Malabsorption is a complex and multifaceted condition characterised by the defective passage of nutrients into the blood and lymphatic streams. Several congenital or acquired disorders may cause either selective or global malabsorption in both children and adults, such as cystic fibrosis, exocrine pancreatic insufficiency (EPI), coeliac disease (CD) and other enteropathies, lactase deficiency, small intestinal bacterial overgrowth (SIBO), autoimmune atrophic gastritis, Crohn's disease, and gastric or small bowel resections. Early recognition of malabsorption is key for tailoring a proper diagnostic work-up for identifying the cause of malabsorption. Patient's medical and pharmacological history are essential for identifying risk factors. Several examinations like endoscopy with small intestinal biopsies, non-invasive functional tests, and radiologic imaging are useful in diagnosing malabsorption. Due to its high prevalence, CD should always be looked for in case of malabsorption with no other obvious explanations and in high-risk individuals. Nutritional support is key in management of patients with malabsorption; different options are available, including oral supplements, enteral or parenteral nutrition. In patients with short bowel syndrome, teduglutide proved effective in reducing the need for parenteral nutrition, thus improving the quality of life of these patients. Primary care physicians have a central role in early detection of malabsorption and should be involved into multidisciplinary teams for improving the overall management of these patients. In this European consensus, involving 10 scientific societies and several experts, we have dissected all the issues around malabsorption, including the definitions and diagnostic testing (Part 1), high-risk categories and special populations, nutritional assessment and management, and primary care perspective (Part 2).

A gluten-free diet (GFD) is becoming increasingly popular, especially among young females, and including those without diagnosed celiac disease (CD). Whether a GFD is appropriate during pregnancy remains unclear. Our primary aim was to evaluate the association of a GFD and neonatal birthweight and incidence of large for gestational age (LGA) and small for gestational age (SGA). Secondarily, we sought associations with other obstetric outcomes.

The data was collected retrospectively from the Tampere University Hospital database. The study period was from January 2015 to April 2021. The diet information was obtained from self-reported questionnaires. All women following a GFD were included. A total of 79 had CD and 291 followed a GFD without CD diagnosis. The latter are referred to here as people without CD avoiding gluten (PWAG). A total of 456 omnivores were randomly chosen to constitute a control group. Outcomes were analyzed by comparing gluten-free groups to a control group.

The median birth weight was higher in the GFD group compared to the controls (3533 vs. 3440 g, P < 0.003), but the incidences of SGA or LGA did not differ between the study groups. The incidence of pregnancy complications was comparable between the groups. Induction of labor was more frequent (aOR 1.52; 95% CI: 1.12-2.08), and the duration of labor was longer (aOR1.56; 95% CI: 1.18-2.06) in the GFD group, especially among PWAG. However, no difference in the cesarean section rate were found between the groups.

In the present retrospective cohort study, a GFD did not appear to be associated with adverse pregnancy or neonatal outcomes.

Celiac disease (CeD) is a chronic immune-mediated disorder of the small intestine triggered by the ingestion of dietary gluten. This narrative review aims to summarize and critically evaluate the recent literature on the association between CeD and infertility, with an emphasis on identifying patterns and inconsistencies. Previous studies have reported conflicting findings: while some demonstrate a higher prevalence of unexplained infertility in patients with CeD, others do not support this association. Overall, untreated CeD may be a contributing factor to infertility, especially unexplained cases, and a gluten-free diet (GFD) might improve fertility outcomes. However, the general prevalence of infertility in CeD patients does not appear to exceed that of the general population. This review includes evidence on both male and female infertility and examines possible pathophysiological mechanisms, including nutritional deficiencies, immune-mediated effects, and sexual dysfunction. Further high-quality prospective studies are needed to determine the true impact of CeD on reproductive health and to inform screening guidelines.

There is a female predominance of diagnosed coeliac disease with sex-related differences in clinical presentation. Delayed menarche, infertility and pregnancy complications have been linked to poor nutritional status and autoimmune mechanisms, but women's health data in coeliac disease are scant and contradictory.

To describe rates of women's health disorders in US patients with coeliac disease.

We used TriNetX, a database of 80 healthcare organisations, for a retrospective observational analysis. Coeliac disease was identified using ICD-10 code (K90.0) and positive coeliac serology. Women aged 10-60 years with coeliac disease were compared to ambulatory women without a diagnosis of coeliac disease or positive coeliac serology. We divided women into age groups matched by propensity score.

We identified > 25,000,000 outpatient women without coeliac disease, and 9368 with coeliac disease. Patients with coeliac disease were younger (mean 25 vs. 28.5 years) and had lower mean BMI (24.6 vs. 26.1). Women with coeliac disease had higher odds of later women's health conditions including absent/rare menstruation (4.6% vs. 2.0%; OR 2.34), infertility (1.4% vs. 0.9%; OR 1.69), polycystic ovarian syndrome (3.3% vs. 1.0%; OR 3.2), menopausal disorders (4.3% vs. 1.56%; OR 285) and primary ovarian failure (0.96% vs. 0.16%; OR 6.25).

Women with coeliac disease have higher frequencies of subsequent women's health disorders related to ovarian function, menstruation, fertility and menopause. Clinicians should be aware of these associations to detect women's health disorders during longitudinal coeliac care and promptly refer for a multidisciplinary approach with obstetrics and gynaecology.

This review examines nutritional needs during pregnancy and lactation, focusing on the critical nutrients required for both maternal and fetal health. Essential nutrients such as folic acid, vitamin D, iron, calcium, and omega-3 fatty acids play a significant role in supporting fetal development and minimizing the risk of complications like gestational diabetes, hypertension, and preterm birth. Various dietary patterns, including the Mediterranean, vegetarian/vegan, and gluten-free diets, were evaluated for their adequacy and potential benefits. The Mediterranean diet was highlighted for its protective effects against pregnancy-related health issues. In contrast, the review identified vegetarian and vegan diets as requiring careful planning to ensure sufficient intake of key nutrients. Additionally, the review explored the implications of gestational diabetes and dietary strategies for managing blood sugar levels. The effects of intermittent fasting during pregnancy were also discussed, with mixed evidence regarding its safety and impact on pregnancy outcomes. Overall, the review stresses the importance of tailored nutritional guidance to ensure optimal health for both the mother and the developing fetus during pregnancy and lactation.

Proper regulation of intestinal permeability is essential for maintaining the integrity of the intestinal mucosal barrier. An abnormal increase in permeability can significantly contribute to the onset and progression of various diseases, including autoimmune disorders, metabolic conditions, allergies, and inflammatory bowel diseases. The potential connection between intestinal permeability and maternal health during pregnancy is increasingly recognized, yet a comprehensive review remains lacking. Pregnancy triggers a series of physiological structural adaptations and significant hormonal fluctuations that collectively contribute to an increase in intestinal permeability. Although an increase in intestinal permeability is typically a normal physiological response during pregnancy, an abnormal rise is associated with immune dysregulation, metabolic disorders, and various pregnancy-related complications, such as recurrent pregnancy loss, gestational diabetes mellitus, overweight and obesity during pregnancy, intrahepatic cholestasis of pregnancy, and preeclampsia. This paper discusses the components of the intestinal mucosal barrier, the concept of intestinal permeability and its measurement methods, and the mechanisms and physiological significance of increased intestinal permeability during pregnancy. It thoroughly explores the association between abnormal intestinal permeability during pregnancy and maternal diseases, aiming to provide evidence for the pathophysiology of disease development in pregnant women. Additionally, the paper examines intervention methods, such as gut microbiota modulation and nutritional interventions, to regulate intestinal permeability during pregnancy, improve immune and metabolic states, and offer feasible strategies for the prevention and adjuvant treatment of clinical pregnancy complications.

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3-5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.

Data on pregnancy outcomes in patients with alopecia areata (AA) are limited. The aim of this study is to determine the association between maternal AA and risk of adverse birth outcomes in children. A retrospective cohort study was conducted on 45,328 children born to mothers with AA and 4,703,253 controls born to mothers without AA using the Korean National Health Insurance Claims database from 2002 to 2016. Multivariate logistic regression analyses were performed to evaluate the association between maternal AA and the birth outcomes of their children. Infants born to mothers with AA exhibited a significantly higher risk of preterm birth (odds ratio [OR] 1.39, 95% CI 1.33-1.45; adjusted OR [aOR] 1.07, 95% CI 1.01-1.13), low birthweight (OR 1.36, 95% CI 1.30-1.42; aOR 1.11, 95% CI 1.05-1.17), and Caesarean section birth (OR 1.24, 95% CI 1.22-1.26; aOR 1.12, 95% CI 1.08-1.15) than controls. In addition, the risk of congenital malformations was also significantly higher in infants born to mothers with AA (OR 1.19, 95% CI 1.15-1.22; aOR 1.10, 95% CI 1.07-1.14), especially for malformations of the urinary (OR 1.33, 95% CI 1.19-1.48; aOR 1.16, 95% CI 1.04-1.29) and musculoskeletal (OR 1.19, 95% CI 1.12-1.27; aOR 1.12, 95% CI 1.05-1.19) systems, than controls. Maternal AA is associated with an increased risk of adverse birth outcomes in infants.

Celiac disease (CD) is an inflammatory enteropathy that has been associated to obstetric and gynecological disorders. However, it is still not adequately tested by gynecologists due to the misconception that it is solely a gastrointestinal disease. This underestimation requires the development of targeted interventions.

This study aims to evaluate the association between CD and obstetric/gynecological complications, highlight the importance of informing patients about CD manifestations, and assess the patient satisfaction with the information provided by healthcare professionals on the disease.

A digital survey was administered to celiac women via the Italian Celiac Association's website.

We analyzed 493 questionnaires. Obstetric and gynecological disorders led to the diagnosis of CD in 11.7% of interviewed. The study revealed that untreated CD patients are more predisposed to miscarriages (41.8% vs 34% before/after diagnosis, respectively, p = 0.111), anemia in pregnancy (71.4% vs 40.4% before/after diagnosis, respectively, p < 0.001) and the risk of low birth weight (newborns weighing < 1500 g were 4.0% before and 1.1% after the gluten-free diet, p = 0.028). Women with CD, both before and after gluten-free diet, had higher infertility rates (about 19%) than the general population. Additionally, 73% of interviewees were dissatisfied with the information they received from health professionals about the reproductive implications of CD.

Our research contributes to a deeper understanding of the intersection between CD and reproductive outcomes, highlighting the main obstetric and gynecological problems related to it. It emphasizes the importance of patient's perspective and the need for greater awareness about celiac disease from healthcare workers.

Part II of the Australasian guideline for the investigation and management of recurrent pregnancy loss (RPL) provides evidence-based guidance on the management of RPL provided. The implications of inherited and acquired thrombophilia with respect to RPL and suggestions for clinical management are provided. Autoimmune factors, including human leukocyte antigen, cytokines, antinuclear antibodies and coeliac antibodies, and guidance for management are discussed. Infective, inflammatory and endometrial causes of RPL are discussed in detail. Environmental and lifestyle factors, male factor and unexplained causes are outlined. Levels of evidence and grades of consensus are provided for all evidence-based statements.

The relatively few conditions and family member types (e.g., sibling, parent) considered in investigations of family health history in autism spectrum disorder (ASD, or autism) limits understanding of the role of family history in autism etiology. For more comprehensive understanding and hypothesis-generation, we produced an open-source catalog of autism associations with family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. All live births in Denmark, 1980-2012, of Denmark-born parents (1,697,231 births), and their 3-generation family members were followed through April 10, 2017 for each of 90 diagnoses (including autism), emigration or death. Adjusted hazard ratios (aHR) were estimated via Cox regression for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person; aHRs also calculated for sex-specific co-occurrence of each disorder. We obtained 6462 individual family history aHRS across autism overall (26,840 autistic persons; 1.6% of births), by sex, and considering intellectual disability (ID); and 350 individual co-occurrence aHRS. Results are cataloged in interactive heat maps and down-loadable data files: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries: https://public.tableau.com/app/profile/diana.schendel/viz/ASDPlots_16918786403110/e-Figure5. While primarily for reference material or use in other studies (e.g., meta-analyses), results revealed considerable breadth and variation in magnitude of familial health history associations with autism by type of condition, family member type, sex of the family member, side of the family, sex of the index person, and ID status, indicative of diverse genetic, familial, and nongenetic autism etiologic pathways. Careful attention to sources of autism likelihood in family health history, aided by our open data resource, may accelerate understanding of factors underlying neurodiversity.

Celiac disease is a systemic autoimmune disorder triggered by dietary gluten ingestion. The classic clinical presentation is characterized by diarrhea with malabsorption and weight loss; however, the spectrum of possible initial symptoms is broad. Affected individuals may be asymptomatic or may suffer from extraintestinal manifestations that can include metabolic bone disorders, thyroid dysfunction, neurologic manifestations, amenorrhea, or impaired fertility. Several studies have demonstrated an association between celiac disease and infertility and worsened pregnancy outcomes. Numerous possible mechanisms through which celiac disease could be associated with women's fertility have been proposed in the literature.

This study aimed to investigate the changes in serum Anti-Müllerian Hormone (AMH) levels, sex hormone levels, follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratio in patients with celiac disease (CeD), and their correlation with clinical characteristics and nutrient levels.

This cross-sectional study collected clinical and biochemical data from a total of 67 females diagnosed with CeD and 67 healthy females within the reproductive age range of 18-44 years. The study was conducted at a tertiary hospital between September 2016 and January 2024. Both groups underwent comprehensive clinical and laboratory assessments. Serum levels of AMH and sex hormones were quantified using chemiluminescence immunoassay, and their associations with CeD clinical features and nutrient levels were thoroughly analyzed.

The study included 67 patients and 67 controls with a mean age of 36.7±7.6 years. No statistically significant differences were found between the two groups in mean age, BMI, FSH, LH, E2, P levels, FSH/LH, menstrual irregularities, abortions history, parity, and gravidity (all P>0.05). However, AMH, T, FER, FA, Zn, and Se levels were significantly lower, and PRL levels were higher in the CeD group (all P<0.05). Spearman's correlation analysis showed that AMH levels were negatively correlated with age, tTG level, disease duration, and Marsh grading (P<0.05).

This study highlights the association between impaired ovarian function in CeD patients and disease severity and nutrient levels. Early detection and intervention for ovarian function abnormalities are imperative to enhance fertility potential in CeD patients.

Abnormalities in the reproductive functions are often ignored while evaluating a patient with celiac disease (CeD). We evaluated the entire reproductive functions in female patients with CeD.

In a case control study between 2020 and 2021 using detailed questionnaire, we evaluated reproductive functions (age at menarche, menstrual pattern, fertility, pregnancy outcome and menopause) in biopsy-proven female patients with CeD of age >10 years. The questionnaire was administered either in person or telephonically. Age-matched healthy female controls (twice the number) were also recruited.

Of 1086 CeD patients, 470 were females and 288 were included. As compared with controls (n = 586), females with CeD had higher age at menarche (14.6 ± 2.0 vs 13.6 ± 1.5 years; P = 0.001), delayed menarche (30.8% vs 11.4%; P = 0.001), abnormal menstrual pattern (39.7% vs 25.8%; P < 0.001), involuntary delay in conception at > 1 year (33.8% vs 11.8%; P = 0.01), current infertility rate (10.5% vs 5.2%;P = 0.028), and poorer overall pregnancy outcomes (abortion [23.5% vs 12.8%; P = 0.001], pre-term birth [16.3% vs 3.7%; P = 0.001]).

Either one or more aspect of reproductive functions and pregnancy outcome is affected adversely in three-fourth female patients with CeD.

Background: A healthy pregnancy begins with an adequate endometrial state, even before the arrival of a blastocyst. Proper endometrial priming and the development of a tolerogenic decidua are key steps in creating the perfect environment for implantation and pregnancy. In these processes, the involvement of the maternal immune system seems to be of great relevance, modulating the different decidual immune populations to prepare the endometrium for a potential pregnancy. However, certain local pathologies of an inflammatory and autoimmune nature appear to have a direct impact on these phenomena, thus altering patients' reproductive outcomes. Methods: This literature review analyzes original articles, reviews, systematic reviews, and meta-analyses published between 1990 and 2024, concerning the impact of different inflammatory and autoimmune conditions on endometrial status and fertility. The included papers were obtained from Medline (Pubmed) and the Cochrane library. Results: There is evidence that endometriosis, adenomyosis, and chronic endometritis, through the promotion of a chronic inflammatory environment, are capable of altering endometrial immune populations, and, thus, processes essential for early pregnancy. Among other effects, these conditions have been linked to impaired decidualization, alterations in progesterone responsiveness, and hindered placentation. Similarly, antiphospholipid syndrome (APS), thyroid dysfunction, diabetes, and other pathologies related to glucose and gluten metabolism, due to their autoimmune nature, also appear to have a local impact on the uterine environment, affecting reproductive success through different mechanisms, including altered hormonal response and, again, impaired decidualization. Conclusions: The management of inflammatory and autoimmune diseases in assisted reproduction patients is gaining importance due to their direct impact on the endometrium. It is necessary to follow current expert recommendations and established therapeutic approaches in order to improve patients' prospects, ranging from antibiotic treatment in chronic endometritis to heparin and aspirin in APS, as well as hormonal treatments for endometriosis/adenomyosis or a gluten-free diet in celiac disease. All of them and the rest of the therapeutic perspectives, both current and under investigation, are presented throughout this work, assessing the possible improvements for reproductive outcomes.

The relatively few conditions and family members investigated in autism family health history limits etiologic understanding. For more comprehensive understanding and hypothesis-generation we produced an open-source catalogue of autism associations with family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. All live births in Denmark, 1980-2012, of Denmark-born parents (1,697,231 births), and their 3-generation family members were followed through April 10, 2017 for each of 90 diagnoses (including autism), emigration or death. Adjusted hazard ratios (aHR) were estimated via Cox regression for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person; aHRs also calculated for sex-specific co-occurrence of each disorder. We obtained 6,462 individual family history aHRS across autism overall (26,840 autistic persons; 1.6% of births), by sex, and considering intellectual disability (ID); and 350 individual co-occurrence aHRS. Results are catalogued in interactive heat maps and down-loadable data files: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries: https://public.tableau.com/views/ASDPlots_16918786403110/e-Figure5. While primarily for reference material or use in other studies (e.g., meta-analyses), results revealed considerable breadth and variation in magnitude of familial health history associations with autism by type of condition, family member type, sex of the family member, side of the family, sex of the index person, and ID status, indicative of diverse genetic, familial, and non-genetic autism etiologic pathways. Careful attention to sources of autism likelihood in family health history, aided by our open data resource, may accelerate understanding of factors underlying neurodiversity.

Millions of children and adults worldwide suffer from undiagnosed and untreated celiac disease (CeD). The clinical picture of CeD is highly heterogeneous and comprises manifestations that can affect almost the whole body. This narrative overview is aimed at characterizing diseases and complaints that are associated with unrecognized CeD and that frequently involve sites other than the gastrointestinal (G.I.) tract, i.e., dental, otorhinolaryngological, and ocular complications; skin and hair abnormalities; afflictions of the bones, joints, and muscles; cardiovascular affectations; kidney diseases; neuro-psychiatric disorders; and gynecological-obstetrical manifestations. The association between CeD and extra-GI manifestations is frequently overlooked, which leads to a delay in diagnosis. Most CeD-mediated disorders can be treated with a strict gluten-free diet (GFD), but some of them are irreversible unless CeD is diagnosed in time. Some manifestations can be classified as risk factors for CeD, and CeD screening tests for affected patients should be selectively considered. Apart from gastroenterologists, specialists in other medical disciplines can play an important role in identifying people with unrecognized CeD and may help prevent its progress and long-term complications. Further comprehensive investigations are necessary to clarify the pathogenesis of extra-GI manifestations and the effect of a GFD.

Is age at menarche associated with fecundability?

Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability.

Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive.

We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies.

We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive.

We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years.

The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate.

Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly.

This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests.

N/A.

There is a high prevalence of autoimmune conditions in women specially in the reproductive years; thus, the association with adverse pregnancy outcomes has been widely studied. However, few autoimmune conditions/adverse outcomes have been studied more than others, and this umbrella review aims to consolidate existing knowledge in this area with the aim to provide new knowledge and also identify gaps in this research area.

Medline, Embase, and Cochrane databases were searched from inception to December 2023. Screening, data extraction, and quality appraisal (AMSTAR 2) were done by two independent reviewers. Data were synthesised narratively and quantitatively. Relative risks (RR)/odds ratio (OR) with 95% confidence intervals were reported.

Thirty-two reviews were included consisting of 709 primary studies. The review reported the association between 12 autoimmune conditions and 16 adverse pregnancy outcomes. Higher risk of miscarriage is reported in women with Sjögren's syndrome RR 8.85 (95% CI 3.10-25.26) and systemic lupus erythematosus (SLE) OR 4.90 (3.10-7.69). Pre-eclampsia was reported higher in women with type 1 diabetes mellitus (T1DM) OR 4.19 (3.08-5.71) and SLE OR 3.20 (2.54-4.20). Women reported higher risk of diabetes during pregnancy with inflammatory bowel disease (IBD) OR 2.96 (1.47-5.98). There was an increased risk of intrauterine growth restriction in women with systemic sclerosis OR 3.20 (2.21-4.53) and coeliac disease OR 1.71 (1.36-2.14). Preterm birth was associated with T1DM OR 4.36 (3.72-5.12) and SLE OR 2.79 (2.07-3.77). Low birth weight babies were reported in women with women with SLE or systemic sclerosis OR 5.95 (4.54-7.80) and OR 3.80 (2.16-6.56), respectively. There was a higher risk of stillbirth in women with T1DM OR 3.97 (3.44-4.58), IBD OR 1.57 (1.03-2.38), and coeliac disease OR 1.57 (1.17-2.10). T1DM in women was associated with 32% lower odds of small for gestational age baby OR 0.68 (0.56-0.83).

Pregnant women with autoimmune conditions are at a greater risk of developing adverse pregnancy outcomes. Further research is required to develop better preconception to postnatal care for women with autoimmune conditions.

Over-activation of endometrial inflammasome NALP-3 (Nod-like receptor family pyrin domain containing 3) can be found in recurrent pregnancy loss (RPL) women probably due to leaky gut and passage into circulation of lipopolysaccharides (LPS). Leaky gut can be caused by exposure to gluten in RPL women genetically predisposed to celiac disease, positive for Human Leukocyte Antigen (HLA)-DQ2/DQ8 haplotype. Oral administration of Bifidobacterium longum ES1 (GliadinES®) can inactivate gluten peptides toxicity to epithelial gut cells and improve gut barrier.

We investigated by enzyme-linked immunoassay: (a) serum levels of LPS and zonuline (a marker of leaky gut); (b) LPS, NALP-3, caspase-1, interleukine (IL)-1β and IL-18 concentration in endometrial fluids, in untreated women with uncomplicated pregnancies (negative HLA-DQ2/DQ8 haplotype) (n = 22) and in women with unexplained RPL, HLA-DQ2/DQ8 positive (n = 22), before and after daily oral administration for 3 months of GliadinES®.

RLP women showed higher serum levels of LPS (p < 0.0001) and higher concentration of LPS (p < 0.0001), NALP-3 (p < 0.01); Caspase-1 (p < 0.0001), IL-1β (p < 0.0001), and IL-18 (p < 0.0001) in endometrial fluids compared to controls. GliadinES® treatment significantly reduced serum levels of both LPS (p < 0.0001) and zonuline (p < 0.01), as well as LPS (p < 0.5), NALP-3 (p < 0.01), Caspase-1 (p < 0.001), IL-1β (p < 0.001), and IL-18 (p < 0.01) concentrations in endometrial fluids of RPL women.

RPL women positive for HLA-DQ2/DQ8 haplotype show increased circulating and endometrial levels of LPS and endometrial inflammasome NALP-3 over-activation. Oral administration of GliadinES® can reduce gut permeability, decrease serum levels of LPS and, contextually, improve endometrial inflammation in this specific subset of RPL women.

Preterm birth defined as delivery before 37 gestational weeks is a leading cause of neonatal and infant morbidity and mortality. The aim of this study is to summarize the evidence from meta-analyses of observational studies on risk factors associated with PTB, evaluate whether there are indications of biases in this literature, and identify which of the previously reported associations are supported by robust evidence.

We searched PubMed and Scopus until February 2021, in order to identify meta-analyses examining associations between risk factors and PTB. For each meta-analysis, we estimated the summary effect size, the 95% confidence interval, the 95% prediction interval, the between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. Evidence was graded as robust, highly suggestive, suggestive, and weak.

Eighty-five eligible meta-analyses were identified, which included 1480 primary studies providing data on 166 associations, covering a wide range of comorbid diseases, obstetric and medical history, drugs, exposure to environmental agents, infections, and vaccines. Ninety-nine (59.3%) associations were significant at P < 0.05, while 41 (24.7%) were significant at P < 10-6. Ninety-one (54.8%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 37 (22.3%) and 12 (7.2%) associations, respectively. We evaluated all associations according to prespecified criteria. Seven risk factors provided robust evidence: amphetamine exposure, isolated single umbilical artery, maternal personality disorder, sleep-disordered breathing (SDB), prior induced termination of pregnancy with vacuum aspiration (I-TOP with VA), low gestational weight gain (GWG), and interpregnancy interval (IPI) following miscarriage < 6 months.

The results from the synthesis of observational studies suggest that seven risk factors for PTB are supported by robust evidence. Routine screening for sleep quality and mental health is currently lacking from prenatal visits and should be introduced. This assessment can promote the development and training of prediction models using robust risk factors that could improve risk stratification and guide cost-effective preventive strategies.

PROSPERO 2021 CRD42021227296.

Celiac disease (CD) is an autoimmune condition that is initiated in genetically susceptible individuals by the exposure of the intestines to gluten, and the early start of symptoms is related to malabsorption. Atypical variants of the illness are often identified in adulthood and are frequently associated with manifestations outside of the intestines, including metabolic osteopathy, anemia, and dermatitis herpetiformis. But also, empirical data suggest a correlation between CD and reproductive abnormalities, including repeated abortions. Infertility and repeated miscarriages frequently manifest in women diagnosed with CD and may serve as the initial clinical indication of a subclinical form. Furthermore, the condition may manifest as amenorrhea, infertility, and the delivery of infants with a low birth weight. Regarding the mechanisms of CD in infertility, along with the anti-tTG action to hinder the invasiveness of trophoblast, these antibodies could damage endometrial angiogenesis, which has been shown in in vitro models with human endometrial cells and in vivo in murine models. Another important aspect is the role of nutrient deficiencies, such as zinc deficiency (connected to impaired hormone production, secondary amenorrhea, and pre-eclampsia) and folic acid, etc. Therefore, our objective was to conduct a comprehensive review of the existing literature pertaining to this specific topic and to elucidate the role of the autoantibodies in its pathogenesis.

Celiac disease (CD) is a gluten related disorder which affects all age-groups and occurs in genetically susceptible population after introduction of gluten in diet. The worldwide prevalence of CD is ~1% and it is higher in certain "at-risk groups". The clinical features are variable, ranging from classical diarrhea to an asymptomatic state. Diagnosis requires serology and duodenal histology although a non-biopsy diagnosis is recommended by European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for a select group of children. Treatment of CD is with a life-long strict gluten free diet (GFD) along with correction of nutritional deficiencies. Regular follow-up to assess compliance and efficacy of GFD is mandatory. Non-responsive CD needs evaluation by a specialist as it can be due to incorrect diagnosis, poor dietary compliance, coexisting conditions like small bowel bacterial overgrowth, pancreatic insufficiency etc. and lastly, refractory CD. Most patients diagnosed as CD in childhood receive no medical or dietary supervision after transition to adulthood and nearly a third are non-compliant to GFD. No requirement of medications, patient's perception of understanding GFD and absence of symptoms with intermittent non-compliance leads to neglect of care after transition. Poor dietary adherence leads to nutritional deficiencies, osteoporosis, fertility issues and risk of malignancy. It is mandatory that the patients know about CD, need of strict GFD, regular follow-up, disease complications, and are capable of communicating with the health-care personnel before transition. Formulating a phased transition care program with joint pediatric and adult clinics is required for a successful transition and improving the long-term outcome.

What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature?

The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI.

UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation.

The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated.

Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee.

This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided.

Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised.

The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI.

The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose.

This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

Environmental enteric dysfunction (EED) is a subclinical syndrome of intestinal inflammation, malabsorption and barrier disruption that is highly prevalent in low- and middle-income countries in which poverty, food insecurity and frequent exposure to enteric pathogens impair growth, immunity and neurodevelopment in children. In this Review, we discuss advances in our understanding of EED, intestinal adaptation and the gut microbiome over the 'first 1,000 days' of life, spanning pregnancy and early childhood. Data on maternal EED are emerging, and they mirror earlier findings of increased risks for preterm birth and fetal growth restriction in mothers with either active inflammatory bowel disease or coeliac disease. The intense metabolic demands of pregnancy and lactation drive gut adaptation, including dramatic changes in the composition, function and mother-to-child transmission of the gut microbiota. We urgently need to elucidate the mechanisms by which EED undermines these critical processes so that we can improve global strategies to prevent and reverse intergenerational cycles of undernutrition.

Preterm birth defined as delivery before 37 gestational weeks, is a leading cause of neonatal and infant morbidity and mortality. Understanding its multifactorial nature may improve prediction, prevention and the clinical management. We performed an umbrella review to summarize the evidence from meta-analyses of observational studies on risks factors associated with PTB, evaluate whether there are indications of biases in this literature and identify which of the previously reported associations are supported by robust evidence. We included 1511 primary studies providing data on 170 associations, covering a wide range of comorbid diseases, obstetric and medical history, drugs, exposure to environmental agents, infections and vaccines. Only seven risk factors provided robust evidence. The results from synthesis of observational studies suggests that sleep quality and mental health, risk factors with robust evidence should be routinely screened in clinical practice, should be tested in large randomized trial. Identification of risk factors with robust evidence will promote the development and training of prediction models that could improve public health, in a way that offers new perspectives in health professionals.

There is a symbiotic relationship between gut microbiota and human beings. Imbalance of the gut microbiota will cause pathological damages to humans. Although many risk factors are associated with missed abortion (MA), the pathological mechanism of it is still unclear. Here, we analyzed gut flora of the patients with MA by S16 high-throughput sequencing. The possible pathogenic mechanisms of the MA were explored. Fecal samples from 14 healthy controls and 16 MA patients were collected to do 16S rRNA gene high-throughput sequencing analysis. The abundance of the Bacteroidetes, Proteobacteria, Actinobacteria, Escherichia, Streptococcus_ Salivarius, and Lactobacillus was significantly reduced in the MA group, while, the abundance of the Klebsiella was significantly increased in the MA patients. The Ruminococcaceae and [Eubacterium]_coprostanoligenes_group were found only in the specimens of the MA patients. The Fabrotax function prediction analysis showed that four photosynthesis function bacteria (cyanobateria, oxygenic_photoautotrophy, photoautotrophy, and phototrophy) only existed in the MA group. In the analysis of the BugBase microbiome function prediction, the Escherichia of the MA group is significantly reduced compared to that of the healthy controls in the items of that Contains_Mobile_Elements, Facultatively_Anaerobic, Forms_Biofilms, Potentially_Pathogenic.png, Gram_Nagative, and Stress_Tolerant_relabundance. These alterations may affect the stability of the host's immune, neural, metabolic and other systems by interfering with the balance of the gut microbiota or by the metabolites of those bacteria, causing the MA. This study explored the possible pathogenic factors of the gut microbiota of the MA. The results provide evidence to figure out the pathogenesis of the MA.

Globally, 13% of the population has difficulty conceiving. In Russia, the proportion of infertile marriages ranges from 8 to 17.5%, with half of all forms of female infertility being the uterine form. The main etiological factors for impaired endometrial receptivity are infectious diseases leading to the development of chronic endometritis (most often found in tuboperitoneal infertility), dishormonal background associated with the development of hyperplastic processes in endocrine infertility, uterine fibroids, chronic endometritis and endometriosis. The frequency of detection of uterine cavity diseases in patients with repeated unsuccessful IVF programs ranges from 18 to 50%. The review examines the etiological factors and other causes of endometrial pathology leading to the development of chronic endometritis, possible mechanisms for the development of impaired growth and receptivity of the endometrium, and, as a consequence, the impossibility of pregnancy. Therapeutic strategies for restoring endometrial thickness and receptivity using pharmacological and non-pharmacological methods are described. Based on the analysis of literature data, it is shown that the use of physiotherapeutic factors in treatment programs that have pronounced anti-inflammatory, immuno- and hormone-modulating, reparative-regenerative, metabolic, vasocorrective and defibrosing effects allows for a relatively short period of time to improve endometrial receptivity, normalize hormonal levels and restore fertility in women of reproductive age, which ensures the possibility of successful embryo implantation, fetal development and childbirth.

The incidence of Idiopathic Recurrent Pregnancy Loss (RPL) is doubled in patients suffering from Celiac Disease (CD) compared to healthy populations. CD genetic components are HLA class II genes known as HLA-DQ2 and DQ8. Genetically susceptible women can remain asymptomatic even though they are exposed to a doubled risk of RPL compared to the general population. Furthermore, CD has been associated with microbiota alterations. The aim of this study is to evaluate endometrial and vaginal microbiota in HLA-DQ2/DQ8 positive and negative RPL patients compared to healthy pregnant women. Endometrial and vaginal microbiota of 3 subgroups were evaluated: 15 HLA-DQ2/DQ8 positive RPL women, 25 HLA DQ2/DQ8 negative RPL women (for a total of 40 RPL women) and 7 healthy fertile controls with previous uncomplicated pregnancies (all HLA-DQ2/DQ8 negative). The 2 RPL subgroups (HLA-DQ2/DQ8 positive and negative) showed a different endometrial and vaginal composition in the Lactobacillacae family compared to controls: Lactobacillus acidophilus was absent both in the vaginal and endometrial samples of RPL women, while Lactobaciluus iners, which can favor a less stable vaginal microbiota, was found only in RPL women (26.4% in HLA DQ2/DQ8 positive and 22.1% HLA DQ2/DQ8 negative) in both the vaginal and endometrial districts. In conclusion, both HLA DQ2/DQ8 positive-RPL and HLA DQ2/DQ8 negative-RPL women showed different endometrial and vaginal microbiota composition compared to healthy controls.

Celiac disease (CD) is a common chronic inflammatory disorder occurring in genetically predisposed individuals secondary to gluten ingestion. CD usually presents with gastrointestinal symptoms such as pain, bloating, flatulence, and constipation or diarrhea. However, individuals can present in a nonclassical manner with only extraintestinal symptoms. The neurological manifestations of CD include ataxia, cognitive impairment, epilepsy, headache, and neuropathy. A lifelong gluten-free diet is the current recommended treatment for CD. This review discusses the relevant neurological manifestations associated with CD and the novel therapeutics. Further research is required to get a better understanding of the underlying pathophysiology of the neurological manifestations associated with CD. Clinicians should keep CD in the differential diagnosis in individuals presenting with neurological dysfunction of unknown cause.

Celiac disease (CeD) is a chronic gluten-induced enteropathy with plethoric manifestations. The typical manifestations of CeD such as chronic diarrhea and malabsorption are widely recognized, however, many patients have atypical manifestations like iron deficiency anemia, idiopathic short stature, hypertransaminesemia or infertility, etc. These patients often present to the primary care physicians and/or non-gastrointestinal specialties. However, due to a lack of awareness among the healthcare professionals about the various atypical manifestations, many patients are not screened for CeD. In this review, we have summarized the available literature about the prevalence of CeD in various gastrointestinal (chronic diarrhea) and non-gastrointestinal conditions (iron deficiency anemia, short stature, cryptogenic hypertransaminesemia, cryptogenic cirrhosis or idiopathic ataxia etc.) where the diagnosis of CeD should be con-sidered. In addition, we also discuss special scenarios where screening for CeD should be considered even in absence of symptoms such as patients with type 1 diabetes, Down's syndrome, and first-degree relatives of patients with CeD. Further, we discuss the diagnostic performance and limitations of various screening tests for CeD such as IgA anti-tissue transglutaminase antibodies, anti-endomysial antibodies and anti-deamidated gliadin antibodies. Based on the current recommendations, we propose a diagnostic algorithm for patients with suspected CeD.

The best-known symptoms of coeliac disease are related to the gastrointestinal tract, but the disease may also present with various systemic manifestations outside the intestine. Some of these consequences may remain permanent in undiagnosed individuals or if the diagnostic delay is prolonged. However, for many of the systemic manifestations, the scientific evidence remains scant and contradictory.

We conducted a narrative review of the most thoroughly studied and clinically relevant systemic consequences of coeliac disease, especially those that could be prevented or alleviated by early diagnosis. The review is intended particularly for physicians encountering these patients in daily clinical practice.

The possible systemic consequences of coeliac disease extend to multiple organ systems, the best studied of which are related to skeletal, reproductive, cardiovascular and neurological systems. Furthermore, the disease is associated with an elevated risk of psychiatric comorbidities, non-Hodgkin lymphomas and intestinal adenocarcinoma.

The various systemic consequences of coeliac disease play a significant role in the overall health of patients. Early diagnosis and treatment with a gluten-free diet appear to be beneficial for most, but not all of these conditions. The possible negative metabolic and psychosocial effects of the diet should be acknowledged during follow-up.

Coeliac disease is a lifelong immune-mediated enteropathy with systemic features associated with increased morbidity and modestly increased mortality. Treatment with a strict gluten-free diet improves symptoms and mucosal damage but is not curative and low-level gluten intake is common despite strict attempts at adherence. Regular follow-up after diagnosis is considered best-practice however this is executed poorly in the community with the problem compounded by the paucity of data informing optimal approaches. The aim of dietary treatment is to resolve symptoms, reduce complication risk and improve quality of life. It follows that the goals of monitoring are to assess dietary adherence, monitor disease activity, assess symptoms and screen for complications. Mucosal disease remission is regarded a key measure of treatment success as healing is associated with positive health outcomes. However, persistent villous atrophy is common, even after many years of a gluten-free diet. As the clinical significance of asymptomatic enteropathy is uncertain the role for routine follow-up biopsies remains contentious. Symptomatic non-responsive coeliac disease is common and with systematic follow-up a cause is usually found. Effective models of care involving the gastroenterologist, dietitian and primary care doctor will improve the consistency of long-term management and likely translate into better patient outcomes. Identifying suitable treatment targets linked to long-term health is an important goal.