants with neural tube defects. But researchers haven't gone so far as to conclusively link celiac disease itself to such defects. A recent prospective study did not show any higher risk of birth defects in infants of women with celiac disease over the general population.

 Although there are no conclusive studies, it's recommended that women with celiac disease who plan to conceive or are already pregnant increase their iron and folate intake over and above taking standard prenatal vitamins.

The most important step in diagnosing celiac disease is to develop clinical awareness and suspicion. After that, serologic tests are the next step. The tests most often used measure antibodies against the breakdown products of glutens and the enzymes that mediate the tissue damage in the disease. These are antigliadin (AGA), antiendomysial (EMA), or anti-tissue transglutaminase (tTGA) IgA and IgG antibodies by enzyme-linked immunoassays or immunofluorescence.

The sensitivity and specificity for the AGA and TTGA tests are between 75% and 95% but the sensitivity and specificity are close to 100% for the EMA assay.

The latter assay is based on an immunofluorescence evaluation that must be interpreted by an experienced pathologist and is therefore time- consuming and expensive. Most clinicians will start with an AGA or tTGA test and, if positive, confirm the serological findings with the EMA. These serologic tests are considered helpful in the diagnosis but not definitive.

Biopsy of the small bowel while the patient is on a gluten-containing diet is the diagnostic gold standard and is important in patient management, given that [treatment involves lifelong dietary restriction.] This is performed by endoscopy with at least three biopsies from either the distal duodenum or the proximal jejunum.

The histologic features of the small intestine seen in celiac disease are small bowel villous atrophy, infiltration of the lamina propria with inflammatory cells, and intestinal crypt hyperplasia as mentioned. 

Radiologic imaging is not helpful in diagnosing celiac disease but can help rule out other possible diagnoses of GI disease, such as malignancy. 

Celiac disease has been implicated in subfertility and recurrent spontaneous abortions. Women with known celiac disease have a shortened fertile period. They experience menarche at a later age and have an earlier menopause. Celiac disease affects some 4% to 8% of women who are diagnosed with unexplained infertility.

The subfertility may possibly manifest either as a decrease in fecundity or as an increased rate of spontaneous abortion.

Some suggest screening women with otherwise unexplained infertility for celiac disease as it may occur with a higher prevalence in this group.

The specific cause of these effects on fertility is still unknown but adequate treatment with a gluten-free diet seems to greatly reduce these negative outcomes. 

[The disease seems to increase the risk of intrauterine growth restriction (IUGR), low birthweight-or both.] A large, Swedish, retrospective, population-based study in 2005 showed that infants of mothers with celiac disease who were diagnosed after delivery (therefore untreated during pregnancy) were at greater risk for IUGR, low or very low birthweight, preterm birth, and cesarean delivery. The study also showed that infants of mothers with celiac disease who were diagnosed before pregnancy and 

 had no greater risk for adverse fetal outcomes than the general population. Other smaller studies also suggest an increased risk of IUGR in women with celiac disease, which may resolve with a gluten-free diet. 

[Dietary restriction of glutens-the mainstay of treatment-is the only accepted treatment for celiac disease.] While this can be challenging for those used to eating wheat products, many of the manifestations of the disease resolve with strict avoidance of any food or food product containing glutens. Although the gluten-free diet resolves histologic GI features in most patients, 10% may be refractory. Furthermore, the recovery period is long and may take more than 10 years. Supplemental iron, calcium, zinc, magnesium, folate, and B

 may also be necessary. Corticosteroids can improve unresponsive disease.

There's no cure for celiac disease, which requires treatment with lifelong dietary restriction. Due to an often insidious presentation, a high index of suspicion-especially in women with GI symptoms-will increase detection. The resulting reproductive complications include subfertility, an increased rate of miscarriage, and low-birthweight babies. [For most women, the complications can be easily resolved with strict adherence to a gluten-free diet and supplementation with iron and folate, especially during the reproductive years.] Less common manifestations of the disease include insulin-dependent diabetes mellitus, lymphoma, osteoporosis, and autoimmune thyroid disease, which must be considered in the long-term care of the patient.

Bradley RJ, Rosen MP. Subfertility and gastrointestinal disease: 'unexplained' is often undiagnosed. 

Chand N, Mihas AA. Celiac disease: current concepts in diagnosis and treatment. 

Tata LJ,Card TR, Logan RF, et al. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study

Farrell RJ, Kelly CP. Diagnosis of celiac sprue. 

Sheiner E, Peleg R, Levy A. Pregnancy outcome of patients with known celiac disease. 

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Half of all adults with this autoimmune disorder don't have the classic GI symptoms, which include bloating and diarrhea. So should you screen women with otherwise unexplained infertility for it? Other ob/gyn complications in women with celiac disease include miscarriage, iron deficiency anemia, and IUGR.

Aimee Seungdamrong, MD

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