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Celiac Disease and Its Effect on Human Reproduction
A Review
Shelly Soni, M.D., and Shawky Z. A. Badawy, M.D.
Celiac disease is an intestinal inflammatory disease that is triggered by gluten in the diet. Patients present with a wide array of symptoms due to malabsorption that include diarrhea, abdominal pain, bloating and weight loss. In women, this disease may have implications on menstrual and reproductive health. The symptom complex includes delayed menarche, early menopause, secondary amenorrhea, infertility, recurrent miscarriages and intrauterine growth restriction. These women benefit from early diagnosis and treatment. Therefore, celiac disease should be considered and screening tests performed on women presenting with menstrual and reproductive problems and treated accordingly. The objective of this article is to review the current literature on celiac disease and its association with the above-mentioned disorders. (J Reprod Med 2010;55:3–8)
Keywords: amenorrhea; celiac disease; infertility, female; menstruation; miscarriage.
 Celiac disease should be suspected
in females with menstrual abnormalities, infertility and adverse pregnancy outcome. Celiac disease constitutes one of the important causes of malabsorption syndrome. It is an autoimmune disorder characterized by inflammatory injury of the small intestinal mucosa secondary to gluten intolerance. Etiology is multifactorial, including environmental, genetic and immunologic factors.1 Environmental component is due to the presence of gluten proteins in the diet, including wheat, rye, barley and oats. The incidence is high in Caucasians and low in Asians and African Americans. The incidence in first-degree relatives is 10%, suggesting a genetic etiology.1 Genetically predisposed individuals include those with HLA phenotypes DQ22, DQ8 and DQ2 half-heterodimer, which are associated with celiac disease. The presence of IgA antigliadin, IgA antiendomysial and IgA anti-tTG antibodies suggests an immunologic etiology. It is, however, not known whether such antibodies are primary or secondary to the tissue damage.
Celiac disease affects children as well as adults.3 The characteristic presentation includes diarrhea, abdominal pain and weight loss. However, cases of the disease without the classic symptoms of malabsorption have been described.4 It has also been recognized that the subclinical disease and its extraintestinal manifestations are even more common than the classic pattern.5 The disease has a significant effect on menstrual and reproductive health of women.
This article reviews the current knowledge about the pathophysiology of the disease, its association with menstrual and reproductive disorders in females, proposed etiologies behind these disorders and benefits of treatment.
Treating the disease has a benefit
and may lead to prevention of symptoms and improvement in the quality of life. Pathophysiology
Whether celiac disease is a chronic autoimmune disorder is controversial, as the intestinal epithelium reverts to normal on a gluten-free diet, and autoimmune disorders occur less frequently if the disease is treated at a young age.6 Celiac disease is an inflammatory disorder that affects a large number of ethnic groups but mostly people of European origin, including those living in North America and Australia. The incidence in Europe and the United States is close to 1 in 250.7,8 One study showed the disease affects females more than males, with a female:male ratio of 2.7:1.9
The pathologic abnormalities are mostly present in the proximal part of the small intestine and decrease in severity with distal progression. In severe cases, however, the lesion can extend to the ileum and also may affect the stomach and colon.1 The characteristic histologic appearance of small intestinal mucosa is absence or reduced height of villi, resulting in a flat appearance with crypt hyperplasia and increased lymphocytes and plasma cells in the lamina propria. These changes disappear following elimination of gluten from the diet.1
The classic symptoms of celiac disease include diarrhea, abdominal pain, abdominal distension, weight loss associated with anemia and vitamin deficiency. In children, these symptoms appear at the time of weaning, with the introduction of cereals in the diet. Thus, the infant may present with impaired growth around 4–24 months of age.10 Other symptoms in adults include feeling tired all the time, muscle pain and family history of anemia (Figure 1 and Table I).11 Many patients may have only subtle variations, or the disease may even be silent, with no symptoms at all.12
In addition to gastrointestinal manifestations in women, symptoms include menstrual disturbances, reproductive disorders and infertility. Infertility may be the first presenting symptom of subclinical celiac disease.2 Frequently observed menstrual disorders include late menarche, early menopause and secondary amenorrhea.13-17 Various authors have also shown that women with celiac disease may present with infertility, subfertility, recurrent miscarriages and intrauterine growth restriction.12,18,19
  Celiac Disease and Menstrual Disorders One of the early studies was conducted by Fergusson et al.13 They examined 74 patients with celiac disease, 54 on a normal diet and 20 on a gluten-free diet. The authors found that menarche was significantly delayed in untreated patients when compared to those on a gluten-free diet (15±2 vs. 13.5±1 years, respectively). Additionally, 16 of 54 untreated patients experienced secondary amenorrhea of more than 3 months’ duration as compared to 2 patients on a gluten-free diet. Further, menopause occurred earlier in untreated patients (45±5 vs. 53±1.2). We reviewed the literature and found that various studies have shown comparable results (Table II).
 A recent study published in 2004 by Kotze et al16 demonstrated the effect of the degree of malnutrition on menstrual dysfunction in patients with celiac disease. Delayed menarche appeared in all the subgroups of women with malnutrition. The incidence was higher in women with moderate malnutrition when compared with those without malnutrition (p=0.030) and with women with mild malnutrition (p=0.010). The authors also compared the age at menarche in patients adherent to a gluten-free diet and those who were not. The latter group presented with a delay in menarche when compared to the former group.
Celiac Disease and Infertility Several studies have demonstrated an association of celiac disease with subfertility and infertility. One of the case-control studies done by Sher et al17 showed the mean number of children born to women with celiac disease was significantly lower, 1.9 (SD±0.9) as compared to 2.5 (SD±1.2) in controls. Conversely, Collin and colleagues11 investigated the incidence of subclinical celiac disease in patients with infertility. Four (2.7%) of 150 women in the infertility group and none of the 150 control subjects were found to have celiac disease (p=0.06). All 4 women with celiac disease suffered from infertility of unexplained origin. A similar case-control study conducted by Meloni et al18 in Sardinia found that 2 of 25 women (8%) with unexplained infertility had celiac disease.
It is possible that reproductive disorders are the first symptoms of celiac disease. Around 10–15% of patients coming to infertility clinics are designated as having unexplained infertility, and nonspecific treatment is started.19 However, diagnosing an etiology and starting a definite treatment will be more beneficial to these women. Infertility can be a consequence of various medical morbidities, like celiac disease and other gastrointestinal disorders, which should be ruled out. Thus, various authors have suggested that screening for celiac disease should be part of a diagnostic program for women with unexplained infertility.20,21 Observations have also shown that the incidence of infertility is not higher in patients on gluten-free diets.17 In 1 of the studies, celiac patients being followed up for infertility conceived after eliminating gluten from their diets.12
Effect of Celiac Disease on Pregnancy Evidence is mounting for an association of celiac disease with recurrent miscarriages and intrauterine growth restriction. In 1975, Ogborn22 studied 60 pregnancies in 25 patients with celiac disease. He concluded that recurrent miscarriages and intrauterine growth restriction were the main obstetric problems associated with celiac disease and that the severity was reduced by adhering to a strict gluten-free diet. The rates of miscarriages were significantly reduced to 4% after adhering to a gluten-free diet as compared to 21% in untreated women. However, both groups had a high rate of low birth weight, 16% and 18% in untreated women and those on a gluten-free diet, respectively. Norgard et al23 carried out a historical cohort study in Danish hospitals from 1977 to 1992. The study included 211 newborns to 127 women with celiac disease and 1,260 control deliveries. Before celiac patients were hospitalized, the mean birth weight of their newborns was 238 g lower than that of the control women after adjustment for potential confounders. However, after celiac patients were first hospitalized and treated, the researchers found no increased risk of intrauterine growth restriction. Their study indicated that the treatment of these women is important in the prevention of fetal growth restriction. Researchers have tried to assess the frequency of subclinical celiac disease in women with history of recurrent miscarriages or intrauterine growth restriction of unknown cause. Gasbarrini et al24 evaluated 44 patients with a history of recurrent spontaneous miscarriages, 39 patients with a history of intrauterine growth restriction and 50 healthy controls for the presence of serum IgA antiendomysial and IgG antitransglutaminase antibodies. Those with positive titers underwent jejunal biopsy, and the diagnosis was confirmed by the presence of villous atrophy. Three of 40 (8%) patients with recurrent spontaneous miscarriages, 6 of 39 (15%) patients with intrauterine growth restriction and none of the controls had positive serology tests. Jejunal biopsy samples confirmed the diagnosis in 8 of 9 patients with positive serology tests who agreed to endoscopy. Their study suggests subclinical celiac disease as an etiologic factor in recurrent miscarriages and intrauterine growth restriction. This can be detected by serologic screening tests. Similar results were also recognized by Martinelli et al,21 Sheiner et al,25 Sharma et al26 and Ludvigsson et al27 in their respective studies. Furthermore, these authors have also suggested that careful surveillance should be performed during pregnancy as the frequency of adverse perinatal outcome is reduced in patients who are compliant with a gluten-free diet. Ludvigsson and colleagues27 also emphasized the role of treatment in prevention of adverse fetal outcomes. A single case-control study has also demonstrated that the duration of breast-feeding was decreased in untreated mothers with celiac disease, which was effectively corrected by treatment with a gluten-free diet.28
It is challenging to identify women
with silent celiac disease and treat them with a gluten-free diet and nutrient supplements, which may lead to prevention of menstrual and other reproductive dysfunction. Effect of Pregnancy on Celiac Disease
There have been some concerns about reactivation or unmasking of previously undiagnosed celiac disease during pregnancy and during the postpartum period. Various authors have reported cases in which celiac disease was diagnosed for the first time after delivery. Malnick et al29 reported 3 cases in which previously healthy women presented with diarrhea, weight loss and malabsorption after delivery, and a diagnosis of celiac disease was subsequently made. Similarly, Corrado et al30 reported 10 cases of celiac disease diagnosed after pregnancy. The appearance of new autoimmune disease during pregnancy and the early postpartum period is not unusual and has been previously described for rheumatoid arthritis, systemic lupus erythematosus and other connective tissue disorders.31,32 Authors have suggested that this exacerbation may be because of higher levels of sex hormones during pregnancy and their marked effect on the immune system.29
Proposed Etiologies and Management Whether celiac disease is a chronic autoimmune disease is controversial, as the intestinal epithelium reverts to normal on a gluten-free diet and autoimmune disorders occur less frequently if the disease is treated at a young age. This inflammatory disorder damages the small intestinal mucosa, leading to malabsorption of various nutrients. Originally thought to be a childhood disease, it can nevertheless present at any age, ranging from the first year of life to the eighth decade.1 The above-mentioned studies clearly showed an impact of celiac disease on menstrual and reproductive functions in females. The mechanism behind these abnormalities has yet to be clarified, though various theories have been suggested. An association between amenorrhea and malnutrition has been established in the past.16,33 Malnutrition and weight loss can directly influence the hypothalamic-pituitary functions and lead to diminished secretion of gonadotropins. A variety of nutrients, such as iron, folate, zinc, selenium and fat-soluble vitamins, are essential for reproductive function and embryonic organogenesis, and their deficiency has an adverse outcome on pregnancy.
However, many individuals have no gastrointestinal symptoms and no features of malabsorption but may still have reproductive alterations (silent celiac disease). Hyperprolactinemia has been observed in 25% of patients with celiac disease and may lead to ovulatory dysfunction and thus have an adverse impact on menstrual and reproductive function.15,20 In addition, marked endocrine abnormalities have been reported in males with celiac disease that include increased plasma testosterone and free testosterone index, reduced dihydrotestosterone and raised serum luteinizing hormone, a pattern of abnormalities indicative of androgen resistance.34,35 Another hypothesis suggests the role of autoimmunity as a culprit in these manifestations. Celiac disease is frequently associated with various other autoimmune diseases, like type 1 diabetes mellitus, dermatitis herpetiformis and thyroid diseases.36-38 Autoimmunity may affect ovarian reproductive function as well as pregnancy outcome. Previously, authors have suggested that disruption of immunity in patients with celiac disease leads to an adverse outcome of pregnancy.17,21,39 However, alterations in immune status during pregnancy may lead to development of gluten intolerance and unmask celiac disease in pregnancy.40,41 Last, celiac disease may also be associated with long-lasting oxidative stress. The role of oxidative stress in subclinical forms of the disease was highlighted by Odetti et al.42 In their study, the levels of markers of oxidative stress derived from both protein (carbonyl groups) and lipids (thiobarbituric acid–reactive substances) were significantly higher in celiac disease patients. Even in asymptomatic celiac patients a redox imbalance persisted that may have an impact on menstrual and reproductive function. There have been no subsequent studies to evaluate these markers in celiac patients.
The treatment of celiac disease involves removing gluten from the diet; that includes wheat, rye and barley. Oats are tolerated by most. It is known that unfavorable events associated with celiac disease may be prevented by a gluten-free diet. Patient education plays an important role in management. Many women mistakenly believe that a gluten-free diet will deprive their developing fetus of nutrients needed and hurt the growing baby. The importance of a gluten-free diet should be emphasized by the physician. Though there are no adequate data regarding the nutrient requirements of pregnant women with celiac disease, periconceptional nutrient supplementation should be considered for these women. Iron and folic acid requirements increase during pregnancy. Pregnant women with celiac disease are at high risk of developing iron and folate deficiency anemia, which should be closely monitored and corrected. The patient should be assessed for other deficiencies of vitamins and minerals, including B12, fat-soluble vitamins, iron and calcium, and any such deficiencies should be treated. Careful surveillance should be performed during the antenatal period for the early detection of intrauterine growth restriction.
Conclusion Celiac disease has a significant impact on women’s health. Evidence in the literature suggests that celiac disease should be suspected in females with menstrual abnormalities, infertility and adverse pregnancy outcome. All health care providers should be aware of these diverse manifestations of the disease. Treating the disease has a benefit and may lead to prevention of symptoms and improvement in the quality of life.
Screening for celiac disease as part of the workup for patients with unexplained infertility, recurrent spontaneous miscarriages and unexplained intrauterine growth restriction should be considered. It is challenging to identify women with silent celiac disease and treat them with a gluten-free diet and nutrient supplements, which may lead to prevention of menstrual and other reproductive
dysfunction. References
From the Department of Obstetrics and Gynecology, State University of New York, Upstate Medical University, Syracuse, New York.
Address correspondence to: Shawky Z. A. Badawy, M.D., Department of Obstetrics and Gynecology, 736 Irving Avenue, Syracuse, NY 13210 (badawys@upstate.edu). Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.
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