Abstract and Introduction
Abstract
Study Question: How does celiac disease (CD) influence women's reproductive life, both prior to and after the diagnosis?
Summary Answer: Prior to the diagnosis of CD, an increased risk of adverse pregnancy outcomes was seen, whereas after the diagnosis, no influence on reproductive outcomes was found.
What is Known Already: CD has been associated with several conditions influencing female reproduction and pregnancy outcomes including spontaneous abortion and stillbirth.
Study Design, Size, Duration: A nationwide matched cohort study following 6319 women diagnosed with CD and 63166 comparison women and identifying reproductive events between the ages of 15 and 50 years.
Participants/Materials, Setting, Methods: Through linkage of several Danish national health registers, we identified all women diagnosed with CD between 1977 and 2016. We identified an age- and sex-matched comparison cohort and obtained data on reproductive outcomes for both cohorts. Adjusted stratified Cox and logistic regression models were used to estimate differences in reproductive outcomes between women with and without CD.
Main Results and the Role of Chance: Comparing women with diagnosed CD with the non-CD women, the chance of pregnancy, live birth and risk of stillbirth, molar and ectopic pregnancy, spontaneous abortion and abortion due to foetal disease was the same. However, prior to being diagnosed, CD women had an excess risk of spontaneous abortion equal to 11 extra spontaneous abortions per 1000 pregnancies (adjusted odds ratio (OR) = 1.12, 95% CI: 1.03, 1.22) and 1.62 extra stillbirths per 1000 pregnancies (adjusted OR = 1.57, 95% CI: 1.05, 2.33) compared with the non-CD women. In the period 0–2 years prior to diagnosis fewer pregnancies occurred in the undiagnosed CD group, equal to 25 (95% CI: 20–31) fewer pregnancies per 1000 pregnancies compared to the non-CD group and in addition, fewer undiagnosed CD women initiated ART-treatment in this period, corresponding to 4.8 (95% CI: 0.9, 8.7) fewer per 1000 women compared to non-CD women.
Limitations, Reasons for Caution: Validity of the diagnoses in the registers was not confirmed, but reporting to the registers is mandatory for all hospitals in Denmark. Not all spontaneous abortions will come to attention and be registered, whereas live- and stillbirths, ectopic and molar pregnancies and abortion due to foetal disease are unlikely not to be registered. We adjusted for several confounding factors but residual confounding cannot be ruled out.
Wider Implications of the Findings: These findings suggest that undiagnosed CD can affect female reproduction and the focus should be on early detection of CD in risk groups.
Study Funding/Competing Interest(S): This study was funded by the Health Research Fund of Central Denmark Region and The Hede Nielsens Foundation, Denmark. The authors report no conflicts of interest in this work.
Introduction
Celiac disease (CD) is an immune-mediated disease with a permanent gluten-sensitive enteropathy caused by the ingestion of gluten proteins from wheat, barley and rye. Gluten proteins induce T-cell mediated inflammation in the small-bowel and an autoimmune response to self-proteins, mainly tissue-transglutaminase (Sollid, 2002). The classical symptoms are diarrhoea, vitamin and mineral deficiencies and failure to thrive (Wierdsma et al., 2013). However, most patients suffer from mild symptoms or non-classical symptoms, and therefore, the disease often remains undetected for many years (Tiboni et al., 2006). The disease is diagnosed by serology and confirmed by biopsies of the small-bowel classifying the degree of inflammation and villous atrophy. CD affects up to 1% of the population in Europe and the USA with some regional differences (Catassi et al., 2015). In Denmark, 180/100 000 persons had a diagnosis of CD in 2016, with a female/male ratio of 2:1 (Grode et al., 2018), but a screening study found a prevalence of 479/100 000 Danes (Horwitz et al., 2015), indicating that undiagnosed CD is frequent and that CD autoimmunity and inflammation of the small-bowel may be present before the clinical symptoms leading to a diagnosis.
CD has been associated with several conditions influencing female reproduction and pregnancy outcomes. A meta-analysis by Singh et al. (2016) showed that women with infertility had 3.5 times higher odds of having CD, and women with unexplained infertility had six times higher odds of having CD compared to controls (Singh et al., 2016). To date, several studies found higher risk of delayed menarche, early menopause, endometriosis, recurrent pregnancy loss, intrauterine growth restriction (IUGR), preterm delivery, postpartum haemorrhage, low birth weight (LBW) and stillbirth in women with CD compared to non-CD women (Bona et al., 2002; Ludvigsson et al., 2005b; Freeman, 2010; Khashan et al., 2010; Kumar et al., 2011; Santonicola et al., 2011; Stephansson et al., 2011; Abdul Sultan et al., 2014; Tersigni et al., 2014). However, other studies found no association between CD in women and reproductive outcomes (Tata et al., 2005b; Sharshiner et al., 2013; Dhalwarni et al., 2014). Besides effects of vitamin and mineral deficiencies, there is very little research on the possible mechanisms of CD affecting reproduction. Ludvigsson et al. (2005) studied offspring of celiac mothers and reported a lower placental weight in mothers who were later diagnosed with CD compared to non-CD mothers, which could explain the LBW and IUGR. In addition, it has been demonstrated that transglutaminase antibodies affect the angiogenesis in the endometrium (Di Simone et al., 2013), is involved in apoptosis and delayed injury healing affecting the embryo–maternal interface after implantation (Di Simone et al., 2010; Sóñora et al., 2014) and seem to inhibit placental tissue transglutaminase activity (Anjum et al., 2009). The disease is frequently diagnosed during childhood or the childbearing years and women with CD may have concerns regarding whether the disease influences their capability to reproduce. The aim of this population-based nationwide study was to examine how CD in women and several reproductive outcomes are associated, both prior to and after diagnosis of CD, using data from the Danish national registries.
Hum Reprod. 2018;33(8):1538-1547. © 2018 Oxford University Press
