National Pregnancy and Infant Loss Awareness Month
Celiac Disease in Denmark: A Nationwide Study of Pregnancy Outcomes
By: Selina Martinez, DO
Editor’s Note: FACTS continues our series on adverse pregnancy outcomes as part of Pregnancy & Infant Loss Awareness Month with a research summary of a nationwide matched cohort study that explores the implications of celiac disease for female reproductive health across the entire Danish population. Celiac disease (CD) affects women at a 2:1 ratio compared to men, and the symptoms among women often go beyond nutrient deficiencies and unintended weight loss. As part of the FACTS elective, Selina Martinez summarized a 2018 research article published in Human Reproduction that compared pregnancy outcomes among women diagnosed with CD to a matched subset of women without CD.
Celiac disease (CD) is an immune-mediated condition marked by a T-cell response to gluten proteins in wheat, barley, and rye that causes inflammation and damage in the small intestine. Celiac disease causes a range of symptoms, including diarrhea, vitamin and mineral deficiencies, and a failure to thrive. Among women, CD has also been associated with several conditions affecting reproduction and pregnancy outcomes. About 1% of the population in Europe and the United States are diagnosed with CD, although it is more prevalent in certain countries, such as Denmark, where it affects 180 out of 100,000 people. 
Celiac Disease and Fertility
Data has been mixed on the role that celiac disease plays in female fertility. A meta-analysis by Singh et al.  indicated that women with infertility had 3.5 times higher odds of having CD, and women with unexplained infertility were 6 times more likely to have CD compared to controls. However, other studies found no association between CD and reproductive outcomes.  Beyond investigating associated vitamin and mineral deficiencies, little research has been conducted on the mechanisms of how CD may affect reproduction.
The 2018 study by Grode et al.  examines reproductive life in women with celiac disease in Denmark. This matched cohort study utilized data from national registries to compare reproductive outcomes in women both before and after diagnosis of CD.
Researchers gathered data from the Danish National Patient Register, which contains information on inpatient hospitalizations, outpatient visits, and emergency visits. Each Danish citizen is given a personal registration number at birth or immigration, which links patients to national data from different registries. The population comprised the entire Danish female population of reproductive age (15-50 years old) between 1977 and 2016. Women with CD were identified using ICD codes, and the first occurrence of CD was marked as the date of diagnosis. To create a control group, women without celiac were randomly selected through the Danish Civil registration system. For every one woman with CD, ten women without CD with the same birth date and living in Denmark on the same date of diagnosis were identified.
Researchers examined pregnancy outcomes, including births (both live and still births), molar pregnancy, ectopic pregnancy, spontaneous abortion, induced abortion due to fetal disease, and other induced abortions. Pregnancy rates were estimated for both groups using a stratified Cox proportional hazards model to estimate crude and adjusted hazard ratios with a 95% CI. The time since the date of diagnosis was used as the time scale.
The probability of different pregnancy outcomes was analyzed using a logistic regression model to estimate the odds ratio with a 95% CI. Robust standard errors were used as several women contributed more than one pregnancy to the outcomes. Adjustments were made for parity as well as other autoimmune conditions, such as type I diabetes and autoimmune thyroid disease. To explore outcomes in women prior to their CD diagnosis, pregnancy and outcome were analyzed using a logistic regression in women 0-2 years before diagnosis, 3-5 years, and >5 years.
The CD cohort consisted of 6,319 women, compared with 63,166 matched women without CD. Of women with CD, 60.3% were diagnosed during their reproductive years and 15% were diagnosed before the age of 15. At date of diagnosis, both the average number of pregnancies and mean age at first pregnancy were comparable between the two groups. No significant age difference was seen between the CD and non-CD groups in terms of when a first pregnancy was achieved. In the period of 0-2 years before diagnosis, 25 out of 1,000 fewer pregnancies were observed in the CD group compared to the control group. In this same 0-2 years pre-diagnosis group, 27 per 1,000 fewer live births were seen. The highest risk of adverse pregnancy outcomes, including still birth and spontaneous abortion, was seen in women 5 years before their diagnosis of CD. There was also a small statistically significant increased risk of ectopic pregnancy in patients >5 years before their diagnosis. There was no increased risk of abortion due to fetal disease during any of the time intervals.
The research by Grode et al. is highly relevant to women’s health and family planning . Analysis of this Danish cohort demonstrated that women diagnosed with CD had the same chance of becoming pregnant and having a pregnancy ending in a live birth as women without CD. Furthermore, they had the same risk of different adverse pregnancy outcomes. However, women diagnosed with CD had a higher probability of having experienced an adverse pregnancy outcome prior to diagnosis, particularly miscarriages and stillbirths. This suggests that once a woman begins following a gluten-free diet, the risk of adverse pregnancy outcomes normalizes.
“Women diagnosed with celiac disease had a higher probability of having experienced an adverse pregnancy outcome prior to diagnosis, particularly miscarriages and stillbirths. This suggests that once a woman begins following a gluten-free diet, the risk of adverse pregnancy outcomes normalizes.”
The results of this study parallel previous studies done in Sweden by Zunga et al.  and in the UK by Dhalwarni et al., which similarly found that women had decreased fertility 2 years prior to diagnosis. This combined data stresses the importance of early detection of CD.
Limitations of the study include the singular confirmation of CD using ICD10 codes, with no histologic confirmation. Additionally, the rate of spontaneous abortion may have been underestimated, as not all couples seek medical attention for this. Although the study adjusted for type I diabetes, autoimmune thyroid disease, Turner syndrome, and Down syndrome, there were additional confounders that were not adjusted for; maternal BMI, smoking status, and ethnicity were not factored into the analysis.
Strengths of the study include the extensive patient population collected via the national registry system and the longitudinal nature of the study, following patients for a 40-year period. Additionally, the comparison of patient data at specific time intervals prior to diagnosis was valuable.
Fertility Awareness and Celiac Disease
This research raises important questions to address in future research. For instance, if the women were cycle tracking or using FABMs prior to their diagnosis of CD, how would this vary their pregnancy outcomes? Are higher rates of infertility prior to diagnosis related to a hormonal imbalance or due to the vitamin deficiencies, malnutrition, or something entirely different? Given that women with CD are also at higher risk for autoimmune thyroiditis, it raises the question: How many women who experienced infertility or miscarriage prior to their diagnosis of CD also had thyroid dysfunction? This research article begins to explore the many questions of how CD influences fertility, but there is still much to uncover.
“Given that women with celiac disease are also at higher risk for autoimmune thyroiditis, it raises the question: How many women who experienced infertility or miscarriage prior to their diagnosis of CD also had thyroid dysfunction?
 Grode LB, Bech BH, Plana-Ripoll O, et al. Reproductive life in women with celiac disease; a nationwide, population-based matched cohort study. Hum Reprod. 2018;33(8):1538-1547. doi:10.1093/humrep/dey214.
 Singh P, Arora S, Lal S, Strand TA, Makharia GK. Celiac Disease in Women With Infertility: A Meta-Analysis. J Clin Gastroenterol. 2016;50(1):33-39. doi:10.1097/MCG.0000000000000285
 Tata LJ, Card TR, Logan RF, Hubbard RB, Smith CJ, West J. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology. 2005;128(4):849-855. doi:10.1053/j.gastro.2005.02.017
 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. doi:10.1136/gut.2010.219030
 Dhalwani NN, West J, Sultan AA, Ban L, Tata LJ. Women with celiac disease present with fertility problems no more often than women in the general population. Gastroenterology. 2014;147(6):1267-e14. doi:10.1053/j.gastro.2014.08.025
ABOUT THE AUTHOR
Selina Martinez graduated from Arizona College of Osteopathic Medicine and is currently a family medicine resident at St. Joseph Hospital Family Medicine residency in Denver, CO. She is originally from Santa Fe, New Mexico and has a strong interest in women’s health.