title: Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms.
abstract: BACKGROUND
  An increased risk of reproductive failures in women with celiac disease (CD) has been shown by several studies but a comprehensive evaluation of this risk is lacking. Furthermore, the pathogenic mechanisms responsible for obstetric complications occurring in CD have not been unraveled.
  
  
  METHODS
  To better define the risk of CD in patients with reproductive disorders as well as the risk in known CD patients of developing obstetric complications, we performed an extensive literature search of Medline and Embase databases. Odds ratio (OR) and relative risk (RR) with 95% confidence intervals (95% CI) were used in order to combine data from case-control and cohort studies, respectively. All data were analyzed using Review Manager software. In addition, we summarized and discussed the current hypotheses of pathogenic mechanisms potentially responsible for obstetric complications occurring in CD.
  
  
  RESULTS
  Patients with unexplained infertility, recurrent miscarriage or intrauterine growth restriction (IUGR) were found to have a significantly higher risk of CD than the general population. The OR for CD was 5.06 (95% CI 2.13-11.35) in patients with unexplained infertility, 5.82 (95% CI 2.30-14.74) in women experiencing recurrent miscarriage and 8.73 (95% CI 3.23-23.58) in patients with IUGR. We did not observe an increased risk of CD in women delivering small-for-gestational age or preterm babies. Furthermore, we found that in celiac patients, the risk of miscarriage, IUGR, low birthweight (LBW) and preterm delivery is significantly higher with an RR of 1.39 (95% CI 1.15-1.67), 1.54 (95% CI 1.22-1.95), 1.75 (95% CI 1.23-2.49) and 1.37 (95% CI 1.19-1.57), respectively. In addition, we observed that the risk for IUGR, LBW and preterm delivery was significantly higher in untreated patients than in treated patients. No increased risk of recurrent miscarriage, unexplained stillbirth or pre-eclampsia was found in celiac patients. In vitro studies have provided two main pathogenic models of placental damage at the feto-maternal interface. On the embryonic side of the placenta, a direct binding of anti-transglutaminase (-TG) antibodies to trophoblast cells and, thus, invasiveness reduction via an apoptotic damage, has been proposed. Anti-TG antibodies may also be detrimental to endometrial angiogenesis as shown in vitro in human endometrial endothelial cells (cultures and in vivo in a murine model). The angiogenesis inhibition seems to be the final effect of anti-TG antibody-mediated cytoskeletal damage in endometrial endothelial cells.
  
  
  CONCLUSIONS
  Physicians should investigate women with unexplained infertility, recurrent miscarriage or IUGR for undiagnosed CD. Women with CD show an increased risk of miscarriage, IUGR, LBW and preterm delivery. However, the risk is significantly reduced by a gluten-free diet. These patients should therefore be made aware of the potential negative effects of active CD also in terms of reproductive performances, and of the importance of a strict diet to ameliorate their health condition and reproductive health. Different mechanisms seem to be involved in determining placental tissue damage in CD patients.
authors.affiliation: Department of Obstetrics and Gynecology, Università Cattolica Del Sacro Cuore, Policlinico A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tersigni
authors.affiliation: Department of Obstetrics and Gynecology, Università Cattolica Del Sacro Cuore, Policlinico A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Castellani
authors.affiliation: Institute of Public Health, Università Cattolica Del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: de Waure
authors.affiliation: Department of Obstetrics and Gynecology, Università Cattolica Del Sacro Cuore, Policlinico A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fattorossi
authors.affiliation: Institute of Physics, Università Cattolica Del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Spirito
authors.affiliation: Department of Internal Medicine, Università Cattolica Del Sacro Cuore, Policlinico A. Gemelli, 00168 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gasbarrini
authors.affiliation: Department of Obstetrics and Gynecology, Università Cattolica Del Sacro Cuore, Policlinico A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Department of Obstetrics and Gynecology, Università Cattolica Del Sacro Cuore, Policlinico A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy nicolettadisimone@rm.unicatt.it.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Di Simone
mesh_terms: D001327:Autoimmune Diseases / Q000150:complications; D002446:Celiac Disease / Q000150:complications*; D015331:Cohort Studies; D003677:Deficiency Diseases / Q000150:complications; D005260:Female; D005865:Gestational Age; D006801:Humans; D007230:Infant, Low Birth Weight / Q000502:physiology; D007247:Infertility, Female / Q000209:etiology*; D016017:Odds Ratio; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology*; D012307:Risk Factors
keywords: angiogenesis; celiac disease; endometrium; pregnancy; trophoblast