Pica Syndromes and Iron Deficiency Anemia Treatment: A Mini Review
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear authors,
thank you very much for sending this interesting article to the Journal Hemato by MDPI. Your article is entitled "Pica Syndromes and Iron Deficiency Anemia Treatment: A Mini Review".
I did upload my review comments and hope that my comments are helpful and may improve your manuscript.
This mini review explores the complex relationship between pica—a compulsive craving and consumption of non-nutritive substances—and iron deficiency anemia (IDA), particularly in adults and pregnant women. The authors reviewed studies published between 2015 and 2025 to assess the prevalence, characteristics, and treatment outcomes of pica in IDA patients.
Pica, especially forms like pagophagia (ice), geophagia (clay), and amylophagia (starch), appears to be both a clinical symptom of and behavioral response to iron deficiency. Evidence shows that effective iron supplementation, both oral and intravenous, typically leads to the resolution of pica behaviors. Oral iron remains first-line therapy, particularly in alternate-day dosing to enhance absorption and reduce gastrointestinal side effects. IV iron is reserved for cases of intolerance or need for rapid correction (e.g., pregnancy, malabsorption, or severe anemia).
The review also addresses cultural and physiological factors, side effects of pica (e.g., dental damage, toxin exposure), and future directions, such as the potential role of zinc and the utility of pica as a screening tool in low-resource settings. Ultimately, the authors advocate for awareness of pica as a diagnostic clue and recommend iron therapy as a curative treatment.
Comments for author File: 
Comments.pdf
Author Response
Comment 1: The article is dense and would benefit from a more clearly defined structure (e.g., subheadings within the “Forms of Pica” or "Management" sections) to help readers navigate the different pica syndromes and treatment pathways more easily.
Response 1: Yes, we agree that it is a good point. We have divided the Forms of pica into subheadings for the specific forms. And then we subdivided the iron therapy section into its respective first-line and second-line options sections.
Comment 2: Multiple statements repeat the idea that “pica resolves with iron supplementation.” This could be streamlined to enhance conciseness and focus on novel findings or mechanistic insights
Response 2: We have tried to remove the unnecessary mention of pica resolving with iron supplementation where possible, however the place where it features most is in the Forms of Pica (section 4) portion. And the point of this section is to demonstrate how every form of pica resolves with iron supplementation, so it's necessary to mention the results of the study.
Comment 3: While hypotheses are mentioned (e.g., ice improving cerebral perfusion), the physiological basis of pica is underexplored. More emphasis on neurobiological or biochemical theories would strengthen the scientific depth.
Response 3: Yes we agree with that point, so we've added section 3, it is a brief paragraph about possible neurobiological mechanisms of pica in IDA.
Comment 4:The article has separate tables for pica types and iron formulations, but lacks a synthesized table linking treatment modality to pica resolution rates, side effects, or patient populations.
Response 4: Yes we agree, we have added Table 4 which, describes the proposed information in table format.
Comment 5:Although the focus is on adults, including a brief note on how pica manifests differently (or similarly) in younger/elderly and disabled populations could broaden clinical relevance.
Response 5: Yes we agree, we have a added a small paragraph about pica presentation in children and how that differs from that in adults. We were not able to find any notable differences in pica presentation in the elderly or disabled. This is paragraph 4 of the Introduction (Section 1) on page 2.
Comment 6: The manuscript contains several grammatical issues and overly long sentences.
Response 6: You are right, we have strived to split overly long and wordy sentences into simpler sentences to improve the flow and readability
Comment 7: Most referenced studies are from high-income or Western contexts. Including more data from low- and middle-income countries, where pica is culturally normative, would offer a more global perspective. Why do the authors focus on english written articles. Especially in this very rare topic, the implementation of more languages may be very helpful.
Response 7: We agree, we have now included studies from India, Turkey, Pakistan, Myanmar, Iran, Morocco, Malawi, Ethiopia, and Sudan. These include references 7, 8, 9, 10, 12, 15, 20, 21, 36, and 37.
Comment 8:While the article mentions OCD and schizophrenia, it doesn't delve into how these might complicate treatment or affect diagnosis. This area deserves further analysis or at least a paragraph.
Response 8: We agree. We have detailed on paragraph 6 on page 3, line 100 the method to differentiate pica caused by IDA vs the one caused by OCD/Schizophrenia.
Comment 9: The limitations section briefly mentions study design bias, but doesn't acknowledge gaps in standard diagnostic criteria for pica or iron deficiency across studies, which would affect comparability.
Response 9: Agreed, we have added this to our paper on page 12 under the Limitations section, line 476.
Comment 10: There is a need for a paragraph on iron deficiency diagnostic
Response 10: Agreed. We have added paragraph 6, line 102, on page 3 to address IDA diagnostics and the associated lab values you would expect to find. We have decided not to add the graph about differentiating IDA and Anemia of chronic disease, as it is not directly relevant to pica. We have explained how to distinguish between IDA and ACD on lines 112-114.
Comment 11 and 13: Acute Phase Reaction pathway and Modern diagnostic of anemia in ACD
Response 11 & 13: We have decided not to expand on the pathway of anemia of chronic disease or diagnosing IDA in critically ill patients, as that is not relevant to the presentation of pica. We believe that talking about ACD to this extent would muddy the water. IDA is being discussed in the context of pica presentation. ACD is not linked with pica presentation according to the literature, and thus is out of the scope of this review.
Comment 12: Common Diagnostic Causes of IDA
Response 12: We agree, we have added section 2 starting from line 144 detailing the most common causes of IDA and how to diagnose these conditions. We have not discussed diagnostic causes of anemia in general however as we feel it is out of the scope of this review.
Reviewer 2 Report
Comments and Suggestions for AuthorsSuggestions to improve the manuscript
- In the introduction it would be helpful to add some information on how to manage the differential diagnosis between IDA and eating disorder, adding some clinical elements that can suggest one of the 2 different conditions.
- there are other new formulations that are not mentioned, such as bisglycinate iron, with adequate efficacy and minor side effects (see ref. 10.1007/s00277-020-03906-w)
Author Response
Comment 1: In the introduction, it would be helpful to add some information on how to manage the differential diagnosis between IDA and eating disorder, adding some clinical elements that can suggest one of the 2 different conditions.
Response 1: It is difficult to compare the two because in an eating disorder such as Anorexia Nervosa you would present with an IDA due to restricted intake. So the two are not different conditions; rather, IDA is a finding that would occur in anorexia nervosa. We have mentioned anorexia nervosa under our new Section 2 which briefly discusses causes of IDA. It is found on page 4, line 167
Comment 2: There are other new formulations that are not mentioned, such as bisglycinate iron, with adequate efficacy and minor side effects (see ref. 10.1007/s00277-020-03906-w)
Response 2: Yes, thank you that is a valuable addition to the paper, we have mentioned it on page 8, paragraph 2, line 339 and 347-349.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThank you very much for all your work.
