May 2016 Issue

Celiac Disease & Women's Health
By Christen C. Cooper, MS, RDN
Today's Dietitian
Vol. 18 No. 5 P. 22

Research suggests a gluten-free diet may prevent celiac disease's negative effects on fertility, pregnancy, and other women's health outcomes.

For three years, Jessica, aged 30, tried to conceive and carry a baby to term. When she finally did conceive, she miscarried. Jessica's doctor suggested she take the fertility drug clomiphene combined with intrauterine insemination since she was diagnosed with unexplained infertility. The combined treatment enabled Jessica to conceive and carry her pregnancy to term, though she gave birth to a low-birth-weight (LBW), albeit healthy, baby girl. One year later, Jessica was eager to expand her family, but once again she couldn't conceive. A visit with an RD to learn how to transition from being a meat-eater to a vegetarian led to a discussion about her infertility. Her dietitian took a detailed history of her eating habits, emotional and physical well-being, and gastrointestinal (GI) health. She suspected Jessica might have celiac disease even though she didn't present with the common GI symptoms associated with the condition. The RD suggested she get tested for celiac disease, explaining that if the results are positive, eating a gluten-free diet could restore her reproductive health.

"We used to think all people with celiac disease presented with [GI] symptoms and were underweight. We now know that this isn't true," says Rachel Begun, MS, RDN, CDN, a culinary nutritionist and gluten-free lifestyle expert who serves as a voluntary scientific/medical advisory council member for Beyond Celiac, a nonprofit organization dedicated to raising awareness of celiac disease and gluten intolerance. "Celiac disease is systemic and can affect any body system, which means everyone presents differently. Over 300 symptoms have been documented for celiac disease. Symptoms differ from person to person and overlap with many other conditions, making it tricky to diagnose."

According to research, classic celiac disease symptoms include chronic diarrhea, steatorrhea, abdominal distension, vomiting, growth retardation, and fatigue. However, as early as 1970, Morris and colleagues recognized that celiac disease might affect the female reproductive system.1 Gynecologic conditions that have been studied for their relationship with celiac disease include late menarche, amenorrhea, decreased fertility, elevated rates of Cesarean section, small for gestational age (SGA) and LBW babies, higher rates of miscarriage, and preeclampsia.2 Most studies suggest there may be an association between celiac disease and reproductive complications but that the complications largely can be resolved by adherence to a gluten-free diet. This article will explore recent evidence on links between women's reproductive health and celiac disease and offer ways in which nutrition professionals can counsel clients and patients, improve the rate of diagnosis, and help women achieve better health for themselves and their future children.

Celiac Disease and Fertility
Celiac disease is an autoimmune disorder that occurs in genetically susceptible individuals when they're exposed to gluten, a dietary protein commonly found in the Western diet. The only known treatment is a lifelong gluten-free diet, which presents considerable lifestyle challenges.

The prevalence of celiac disease varies by world region and population. A US-based survey suggested that, as of 2001, the prevalence of celiac disease was about 1 in every 133 people.3 However, it seems that celiac disease affects women disproportionately; about three women for every man are diagnosed with the condition.4 The most common means of diagnosis today is a blood test for immune markers, followed by intestinal biopsy for confirmation. Celiac disease can be elusive, however, because symptoms vary widely. In fact, only 20% to 50% of affected individuals have recognizable symptoms, and therefore the disease sometimes goes undiagnosed or misdiagnosed.3 As a result, some patients incur years of multisystemic damage and infertility, as in Jessica's case, before diagnosis and treatment.

In 2014, Tersigni and colleagues published a large meta-analysis on female reproductive disorders and celiac disease in Human Reproduction Update. This analysis demonstrated that patients with unexplained infertility had a fivefold increased risk of celiac disease compared with women in the general population. The authors suggest that for asymptomatic women with celiac disease, infertility may be the first clinical feature that appears and may lead to diagnosis. The researchers indicate that the fertile life span of women with celiac disease often is shortened by later age of menarche, secondary amenorrhea, and/or earlier menopause onset. However, they also found no significant differences in fertility rates between women diagnosed with celiac disease and those without the condition after those women diagnosed successfully adopted a gluten-free diet. This suggests the importance of early diagnosis and treatment for women.

In a large Swedish cohort study by Zugna and colleagues published in the November 2010 issue of the journal Gut, women with and without celiac disease had similar fertility rates, except that women with the condition had decreased fertility during the two years before diagnosis. Sher and Mayberry, in a study published in a May 1996 supplement to Acta Pediatrica, looked at celiac disease and the fertile life span. In a case-control study that matched women of the same age with and without celiac disease, the mean age of menarche for women with the condition was 13.6 vs 12.7 in those without it, and the mean age of menopause was 47.6 vs 50.1 years, respectively. The patients with celiac disease delivered fewer children (1.9) compared with controls (2.5). This difference narrowed when patients with celiac disease were treated with a gluten-free diet. After the dietary modification, the fertility rate differences narrowed to 0.5 children for women with celiac disease vs 0.7 for women without it. In short, the gluten-free diet seems to remedy fertility in many, if not most, female patients.

Dhalwani and colleagues published a prospective study involving nearly 2.5 million British women in the December 2014 issue of Gastroenterology. Their study resulted in small but not statistically significant differences in fertility problems in women with celiac disease and those without it, except for women who were diagnosed with celiac disease between the ages of 25 and 29. Dhalwani's team hypothesized that the women diagnosed with celiac disease may have experienced a shorter fertility period since their diagnosis took place after their childbearing years had begun.

In addition, Moleski and colleagues, in a retrospective case-control study of 970 women published in the April-June 2015 issue of Annals of Gastroenterology, found no significant differences in fertility among patients with celiac disease and those without it, and yet discovered that fewer women with the condition gave birth after one or more pregnancies. This again suggests that the shortened fertility window of women with celiac disease affects the number of children they ultimately conceive.

Tata and colleagues, in a case-control study published in the April 2005 issue of Gastroenterology, matched 1,521 women with celiac disease with 7,732 women without celiac disease, finding that women with the condition tended to have children later than women without it. This may have been attributed to delayed fertility until after celiac disease diagnosis and treatment. However, other factors, such as the higher education and socioeconomic levels of women with celiac disease in the study, also may have played roles. In addition, when the researchers examined how fertility in women with celiac disease changed after diagnosis and treatment, they concluded that the overall fertility (for the total number of childbearing years) of patients with celiac disease was equivalent to that of patients without celiac disease, even in untreated patients. However, again, these results might have been attributed to nondisease-related factors.

Pregnancy Complications
Similar to its impact on fertility, research suggests that pregnancy complications such as miscarriages, LBW, and preeclampsia affect celiac disease patients at rates higher than those without the disease, but that many of the conditions can be mitigated with a gluten-free diet.

Moleski found that among women with celiac disease, the rate of miscarriage was 50.6%, significantly higher than the rate among controls at 40.6%. However, in women with celiac disease who had experienced miscarriage, 84.7% reported that the complication occurred before diagnosis. In addition, the women with celiac disease were almost 24% more likely to have had at least one premature delivery than those in the control group. Women in the celiac disease group also reported a greater, but not statistically significant, rate of Cesarean delivery (39.5%) compared with controls (31.2%). Sher and Mayberry found similar trends in pregnancy outcomes in women with celiac disease vs women without it, with the celiac disease group having a higher rate of miscarriage before diagnosis. However, the rates of miscarriage postdiagnosis were similar between the celiac and nonceliac disease groups.

Tersigni and colleagues found that the risk of miscarriage for women with celiac disease was 39% higher than for women without the disease. In addition, the risk of LBW for babies born to women with celiac disease was 75% higher than for babies born to mothers without it. Again, this analysis showed that the risks of these complications were largely mitigated by a gluten-free diet. Tersigni's analysis also found no greater risk of recurrent miscarriage, unexplained stillbirth, or preeclampsia in celiac disease patients compared with nonceliac disease patients.

Tata and colleagues found that the risks of Cesarean birth and miscarriage were "moderately" higher among women in the celiac disease group compared with controls (33% and 31%, respectively). However, the risks of assisted birth, breech birth, preeclampsia, and a host of other complications were similar between the groups.

Since celiac disease involves malabsorption of many nutrients, Tata and colleagues also studied the rates of neural tube defects, which can result from folate deficiency. None of the 1,521 women diagnosed with celiac disease in the study gave birth to a baby with a neural tube defect. Similarly, Dickey and colleagues, in a study published in the February 1996 issue of Clinical Genetics, found no association between maternal celiac disease and fetal abnormalities.

The Pathogenesis
Experts believe there are at least two potential ways celiac disease may lead to gynecological complications. The first is malabsorption of key nutrients, which may be one source of the disease's pathogenesis. In the presence of celiac disease, nutrients critical to pregnancy maintenance and fetal growth, such as zinc, selenium, and folic acid, commonly are malabsorbed. According to a July 1994 study published in Experientia, Bedwal and Bahuguna found that selenium and zinc deficiency affect the synthesis of follicle-stimulating hormone and luteinizing hormone, which are important to menstruation, pregnancy maintenance, and the avoidance of preeclampsia. Kotze showed in an August 2004 study published in the Journal of Clinical Gastroenterology that adherence to a gluten-free diet, which eventually ameliorates nutrient deficiencies, improves reproductive functions in women diagnosed with celiac disease. However, several studies included in Tersigni and colleagues' meta-analysis suggest that infertility and other complications occurred in women who weren't nutrient deficient, leading to the conclusion that more research is needed to discern the effects of malabsorption on the reproductive health of patients with celiac disease.

The second way celiac disease may affect reproductive health is through autoimmune mechanisms resulting from the condition itself. Some scientists believe that the antibodies produced in the intestine may cause intestinal and neurological damage. This, in turn, may affect the reproductive system, including embryo implantation and placental development. Dieterich and colleagues as well as Mäki found that women diagnosed with celiac disease who consumed a gluten-containing diet showed higher levels of serum antibodies related to celiac disease.5,6 In fact, a 2007 study by Hadziselimovic and colleagues published in Fetal Pediatric Pathology found that celiac disease might contribute to the apoptosis of cells that make proteins and hormones critical to placental and pregnancy maintenance. This, the authors posit, may contribute to the risk of miscarriage and other complications. Other studies also have revealed negative effects of antibodies on placental development.

Role of RDs
Tersigni and colleagues assert that there isn't sufficient evidence to recommend celiac disease screening for women with SGA infants, who have experienced a preterm birth, or who have preeclampsia. However, they do recommend celiac disease testing for women facing unexplained infertility, recurrent miscarriage, or intrauterine growth restriction. It's important for nutrition professionals to make patients aware of the potential negative effects of untreated celiac disease for both their reproductive and general health, and that of their unborn infants.

RDs also can play an important role in helping to identify symptoms that may signal celiac disease and help diagnosed patients adopt a gluten-free diet. Since celiac disease symptoms can be elusive, dietitians must be aware of the complex nature of treating patients. RDs often are the first health care professionals women who are looking to start a family may see, as they want to live more healthfully for their babies, Begun says. "If you have a patient that's having unexplained fertility issues, it can't hurt to recommend that she get tested for celiac disease," she adds.

Nancy Farrell, MS, RDN, spokesperson for the Academy of Nutrition and Dietetics and a celiac disease specialist, believes the RD's approach should be to treat the "whole person and gain patient trust." Farrell emphasizes that in order to achieve the most favorable patient outcomes, RDs should focus on "listening to what is and isn't said, understanding [a patient's] complete medical history, and having compassion and empathy." She also stresses that nutrition professionals should be aware that celiac disease patients also may have symptoms that don't necessarily involve the digestive tract and, therefore, a more holistic approach may be needed to help relieve symptoms. An awareness of the multisystemic effects of autoimmune conditions such as celiac disease can help RDs offer the best care for patients.

Begun adds, "As the health care community begins to recognize that people with celiac disease present in a variety of ways, we can do a better job of getting people diagnosed so they can start their gluten-free lifestyles and get on the road to better health."

— Christen C. Cooper, MS, RDN, is a doctoral candidate in nutrition education at Teachers College at Columbia University in New York City.

References
1. Morris JS, Adjukiewicz AB, Read AE. Coeliac infertility: an indication for dietary gluten restriction? Lancet. 1970;1(7640):213.

2. Moleski SM, Lindenmeyer CC, Voloski JJ, et al. Increased rates of pregnancy complications in women with celiac disease. Ann Gastroenterol. 2015;28(2):236-240.

3. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163(3):286-292.

4. Green PHR, Stavropoulos SN, Panagi SG, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol. 2001;96(1):126-131.

5. Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997; 3(7):797-801.