The Impact of a Gluten-Free Diet on Pregnant Women with Celiac Disease: Do We Need a Guideline to Manage Their Health?
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis review manuscript addresses the very important issue of the healthy and most appropriate diet for pregnant celiac women. The authors discuss the risk of the standard gluten-free diet on maternal celiac pregnancy and fetal development and explore whether there is a need for specific guidelines for pregnant women with celiac disease already on a GFD or whether there is a need for an amendment in the current CD guidelines for celiac disease.
The review is well presented and the topic is of major clinical interest. However, in my opinion, there are two further issues which are worth mentioning. 1) the authors should further stress the crucial role of maintaining a strict GFD regimen before planning pregnancy and also during pregnancy recalling the risk of secondary autoimmunity developing in celiac diseases that can be prevented by strict GFD, such as thyroid autoimmune disorders, liver diseases (chronic hypertransaminasemia), neurological disorders that are well-known extraintestinal-associated disorders in celiac disease, as previously demonstrated (Digestion. 2001;64(1):61-5. doi: 10.1159/000048840; Anti tissue transglutaminase antibodies as predictors of silent coeliac disease in patients with hypertransaminasaemia of unknown origin. Dig Liver Dis. 2001 Jun-Jul;33(5):420-5. ; Allergy Asthma Clin Immunol. 2021 May 28;17(1):53. doi: 10.1186/s13223-021-00557-y) as well as the production of autoantibodies to cytoskeleton components such as anti-actin antibodies that have been specifically related to celiac disease as previously demonstrated (Anti-actin IgA antibodies in severe coeliac disease. Clin Exp Immunol. 2004 Aug;137(2):386-92.); 2) the importance of celiac disease screening in female patients before pregnancy because atypical celiac disease clinical presentation in adult patients are not rare and should be investigated also in atopics as well as patients with neurological disorders possibly related to vitamin malabsorption as well as antineuronal/antiganglioside antibodies, as previously demonstrated (Prevalence of silent coeliac disease in atopics. Dig Liver Dis. 2000 Dec;32(9):775-9; Allergy Asthma Clin Immunol. 2021 May 28;17(1):53. doi: 10.1186/s13223-021-00557-y.).
Comments on the Quality of English LanguageSome minor style language changes should be made.
Author Response
We would like to reviwers for their valuable contributions. The reviwers mainly emphaize the impact of secondary autoimmunity on pregnancy outcomes. We thank for your valuable contributations. According to our knowladge, there are limited informations about secondary autoimmunity in celiac patients. This part is explanied in the line 102-109.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsThis review manuscript, addresses the risk of standard gluten-free diet (designed for CD patients) designed on maternal celiac pregnancy and fetal development and the authors explored if there is a need of specific guidelines for pregnant CD women already on a GFD or there is a need of an amendment in the current CD guidelines or amendments in the guidelines to provide recommendations on a GFD with optimised nutrition to meet nutrient needs for CD pregnant women.
After discussing the nutritional pregnancy-spceific need of CD women, the authors concluded that there is a need of a specific guidelines or amendments in the current CD guidelines for the pregnant women with
CD already on gluten-free diet to provide recommendations on a GFD with optimized nutrition to meet nutrient needs for CD pregnant women.
The topic is of interest, however discussing the nutritional risk factors in maternal celiac pregnancy and the influence on fetus development, they focus only on nutritional risk factors. However, the authors should also recall previous studies demonstrating that CD patients frequently develop serum autoantibodies that are associated with the well-known extraintestinal manifestations of CD. These serum autoantibody development are related with the hypothesis of the "secondary autoimmunity" driven by tissue transglutaminase that can deamidate or crosslink several external or self antigens, such as intracelluler or matrix proteins, creating more potent antigens or antigenic neoepitopes. This increased production of neoepitopes could be of importance for the secondary autoimmunity (Coeliac disease and secondary autoimmunity. Dig Liver Dis. 2002 Jan;34(1):13-5. doi: 10.1016/s1590-8658(02)80053-6.) observed in CD, as demonstrated by studies describing the development of anti-actin IgA antibodies (Anti-actin IgA antibodies in severe coeliac disease. Clin Exp Immunol. 2004 Aug;137(2):386-92. doi: 10.1111/j.1365-2249.2004.02541.x. ), anti-neuronal and antiganglioside antibodies (Gastroenterology. 2007 Jul;133(1):195-206. doi: 10.1053/j.gastro.2007.04.070; Allergy Asthma Clin Immunol. 2021 May 28;17(1):53. doi: 10.1186/s13223-021-00557-y.), as well as anti-thyroid antibodies (Coeliac disease in patients with autoimmune thyroiditis. Digestion. 2001;64(1):61-5. doi: 10.1159/000048840. ).
This "secondary autoimmunity" could account for pregnancy complication in CD women irrespective of nutritional factors.
These literature studies should be recalled in order to comprehensively address the important topic of extraintestinal complications of celiac disease such as pregnancy related complications.
Comments on the Quality of English Languageminor editing of english style is required
Author Response
We would like to reviwers for their valuable contributions. The reviwers mainly emphaize the impact of secondary autoimmunity on pregnancy outcomes. We thank for your valuable contributations. According to our knowladge, there are limited informations about secondary autoimmunity in celiac patients. This part is explanied in the line 102-109.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsThis review highlights the importance of a healthy and balanced diet for pregnant women, particularly those with celiac disease (CD) who are already on a gluten-free diet (GFD). It rightly emphasizes the impact of poor nutrition on both the mother and infant's health, leading to pregnancy-related complications and undesirable effects on the fetus. The review identifies a gap in existing CD guidelines, as they primarily focus on screening, diagnosis, treatment, and management, but do not provide evidence-based approaches to determine the appropriate energy and nutrient requirements for pregnant women with celiac disease.
The call for specific guidelines or recommendations tailored to pregnant women with celiac disease is justified, considering the potential risks associated with poorly managed CD, such as miscarriages, preterm labor, low birth weight, and stillbirths. The review rightly points out that the current guidelines lack information on recommended energy requirements, weight gain during pregnancy, macronutrient distribution, and the intake of vitamins and minerals through diet and/or supplementation for this specific population.
The proposed guidelines are expected to cover crucial aspects, including the recommended amount of energy, target macronutrient distribution, advised intake of vitamins and minerals, the timing for supplementation initiation, and recommended portions of gluten-free food during pregnancy. These guidelines would serve to optimize nutrition, meeting the nutrient needs of both pregnant women with celiac disease and their infants.
The review effectively concludes by recommending and advocating for the development of such guidelines or presiding papers in the future. This call is essential for addressing the unique nutritional requirements of pregnant women with celiac disease, ensuring their well-being and that of their infants. Overall, the critical review successfully highlights an important gap in the existing literature and emphasizes the need for specific guidelines in this particular area of maternal health.
Author Response
We would like to reviwers for their valuable contributions. The reviwers mainly emphaize the impact of secondary autoimmunity on pregnancy outcomes. We thank for your valuable contributations. According to our knowladge, there are limited informations about secondary autoimmunity in celiac patients. This part is explanied in the line 102-109.
Author Response File: Author Response.docx
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors stated thay there are limited informations about secondary autoimmunity in celiac patients (line 102-109). However, in my opinion, there are several studies demonstrating a signficant association of celiac disease with extraintestinal disorders that are frequently marked by serum autoantibodies as recalled in the first review report. Importantly, the introduction of gluten free diet may produce clinical improvement in some subgroups of celiac disease patients with extraintestinal autoimmune disorders, as reported in previous studies. Even if firm conclusions cannot be drawn, the hypothesis of secondary autoimmunity should be considered to explain pregnancy complications.
Author Response
Dear Reviewer;
Thank you for your last comment. In additional file, we extensively responded to your comments.
Best regards;
Author Response File: Author Response.docx
