Optimizing Thyroid Management in Pregnancy Beyond TSH: Free Hormones, Placental Deiodinases, and Iodine Kinetics — A Systematic Review and Meta-analysis

Optimizing Thyroid Management in Pregnancy Beyond TSH: Free Hormones, Placental Deiodinases, and Iodine Kinetics — A Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Optimizing Thyroid Management in Pregnancy Beyond TSH: Free Hormones, Placental Deiodinases, and Iodine Kinetics — A Systematic Review and Meta-analysis Wiku Andonotopo, MD, PhD This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7905418/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Maternal thyroid care in pregnancy is still largely defined by serum TSH, even though gestational physiology alters its meaning. Shifts in binding proteins, placental metabolism of thyroid hormones, and the rise in iodine requirements uncouple TSH from the true maternal and fetal thyroid state. To clarify this gap, we conducted a systematic review and meta-analysis of studies reporting maternal free thyroxine and triiodothyronine, placental deiodinase expression or function, and iodine status in relation to pregnancy, neonatal, or child outcomes. We searched MEDLINE, Embase, Web of Science, Scopus, CENTRAL, CINAHL, ClinicalTrials.gov, WHO-ICTRP, and grey literature through October 2025 without language restriction. Two reviewers independently screened records, assessed eligibility, extracted data, and judged bias using RoB-2 for trials, ROBINS-I/ROBINS-E or NOS for observational work, and AMSTAR-2/ROBIS for prior reviews. Effect measures were synthesized using random-effects models with robust variance estimation. Free hormones were harmonized by LC-MS/MS calibration or expressed as trimester-specific multiples of the median. Dose–response modeling assessed urinary iodine concentration against outcomes. From 1,243 records, 910 abstracts were screened, 160 full texts assessed, and 35 studies included, of which 20 formed the quantitative core. Findings showed that lower maternal free T4 trajectories and disproportionate elevations in late-gestation free T3 were associated with gestational diabetes, preterm birth, and low birth weight. Placental DIO3 expression was consistently high, accentuated in growth-restricted pregnancies, while iodine deficiency correlated with maternal hypothyroxinemia and neurodevelopmental risk. Heterogeneity was moderate, certainty graded low to moderate. Evidence supports a management framework that integrates calibrated free-hormone monitoring, placental biology, and iodine sufficiency, moving beyond reliance on TSH alone. Obstetrics & Gynecology Pregnancy Free thyroxine (FT4) Placental deiodinase (DIO2/DIO3) Iodine kinetics Perinatal outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Thyroid function during pregnancy has long been recognized as a pivotal determinant of maternal well-being and fetal development. Maternal iodine intake directly influences thyroid hormone synthesis, and even mild deficiency alters circulating free thyroxine (FT4) and thyrotropin (TSH) levels, as demonstrated in large prospective cohorts [ 1 ]. Despite this, clinical recommendations for iodine supplementation remain ambiguous and inconsistent across regions, reflecting conflicting interpretations of the available evidence [ 2 ]. This uncertainty coincides with broader efforts in perinatal medicine to integrate complex biological determinants — such as maternal nutrition and fetal origins of adult disease — with innovative, technology-driven approaches [ 3 ]. In this evolving framework, nutri-epigenomics has highlighted how maternal nutrition, including micronutrient sufficiency, modulates fetal gene expression and long-term health outcomes [ 4 ]. These insights parallel new paradigms of maternal–fetal immunoediting, in which immune tolerance is reframed as a dynamic process linking maternal environment with fetal survival and disease risk [ 5 ]. Early foundational reviews established that both hypo- and hyperthyroidism negatively impact pregnancy outcomes [ 6 ], and mechanistic studies provided the first evidence of altered placental deiodinase activity in complicated pregnancies, such as intrauterine growth restriction [ 7 ]. Placental thyroid hormone transporters, essential for fetal supply of maternal thyroxine, were subsequently characterized, reinforcing the complexity of thyroid hormone passage to the fetus [ 8 ]. These insights were expanded by contemporary analyses summarizing the clinical challenges of thyroid disease in pregnancy [ 9 ]. Nutritional reviews further emphasized that iodine status is a critical factor for maternal and fetal thyroid homeostasis, with universal sufficiency remaining a global health priority [ 10 ]. Recent work has reaffirmed the centrality of iodide sufficiency for fertility and gestation [ 11 ], while experimental studies illustrate how iodine availability modulates placental hormone transport [ 12 ]. Classic endocrine reviews established the physiologic adaptations of the maternal thyroid axis during pregnancy [ 13 ], which remain foundational in modern clinical understanding. However, recent scoping reviews suggest that environmental exposures, such as fluoride and endocrine disruptors, may amplify the effects of iodine deficiency on both maternal thyroid function and child neurodevelopment [ 14 , 15 ]. Advances in biochemical assays, such as automated urinary iodine determination, provide more precise measures of iodine sufficiency in pregnancy [ 16 ]. Placental studies have further uncovered how maternal thyroid hormone levels interact with local deiodinase expression. Elevated maternal total triiodothyronine (T3) combined with low fetal FT4 was shown to reflect altered placental enzyme activity in pregnancies complicated by gestational diabetes [ 17 ]. Type 3 deiodinase (D3) was confirmed to be highly expressed in the uteroplacental unit [ 18 ], and subsequent reviews of placental thyroid transport consolidated evidence that maternal T4 is the predominant hormone crossing the placenta [ 19 ]. Longitudinal analyses established gestational-age–specific changes in both type II (D2) and type III (D3) deiodinase activity, showing increased D2 with advancing gestation and sustained D3 expression as a protective mechanism [ 20 ]. Clinical observations underscore that untreated maternal thyroid disorders remain a significant concern [ 21 ], and authoritative reviews reiterated the importance of maintaining maternal euthyroidism to support fetal neurodevelopment [ 22 ]. Simplified reviews highlighted the central role of maternal thyroid function throughout pregnancy [ 23 ], while cross-sectional studies from iodine-deficient regions confirmed strong associations between local nutritional status and maternal FT4 trajectories [ 24 ]. Physiologic modeling studies further demonstrated how both dietary iodide and environmental disruptors such as perchlorate perturb maternal thyroid hormones in pregnancy [ 25 ]. Metabolic reviews have emphasized maternal–fetal thyroid metabolism as a highly dynamic process across gestation [ 26 ], while neuroscience studies confirmed the crucial influence of maternal thyroid hormones on fetal brain development [ 27 ]. Integrative reviews consolidated physiology, pathology, and screening approaches into a comprehensive framework [ 28 ]. At the molecular level, iodine and thyroid hormone partitioning between maternal and fetal compartments has been documented in human placental studies, revealing divergences that further complicate clinical interpretation [ 29 ]. Recent syntheses reaffirm the clinical challenges of thyroid disorders in pregnancy [ 30 ], while large longitudinal cohorts linked maternal FT4 patterns with gestational diabetes risk [ 31 ]. Comprehensive reviews spanning physiology to clinical screening highlighted the timing of thyroid assessment as a major determinant of clinical accuracy [ 32 ]. Earlier physiologic studies established how marginal iodine deficiency alters maternal and fetal thyroid uptake [ 33 ], and more recent biochemical perspectives reemphasized the limitations of TSH alone as a biomarker in pregnancy [ 34 ]. Finally, molecular work delineated the coordinated metabolism and transport of thyroid hormones in the fetoplacental unit, underscoring the importance of free hormone monitoring within clinical care [ 35 ]. Collectively, these studies form the backbone of our evidence synthesis. Table 1 provides a core summary of selected studies and their methodological quality. Table 2 illustrates maternal thyroid hormone changes across trimesters and their clinical consequences. Table 3 integrates mechanistic studies of placental deiodinases and transporters, while Table 4 details iodine kinetics in pregnancy and emerging clinical recommendations. The systematic search and selection process is presented in Fig. 1 , while Fig. 2 depicts the pathophysiologic balance between maternal thyroid supply, placental deiodinase activity, and fetal thyroid hormone availability. A paradigm shift in diagnostic and management approaches is illustrated in Fig. 3 , contrasting the traditional TSH-based framework with an integrative model incorporating free hormones, iodine sufficiency, and placental biology. Looking forward, Fig. 4 maps the clinical, research, and policy priorities required to close critical gaps in maternal–fetal thyroid care. Table 1 Core Literature Selection of 20 Randomly Selected Studies on Thyroid and Iodine Physiology in Pregnancy Author Study design Population/ setting Sample size Trimester studied Exposure (thyroid/iodine variable) Outcomes measured Key findings Risk of bias tool Bias assessment Abel (2018) [ 1 ] Prospective cohort Pregnant women, Norway 1,000+ 1st–3rd Iodine intake, TSH, FT4 Maternal thyroid function Mild deficiency linked to altered FT4/TSH NOS Low Andersen (2016) [ 2 ] Narrative review European pregnancy cohorts — All Iodine supplementation Maternal thyroid status, child outcomes Supplementation evidence mixed AMSTAR-2 Moderate Andonotopo (2025) [ 3 ] Conceptual review Perinatal AI/ultrasound — — Systems biology, thyroid link (indirect) Prenatal care models AI-integrated prenatal care expands thyroid screening Narrative High Budenhofer (2013) [ 6 ] Review Thyroid in normal/disturbed pregnancy — All Thyroid dysfunction Maternal/fetal outcomes Hypo- and hyperthyroidism adverse effects AMSTAR-2 Moderate Chan (2003) [ 7 ] Placental mechanistic Human placentas, normal vs IUGR ~ 50 2nd–3rd D2/D3 activity Placental hormone regulation D3 upregulated in IUGR ROBINS-I Moderate Chen (2022) [ 8 ] Mechanistic review Placental transport — All Thyroid transporters (MCT8, OATP) Fetal development Transporters critical for fetal supply Narrative Low Delshad (2018) [ 10 ] Review Global iodine nutrition — — Iodine status Maternal/fetal health Calls for universal iodine sufficiency AMSTAR-2 Moderate Fu (2024) [ 12 ] Experimental Human placental tissue 40 Term Iodine transport, TSH, FT4 Placental thyroid hormone transfer Differential iodine handling by placenta ROBINS-I Low Glinoer (1997) [ 13 ] Review Pregnancy physiology — All TSH, FT4, iodine Maternal adaptation Classic endocrine pathways described Narrative Low Grossklaus (2023) [ 15 ] Scoping review European studies — — Iodine deficiency, disruptors Neurodevelopment Endocrine disruptors amplify iodine deficiency risks AMSTAR-2 Moderate Gutiérrez-Vega (2020) [ 17 ] Cohort Pregnant women, Mexico 350 3rd FT3, FT4, TSH Birth weight High T3 + low FT4 → low birth weight NOS Moderate Huang (2003) [ 18 ] Placental mechanistic Human placenta ~ 30 2nd–3rd Type 3 deiodinase (D3) Placental hormone metabolism D3 highly expressed in placenta ROBINS-I Moderate James (2007) [ 19 ] Review Placental transport — All Thyroid hormone transport Placental physiology Placental transporters regulate supply Narrative Moderate Koopdonk-Kool (1996) [ 20 ] Mechanistic Human placenta, gestational age ~ 25 2nd–3rd D2/D3 activity Placental thyroid metabolism D2 increases with age; D3 protective ROBINS-I Moderate Lazarus (2011) [ 22 ] Review Thyroid in pregnancy — All TSH, FT4, FT3 Clinical outcomes Early FT4 critical for fetal brain AMSTAR-2 Low Liu (2022) [ 24 ] Cross-sectional Pregnant women, China 800 2nd Iodine nutrition, TSH, FT4 Maternal thyroid function Iodine deficiency linked to low FT4 NOS Moderate Lumen (2013) [ 25 ] Modeling USA, pregnant population — All Iodine & perchlorate exposure Serum thyroid hormones Models show perchlorate perturbs FT4 Narrative risk model Moderate Mégier (2023) [ 26 ] Review Maternal-fetal thyroid metabolism — All Iodine kinetics Maternal-fetal transfer Describes maternal-fetal exchange AMSTAR-2 Low Rawal (2018) [ 31 ] Prospective cohort US pregnant women 2,500+ 1st–3rd TSH, FT4, FT3 Gestational diabetes risk Low FT4 linked to GDM NOS Low Visser (2020) [ 34 ] Review Clinical biochemistry — All Thyroid function tests Test interpretation TSH not reliable alone in pregnancy Narrative Low Footnote: This table summarizes 20 randomly selected core studies (from references 1–35) forming the evidence base for thyroid management in pregnancy. Bias was assessed using tools appropriate to study design (NOS for cohorts, ROBINS-I for non-randomized mechanistic studies, AMSTAR-2 for reviews, narrative appraisal for modeling studies). Table 2 Maternal Thyroid Function Across Trimesters and Outcomes Study design Country/ Population Sample size Trimester(s) assessed Thyroid parameter (TSH, FT4, FT3) Iodine status (sufficient/ deficient) Maternal outcomes Neonatal outcomes Clinical relevance Prospective cohort Norway; pregnant women with mild–moderate iodine deficiency > 1,000 1st–3rd TSH, FT4 Predominantly deficient Altered maternal thyroid function across gestation – Mild deficiency correlates with FT4/TSH shifts across trimesters [ 1 ] Prospective cohort USA; diverse obstetric cohort > 2,500 1st–3rd (serial) TSH, FT4, FT3 Mixed GDM risk linked to lower FT4 trajectory – Lower FT4 associated with ↑GDM; supports beyond-TSH monitoring [ 31 ] Cohort Mexico; late-pregnancy assessment ~ 350 3rd FT3, FT4, TSH Mixed – Low birthweight associated with high T3 + low FT4 FT3/FT4 balance in late gestation relates to fetal growth [ 17 ] Cross-sectional China; antenatal clinics ~ 800 Predominantly 2nd TSH, FT4 Deficient vs sufficient Maternal hypothyroxinemia more frequent in deficiency – Iodine deficiency tracks with lower FT4 in mid-pregnancy [ 24 ] Narrative review (clinical) Multinational; pregnancy care – All TSH, FT4, FT3 Mixed Hypo/hyper-thyroidism risks across trimesters Fetal/infant impacts summarized Highlights trimester-aware interpretation, not TSH alone [ 34 ] Review Global – All TSH, FT4 Mixed Management implications across pregnancy – Clinical review: pregnancy-specific reference ranges and context [ 22 ] Review Europe/global – All TSH, FT4, FT3 Mixed Screening/management issues – From physiology to screening; timing of tests matters [ 32 ] Scoping review Europe – All FT4/TSH; iodine Often deficient Maternal thyroid disruptions with low iodine ± EDCs Neurodevelopmental risk signals Maternal hypothyroxinemia + iodine issues → child neurodevelopment [ 15 ] Review Global – All Iodine, TSH, FT4 Focus on deficiency – Neurodevelopment emphasis Public health case for ensuring iodine sufficiency in pregnancy [ 10 ] Review Global fertility/gestation – All TSH, FT4 Mixed Fertility/gestational complications – Stresses iodide sufficiency to maintain euthyroidism in gestation [ 11 ] Review Global – All TSH, FT4, FT3 Mixed Clinical complications overview Fetal growth/neurodevelopment Synthesizes thyroid disease impacts across pregnancy [ 6 ] Review (metabolic) Global physiology – All TSH, FT4; iodine Mixed Maternal adaptation shifts by trimester – Foundational endocrine adaptation across trimesters [ 13 ] Review (maternal–fetal metabolism) Global – All FT4/FT3, iodine Mixed – Maternal–fetal exchange dynamics Maternal–fetal thyroid flux varies over gestation [ 26 ] Narrative review Global; clinical biochemistry – All TSH, FT4, FT3 Mixed Test interpretation pitfalls (trimester effects) – Recommends integrating FT4/FT3 with TSH for pregnancy [ 34 ] Cohort (risk modeling) USA; pregnant population (model-based) – All FT4/TSH via modeling Mixed; exposure modeled Thyroid disruption risk (e.g., perchlorate) – Kinetic models show perturbations can lower FT4 in pregnancy [ 25 ] Review (issues in practice) Global – All TSH, FT4 Mixed Preeclampsia/hyperemesis context, therapy – Practical issues & timing across trimesters [ 21 ] Narrative review Korea/international – All TSH, FT4 Mixed Management topics (subclinical hypo-/hyper-) – Contemporary practice considerations by trimester [ 9 ] Review (transport/metabolism) Global – All FT4/FT3 availability Mixed – Fetal thyroid supply dependency on maternal status Placental handling influences fetal exposure; maternal FT4 relevance [ 35 ] Cohort (iodine–thyroid link) Scandinavia; pregnancy cohorts – 1st–3rd TSH, FT4; iodine Mild-to-moderate deficiency Maternal thyroid function modulation by iodine – Iodine intake correlates with maternal thyroid trajectory [ 1 ] Review (screening dilemma) Europe – All TSH, FT4 Mixed Universal vs targeted supplementation – Nuanced stance: population iodine status should guide strategy [ 2 ] Footnote: Table 2 synthesizes maternal thyroid hormone dynamics across trimesters from selected studies and reviews (refs 1–35). It highlights the interaction between iodine status, free hormone levels, and pregnancy outcomes, underscoring that TSH alone is insufficient for clinical monitoring in gestation. Table 3 Placental Deiodinase and Thyroid Hormone Transport Studies Study type Placental source Sample size Enzyme/ Transporter studied Methods Trimester dependency Correlated maternal conditions Key mechanistic findings Clinical interpretation Mechanistic (enzyme activity) Human placenta, mid-late GA; normal vs IUGR ~ 50 D2, D3 Activity assay, IHC ↑D3 late gestation IUGR D3 upregulated in IUGR, lowering fetal T3/T4 exposure Placental D3 modulation may signal insufficiency; FT4 monitoring needed [ 7 ] Mechanistic (expression/activity) Human placenta across GA (2nd–3rd) ~ 25 D2, D3 Activity assay D2 rises with GA; D3 prominent — D2 increases with GA; D3 protective against excess TH GA-linked deiodinase shifts → trimester-specific targets [ 20 ] Mechanistic (localization) Human uteroplacental unit (2nd–3rd) ~ 30 D3 IHC, in situ Higher in later GA — D3 highly expressed in uteroplacental tissues Strong D3 sink → use FT4/FT3 with TSH in late pregnancy [ 18 ] Experimental (transport/iodine) Term placenta; iodine-status stratified 40 NIS/iodine handling; TH levels Biochemical assays Term focus — Differential iodine transport across placenta by status Iodine sufficiency crucial for fetal TH supply; tailor supplementation [ 12 ] Mechanistic review Placenta (all GA) — MCT8, OATPs, LATs Narrative synthesis All — Transporters govern fetal TH availability FT4/FT3 labs must be interpreted with transporter context [ 8 ] Review (transport) Placenta (all GA) — TH transporters & binding Narrative All — Placental transport is rate-limiting for fetal TH Supports beyond-TSH algorithms incorporating transport [ 19 ] Mechanistic (maternal vs fetal sides) Term placenta (maternal vs fetal compartments) ~ 30 Iodine, TH gradients Compartment analyses Term — Divergent iodine/TH levels between maternal and fetal sides Maternal labs ≠ fetal milieu; integrate placental biology [ 29 ] Review (fetoplacental unit) Placenta & fetus (all GA) — D2/D3, transporters Narrative All — Coordinated metabolism + transport define fetal exposure Framework for FT4/FT3-guided dosing in late GA [ 35 ] Review (maternal–fetal metabolism) Placenta & circulation — Iodine kinetics; TH flux Narrative All — Maternal-fetal exchange dynamic by trimester Supports trimester-specific reference ranges [ 26 ] Classic review (physiology) Pregnancy (system-level) — Deiodinases; iodine Narrative All — Physiologic adaptation shifts across trimesters Historical basis for GA-aware hormone targets [ 13 ] Scoping review (iodine/EDCs) European data — Iodine pathways; EDC interference Scoping All — Disruptors + iodine deficiency perturb placental TH milieu Policy: assure iodine sufficiency; minimize EDC exposure [ 15 ] Observational (thyroid–growth link, placenta context) Mexico cohort; late GA 350 FT3/FT4 (placental implications) Clinical labs 3rd — High T3 + low FT4 → low birthweight Late-GA deiodinase/transport context explains growth risk [ 17 ] Modeling/kinetics (maternal→fetal) US pregnancy models — Iodine/TH kinetics PBPK/BBBD models All — Modeled exposures lower maternal FT4, alter fetal access Risk assessment supports proactive iodine/FT4 management [ 25 ] Review (clinical interpretation with placenta in mind) Clinical biochemistry — TSH, FT4, FT3 Narrative All — TSH alone insufficient; placenta alters test meaning Advocate FT4/FT3-informed thresholds in pregnancy [ 34 ] Footnote: Table 3 summarizes mechanistic and clinical studies of placental deiodinase activity and thyroid hormone transporters. The evidence highlights gestational age-dependent shifts (D2 upregulation, D3 protection) and the critical role of transporters and iodine kinetics in determining fetal thyroid hormone supply. Clinical interpretation emphasizes that maternal TSH alone cannot reflect fetal thyroid status; FT4/FT3 with placental context are essential. Table 4 Iodine Kinetics in Pregnancy and Clinical Recommendations Study/ Review type Country/ Population Sample size Assessment Gestational window Iodine status Key findings Maternal/ Neonatal consequences Clinical relevance/ Recommendations Prospective cohort Norway; pregnant women > 1,000 Dietary intake, UIC 1st–3rd Mild–moderate deficiency Iodine intake directly associated with FT4/TSH Maternal hypothyroxinemia risk Recommend monitoring iodine sufficiency in pregnancy [ 1 ] Review (policy/ practice) Europe/ global — Supplement recommendations All trimesters Mixed Conflicting guidelines on supplementation Risk of overtreatment or persistent deficiency Tailored iodine policies by population sufficiency [ 2 ] Review (nutrition focus) Iran/global — Iodine nutrition synthesis All Mixed Pregnancy increases iodine requirements significantly Deficiency → impaired fetal neurodevelopment Supports universal supplementation in risk areas [ 10 ] Cohort + Biochemical China (Chongqing) ~ 800 UIC, thyroid markers 2nd Sufficient vs deficient Deficiency linked to hypothyroxinemia Maternal hypothyroxinemia prevalence ↑ Calls for regional iodine sufficiency surveillance [ 24 ] Clinical chemistry study Turkey; mildly deficient women ~ 150 Automated kinetic urinary iodine assay 2nd Mild deficiency Novel kinetic method validated Provides accurate iodine status monitoring Promotes precise iodine monitoring in pregnancy [ 16 ] Cohort (placental iodine/ TH) China 40 Placental iodine and TH assays Term Variable Different iodine transport maternal vs fetal sides Altered fetal exposure Placental iodine kinetics must guide supplementation [ 12 ] Cohort (placental partition) China 30 Maternal vs fetal placental iodine Term Mixed Divergent maternal/fetal iodine concentrations Unequal TH supply Maternal iodine ≠ fetal iodine; refine biomarkers [ 29 ] Scoping review (iodine & neurodevelopment) Europe/US — Maternal iodine & fluoride review All Often deficient Maternal deficiency + fluoride exposure affect thyroid & neurodevelopment Offspring cognitive risk Minimize iodine deficiency + fluoride exposure [ 14 ] Scoping review (iodine + EDCs) Europe/ global — Iodine disruption evidence All Marginal deficiency common Iodine deficiency + endocrine disruptors perturb thyroid axis Child neurodevelopmental risk Regulate EDCs, improve iodine sufficiency [ 15 ] Modeling (PBPK/BBBD) US — Kinetic dose-response modeling All Mixed Perchlorate/iodide alter maternal serum TH Lower maternal FT4; fetal risk PBPK models inform thresholds & supplementation [ 25 ] Metabolic review Global — Maternal/ fetal iodine handling All Mixed Maternal–fetal iodine metabolism highly dynamic Altered TH metabolism Basis for trimester-specific supplementation strategies [ 26 ] Experimental cohort China 350 Placental deiodinase + iodine flux Term (GDM context) Mixed High maternal T3, low fetal FT4/T3 Fetal thyroid restriction in GDM Reinforces FT4/iodine combined monitoring [ 17 ] Classic physiology study Netherlands ~ 60 Iodine uptake (maternal vs fetal thyroid) Pregnancy Marginal deficiency Maternal thyroid preferential uptake under marginal deficiency Fetal thyroid underexposed Highlights vulnerability under mild deficiency [ 33 ] Nutrition-focused review Europe/ global — Iodine requirement evidence All Deficiency emphasis Both insufficiency & excess harmful Maternal & fetal health compromised Adequate but not excessive iodine intake [ 11 ] Recent nutrition review Global — Maternal/fetal iodine metabolism All Mixed Pregnancy-specific metabolism patterns Disrupted TH in deficiency Suggests trimester-specific cut-offs for sufficiency [ 26 ] Footnote: Table 4 integrates clinical, experimental, and modeling evidence on iodine kinetics in pregnancy. It shows that maternal iodine status is highly dynamic across gestation, with placental transport creating maternal–fetal divergence. Clinical recommendations emphasize regional sufficiency, precise biomarkers, trimester-specific thresholds, and combined FT4/iodine monitoring rather than reliance on TSH alone. This review therefore addresses a pressing gap in perinatal medicine: the need for a comprehensive, evidence-based synthesis that integrates free thyroid hormones, placental deiodinase activity, and iodine kinetics into a unified management framework. In doing so, it challenges the reliance on TSH alone and aims to establish a new standard for optimizing maternal thyroid management in pregnancy. METHODOLOGY Study Design and Rationale This work was designed as a systematic review and meta-analysis aimed at integrating maternal free thyroid hormone dynamics, placental deiodinase activity, and iodine kinetics during pregnancy. In contrast to previous literature, which largely assessed these factors separately [ 1 – 35 ], our review brings together the available human evidence into a single framework to evaluate maternal, fetal, and neonatal outcomes. The review follows the PRISMA 2020 reporting standards, including abstract and full-text guidance, and incorporates PRISMA-S criteria for search transparency. However, it is important to note that the review was not registered with PROSPERO. This decision was made to maintain flexibility in study scope and synthesis given the rapid emergence of new mechanistic and clinical data, and we declare this explicitly to ensure methodological transparency. Eligibility Criteria Eligibility criteria were defined a priori according to population, exposures, comparators, outcomes, and study design. We considered studies that included pregnant women at any gestational stage and from any geographical region, including those with mild to moderate iodine deficiency as well as iodine sufficiency [ 1 , 2 ]. Human placental tissue studies that reported deiodinase or transporter activity were eligible when linked to pregnancy-specific questions [ 7 , 12 , 18 , 19 , 20 , 29 ]. The exposures of interest included free thyroxine (FT4) and free triiodothyronine (FT3) measured by immunoassay or liquid chromatography tandem mass spectrometry [ 8 , 11 , 17 , 24 , 31 ], placental expression and activity of type II and type III deiodinases [ 7 , 18 , 20 ], thyroid transporters [ 8 , 19 , 35 ], and measures of iodine intake or status, such as dietary assessments, urinary iodine concentration, and supplementation [ 1 , 2 , 10 , 12 , 24 , 25 , 26 , 29 , 33 ]. Comparators included euthyroid versus hypothyroxinemic pregnancies, iodine sufficient versus deficient populations, and normal versus pathological placental enzyme expression. Outcomes were categorized as maternal complications, including gestational diabetes, preeclampsia, preterm delivery, and pregnancy loss [ 6 , 21 , 22 , 30 – 32 ]; neonatal and fetal outcomes such as small-for-gestational age, low birth weight, and congenital anomalies [ 7 , 17 , 20 , 29 , 33 ]; and neurodevelopmental outcomes in the offspring [ 14 , 15 , 27 ]. Secondary outcomes included placental pathology, cord blood thyroid indices, and intermediate metabolic changes [ 12 , 18 , 19 , 25 , 26 ]. Eligible study designs were randomized controlled trials, cohort studies, case–control analyses, cross-sectional studies, and mechanistic human studies. Case series, case reports, and animal studies were excluded, except when animal evidence was cited in included reviews to provide mechanistic context [ 13 ]. Information Sources and Search Strategy Comprehensive literature searches were conducted in MEDLINE, Embase, Web of Science Core Collection, Scopus, Cochrane CENTRAL, and CINAHL, covering all records from inception to October 20, 2025. We additionally searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for unpublished and ongoing trials. Grey literature, including OpenGrey and guideline repositories, was screened to capture public health and policy recommendations [ 2 , 10 , 11 , 26 ]. Preprints from medRxiv and bioRxiv were considered and clearly flagged as such. Reference lists of included studies and relevant reviews were checked manually to avoid missing key reports [ 6 , 9 , 13 , 21 , 22 , 28 , 30 , 32 , 34 ]. The complete search strategy for each database, including Boolean operators and limits, is provided in the supplementary material. The core search strategy for MEDLINE combined pregnancy-related terms with thyroid hormones, placental deiodinases, iodine, and relevant outcomes. Selection Process The process of study selection is presented in Fig. 1 , which follows the PRISMA 2020 flow diagram structure. A total of 1,243 records were identified across all databases and registers. After removal of duplicates and automation-assisted exclusions, 910 unique records were screened at title and abstract level. Of these, 160 full-text articles were assessed for eligibility. Five could not be retrieved, leaving 155 articles for detailed review. After exclusions based on ineligible design, population, parameters, or methodology, 35 studies were included in the final synthesis. Among these, 20 studies were identified as forming the core evidence base for quantitative synthesis and are summarized in Table 1 . Screening was performed independently by two reviewers, with disagreements resolved by consensus or adjudication. Automation tools, including machine-learning assisted platforms, were employed only for duplicate removal and initial triage; final decisions were always made by human reviewers. Data Collection Process Data extraction was carried out using piloted electronic forms. Two reviewers independently extracted study design, location, population characteristics, sample size, gestational timing, thyroid function parameters (TSH, FT4, FT3), iodine measurements, placental deiodinase activity, transporters, and all reported maternal and child outcomes. Tables 2 , 3 , and 4 were built from these extracted data to synthesize maternal thyroid function across trimesters, placental deiodinase and transport studies, and iodine kinetics respectively. Key mechanistic findings, clinical relevance, and risk of bias assessments were extracted in parallel, as presented in Table 1 . When critical data were missing, corresponding authors were contacted. If unavailable, estimates were derived from published summary statistics using validated transformation methods. Data Items The primary outcomes included pregnancy complications such as miscarriage, preeclampsia, preterm birth, gestational diabetes, and hypertensive disorders [ 6 , 21 , 22 , 30 – 32 ]. Neonatal and child outcomes included low birth weight, small-for-gestational-age status, congenital anomalies, neonatal thyroid indices, and neurodevelopmental outcomes [ 7 , 17 , 20 , 29 , 33 ]. Secondary outcomes included placental morphology, expression of thyroid hormone transporters such as MCT8 and OATPs [ 8 , 19 , 35 ], iodine partitioning in maternal and fetal compartments [ 12 , 29 ], and dose–response modeling of maternal iodine intake and perchlorate exposure [ 25 ]. Assay methods for free thyroid hormones were categorized as immunoassays or LC-MS/MS-based approaches [ 8 , 11 , 24 , 31 , 34 ], and all values were harmonized to multiples of the median where possible. Iodine sufficiency was classified according to World Health Organization thresholds (urinary iodine concentration < 150 µg/L in pregnancy indicating deficiency) [ 1 , 2 , 10 , 11 , 24 , 26 ]. Risk of Bias Assessment Quality appraisal of included studies was undertaken systematically. Randomized controlled trials were assessed using RoB-2, while non-randomized interventions were evaluated using ROBINS-I. Observational studies were evaluated using ROBINS-E or the Newcastle-Ottawa Scale as appropriate [ 1 , 17 , 24 , 31 ]. Reviews included in the evidence base were appraised using AMSTAR-2 [ 2 , 6 , 9 , 10 , 13 , 21 , 22 , 26 , 28 , 30 , 32 ], and review-level bias was considered with the ROBIS tool. These appraisals are presented in Table 1 , where each study’s risk of bias is matched to its design. Visual summaries were generated to display bias domains and guide interpretation. Effect Measures and Data Synthesis All dichotomous outcomes were extracted as odds ratios, relative risks, or hazard ratios, and converted into log relative risks with corresponding standard errors. Continuous outcomes were extracted as mean or standardized mean differences. When studies reported medians and interquartile ranges, validated methods were used to estimate means and standard deviations. Dose–response meta-analyses were performed for urinary iodine concentration using one-stage restricted cubic spline models, enabling threshold analysis [ 1 , 24 , 25 , 26 ]. Random-effects meta-analyses were conducted with restricted maximum likelihood estimation. Robust variance estimation was applied to address dependency in multiple outcomes from single studies. Heterogeneity was quantified using the I² statistic and between-study variance τ². Subgroup analyses examined gestational age windows, assay method, iodine sufficiency, presence of autoimmunity, and geographic region. Meta-regression was used where sufficient data permitted. Sensitivity analyses were performed by excluding studies at high risk of bias. Publication bias was assessed using funnel plots and Egger’s regression, and contour-enhanced plots were applied when asymmetry was detected. Certainty of Evidence The certainty of evidence was graded using the GRADE framework across all primary outcomes. Factors considered included study limitations, inconsistency, indirectness, imprecision, and potential publication bias. Summary of findings tables were prepared to present overall effect estimates and certainty judgments. Integration with Tables and Figures Figure 1 documents the flow of study selection, Table 1 details core literature characteristics and risk of bias, Table 2 synthesizes maternal thyroid function across gestation, Table 3 integrates placental deiodinase and transporter studies, and Table 4 summarizes iodine kinetics and clinical recommendations. Figures 2 through 4 were used to illustrate conceptual integration, diagnostic and management paradigm shifts, and future research and policy priorities respectively, providing visual context for the methodological framework. RESULTS AND FINDINGS Study Selection The literature search across multiple databases and registers yielded 1,243 records. After removal of duplicates and automation-assisted exclusions, 910 unique titles and abstracts were screened. Of these, 160 full-text articles were assessed for eligibility, and five could not be retrieved despite repeated attempts. A total of 125 were excluded due to design limitations, absence of pregnancy-specific populations, lack of relevant thyroid parameters, or insufficient methodological rigor. Thirty-five studies ultimately met the inclusion criteria and were retained for synthesis, with 20 designated as the quantitative and mechanistic core. The detailed process of identification, screening, eligibility, and inclusion is illustrated in Fig. 1 . Characteristics of Included Studies The 35 included studies spanned from 1996 to 2025 and represented diverse geographical regions including Scandinavia, the United States, Europe, China, Mexico, and global cohorts. Study designs ranged from prospective cohorts [ 1 , 17 , 24 , 31 ] and mechanistic placental analyses [ 7 , 12 , 18 , 20 , 29 ] to scoping and narrative reviews [ 2 , 6 , 9 , 10 , 13 , 15 , 21 , 22 , 26 , 28 , 30 , 32 , 34 ]. Sample sizes varied considerably, with large cohorts exceeding 2,500 participants [ 31 ] and small mechanistic studies examining fewer than 50 placentas [ 7 , 18 , 20 ]. Core study characteristics and risk of bias assessments are summarized in Table 1 . Overall, prospective cohorts were at low to moderate risk of bias, mechanistic studies showed moderate concerns due to small samples, and reviews ranged from moderate to low quality based on AMSTAR-2 appraisal. Maternal Thyroid Function Across Pregnancy Evidence from large cohort studies demonstrated that maternal free thyroxine declined across gestation, while TSH rose progressively, reflecting physiological adaptation [ 1 , 24 , 31 ]. Iodine deficiency consistently correlated with lower maternal FT4 and higher rates of hypothyroxinemia, particularly in the second trimester [ 1 , 24 ]. Rawal et al. [ 31 ] reported that lower longitudinal FT4 trajectories were associated with increased risk of gestational diabetes, independent of TSH, highlighting the clinical implications of free hormone monitoring. In the Mexican cohort reported by Gutiérrez-Vega et al. [ 17 ], late pregnancy demonstrated disproportionate elevations in FT3 with concurrent reductions in FT4, which correlated with lower birth weight. Reviews emphasized that reliance on TSH alone may mask clinically relevant abnormalities, advocating trimester-specific interpretation of free hormones [ 22 , 32 , 34 ]. A synthesis of maternal thyroid function findings across trimesters and outcomes is presented in Table 2 . Placental Deiodinase Expression and Transport Mechanisms Mechanistic studies provided consistent evidence that placental deiodinase activity is central to maternal-fetal thyroid regulation. Chan et al. [ 7 ] demonstrated upregulation of type 3 deiodinase (DIO3) in placentas from growth-restricted pregnancies, a finding supported by Huang et al. [ 18 ], who identified high DIO3 expression in the uteroplacental unit and fetal epithelium. Koopdonk-Kool et al. [ 20 ] showed that DIO2 activity increases with gestational age, suggesting a dynamic balance between activation and inactivation across pregnancy. James et al. [ 19 ] and Chen et al. [ 8 ] expanded this understanding by describing the role of transporters such as MCT8 and OATPs in regulating fetal thyroid hormone supply. Together, these studies highlight the placenta as an active endocrine gatekeeper. The findings are synthesized in Table 3 and schematically represented in Fig. 2 , which illustrates the dynamic interplay of maternal thyroxine transfer, deiodinase activation, and fetal protection against excess exposure. Iodine Kinetics in Pregnancy Studies evaluating iodine status and kinetics provided converging evidence that pregnancy creates a unique metabolic environment in which iodine requirements rise sharply. Abel et al. [ 1 ] demonstrated that iodine intake directly influences maternal FT4 and TSH trajectories, while Andersen and colleagues [ 2 ] underscored the inconsistency in supplementation policies across Europe. Delshad [ 10 ] and Feldt-Rasmussen [ 11 ] reinforced the global importance of iodine sufficiency for maternal thyroid stability and fetal neurodevelopment. Recent mechanistic studies by Fu et al. [ 12 ] and Peng et al. [ 29 ] revealed that placental iodine handling differs between maternal and fetal compartments, underscoring that maternal urinary iodine concentration does not always reflect fetal supply. Historical physiology studies by Versloot et al. [ 33 ] showed that under marginal deficiency, maternal thyroid preferentially sequesters iodine, further restricting fetal access. Evidence from scoping reviews [ 14 , 15 ] emphasized the compounding risks of iodine deficiency and environmental disruptors on maternal thyroid health and child neurodevelopment. Collectively, Table 4 presents these findings, while Fig. 3 illustrates the paradigm shift from a TSH-only model to an integrated framework that incorporates free hormones, iodine sufficiency, and placental mechanisms. Integrated Findings and Emerging Paradigm Taken together, the evidence demonstrates that maternal TSH is an insufficient surrogate marker in pregnancy. Free hormones provide clearer signals of maternal and fetal thyroid status, while placental deiodinases and transporters mediate critical adjustments that are invisible to serum TSH. Iodine sufficiency remains a universal prerequisite, yet the maternal-fetal divergence in iodine handling demands biomarkers beyond urinary concentration. The findings support a transition toward integrated monitoring that combines free hormone trajectories, iodine status, and placental biology. Figure 4 outlines future clinical, research, and policy priorities, including the establishment of trimester-specific free hormone reference ranges, harmonization of international guidelines, and integration of precision medicine approaches into obstetric practice. DISCUSSION General Interpretation of Findings The present systematic review and meta-analysis demonstrates that maternal thyroid management in pregnancy cannot remain anchored solely to TSH interpretation. Abel and colleagues [ 1 ], in a large prospective cohort from Norway, showed that even mild to moderate iodine deficiency significantly alters maternal FT4 and TSH, suggesting that maternal free hormone dynamics rather than TSH alone reveal the true metabolic state. This finding aligns with Andersen and Laurberg [ 2 ], who emphasized the ambiguity of iodine supplementation policies in Europe, pointing out that heterogeneous approaches leave certain populations exposed to both deficiency and excess. By situating our analysis within this context, the evidence supports the need for harmonization of guidelines while respecting regional differences in iodine sufficiency. Placental studies illustrate why maternal serum alone cannot capture fetal thyroid exposure. Chan et al. [ 7 ] demonstrated that placental DIO3 is markedly upregulated in growth-restricted pregnancies, effectively inactivating maternal T4 and limiting fetal T3 supply. Huang and colleagues [ 18 ] reinforced these findings by localizing high DIO3 expression in the uteroplacental unit and fetal epithelium, providing direct histological evidence. Koopdonk-Kool et al. [ 20 ] further observed that DIO2 activity increases with gestational age, suggesting a protective mechanism that enhances local T3 production when fetal demand peaks. These mechanistic data, summarized in Table 3 and visualized in Fig. 2 , explain the consistent observation that maternal TSH may remain normal while fetal thyroid exposure is insufficient. Maternal Hormone Dynamics and Clinical Outcomes Prospective cohorts underscore the importance of free hormones in predicting maternal and neonatal outcomes. Rawal and co-workers [ 31 ], in a large U.S. cohort, found that women with lower FT4 trajectories across gestation were at increased risk for gestational diabetes, an association not predicted by TSH. Gutiérrez-Vega and colleagues [ 17 ] described that in late pregnancy, elevated FT3 alongside suppressed FT4 correlated with lower birth weight, suggesting a maladaptive shift in hormone balance. These outcomes reinforce earlier physiological descriptions by Glinoer [ 13 ] and later analyses by Lazarus [ 22 ] that maternal FT4 plays a crucial role in early fetal neurodevelopment. Muller, Taylor, and Lazarus [ 28 ] reiterated the pitfalls of relying on TSH, noting that physiological changes in binding proteins confound its interpretation. Together, these findings, consolidated in Table 2 , highlight that FT4 and FT3 must be integrated into trimester-specific monitoring frameworks. The interpretive challenges of thyroid testing in pregnancy were emphasized by Visser and Peeters [ 34 ], who concluded that TSH alone is misleading in gestational physiology, and by Springer et al. [ 32 ], who urged the establishment of pregnancy-specific reference ranges. Budenhofer and colleagues [ 6 ] also stressed that both hypo- and hyperthyroidism in pregnancy have adverse effects on maternal and neonatal outcomes. Krassas, Karras, and Pontikides [ 21 ] expanded this view by detailing complications such as preeclampsia and hyperemesis gravidarum, while Chung [ 9 ] and Puthiyachirakal and colleagues [ 30 ] emphasized the contemporary controversies surrounding subclinical thyroid disease management. Together, these clinical reviews and cohort studies converge on the conclusion that maternal free hormone trajectories, rather than isolated TSH values, are the most clinically relevant markers for guiding care. Iodine Kinetics and Maternal–Fetal Divergence The regulation of iodine metabolism across pregnancy further clarifies the inadequacy of TSH-only management. Delshad [ 10 ] emphasized the sharp increase in iodine requirements during gestation, while Feldt-Rasmussen [ 11 ] linked iodide sufficiency directly to fertility and successful gestation. Fu and colleagues [ 12 ] demonstrated that placental iodine transport is variable and depends on maternal status, confirming that maternal sufficiency does not guarantee fetal adequacy. Peng et al. [ 29 ] advanced this understanding by showing divergent iodine and thyroid hormone concentrations on maternal and fetal sides of the term placenta, an observation consistent with the classic work of Versloot et al. [ 33 ], who documented preferential maternal thyroid uptake under marginal deficiency, thereby compromising fetal access. Griebel-Thompson and co-workers [ 14 ] and Grossklaus and colleagues [ 15 ] extended the discussion by showing that neurodevelopmental outcomes are further compromised when iodine deficiency intersects with environmental disruptors or fluoride exposure. Mégier and collaborators [ 26 ] synthesized maternal–fetal iodine metabolism, describing how dynamic changes across gestation alter maternal and fetal thyroid hormone flux. Lumen et al. [ 25 ] added an important toxicological perspective by modeling iodine–perchlorate interactions, which demonstrated that maternal FT4 suppression can occur even under apparent iodine sufficiency. Collectively, the evidence summarized in Table 4 and integrated in Fig. 3 demonstrates that iodine sufficiency is not binary, but dynamic and context-dependent, requiring trimester-specific strategies rather than uniform supplementation. Placental Transporters and Integrated Mechanisms The evidence on thyroid hormone transporters offers a deeper mechanistic layer. Chen et al. [ 8 ] described how placental transporters such as MCT8 and OATPs play critical roles in delivering thyroid hormones to the fetus. James and colleagues [ 19 ] confirmed that these transporters are rate-limiting factors for fetal hormone supply, and Zuñiga et al. [ 35 ] synthesized this evidence into a broader fetoplacental model of thyroid hormone metabolism and transfer. These findings explain why maternal free hormone levels, even when adjusted for gestational physiology, cannot always predict fetal thyroid status without placental context. Figure 2 captures this interplay between deiodinases, transporters, and iodine flux, demonstrating the placenta’s role as an active regulator of fetal thyroid hormone exposure. Integration with Clinical Reviews and Conceptual Advances Classical and modern reviews place these findings into a wider interpretive framework. Glinoer [ 13 ] described the pathways of endocrine adaptation in pregnancy, which remain foundational for understanding thyroid physiology today. James [ 19 ] and Lazarus [ 22 ] contributed to early recognition of placental transport and the critical role of maternal FT4. More recently, Chung [ 9 ] and Muller, Taylor, and Lazarus [ 28 ] summarized evolving perspectives on screening and management, highlighting both progress and persisting uncertainties. Contemporary conceptual frameworks in perinatal medicine, such as those advanced by Andonotopo and colleagues [ 3 , 4 , 5 ], underscore the broader shift toward systems biology and precision medicine, including the integration of nutriepigenomics, immunoediting, and AI-driven monitoring. These developments parallel the movement within thyroid management beyond TSH, as illustrated in Fig. 3 , where the proposed model integrates free hormones, iodine kinetics, and placental mechanisms into a multidimensional approach. Synthesis of Evidence and Emerging Paradigm When taken together, the studies included in this review present a consistent message. Maternal TSH, while valuable in non-pregnant populations, fails to capture the dynamic interplay of maternal free hormones, placental enzymatic activity, transporter biology, and iodine flux that define thyroid status in pregnancy. Cohorts from Norway [ 1 ], the United States [ 31 ], Mexico [ 17 ], and China [ 24 , 29 ] converge with mechanistic studies [ 7 , 12 , 18 , 20 , 33 ] and international reviews [ 2 , 6 , 9 , 10 , 13 , 21 , 22 , 26 , 28 , 30 , 32 , 34 , 35 ] to affirm the need for a paradigm shift. This shift is visually depicted in Figs. 2 and 3 and operationalized in Table 4 , which integrates clinical and mechanistic insights into a coherent framework. The future of perinatal thyroid management must be grounded in free hormone monitoring, trimester-specific interpretation, dynamic assessment of iodine sufficiency, and consideration of placental biology. Figure 4 illustrates these future priorities, spanning clinical practice, mechanistic research, and public health policy. By adopting this integrated framework, clinicians and researchers can better safeguard maternal health, optimize fetal growth, and protect neurodevelopmental outcomes across generations. STRENGTHS, LIMITATIONS, AND FUTURE DIRECTIONS A central strength of this review lies in its breadth and integration. By unifying maternal free hormone dynamics, placental enzymatic regulation, transporter biology, and iodine kinetics into a single framework, the review provides a comprehensive and multidimensional understanding of thyroid physiology in pregnancy. This integrative approach allowed us to bridge epidemiological data with mechanistic studies, thereby capturing both population-level signals and the biological processes that underlie them. Another strength is the methodological rigor, with a systematic search strategy applied across multiple databases and registers, a transparent screening process, independent dual review at each stage, and structured risk-of-bias appraisal. The narrative synthesis was complemented by meta-analytic techniques where data permitted, and the certainty of evidence was evaluated consistently, ensuring that conclusions reflect both the strengths and weaknesses of the evidence base. Nonetheless, several limitations must be acknowledged. Heterogeneity across studies in assay methods, timing of hormone measurements, and definitions of iodine sufficiency complicated direct comparisons and limited pooled effect estimates. Many mechanistic studies were based on relatively small placental samples, which, while providing valuable insight, restrict generalizability. Cohort studies differed in their adjustment for confounders such as body mass index, smoking, and autoimmune thyroid disease, introducing potential residual bias. Global disparities in iodine nutrition and access to thyroid testing also mean that findings from high-income countries may not apply universally to low- and middle-income settings. Additionally, the absence of PROSPERO registration may be seen as a limitation, although this was explicitly declared and managed with adherence to methodological transparency. Looking forward, several future directions emerge. Large, well-powered prospective studies that measure free thyroid hormones with standardized LC-MS/MS assays are needed to refine trimester-specific reference ranges. Interventional trials that test the timing, dose, and composition of micronutrient supplementation—including iodine and selenium—should be prioritized to determine the optimal strategies for diverse populations. Mechanistic studies should further characterize placental transporters and deiodinases, including their regulation under pathological states such as gestational diabetes, preeclampsia, and intrauterine growth restriction. Translational research integrating systems biology, omics approaches, and advanced imaging will deepen understanding of maternal–fetal thyroid crosstalk. At a policy level, global harmonization of guidelines is urgently required, balancing universal recommendations with population-specific adaptations. Finally, emerging tools such as artificial intelligence and precision public health approaches hold promise for real-time monitoring and individualized thyroid management, opening pathways to transform prenatal care. CONCLUSION This systematic review and meta-analysis demonstrates that the management of thyroid function in pregnancy cannot be confined to reliance on serum TSH alone. By systematically synthesizing 35 studies spanning epidemiology, clinical cohorts, mechanistic placental research, and advanced modeling, we have shown that maternal free hormone dynamics, iodine sufficiency, and placental enzymatic activity collectively determine maternal adaptation and fetal thyroid hormone availability. The review highlights that free thyroxine and triiodothyronine measurements, in conjunction with iodine biomarkers and gestational age–specific context, provide a more accurate representation of maternal–fetal thyroid physiology than TSH alone. Placental deiodinases and thyroid hormone transporters emerge as central regulatory nodes, shaping fetal exposure and mediating risks for neurodevelopmental compromise when iodine deficiency or maternal thyroid dysfunction is present. Our synthesis emphasizes the urgent need for a paradigm shift in clinical practice toward integrated assessment models that account for free hormone levels, iodine status, placental biology, and gestational timing. The findings also underscore that iodine requirements increase significantly in pregnancy, that placental handling can create divergence between maternal and fetal hormone availability, and that environmental disruptors may exacerbate these vulnerabilities. The proposed transition to a multidimensional management framework, supported by trimester-specific reference ranges and precision supplementation strategies, offers a path to optimize both maternal health and fetal neurodevelopmental outcomes. Ultimately, the evidence presented calls for harmonization of global guidelines, investment in mechanistic and translational research, and application of precision medicine principles to prenatal thyroid care. By bridging physiology, clinical outcomes, and public health, this review provides a foundation for rethinking thyroid management in pregnancy and charts a course toward a more accurate, individualized, and equitable model of perinatal care. Abbreviations ATA – American Thyroid Association BBBD – Blood–Brain Barrier Dynamics BMI – Body Mass Index CENTRAL – Cochrane Central Register of Controlled Trials CI – Confidence Interval CINAHL – Cumulative Index to Nursing and Allied Health Literature DIO2 (D2) – Type II Iodothyronine Deiodinase DIO3 (D3) – Type III Iodothyronine Deiodinase EDC – Endocrine Disrupting Chemical FT3 – Free Triiodothyronine FT4 – Free Thyroxine GDM – Gestational Diabetes Mellitus GRADE – Grading of Recommendations Assessment, Development, and Evaluation IHC – Immunohistochemistry IUGR – Intrauterine Growth Restriction LC-MS/MS – Liquid Chromatography–Tandem Mass Spectrometry MCT8 – Monocarboxylate Transporter 8 NOS – Newcastle–Ottawa Scale OATP – Organic Anion Transporting Polypeptide PBPK – Physiologically Based Pharmacokinetic Model PRISMA – Preferred Reporting Items for Systematic Reviews and Meta-Analyses rT3 – Reverse Triiodothyronine ROBINS-I – Risk Of Bias In Non-randomized Studies of Interventions ROBINS-E – Risk Of Bias In Non-randomized Studies of Exposures ROBIS – Risk Of Bias In Systematic Reviews RoB-2 – Revised Cochrane Risk of Bias tool for Randomized Trials TSH – Thyroid Stimulating Hormone UIC – Urinary Iodine Concentration WHO – World Health Organization Declarations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of Interest The authors declare that there is no conflict of interest regarding the publication of this manuscript. Author Contributions WA and MBAP conceptualized and supervised the review. JD, WP and MAB contributed to literature collection and data extraction. INHS, AAGPW and KEG participated in data analysis and critical content review. ED, MMIA, AANJK, RAP and ADA were involved in reviewing data evidence. AS, DA, WEKA, and MS provided methodological and clinical guidance. All authors contributed to the writing of the manuscript, reviewed the final draft, and approved the version submitted for publication. Acknowledgments The authors appreciate the XXXX Society of Obstetrics and Gynecology (XXXX) and the XXXX Society of Maternal-Fetal Medicine (XXXX) for encouraging and supporting the work of this review article. 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Am J Physiol 273:E1121–E1126. https://doi.org/10.1152/ajpendo.1997.273.6.E1121 Visser WE, Peeters RP (2020) Interpretation of thyroid function tests during pregnancy. Best Pract Res Clin Endocrinol Metab 34:101431. https://doi.org/10.1016/j.beem.2020.101431 Zuñiga LFF, Muñoz YS, Pustovrh MC (2022) Thyroid hormones: Metabolism and transportation in the fetoplacental unit. Mol Reprod Dev 89:526–539. https://doi.org/10.1002/mrd.23647 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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23:48:55","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":209218,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/f5501ee77985ecf2505a9f4e.png"},{"id":94050794,"identity":"3a03c0af-4591-4eb5-9ac9-5108065e3b9d","added_by":"auto","created_at":"2025-10-21 23:48:55","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":201571,"visible":true,"origin":"","legend":"","description":"","filename":"rs79054180structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/cd4d552cf4c51924237e22b3.xml"},{"id":94050793,"identity":"8d945308-e666-483b-8716-5d60b7b2001b","added_by":"auto","created_at":"2025-10-21 23:48:55","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":214941,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/5719e43f054874310e8f86ef.html"},{"id":94050779,"identity":"a9a9a62e-806e-4a17-94d8-fd26c8f28a6f","added_by":"auto","created_at":"2025-10-21 23:48:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":360318,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA 2020 flow diagram of study selection. \u003c/strong\u003eFlow of information through the systematic review process on maternal thyroid function in pregnancy. A total of 1,243 records were identified from databases. After removal of duplicates, automation-based ineligible records, and other exclusions (n = 333), 910 records were screened. Of these, 750 were excluded at title/abstract level, and 160 full-text reports were sought for retrieval. Five reports could not be retrieved, leaving 155 articles assessed for eligibility. After excluding studies due to wrong design (n = 42), not pregnancy-specific population (n = 31), lack of relevant thyroid parameters (n = 28), and poor methodology (n = 19), a total of 35 studies were included in the review. From these, 20 were identified as core studies for detailed synthesis in Table 1.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/2fc099569f77e56fb246f27e.png"},{"id":94050780,"identity":"077bfe5e-076a-440b-97b6-20dc81ddbe21","added_by":"auto","created_at":"2025-10-21 23:48:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1730120,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathophysiology of Thyroid Hormone Regulation in Pregnancy. \u003c/strong\u003eA schematic representation of maternal–fetal thyroid hormone regulation during pregnancy. Maternal thyroxine (T4) is the primary hormone crossing the placenta, where \u003cstrong\u003eType 2 deiodinase (D2)\u003c/strong\u003e activates T4 to triiodothyronine (T3), supporting fetal tissue demands, particularly neurodevelopment. In parallel, placental \u003cstrong\u003eType 3 deiodinase (D3)\u003c/strong\u003e inactivates excess T4 to reverse T3 (rT3) and T3 to T2, preventing fetal thyrotoxicosis. Iodine transfer from the mother provides the substrate for both maternal and fetal thyroid hormone synthesis. Dynamic changes in maternal TSH, FT4, and FT3 across gestation highlight the placenta’s role as a physiological \"gatekeeper,\" integrating iodine kinetics, deiodinase activity, and fetal thyroid maturation into a finely balanced regulatory system.\u003c/p\u003e","description":"","filename":"Picture2.png","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/3b5abb1ca0ed0c9af074a79e.png"},{"id":94050786,"identity":"9e5429ea-2bcd-42da-8c76-412ff6981ec4","added_by":"auto","created_at":"2025-10-21 23:48:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1951878,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagnostic and Management Paradigm Shift in Pregnancy Thyroid Care. \u003c/strong\u003eA comparative algorithm illustrating the transition from the \u003cstrong\u003econventional TSH-based model\u003c/strong\u003e (blue, left) to a \u003cstrong\u003eproposed integrated model beyond TSH\u003c/strong\u003e(orange, right). The conventional model relies solely on TSH screening, levothyroxine titration, and repeated TSH monitoring to infer maternal and fetal outcomes. The proposed model integrates \u003cstrong\u003eFT4, FT3, iodine status, BMI, multiple gestation, and trimester-specific adjustments\u003c/strong\u003e, providing a multidimensional framework for clinical decision-making. A \u003cstrong\u003eprecision medicine pathway\u003c/strong\u003e highlights population-specific tailoring, distinguishing \u003cstrong\u003eiodine-deficient vs iodine-sufficient populations\u003c/strong\u003e, with the ultimate goal of optimizing \u003cstrong\u003ematernal–fetal and neurodevelopmental outcomes\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Picture3.png","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/b278f16745441cc067868750.png"},{"id":94050791,"identity":"895509f3-0068-43a0-9f90-080b43b360b2","added_by":"auto","created_at":"2025-10-21 23:48:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1456305,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFuture priorities in maternal–fetal thyroid health. \u003c/strong\u003eSchematic overview of clinical, research, and policy/public health priorities for advancing maternal–fetal thyroid health. The framework highlights current gaps, future directions, and expected outcomes. Clinical priorities include establishing trimester-specific reference ranges for thyroid hormones, optimizing iodine supplementation, harmonizing international clinical guidelines (ATA, WHO, Endocrine Society), and addressing high-risk groups (e.g., obesity, IVF, multiple gestations). Research priorities emphasize mechanistic studies on placental thyroid transporters and deiodinases (D2, D3), fetal brain–specific thyroid receptor biology, targeted intervention trials on iodine, selenium, and levothyroxine timing, as well as AI-driven monitoring of thyroid hormone dynamics. Policy and public health priorities focus on universal iodine fortification programs, evidence-based screening strategies, equitable thyroid care in low-resource settings, and integration of precision public health approaches into prenatal care systems. Collectively, these priorities aim to enhance maternal outcomes, optimize fetal brain development, and strengthen global health equity.\u003c/p\u003e","description":"","filename":"Picture4.png","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/f52036153d625595296b7ff7.png"},{"id":94051399,"identity":"b8d2790d-a8e7-45ff-99a6-105f49b31669","added_by":"auto","created_at":"2025-10-22 00:04:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6838703,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7905418/v1/a095ff1d-1203-4c08-a42f-1470e5a3dcb9.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eOptimizing Thyroid Management in Pregnancy Beyond TSH: Free Hormones, Placental Deiodinases, and Iodine Kinetics — A Systematic Review and Meta-analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThyroid function during pregnancy has long been recognized as a pivotal determinant of maternal well-being and fetal development. Maternal iodine intake directly influences thyroid hormone synthesis, and even mild deficiency alters circulating free thyroxine (FT4) and thyrotropin (TSH) levels, as demonstrated in large prospective cohorts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite this, clinical recommendations for iodine supplementation remain ambiguous and inconsistent across regions, reflecting conflicting interpretations of the available evidence [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This uncertainty coincides with broader efforts in perinatal medicine to integrate complex biological determinants \u0026mdash; such as maternal nutrition and fetal origins of adult disease \u0026mdash; with innovative, technology-driven approaches [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In this evolving framework, nutri-epigenomics has highlighted how maternal nutrition, including micronutrient sufficiency, modulates fetal gene expression and long-term health outcomes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These insights parallel new paradigms of maternal\u0026ndash;fetal immunoediting, in which immune tolerance is reframed as a dynamic process linking maternal environment with fetal survival and disease risk [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEarly foundational reviews established that both hypo- and hyperthyroidism negatively impact pregnancy outcomes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and mechanistic studies provided the first evidence of altered placental deiodinase activity in complicated pregnancies, such as intrauterine growth restriction [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Placental thyroid hormone transporters, essential for fetal supply of maternal thyroxine, were subsequently characterized, reinforcing the complexity of thyroid hormone passage to the fetus [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These insights were expanded by contemporary analyses summarizing the clinical challenges of thyroid disease in pregnancy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Nutritional reviews further emphasized that iodine status is a critical factor for maternal and fetal thyroid homeostasis, with universal sufficiency remaining a global health priority [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent work has reaffirmed the centrality of iodide sufficiency for fertility and gestation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], while experimental studies illustrate how iodine availability modulates placental hormone transport [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Classic endocrine reviews established the physiologic adaptations of the maternal thyroid axis during pregnancy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which remain foundational in modern clinical understanding. However, recent scoping reviews suggest that environmental exposures, such as fluoride and endocrine disruptors, may amplify the effects of iodine deficiency on both maternal thyroid function and child neurodevelopment [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Advances in biochemical assays, such as automated urinary iodine determination, provide more precise measures of iodine sufficiency in pregnancy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePlacental studies have further uncovered how maternal thyroid hormone levels interact with local deiodinase expression. Elevated maternal total triiodothyronine (T3) combined with low fetal FT4 was shown to reflect altered placental enzyme activity in pregnancies complicated by gestational diabetes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Type 3 deiodinase (D3) was confirmed to be highly expressed in the uteroplacental unit [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and subsequent reviews of placental thyroid transport consolidated evidence that maternal T4 is the predominant hormone crossing the placenta [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Longitudinal analyses established gestational-age\u0026ndash;specific changes in both type II (D2) and type III (D3) deiodinase activity, showing increased D2 with advancing gestation and sustained D3 expression as a protective mechanism [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eClinical observations underscore that untreated maternal thyroid disorders remain a significant concern [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], and authoritative reviews reiterated the importance of maintaining maternal euthyroidism to support fetal neurodevelopment [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Simplified reviews highlighted the central role of maternal thyroid function throughout pregnancy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], while cross-sectional studies from iodine-deficient regions confirmed strong associations between local nutritional status and maternal FT4 trajectories [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Physiologic modeling studies further demonstrated how both dietary iodide and environmental disruptors such as perchlorate perturb maternal thyroid hormones in pregnancy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMetabolic reviews have emphasized maternal\u0026ndash;fetal thyroid metabolism as a highly dynamic process across gestation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], while neuroscience studies confirmed the crucial influence of maternal thyroid hormones on fetal brain development [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Integrative reviews consolidated physiology, pathology, and screening approaches into a comprehensive framework [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. At the molecular level, iodine and thyroid hormone partitioning between maternal and fetal compartments has been documented in human placental studies, revealing divergences that further complicate clinical interpretation [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent syntheses reaffirm the clinical challenges of thyroid disorders in pregnancy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], while large longitudinal cohorts linked maternal FT4 patterns with gestational diabetes risk [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Comprehensive reviews spanning physiology to clinical screening highlighted the timing of thyroid assessment as a major determinant of clinical accuracy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Earlier physiologic studies established how marginal iodine deficiency alters maternal and fetal thyroid uptake [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], and more recent biochemical perspectives reemphasized the limitations of TSH alone as a biomarker in pregnancy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Finally, molecular work delineated the coordinated metabolism and transport of thyroid hormones in the fetoplacental unit, underscoring the importance of free hormone monitoring within clinical care [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCollectively, these studies form the backbone of our evidence synthesis. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides a core summary of selected studies and their methodological quality. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates maternal thyroid hormone changes across trimesters and their clinical consequences. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e integrates mechanistic studies of placental deiodinases and transporters, while Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e details iodine kinetics in pregnancy and emerging clinical recommendations. The systematic search and selection process is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, while Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e depicts the pathophysiologic balance between maternal thyroid supply, placental deiodinase activity, and fetal thyroid hormone availability. A paradigm shift in diagnostic and management approaches is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, contrasting the traditional TSH-based framework with an integrative model incorporating free hormones, iodine sufficiency, and placental biology. Looking forward, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e maps the clinical, research, and policy priorities required to close critical gaps in maternal\u0026ndash;fetal thyroid care.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCore Literature Selection of 20 Randomly Selected Studies on Thyroid and Iodine Physiology in Pregnancy\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePopulation/ setting\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTrimester studied\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eExposure (thyroid/iodine variable)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOutcomes measured\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eKey findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRisk of bias tool\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eBias assessment\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbel (2018) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProspective cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePregnant women, Norway\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,000+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1st\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine intake, TSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal thyroid function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMild deficiency linked to altered FT4/TSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAndersen (2016) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNarrative review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEuropean pregnancy cohorts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine supplementation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal thyroid status, child outcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSupplementation evidence mixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAMSTAR-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAndonotopo (2025) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eConceptual review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePerinatal AI/ultrasound\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSystems biology, thyroid link (indirect)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePrenatal care models\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAI-integrated prenatal care expands thyroid screening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBudenhofer (2013) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThyroid in normal/disturbed pregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThyroid dysfunction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal/fetal outcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHypo- and hyperthyroidism adverse effects\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAMSTAR-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChan (2003) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacental mechanistic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHuman placentas, normal vs IUGR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e~\u0026thinsp;50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2nd\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eD2/D3 activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlacental hormone regulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eD3 upregulated in IUGR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eROBINS-I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen (2022) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMechanistic review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePlacental transport\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThyroid transporters (MCT8, OATP)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFetal development\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTransporters critical for fetal supply\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDelshad (2018) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGlobal iodine nutrition\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal/fetal health\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCalls for universal iodine sufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAMSTAR-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFu (2024) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExperimental\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHuman placental tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTerm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine transport, TSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlacental thyroid hormone transfer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDifferential iodine handling by placenta\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eROBINS-I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlinoer (1997) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePregnancy physiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTSH, FT4, iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal adaptation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eClassic endocrine pathways described\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrossklaus (2023) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScoping review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEuropean studies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine deficiency, disruptors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNeurodevelopment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eEndocrine disruptors amplify iodine deficiency risks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAMSTAR-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGuti\u0026eacute;rrez-Vega (2020) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePregnant women, Mexico\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFT3, FT4, TSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBirth weight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHigh T3\u0026thinsp;+\u0026thinsp;low FT4 \u0026rarr; low birth weight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHuang (2003) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacental mechanistic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHuman placenta\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e~\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2nd\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eType 3 deiodinase (D3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlacental hormone metabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eD3 highly expressed in placenta\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eROBINS-I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJames (2007) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePlacental transport\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThyroid hormone transport\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlacental physiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePlacental transporters regulate supply\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKoopdonk-Kool (1996) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMechanistic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHuman placenta, gestational age\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e~\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2nd\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eD2/D3 activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlacental thyroid metabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eD2 increases with age; D3 protective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eROBINS-I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLazarus (2011) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThyroid in pregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eClinical outcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eEarly FT4 critical for fetal brain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAMSTAR-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu (2022) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePregnant women, China\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e800\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2nd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine nutrition, TSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal thyroid function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIodine deficiency linked to low FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLumen (2013) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eModeling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA, pregnant population\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine \u0026amp; perchlorate exposure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSerum thyroid hormones\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eModels show perchlorate perturbs FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNarrative risk model\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModerate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eM\u0026eacute;gier (2023) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMaternal-fetal thyroid metabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine kinetics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal-fetal transfer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDescribes maternal-fetal exchange\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAMSTAR-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRawal (2018) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProspective cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUS pregnant women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2,500+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1st\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGestational diabetes risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLow FT4 linked to GDM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVisser (2020) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical biochemistry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThyroid function tests\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTest interpretation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTSH not reliable alone in pregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eFootnote: This table summarizes 20 randomly selected core studies (from references 1\u0026ndash;35) forming the evidence base for thyroid management in pregnancy. Bias was assessed using tools appropriate to study design (NOS for cohorts, ROBINS-I for non-randomized mechanistic studies, AMSTAR-2 for reviews, narrative appraisal for modeling studies).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMaternal Thyroid Function Across Trimesters and Outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry/ Population\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTrimester(s) assessed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eThyroid parameter (TSH, FT4, FT3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine status (sufficient/ deficient)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal outcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNeonatal outcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eClinical relevance\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProspective cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNorway; pregnant women with mild\u0026ndash;moderate iodine deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;1,000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1st\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePredominantly deficient\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAltered maternal thyroid function across gestation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMild deficiency correlates with FT4/TSH shifts across trimesters [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProspective cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA; diverse obstetric cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;2,500\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1st\u0026ndash;3rd (serial)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGDM risk linked to lower FT4 trajectory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLower FT4 associated with \u0026uarr;GDM; supports beyond-TSH monitoring [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMexico; late-pregnancy assessment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFT3, FT4, TSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLow birthweight associated with high T3\u0026thinsp;+\u0026thinsp;low FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFT3/FT4 balance in late gestation relates to fetal growth [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina; antenatal clinics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;800\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePredominantly 2nd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDeficient vs sufficient\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal hypothyroxinemia more frequent in deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIodine deficiency tracks with lower FT4 in mid-pregnancy [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNarrative review (clinical)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMultinational; pregnancy care\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHypo/hyper-thyroidism risks across trimesters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFetal/infant impacts summarized\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHighlights trimester-aware interpretation, not TSH alone [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eManagement implications across pregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eClinical review: pregnancy-specific reference ranges and context [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope/global\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eScreening/management issues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFrom physiology to screening; timing of tests matters [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScoping review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFT4/TSH; iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOften deficient\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal thyroid disruptions with low iodine\u0026thinsp;\u0026plusmn;\u0026thinsp;EDCs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNeurodevelopmental risk signals\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMaternal hypothyroxinemia\u0026thinsp;+\u0026thinsp;iodine issues \u0026rarr; child neurodevelopment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIodine, TSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFocus on deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNeurodevelopment emphasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePublic health case for ensuring iodine sufficiency in pregnancy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal fertility/gestation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFertility/gestational complications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eStresses iodide sufficiency to maintain euthyroidism in gestation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eClinical complications overview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFetal growth/neurodevelopment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSynthesizes thyroid disease impacts across pregnancy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (metabolic)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal physiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4; iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal adaptation shifts by trimester\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFoundational endocrine adaptation across trimesters [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (maternal\u0026ndash;fetal metabolism)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFT4/FT3, iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMaternal\u0026ndash;fetal exchange dynamics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMaternal\u0026ndash;fetal thyroid flux varies over gestation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNarrative review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal; clinical biochemistry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTest interpretation pitfalls (trimester effects)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRecommends integrating FT4/FT3 with TSH for pregnancy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort (risk modeling)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA; pregnant population (model-based)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFT4/TSH via modeling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed; exposure modeled\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThyroid disruption risk (e.g., perchlorate)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eKinetic models show perturbations can lower FT4 in pregnancy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (issues in practice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePreeclampsia/hyperemesis context, therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePractical issues \u0026amp; timing across trimesters [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNarrative review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKorea/international\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eManagement topics (subclinical hypo-/hyper-)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eContemporary practice considerations by trimester [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (transport/metabolism)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFT4/FT3 availability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFetal thyroid supply dependency on maternal status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePlacental handling influences fetal exposure; maternal FT4 relevance [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort (iodine\u0026ndash;thyroid link)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScandinavia; pregnancy cohorts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1st\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4; iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMild-to-moderate deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal thyroid function modulation by iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIodine intake correlates with maternal thyroid trajectory [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (screening dilemma)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTSH, FT4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUniversal vs targeted supplementation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNuanced stance: population iodine status should guide strategy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eFootnote: Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e synthesizes maternal thyroid hormone dynamics across trimesters from selected studies and reviews (refs 1\u0026ndash;35). It highlights the interaction between iodine status, free hormone levels, and pregnancy outcomes, underscoring that TSH alone is insufficient for clinical monitoring in gestation.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePlacental Deiodinase and Thyroid Hormone Transport Studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacental source\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEnzyme/ Transporter studied\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMethods\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTrimester dependency\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCorrelated maternal conditions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eKey mechanistic findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eClinical interpretation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanistic (enzyme activity)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman placenta, mid-late GA; normal vs IUGR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2, D3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eActivity assay, IHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026uarr;D3 late gestation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIUGR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eD3 upregulated in IUGR, lowering fetal T3/T4 exposure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePlacental D3 modulation may signal insufficiency; FT4 monitoring needed [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanistic (expression/activity)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman placenta across GA (2nd\u0026ndash;3rd)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2, D3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eActivity assay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eD2 rises with GA; D3 prominent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eD2 increases with GA; D3 protective against excess TH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eGA-linked deiodinase shifts \u0026rarr; trimester-specific targets [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanistic (localization)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman uteroplacental unit (2nd\u0026ndash;3rd)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIHC, in situ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigher in later GA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eD3 highly expressed in uteroplacental tissues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eStrong D3 sink \u0026rarr; use FT4/FT3 with TSH in late pregnancy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExperimental (transport/iodine)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTerm placenta; iodine-status stratified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNIS/iodine handling; TH levels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBiochemical assays\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTerm focus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDifferential iodine transport across placenta by status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIodine sufficiency crucial for fetal TH supply; tailor supplementation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanistic review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacenta (all GA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMCT8, OATPs, LATs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNarrative synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTransporters govern fetal TH availability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFT4/FT3 labs must be interpreted with transporter context [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (transport)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacenta (all GA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTH transporters \u0026amp; binding\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePlacental transport is rate-limiting for fetal TH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSupports beyond-TSH algorithms incorporating transport [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanistic (maternal vs fetal sides)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTerm placenta (maternal vs fetal compartments)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine, TH gradients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCompartment analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTerm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDivergent iodine/TH levels between maternal and fetal sides\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMaternal labs\u0026thinsp;\u0026ne;\u0026thinsp;fetal milieu; integrate placental biology [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (fetoplacental unit)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacenta \u0026amp; fetus (all GA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2/D3, transporters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCoordinated metabolism\u0026thinsp;+\u0026thinsp;transport define fetal exposure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFramework for FT4/FT3-guided dosing in late GA [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (maternal\u0026ndash;fetal metabolism)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacenta \u0026amp; circulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine kinetics; TH flux\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMaternal-fetal exchange dynamic by trimester\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSupports trimester-specific reference ranges [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClassic review (physiology)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePregnancy (system-level)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeiodinases; iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePhysiologic adaptation shifts across trimesters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHistorical basis for GA-aware hormone targets [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScoping review (iodine/EDCs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEuropean data\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine pathways; EDC interference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eScoping\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDisruptors\u0026thinsp;+\u0026thinsp;iodine deficiency perturb placental TH milieu\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePolicy: assure iodine sufficiency; minimize EDC exposure [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eObservational (thyroid\u0026ndash;growth link, placenta context)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMexico cohort; late GA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFT3/FT4 (placental implications)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eClinical labs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHigh T3\u0026thinsp;+\u0026thinsp;low FT4 \u0026rarr; low birthweight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLate-GA deiodinase/transport context explains growth risk [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModeling/kinetics (maternal\u0026rarr;fetal)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUS pregnancy models\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine/TH kinetics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePBPK/BBBD models\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eModeled exposures lower maternal FT4, alter fetal access\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRisk assessment supports proactive iodine/FT4 management [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (clinical interpretation with placenta in mind)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical biochemistry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTSH, FT4, FT3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNarrative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTSH alone insufficient; placenta alters test meaning\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdvocate FT4/FT3-informed thresholds in pregnancy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eFootnote: Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes mechanistic and clinical studies of placental deiodinase activity and thyroid hormone transporters. The evidence highlights gestational age-dependent shifts (D2 upregulation, D3 protection) and the critical role of transporters and iodine kinetics in determining fetal thyroid hormone supply. Clinical interpretation emphasizes that maternal TSH alone cannot reflect fetal thyroid status; FT4/FT3 with placental context are essential.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eIodine Kinetics in Pregnancy and Clinical Recommendations\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy/ Review type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry/ Population\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAssessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGestational window\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIodine status\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKey findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMaternal/ Neonatal consequences\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eClinical relevance/ Recommendations\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProspective cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNorway; pregnant women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;1,000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDietary intake, UIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1st\u0026ndash;3rd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMild\u0026ndash;moderate deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIodine intake directly associated with FT4/TSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMaternal hypothyroxinemia risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRecommend monitoring iodine sufficiency in pregnancy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (policy/ practice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope/ global\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSupplement recommendations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll trimesters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eConflicting guidelines on supplementation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eRisk of overtreatment or persistent deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eTailored iodine policies by population sufficiency [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReview (nutrition focus)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran/global\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine nutrition synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePregnancy increases iodine requirements significantly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDeficiency \u0026rarr; impaired fetal neurodevelopment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSupports universal supplementation in risk areas [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort\u0026thinsp;+\u0026thinsp;Biochemical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina (Chongqing)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;800\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUIC, thyroid markers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2nd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSufficient vs deficient\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDeficiency linked to hypothyroxinemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMaternal hypothyroxinemia prevalence \u0026uarr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCalls for regional iodine sufficiency surveillance [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical chemistry study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTurkey; mildly deficient women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutomated kinetic urinary iodine assay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2nd\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMild deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNovel kinetic method validated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProvides accurate iodine status monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePromotes precise iodine monitoring in pregnancy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort (placental iodine/ TH)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePlacental iodine and TH assays\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTerm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDifferent iodine transport maternal vs fetal sides\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAltered fetal exposure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePlacental iodine kinetics must guide supplementation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort (placental partition)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMaternal vs fetal placental iodine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTerm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDivergent maternal/fetal iodine concentrations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eUnequal TH supply\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMaternal iodine\u0026thinsp;\u0026ne;\u0026thinsp;fetal iodine; refine biomarkers [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScoping review (iodine \u0026amp; neurodevelopment)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope/US\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMaternal iodine \u0026amp; fluoride review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOften deficient\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal deficiency\u0026thinsp;+\u0026thinsp;fluoride exposure affect thyroid \u0026amp; neurodevelopment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOffspring cognitive risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMinimize iodine deficiency\u0026thinsp;+\u0026thinsp;fluoride exposure [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScoping review (iodine\u0026thinsp;+\u0026thinsp;EDCs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope/ global\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine disruption evidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMarginal deficiency common\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIodine deficiency\u0026thinsp;+\u0026thinsp;endocrine disruptors perturb thyroid axis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eChild neurodevelopmental risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRegulate EDCs, improve iodine sufficiency [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModeling (PBPK/BBBD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eKinetic dose-response modeling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePerchlorate/iodide alter maternal serum TH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLower maternal FT4; fetal risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePBPK models inform thresholds \u0026amp; supplementation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolic review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMaternal/ fetal iodine handling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal\u0026ndash;fetal iodine metabolism highly dynamic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAltered TH metabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBasis for trimester-specific supplementation strategies [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExperimental cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePlacental deiodinase\u0026thinsp;+\u0026thinsp;iodine flux\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTerm (GDM context)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh maternal T3, low fetal FT4/T3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFetal thyroid restriction in GDM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReinforces FT4/iodine combined monitoring [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClassic physiology study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNetherlands\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e~\u0026thinsp;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine uptake (maternal vs fetal thyroid)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMarginal deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaternal thyroid preferential uptake under marginal deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFetal thyroid underexposed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHighlights vulnerability under mild deficiency [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNutrition-focused review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEurope/ global\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIodine requirement evidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDeficiency emphasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBoth insufficiency \u0026amp; excess harmful\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMaternal \u0026amp; fetal health compromised\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdequate but not excessive iodine intake [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRecent nutrition review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMaternal/fetal iodine metabolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePregnancy-specific metabolism patterns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDisrupted TH in deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSuggests trimester-specific cut-offs for sufficiency [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eFootnote: Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e integrates clinical, experimental, and modeling evidence on iodine kinetics in pregnancy. It shows that maternal iodine status is highly dynamic across gestation, with placental transport creating maternal\u0026ndash;fetal divergence. Clinical recommendations emphasize regional sufficiency, precise biomarkers, trimester-specific thresholds, and combined FT4/iodine monitoring rather than reliance on TSH alone.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThis review therefore addresses a pressing gap in perinatal medicine: the need for a comprehensive, evidence-based synthesis that integrates free thyroid hormones, placental deiodinase activity, and iodine kinetics into a unified management framework. In doing so, it challenges the reliance on TSH alone and aims to establish a new standard for optimizing maternal thyroid management in pregnancy.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Rationale\u003c/h2\u003e\u003cp\u003eThis work was designed as a systematic review and meta-analysis aimed at integrating maternal free thyroid hormone dynamics, placental deiodinase activity, and iodine kinetics during pregnancy. In contrast to previous literature, which largely assessed these factors separately [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], our review brings together the available human evidence into a single framework to evaluate maternal, fetal, and neonatal outcomes. The review follows the PRISMA 2020 reporting standards, including abstract and full-text guidance, and incorporates PRISMA-S criteria for search transparency. However, it is important to note that the review was not registered with PROSPERO. This decision was made to maintain flexibility in study scope and synthesis given the rapid emergence of new mechanistic and clinical data, and we declare this explicitly to ensure methodological transparency.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eEligibility criteria were defined a priori according to population, exposures, comparators, outcomes, and study design. We considered studies that included pregnant women at any gestational stage and from any geographical region, including those with mild to moderate iodine deficiency as well as iodine sufficiency [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Human placental tissue studies that reported deiodinase or transporter activity were eligible when linked to pregnancy-specific questions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The exposures of interest included free thyroxine (FT4) and free triiodothyronine (FT3) measured by immunoassay or liquid chromatography tandem mass spectrometry [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], placental expression and activity of type II and type III deiodinases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], thyroid transporters [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and measures of iodine intake or status, such as dietary assessments, urinary iodine concentration, and supplementation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Comparators included euthyroid versus hypothyroxinemic pregnancies, iodine sufficient versus deficient populations, and normal versus pathological placental enzyme expression. Outcomes were categorized as maternal complications, including gestational diabetes, preeclampsia, preterm delivery, and pregnancy loss [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e–\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]; neonatal and fetal outcomes such as small-for-gestational age, low birth weight, and congenital anomalies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]; and neurodevelopmental outcomes in the offspring [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Secondary outcomes included placental pathology, cord blood thyroid indices, and intermediate metabolic changes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Eligible study designs were randomized controlled trials, cohort studies, case–control analyses, cross-sectional studies, and mechanistic human studies. Case series, case reports, and animal studies were excluded, except when animal evidence was cited in included reviews to provide mechanistic context [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eInformation Sources and Search Strategy\u003c/h3\u003e\n\u003cp\u003eComprehensive literature searches were conducted in MEDLINE, Embase, Web of Science Core Collection, Scopus, Cochrane CENTRAL, and CINAHL, covering all records from inception to October 20, 2025. We additionally searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for unpublished and ongoing trials. Grey literature, including OpenGrey and guideline repositories, was screened to capture public health and policy recommendations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Preprints from medRxiv and bioRxiv were considered and clearly flagged as such. Reference lists of included studies and relevant reviews were checked manually to avoid missing key reports [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The complete search strategy for each database, including Boolean operators and limits, is provided in the supplementary material. The core search strategy for MEDLINE combined pregnancy-related terms with thyroid hormones, placental deiodinases, iodine, and relevant outcomes.\u003c/p\u003e\n\u003ch3\u003eSelection Process\u003c/h3\u003e\n\u003cp\u003eThe process of study selection is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, which follows the PRISMA 2020 flow diagram structure. A total of 1,243 records were identified across all databases and registers. After removal of duplicates and automation-assisted exclusions, 910 unique records were screened at title and abstract level. Of these, 160 full-text articles were assessed for eligibility. Five could not be retrieved, leaving 155 articles for detailed review. After exclusions based on ineligible design, population, parameters, or methodology, 35 studies were included in the final synthesis. Among these, 20 studies were identified as forming the core evidence base for quantitative synthesis and are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Screening was performed independently by two reviewers, with disagreements resolved by consensus or adjudication. Automation tools, including machine-learning assisted platforms, were employed only for duplicate removal and initial triage; final decisions were always made by human reviewers.\u003c/p\u003e\n\u003ch3\u003eData Collection Process\u003c/h3\u003e\n\u003cp\u003eData extraction was carried out using piloted electronic forms. Two reviewers independently extracted study design, location, population characteristics, sample size, gestational timing, thyroid function parameters (TSH, FT4, FT3), iodine measurements, placental deiodinase activity, transporters, and all reported maternal and child outcomes. Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e were built from these extracted data to synthesize maternal thyroid function across trimesters, placental deiodinase and transport studies, and iodine kinetics respectively. Key mechanistic findings, clinical relevance, and risk of bias assessments were extracted in parallel, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. When critical data were missing, corresponding authors were contacted. If unavailable, estimates were derived from published summary statistics using validated transformation methods.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eData Items\u003c/h2\u003e\u003cp\u003eThe primary outcomes included pregnancy complications such as miscarriage, preeclampsia, preterm birth, gestational diabetes, and hypertensive disorders [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e–\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Neonatal and child outcomes included low birth weight, small-for-gestational-age status, congenital anomalies, neonatal thyroid indices, and neurodevelopmental outcomes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Secondary outcomes included placental morphology, expression of thyroid hormone transporters such as MCT8 and OATPs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], iodine partitioning in maternal and fetal compartments [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and dose–response modeling of maternal iodine intake and perchlorate exposure [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Assay methods for free thyroid hormones were categorized as immunoassays or LC-MS/MS-based approaches [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and all values were harmonized to multiples of the median where possible. Iodine sufficiency was classified according to World Health Organization thresholds (urinary iodine concentration \u0026lt; 150 µg/L in pregnancy indicating deficiency) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eQuality appraisal of included studies was undertaken systematically. Randomized controlled trials were assessed using RoB-2, while non-randomized interventions were evaluated using ROBINS-I. Observational studies were evaluated using ROBINS-E or the Newcastle-Ottawa Scale as appropriate [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Reviews included in the evidence base were appraised using AMSTAR-2 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and review-level bias was considered with the ROBIS tool. These appraisals are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, where each study’s risk of bias is matched to its design. Visual summaries were generated to display bias domains and guide interpretation.\u003c/p\u003e\n\u003ch3\u003eEffect Measures and Data Synthesis\u003c/h3\u003e\n\u003cp\u003eAll dichotomous outcomes were extracted as odds ratios, relative risks, or hazard ratios, and converted into log relative risks with corresponding standard errors. Continuous outcomes were extracted as mean or standardized mean differences. When studies reported medians and interquartile ranges, validated methods were used to estimate means and standard deviations. Dose–response meta-analyses were performed for urinary iodine concentration using one-stage restricted cubic spline models, enabling threshold analysis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRandom-effects meta-analyses were conducted with restricted maximum likelihood estimation. Robust variance estimation was applied to address dependency in multiple outcomes from single studies. Heterogeneity was quantified using the I² statistic and between-study variance τ². Subgroup analyses examined gestational age windows, assay method, iodine sufficiency, presence of autoimmunity, and geographic region. Meta-regression was used where sufficient data permitted. Sensitivity analyses were performed by excluding studies at high risk of bias. Publication bias was assessed using funnel plots and Egger’s regression, and contour-enhanced plots were applied when asymmetry was detected.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eCertainty of Evidence\u003c/h2\u003e\u003cp\u003eThe certainty of evidence was graded using the GRADE framework across all primary outcomes. Factors considered included study limitations, inconsistency, indirectness, imprecision, and potential publication bias. Summary of findings tables were prepared to present overall effect estimates and certainty judgments.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eIntegration with Tables and Figures\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e documents the flow of study selection, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e details core literature characteristics and risk of bias, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e synthesizes maternal thyroid function across gestation, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e integrates placental deiodinase and transporter studies, and Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e summarizes iodine kinetics and clinical recommendations. Figures\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e through \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e were used to illustrate conceptual integration, diagnostic and management paradigm shifts, and future research and policy priorities respectively, providing visual context for the methodological framework.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"RESULTS AND FINDINGS","content":"\u003ch2\u003eStudy Selection\u003c/h2\u003e\u003cp\u003eThe literature search across multiple databases and registers yielded 1,243 records. After removal of duplicates and automation-assisted exclusions, 910 unique titles and abstracts were screened. Of these, 160 full-text articles were assessed for eligibility, and five could not be retrieved despite repeated attempts. A total of 125 were excluded due to design limitations, absence of pregnancy-specific populations, lack of relevant thyroid parameters, or insufficient methodological rigor. Thirty-five studies ultimately met the inclusion criteria and were retained for synthesis, with 20 designated as the quantitative and mechanistic core. The detailed process of identification, screening, eligibility, and inclusion is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003ch2\u003eCharacteristics of Included Studies\u003c/h2\u003e\u003cp\u003eThe 35 included studies spanned from 1996 to 2025 and represented diverse geographical regions including Scandinavia, the United States, Europe, China, Mexico, and global cohorts. Study designs ranged from prospective cohorts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and mechanistic placental analyses [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] to scoping and narrative reviews [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Sample sizes varied considerably, with large cohorts exceeding 2,500 participants [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and small mechanistic studies examining fewer than 50 placentas [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Core study characteristics and risk of bias assessments are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Overall, prospective cohorts were at low to moderate risk of bias, mechanistic studies showed moderate concerns due to small samples, and reviews ranged from moderate to low quality based on AMSTAR-2 appraisal.\u003c/p\u003e\u003ch2\u003eMaternal Thyroid Function Across Pregnancy\u003c/h2\u003e\u003cp\u003eEvidence from large cohort studies demonstrated that maternal free thyroxine declined across gestation, while TSH rose progressively, reflecting physiological adaptation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Iodine deficiency consistently correlated with lower maternal FT4 and higher rates of hypothyroxinemia, particularly in the second trimester [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Rawal et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] reported that lower longitudinal FT4 trajectories were associated with increased risk of gestational diabetes, independent of TSH, highlighting the clinical implications of free hormone monitoring. In the Mexican cohort reported by Gutiérrez-Vega et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], late pregnancy demonstrated disproportionate elevations in FT3 with concurrent reductions in FT4, which correlated with lower birth weight. Reviews emphasized that reliance on TSH alone may mask clinically relevant abnormalities, advocating trimester-specific interpretation of free hormones [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. A synthesis of maternal thyroid function findings across trimesters and outcomes is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003ch2\u003ePlacental Deiodinase Expression and Transport Mechanisms\u003c/h2\u003e\u003cp\u003eMechanistic studies provided consistent evidence that placental deiodinase activity is central to maternal-fetal thyroid regulation. Chan et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] demonstrated upregulation of type 3 deiodinase (DIO3) in placentas from growth-restricted pregnancies, a finding supported by Huang et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], who identified high DIO3 expression in the uteroplacental unit and fetal epithelium. Koopdonk-Kool et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] showed that DIO2 activity increases with gestational age, suggesting a dynamic balance between activation and inactivation across pregnancy. James et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and Chen et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] expanded this understanding by describing the role of transporters such as MCT8 and OATPs in regulating fetal thyroid hormone supply. Together, these studies highlight the placenta as an active endocrine gatekeeper. The findings are synthesized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and schematically represented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, which illustrates the dynamic interplay of maternal thyroxine transfer, deiodinase activation, and fetal protection against excess exposure.\u003c/p\u003e\u003ch2\u003eIodine Kinetics in Pregnancy\u003c/h2\u003e\u003cp\u003eStudies evaluating iodine status and kinetics provided converging evidence that pregnancy creates a unique metabolic environment in which iodine requirements rise sharply. Abel et al. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] demonstrated that iodine intake directly influences maternal FT4 and TSH trajectories, while Andersen and colleagues [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] underscored the inconsistency in supplementation policies across Europe. Delshad [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and Feldt-Rasmussen [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] reinforced the global importance of iodine sufficiency for maternal thyroid stability and fetal neurodevelopment. Recent mechanistic studies by Fu et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and Peng et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] revealed that placental iodine handling differs between maternal and fetal compartments, underscoring that maternal urinary iodine concentration does not always reflect fetal supply. Historical physiology studies by Versloot et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] showed that under marginal deficiency, maternal thyroid preferentially sequesters iodine, further restricting fetal access. Evidence from scoping reviews [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] emphasized the compounding risks of iodine deficiency and environmental disruptors on maternal thyroid health and child neurodevelopment. Collectively, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents these findings, while Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e illustrates the paradigm shift from a TSH-only model to an integrated framework that incorporates free hormones, iodine sufficiency, and placental mechanisms.\u003c/p\u003e\u003ch2\u003eIntegrated Findings and Emerging Paradigm\u003c/h2\u003e\u003cp\u003eTaken together, the evidence demonstrates that maternal TSH is an insufficient surrogate marker in pregnancy. Free hormones provide clearer signals of maternal and fetal thyroid status, while placental deiodinases and transporters mediate critical adjustments that are invisible to serum TSH. Iodine sufficiency remains a universal prerequisite, yet the maternal-fetal divergence in iodine handling demands biomarkers beyond urinary concentration. The findings support a transition toward integrated monitoring that combines free hormone trajectories, iodine status, and placental biology. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e outlines future clinical, research, and policy priorities, including the establishment of trimester-specific free hormone reference ranges, harmonization of international guidelines, and integration of precision medicine approaches into obstetric practice.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eGeneral Interpretation of Findings\u003c/h2\u003e\u003cp\u003eThe present systematic review and meta-analysis demonstrates that maternal thyroid management in pregnancy cannot remain anchored solely to TSH interpretation. Abel and colleagues [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], in a large prospective cohort from Norway, showed that even mild to moderate iodine deficiency significantly alters maternal FT4 and TSH, suggesting that maternal free hormone dynamics rather than TSH alone reveal the true metabolic state. This finding aligns with Andersen and Laurberg [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], who emphasized the ambiguity of iodine supplementation policies in Europe, pointing out that heterogeneous approaches leave certain populations exposed to both deficiency and excess. By situating our analysis within this context, the evidence supports the need for harmonization of guidelines while respecting regional differences in iodine sufficiency.\u003c/p\u003e\u003cp\u003ePlacental studies illustrate why maternal serum alone cannot capture fetal thyroid exposure. Chan et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] demonstrated that placental DIO3 is markedly upregulated in growth-restricted pregnancies, effectively inactivating maternal T4 and limiting fetal T3 supply. Huang and colleagues [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reinforced these findings by localizing high DIO3 expression in the uteroplacental unit and fetal epithelium, providing direct histological evidence. Koopdonk-Kool et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] further observed that DIO2 activity increases with gestational age, suggesting a protective mechanism that enhances local T3 production when fetal demand peaks. These mechanistic data, summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and visualized in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, explain the consistent observation that maternal TSH may remain normal while fetal thyroid exposure is insufficient.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003eMaternal Hormone Dynamics and Clinical Outcomes\u003c/h2\u003e\u003cp\u003eProspective cohorts underscore the importance of free hormones in predicting maternal and neonatal outcomes. Rawal and co-workers [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], in a large U.S. cohort, found that women with lower FT4 trajectories across gestation were at increased risk for gestational diabetes, an association not predicted by TSH. Guti\u0026eacute;rrez-Vega and colleagues [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] described that in late pregnancy, elevated FT3 alongside suppressed FT4 correlated with lower birth weight, suggesting a maladaptive shift in hormone balance. These outcomes reinforce earlier physiological descriptions by Glinoer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and later analyses by Lazarus [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] that maternal FT4 plays a crucial role in early fetal neurodevelopment. Muller, Taylor, and Lazarus [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] reiterated the pitfalls of relying on TSH, noting that physiological changes in binding proteins confound its interpretation. Together, these findings, consolidated in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, highlight that FT4 and FT3 must be integrated into trimester-specific monitoring frameworks.\u003c/p\u003e\u003cp\u003eThe interpretive challenges of thyroid testing in pregnancy were emphasized by Visser and Peeters [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], who concluded that TSH alone is misleading in gestational physiology, and by Springer et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], who urged the establishment of pregnancy-specific reference ranges. Budenhofer and colleagues [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] also stressed that both hypo- and hyperthyroidism in pregnancy have adverse effects on maternal and neonatal outcomes. Krassas, Karras, and Pontikides [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] expanded this view by detailing complications such as preeclampsia and hyperemesis gravidarum, while Chung [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and Puthiyachirakal and colleagues [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] emphasized the contemporary controversies surrounding subclinical thyroid disease management. Together, these clinical reviews and cohort studies converge on the conclusion that maternal free hormone trajectories, rather than isolated TSH values, are the most clinically relevant markers for guiding care.\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003eIodine Kinetics and Maternal\u0026ndash;Fetal Divergence\u003c/h2\u003e\u003cp\u003eThe regulation of iodine metabolism across pregnancy further clarifies the inadequacy of TSH-only management. Delshad [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] emphasized the sharp increase in iodine requirements during gestation, while Feldt-Rasmussen [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] linked iodide sufficiency directly to fertility and successful gestation. Fu and colleagues [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] demonstrated that placental iodine transport is variable and depends on maternal status, confirming that maternal sufficiency does not guarantee fetal adequacy. Peng et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] advanced this understanding by showing divergent iodine and thyroid hormone concentrations on maternal and fetal sides of the term placenta, an observation consistent with the classic work of Versloot et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], who documented preferential maternal thyroid uptake under marginal deficiency, thereby compromising fetal access.\u003c/p\u003e\u003cp\u003eGriebel-Thompson and co-workers [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and Grossklaus and colleagues [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] extended the discussion by showing that neurodevelopmental outcomes are further compromised when iodine deficiency intersects with environmental disruptors or fluoride exposure. M\u0026eacute;gier and collaborators [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] synthesized maternal\u0026ndash;fetal iodine metabolism, describing how dynamic changes across gestation alter maternal and fetal thyroid hormone flux. Lumen et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] added an important toxicological perspective by modeling iodine\u0026ndash;perchlorate interactions, which demonstrated that maternal FT4 suppression can occur even under apparent iodine sufficiency. Collectively, the evidence summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and integrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e demonstrates that iodine sufficiency is not binary, but dynamic and context-dependent, requiring trimester-specific strategies rather than uniform supplementation.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003ePlacental Transporters and Integrated Mechanisms\u003c/h2\u003e\u003cp\u003eThe evidence on thyroid hormone transporters offers a deeper mechanistic layer. Chen et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] described how placental transporters such as MCT8 and OATPs play critical roles in delivering thyroid hormones to the fetus. James and colleagues [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] confirmed that these transporters are rate-limiting factors for fetal hormone supply, and Zu\u0026ntilde;iga et al. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] synthesized this evidence into a broader fetoplacental model of thyroid hormone metabolism and transfer. These findings explain why maternal free hormone levels, even when adjusted for gestational physiology, cannot always predict fetal thyroid status without placental context. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e captures this interplay between deiodinases, transporters, and iodine flux, demonstrating the placenta\u0026rsquo;s role as an active regulator of fetal thyroid hormone exposure.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eIntegration with Clinical Reviews and Conceptual Advances\u003c/h2\u003e\u003cp\u003eClassical and modern reviews place these findings into a wider interpretive framework. Glinoer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] described the pathways of endocrine adaptation in pregnancy, which remain foundational for understanding thyroid physiology today. James [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and Lazarus [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] contributed to early recognition of placental transport and the critical role of maternal FT4. More recently, Chung [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and Muller, Taylor, and Lazarus [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] summarized evolving perspectives on screening and management, highlighting both progress and persisting uncertainties. Contemporary conceptual frameworks in perinatal medicine, such as those advanced by Andonotopo and colleagues [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], underscore the broader shift toward systems biology and precision medicine, including the integration of nutriepigenomics, immunoediting, and AI-driven monitoring. These developments parallel the movement within thyroid management beyond TSH, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, where the proposed model integrates free hormones, iodine kinetics, and placental mechanisms into a multidimensional approach.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003eSynthesis of Evidence and Emerging Paradigm\u003c/h2\u003e\u003cp\u003eWhen taken together, the studies included in this review present a consistent message. Maternal TSH, while valuable in non-pregnant populations, fails to capture the dynamic interplay of maternal free hormones, placental enzymatic activity, transporter biology, and iodine flux that define thyroid status in pregnancy. Cohorts from Norway [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], the United States [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], Mexico [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and China [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] converge with mechanistic studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and international reviews [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] to affirm the need for a paradigm shift. This shift is visually depicted in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and operationalized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, which integrates clinical and mechanistic insights into a coherent framework.\u003c/p\u003e\u003cp\u003eThe future of perinatal thyroid management must be grounded in free hormone monitoring, trimester-specific interpretation, dynamic assessment of iodine sufficiency, and consideration of placental biology. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates these future priorities, spanning clinical practice, mechanistic research, and public health policy. By adopting this integrated framework, clinicians and researchers can better safeguard maternal health, optimize fetal growth, and protect neurodevelopmental outcomes across generations.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec27\" class=\"Section3\"\u003e\u003ch2\u003eSTRENGTHS, LIMITATIONS, AND FUTURE DIRECTIONS\u003c/h2\u003e\u003cp\u003eA central strength of this review lies in its breadth and integration. By unifying maternal free hormone dynamics, placental enzymatic regulation, transporter biology, and iodine kinetics into a single framework, the review provides a comprehensive and multidimensional understanding of thyroid physiology in pregnancy. This integrative approach allowed us to bridge epidemiological data with mechanistic studies, thereby capturing both population-level signals and the biological processes that underlie them. Another strength is the methodological rigor, with a systematic search strategy applied across multiple databases and registers, a transparent screening process, independent dual review at each stage, and structured risk-of-bias appraisal. The narrative synthesis was complemented by meta-analytic techniques where data permitted, and the certainty of evidence was evaluated consistently, ensuring that conclusions reflect both the strengths and weaknesses of the evidence base.\u003c/p\u003e\u003cp\u003eNonetheless, several limitations must be acknowledged. Heterogeneity across studies in assay methods, timing of hormone measurements, and definitions of iodine sufficiency complicated direct comparisons and limited pooled effect estimates. Many mechanistic studies were based on relatively small placental samples, which, while providing valuable insight, restrict generalizability. Cohort studies differed in their adjustment for confounders such as body mass index, smoking, and autoimmune thyroid disease, introducing potential residual bias. Global disparities in iodine nutrition and access to thyroid testing also mean that findings from high-income countries may not apply universally to low- and middle-income settings. Additionally, the absence of PROSPERO registration may be seen as a limitation, although this was explicitly declared and managed with adherence to methodological transparency.\u003c/p\u003e\u003cp\u003eLooking forward, several future directions emerge. Large, well-powered prospective studies that measure free thyroid hormones with standardized LC-MS/MS assays are needed to refine trimester-specific reference ranges. Interventional trials that test the timing, dose, and composition of micronutrient supplementation\u0026mdash;including iodine and selenium\u0026mdash;should be prioritized to determine the optimal strategies for diverse populations. Mechanistic studies should further characterize placental transporters and deiodinases, including their regulation under pathological states such as gestational diabetes, preeclampsia, and intrauterine growth restriction. Translational research integrating systems biology, omics approaches, and advanced imaging will deepen understanding of maternal\u0026ndash;fetal thyroid crosstalk. At a policy level, global harmonization of guidelines is urgently required, balancing universal recommendations with population-specific adaptations. Finally, emerging tools such as artificial intelligence and precision public health approaches hold promise for real-time monitoring and individualized thyroid management, opening pathways to transform prenatal care.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis systematic review and meta-analysis demonstrates that the management of thyroid function in pregnancy cannot be confined to reliance on serum TSH alone. By systematically synthesizing 35 studies spanning epidemiology, clinical cohorts, mechanistic placental research, and advanced modeling, we have shown that maternal free hormone dynamics, iodine sufficiency, and placental enzymatic activity collectively determine maternal adaptation and fetal thyroid hormone availability. The review highlights that free thyroxine and triiodothyronine measurements, in conjunction with iodine biomarkers and gestational age\u0026ndash;specific context, provide a more accurate representation of maternal\u0026ndash;fetal thyroid physiology than TSH alone. Placental deiodinases and thyroid hormone transporters emerge as central regulatory nodes, shaping fetal exposure and mediating risks for neurodevelopmental compromise when iodine deficiency or maternal thyroid dysfunction is present.\u003c/p\u003e\u003cp\u003eOur synthesis emphasizes the urgent need for a paradigm shift in clinical practice toward integrated assessment models that account for free hormone levels, iodine status, placental biology, and gestational timing. The findings also underscore that iodine requirements increase significantly in pregnancy, that placental handling can create divergence between maternal and fetal hormone availability, and that environmental disruptors may exacerbate these vulnerabilities. The proposed transition to a multidimensional management framework, supported by trimester-specific reference ranges and precision supplementation strategies, offers a path to optimize both maternal health and fetal neurodevelopmental outcomes.\u003c/p\u003e\u003cp\u003eUltimately, the evidence presented calls for harmonization of global guidelines, investment in mechanistic and translational research, and application of precision medicine principles to prenatal thyroid care. By bridging physiology, clinical outcomes, and public health, this review provides a foundation for rethinking thyroid management in pregnancy and charts a course toward a more accurate, individualized, and equitable model of perinatal care.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eATA\u003c/strong\u003e – American Thyroid Association\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBBBD\u003c/strong\u003e – Blood–Brain Barrier Dynamics\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBMI\u003c/strong\u003e – Body Mass Index\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCENTRAL\u003c/strong\u003e – Cochrane Central Register of Controlled Trials\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCI\u003c/strong\u003e – Confidence Interval\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCINAHL\u003c/strong\u003e – Cumulative Index to Nursing and Allied Health Literature\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDIO2 (D2)\u003c/strong\u003e – Type II Iodothyronine Deiodinase\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDIO3 (D3)\u003c/strong\u003e – Type III Iodothyronine Deiodinase\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEDC\u003c/strong\u003e – Endocrine Disrupting Chemical\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFT3\u003c/strong\u003e – Free Triiodothyronine\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFT4\u003c/strong\u003e – Free Thyroxine\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGDM\u003c/strong\u003e – Gestational Diabetes Mellitus\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGRADE\u003c/strong\u003e – Grading of Recommendations Assessment, Development, and Evaluation\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIHC\u003c/strong\u003e – Immunohistochemistry\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIUGR\u003c/strong\u003e – Intrauterine Growth Restriction\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLC-MS/MS\u003c/strong\u003e – Liquid Chromatography–Tandem Mass Spectrometry\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMCT8\u003c/strong\u003e – Monocarboxylate Transporter 8\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNOS\u003c/strong\u003e – Newcastle–Ottawa Scale\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOATP\u003c/strong\u003e – Organic Anion Transporting Polypeptide\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePBPK\u003c/strong\u003e – Physiologically Based Pharmacokinetic Model\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePRISMA\u003c/strong\u003e – Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003erT3\u003c/strong\u003e – Reverse Triiodothyronine\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eROBINS-I\u003c/strong\u003e – Risk Of Bias In Non-randomized Studies of Interventions\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eROBINS-E\u003c/strong\u003e – Risk Of Bias In Non-randomized Studies of Exposures\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eROBIS\u003c/strong\u003e – Risk Of Bias In Systematic Reviews\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eRoB-2\u003c/strong\u003e – Revised Cochrane Risk of Bias tool for Randomized Trials\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTSH\u003c/strong\u003e – Thyroid Stimulating Hormone\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eUIC\u003c/strong\u003e – Urinary Iodine Concentration\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWHO\u003c/strong\u003e – World Health Organization\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest regarding the publication of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWA and MBAP conceptualized and supervised the review. JD, WP and MAB contributed to literature collection and data extraction. INHS, AAGPW and KEG participated in data analysis and critical content review. ED, MMIA, AANJK, RAP and ADA were involved in reviewing data evidence. \u0026nbsp;AS, DA, WEKA, and MS \u0026nbsp;provided methodological and clinical guidance. All authors contributed to the writing of the manuscript, reviewed the final draft, and approved the version submitted for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors appreciate the XXXX Society of Obstetrics and Gynecology (XXXX) and the XXXX Society of Maternal-Fetal Medicine (XXXX) for encouraging and supporting the work of this review article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbel MH, Korevaar TIM, Erlund I, Villanger GD, Caspersen IH, Arohonka P et al (2018) Iodine Intake is Associated with Thyroid Function in Mild to Moderately Iodine Deficient Pregnant Women. 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Mol Reprod Dev 89:526\u0026ndash;539. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/mrd.23647\u003c/span\u003e\u003cspan address=\"10.1002/mrd.23647\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Indonesia","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pregnancy, Free thyroxine (FT4), Placental deiodinase (DIO2/DIO3), Iodine kinetics, Perinatal outcomes","lastPublishedDoi":"10.21203/rs.3.rs-7905418/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7905418/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMaternal thyroid care in pregnancy is still largely defined by serum TSH, even though gestational physiology alters its meaning. Shifts in binding proteins, placental metabolism of thyroid hormones, and the rise in iodine requirements uncouple TSH from the true maternal and fetal thyroid state. To clarify this gap, we conducted a systematic review and meta-analysis of studies reporting maternal free thyroxine and triiodothyronine, placental deiodinase expression or function, and iodine status in relation to pregnancy, neonatal, or child outcomes. We searched MEDLINE, Embase, Web of Science, Scopus, CENTRAL, CINAHL, ClinicalTrials.gov, WHO-ICTRP, and grey literature through October 2025 without language restriction. Two reviewers independently screened records, assessed eligibility, extracted data, and judged bias using RoB-2 for trials, ROBINS-I/ROBINS-E or NOS for observational work, and AMSTAR-2/ROBIS for prior reviews. Effect measures were synthesized using random-effects models with robust variance estimation. Free hormones were harmonized by LC-MS/MS calibration or expressed as trimester-specific multiples of the median. Dose\u0026ndash;response modeling assessed urinary iodine concentration against outcomes.\u003c/p\u003e\u003cp\u003eFrom 1,243 records, 910 abstracts were screened, 160 full texts assessed, and 35 studies included, of which 20 formed the quantitative core. Findings showed that lower maternal free T4 trajectories and disproportionate elevations in late-gestation free T3 were associated with gestational diabetes, preterm birth, and low birth weight. Placental DIO3 expression was consistently high, accentuated in growth-restricted pregnancies, while iodine deficiency correlated with maternal hypothyroxinemia and neurodevelopmental risk. Heterogeneity was moderate, certainty graded low to moderate. Evidence supports a management framework that integrates calibrated free-hormone monitoring, placental biology, and iodine sufficiency, moving beyond reliance on TSH alone.\u003c/p\u003e","manuscriptTitle":"Optimizing Thyroid Management in Pregnancy Beyond TSH: Free Hormones, Placental Deiodinases, and Iodine Kinetics — A Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:48:50","doi":"10.21203/rs.3.rs-7905418/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"423e4212-790a-4cb0-8efc-555d8ebf29c4","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56580288,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2025-10-21T23:48:50+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:48:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7905418","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7905418","identity":"rs-7905418","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}