{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:46:10Z","timestamp":1792788370824,"version":"4.5.0"},"update-to":[{"DOI":"10.12688\/f1000research.179360.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000}}],"reference-count":32,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centre for Evidence Based Guidelines, Department of Health Research, Government of India","id":[{"id":"https:\/\/ror.org\/036h6g940","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Background The prevalence of subclinical hypothyroidism (SCH) in the general population is notably high, ranging from 4% to 20%, and varies according to sex and age. SCH has been reported to be associated with multiple adverse pregnancy outcomes in pregnant women. While the therapeutic decision for overt hypothyroidism is fairly straightforward, treatment of SCH, especially the timing of the initiation of therapy, has been a point of discussion. Objective To assess the effect of early initiation of treatment (thyroid hormone therapy) compared to watchful waiting, delayed initiation, or no treatment on progression to overt hypothyroidism, prevention of complications, and associated adverse outcomes through a \"systematic review and meta-analysis (SRMA)\u201d. Methods The SRMA protocol adhered to the \u201cPreferred Reporting Items for Systematic reviews and Meta-Analyses Protocols (PRISMA-P 2015)\u201d guidelines. Only \u201crandomized controlled trials (RCTs)\u201d will be included. The databases \u201cPubMed, Scopus, EMBASE, and the Cochrane Library\u201d will be searched from inception until 30.12.2025. Two stages (title abstract followed by full-text review) and two-pass screening (two authors independently) with a third reviewer adjudication of conflicts will be adopted. Data will be extracted, and the risk of bias will be assessed independently by two authors using a process to resolve differences. The risk of bias for RCTs will be assessed using Cochrane ROB 2.0. Pooled estimates will be calculated for meta-analysis. Subgroup analysis and meta-regression will be performed if heterogeneity was present. The certainty of the evidence will be ascertained through \u201cGRADE (Grading of Recommendations, Assessment, Development, and Evaluation)\u201d. Intended outcomes The SRMA can inform the framing of clinical guidelines for SCH management for all population groups and also intends to bring out gaps in the existing literature for future studies. PROSPERO ID: CRD420251270021 (Date: 08 February 2026)<\/ns3:p>","DOI":"10.12688\/f1000research.179360.2","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T08:44:05Z","timestamp":1786610645000},"page":"555","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Early initiation of thyroid hormone therapy versus watchful waiting or delayed treatment or no treatment in subclinical hypothyroidism: A systematic review and meta-analysis protocol"],"prefix":"10.12688","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3898-5450","authenticated-orcid":false,"given":"Aravind P","family":"Gandhi","sequence":"first","affiliation":[{"name":"Department of Community Medicine Nagpur Maharashtra All India Institute of Medical Sciences - Nagpur"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyani P","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Technical Resource Centre, Centre for evidence-based guidelines Nagpur Maharashtra All India Institute of Medical Sciences - Nagpur"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-7159","authenticated-orcid":false,"given":"Anupriya","family":"Kaliyappan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology & Metabolism Nagpur Maharashtra All India Institute of Medical Sciences - Nagpur"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akash","family":"Bang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Nagpur Maharashtra All India Institute of Medical Sciences - Nagpur"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Gangane","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Nagpur Maharashtra All India Institute of Medical Sciences - Nagpur"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1750-1760","DOI":"10.1001\/jama.2025.13559","article-title":"Hypothyroidism: A Review.","volume":"334","author":"L Chaker","year":"Nov. 2025","journal-title":"JAMA."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"301-316","DOI":"10.1038\/nrendo.2018.18","article-title":"Global epidemiology of hyperthyroidism and hypothyroidism.","volume":"14","author":"P Taylor","year":"May 2018","journal-title":"Nat. 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The PROSPERO registration, PRISMA-P adherence, detailed PICO framework, and provision of extended data (PRESS checklist, search strategies) via Figshare are commendable and support transparency. A few additional methodological points are worth addressing before the review is conducted:<\/b>  \n<b>Author response: <\/b>Thank you for the positive comments and the methodological issues pointed out. We have addressed these points in the revised manuscript and have added a comment-specific response in this file. These suggestions were useful in refining the methods and making the proposed analysis more transparent.  \n<b>Reviewer comment 1: Section 2.8 allows RR, OR, or HR for dichotomous outcomes but does not specify how these will be handled when different included trials report different metrics for the same outcome. Since RR, OR, and HR are not interchangeable (HR incorporates time-to-event structure), pooling them together without a pre-specified rule risks a methodological error. Please state a preferred effect metric per outcome and how studies reporting a different metric will be handled (conversion method, or a separate analysis stratum).<\/b>  \n<b>Author response: <\/b>We thank the reviewer for highlighting this important issue. We agree that RR, OR, and HR are not interchangeable and should not be pooled together as if they represented the same effect measure. We have revised the Data Analysis section to prespecify the approach. For dichotomous outcomes assessed at a defined follow-up time, risk ratio (RR) with 95% confidence interval (CI) will be the preferred effect measure. Where sufficient event and participant data are available, RRs will be calculated from the reported data. Studies for which only an odds ratio (OR) is available and an RR cannot be reliably derived will be analysed separately using ORs rather than pooled directly with RRs. For time-to-event outcomes, hazard ratios (HRs) with 95% CIs will be synthesised separately and will not be combined with RRs or ORs. Where studies report outcomes at substantially different follow-up periods, clinically comparable time points will be synthesised separately. These clarifications have been incorporated into the Data Analysis section.  \n<i>Change made in the manuscript (Data analysis section): For dichotomous outcomes assessed at a defined follow-up time, risk ratios (RRs) with 95% confidence intervals (CIs) will be the preferred effect measure. Studies reporting only odds ratios (ORs), where an RR cannot be reliably derived, will be synthesized separately using ORs. For time-to-event outcomes, hazard ratios (HRs) with 95% CIs will be synthesized separately and will not be pooled with RRs or ORs. Clinically comparable follow-up time points will be analyzed separately where appropriate.<\/i>  \n<b>Reviewer comment 2: The current wording implies REM will be used only when I&sup2;&gt;50%, with a fixed-effect model used otherwise. Since I&sup2; is imprecise with a small number of studies and the fixed-effect model's single-true-effect assumption is rarely justified even with low observed heterogeneity, most current methodological guidance (e.g., Cochrane Handbook) recommends REM as the default regardless of I&sup2;. Please reconsider this decision rule or provide justification for the I&sup2;-based switch.<\/b>  \n<b>Author response: <\/b>We thank the reviewer for this important methodological observation. We would like to point out that the Cochrane Handbook does not specify that a fixed-effect model cannot be used when only a small number of studies are available. However, we agree with the reviewer that there is no definitive binary I&sup2; cut-off for choosing between fixed-effect and random-effects models and that model selection should not be based solely on an arbitrary I&sup2; threshold. Accordingly, we have mentioned our analytical approach. In the present systematic review and meta-analysis, studies will first be assessed for clinical and methodological comparability. Population groups (e.g., adults, pregnant women, older adults), comparator groups (watchful waiting, delayed initiation, or no treatment), and outcomes will be pooled only when they are sufficiently similar to justify quantitative synthesis. After accounting for these characteristics, if residual statistical heterogeneity is present (I&sup2; &gt;0%), a random-effects model will be used for pooling. Where no statistical heterogeneity is observed (I&sup2; = 0%), and the included studies are considered clinically and methodologically comparable, a fixed-effect model will be used. The previous I&sup2; &gt;50% criterion for selecting the random-effects model has therefore been removed from the Data Analysis section.  \n<i>Change made in the manuscript (Data analysis section): Meta-analyses will be conducted separately for clinically meaningful population groups (e.g., Neonates, children, reproductive status including pregnancy and lactation, women with infertility, the geriatric population, and any other clinically distinct disease\/ population group identified during the review). Population groups will be combined only where there is sufficient clinical and methodological similarity and a clear scientific justification for quantitative pooling. Separate meta-analysis will be conducted according to the type of the control group as well (watchful waiting or delayed initiation, or no treatment (C) on progression to overt hypothyroidism). Statistical heterogeneity will be quantified using the I&sup2; statistic. Where no statistical heterogeneity is observed (I&sup2; = 0%) and studies are considered clinically and methodologically comparable, pooled estimates will be calculated using a fixed-effect model. Where residual statistical heterogeneity is present (I&sup2;&gt; 0%) after accounting for relevant clinical and methodological differences, a random-effects model will be used. Where substantial heterogeneity is identified, potential sources will be explored through predefined subgroup analyses (co-morbidities, symptom status, TSH thresholds used for diagnosis (e.g., 4\u20137 mIU\/L, 7\u201310 mIU\/L, &gt;10 mIU\/L, or any other cut-off specified by the included studies for the diagnosis of subclinical hypothyroidism) , autoimmune status, between different comparators, treatment duration, follow-up duration, environmental or geographic, or any other factor identified during the review) and, where sufficient studies are available (&gt;10 studies per meta-analyzable outcome), meta-regression will be undertaken.<\/i>  \n<b>Reviewer comment 3: The pre-specified TSH bands (4\u20137, 7\u201310, &gt;10 mIU\/L) appear intended as a universal subgrouping scheme, but pregnancy-specific TSH reference ranges (trimester-specific, typically ~2.5\u20134.0 mIU\/L upper limit) differ substantially from non-pregnant thresholds. Applying the same bands to pregnant and non-pregnant subgroups could produce clinically meaningless strata for the pregnancy population. Please specify a separate TSH-banding scheme for pregnancy-specific analyses.<\/b>  \n<b>Author response: <\/b>We thank the reviewer for this important observation. The initially specified TSH categories (4\u20137, 7\u201310, and &gt;10 mIU\/L) were based on the author team's clinical experience and preliminary review of the literature and were intended as potential categories for subgroup analysis rather than as universal diagnostic thresholds for subclinical hypothyroidism. We agree with the reviewer that the TSH thresholds used to diagnose subclinical hypothyroidism can vary according to the population, clinical setting, pregnancy\/reproductive status, geographical setting, and diagnostic criteria or guidelines followed by individual studies. Accordingly, we have revised the protocol to avoid restricting subgroup analyses to these prespecified TSH categories. In addition to the proposed categories, we have included an open criterion of \u201cany other TSH cut-off specified by the included studies for the diagnosis of subclinical hypothyroidism.\u201d The exact diagnostic threshold and criteria used in each study will be extracted during data extraction. For population groups with specific diagnostic thresholds, particularly pregnant women, subgrouping will be based on the population- or pregnancy-specific diagnostic criteria and TSH thresholds reported by the included studies rather than applying the proposed general TSH categories uniformly. These changes have been incorporated into the Data Extraction and Data Analysis sections.  \n<i>Change made in the manuscript (Data Analysis): Where substantial heterogeneity is identified, potential sources will be explored through predefined subgroup analyses (co-morbidities, symptom status, TSH thresholds used for diagnosis (e.g., 4\u20137 mIU\/L, 7\u201310 mIU\/L, &gt;10 mIU\/L, or any other cut-off specified by the included studies for the diagnosis of subclinical hypothyroidism) , autoimmune status, between different comparators, treatment duration, follow-up duration, environmental or geographic, or any other factor identified during the review) and, where sufficient studies are available (&gt;10 studies per meta-analyzable outcome), meta-regression will be undertaken.<\/i>  \n<b>Reviewer comment 4: The Discussion states the review will provide an evidence profile including \u201cmortality\u201d, but Table 1\u2019s Critical\/Important outcomes list does not include mortality anywhere. Please resolve this inconsistency, either add mortality explicitly to Table 1's outcome list or remove it from the Discussion framing.<\/b>  \n<b>Author response: <\/b>We thank the reviewer for identifying this inconsistency. Mortality is a clinically relevant outcome for this review, particularly for long-term follow-up and specific population groups. Accordingly, we added mortality to the outcome list in Table 1 and ensured it is consistently included, where relevant in the manuscript.  \n<i>Change made in the manuscript (Table 1 \u2013 Outcomes): \u201cMortality (all-cause and, where reported, cause-specific mortality)\u201d has been added among the prespecified outcomes.<\/i>  \n<b>Reviewer comment 5: No process is described for identifying multiple publications arising from the same trial (e.g., primary report plus secondary or long-term follow-up analyses), which risks double-counting participants in the meta-analysis. Please add a brief statement on how this will be identified and handled (e.g., cross-checking trial registration numbers, contacting authors when unclear).<\/b>  \n<b>Author response:<\/b>\n<b> <\/b>Thank you for pointing this out. We have now added a process for identifying multiple publications from the same study. We will compare trial registration numbers and study details such as the authors, study centers, recruitment period, sample size, and intervention and comparator groups to identify reports that may have originated from the same study. Such publications will be linked and considered as a single study so that the same participants are not included more than once in a meta-analysis. If different reports provide information on different outcomes or follow-up periods, the relevant information will be taken from each report. Where it is not clear whether two publications are from the same study, we will contact the study authors for clarification, where feasible. This has now been added to the Data Extraction Process section.  \n<i>Change made in the manuscript (Data Extraction Process): Multiple publications from the same study will be identified by comparing trial registration numbers and study characteristics, including authors, study centres\/settings, recruitment periods, sample sizes, and intervention and comparator groups. Reports identified as arising from the same study will be linked and considered as a single study. Information from more than one report may be used when they provide data on different outcomes or follow-up periods; however, the same participants will not be included more than once in a meta-analysis. If it is unclear whether publications relate to the same study, the study authors will be contacted for clarification, where feasible.<\/i>","URL":"https:\/\/f1000research.com\/articles\/15-555\/v2#referee-comment-17244","order":2,"name":"referee-comment-17244","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Center for Evidence-Based Guidelines, Department of Health Research, Government of India (Email Dated 25 Nov 2025). The grant was awarded to Aravind P Gandhi (lead author of the manuscript). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}