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. 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. 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. 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.

Antiphospholipid antibodies (aPL) represent an important risk factor for thrombosis and recurrent miscarriage in patients with antiphospholipid syndr

The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman’s immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal–fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies.

Recurrent pregnancy loss (RPL) occurs in 3–5% in about 30% of cases no cause can be found. Women with RPL show higher prevalence of undiagnosed gut disorders. Furthermore, in endometrial tissues of RPL women, higher expression of pro-inflammatory cytokines and Nalp-3 inflammasome has been observed. Aim of this study was to investigate whether an abnormal gut permeability might occur in RPL women and allow passage into systemic circulation of pro-inflammatory molecules able to induce endometrial inflammation. 70 women with idiopathic RPL and 30 healthy women were recruited at the Recurrent Pregnancy Loss Outpatient Unit of the Gemelli Hospital of Rome from March 2013 to February 2017. Enrolled women underwent 51Cr-ethylene-diamine-tetraacetic acid absorption test to evaluate intestinal permeability. Sera obtained from enrolled women were analysed for lipopolysaccharide (LPS) by ELISA. Anxiety and depression state were evaluated by administering STAI-Y and Zung-SDS tests, respectively. Of all recruited individuals, 35 women with idiopathic RPL and 20 healthy controls accepted to undergo diagnostic hysteroscopy and endometrial biopsy. Endometrial lysates were investigated for inflammasome Nalp-3 by Western blot analysis, and caspase-1, IL-1β and IL-18 by ELISA, respectively. Higher prevalence of abnormal intestinal permeability (P < 0.0001), increased circulating levels of LPS (P < 0.05), anxiety (P < 0.05) and depression (P < 0.05) were observed in RLP women compared to controls. Endometrial expression of Nalp-3, caspase-1 and IL-1β was significantly increased in RPL group (P < 0.0001; P < 0.05 and P < 0.001, respectively). IL-18 endometrial levels were not found to be higher in RPL cases. Statistically significant association between higher intestinal permeability and abnormally increased expression of endometrial Nalp-3, was observed in RPL (P < 0.01). Furthermore, higher LPS serum levels, a bacterial-derived activator of Nalp-3 complex, was shown to be statistically associated to abnormal endometrial expression of Nalp-3 inflammasome (P < 0.01) in RPL women. In women with RLP, leaky gut might occur and allow passage into circulation of immune triggers, potentially able to elicit endometrial innate immune response and, thus, to contribute to miscarriage pathogenesis. Diagnosis and treatment of intestinal disorders underlying leaky gut might improve endometrial environment and pregnancy outcome.