Neonatal hyperthyroidism: Distinguishing transient antibody-mediated disease from permanent genetic forms

 Corresponding author: Ashraf T. Soliman Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Neonatal hyperthyroidism: Distinguishing transient antibody-mediated disease from permanent genetic forms Ashraf T. Soliman 1, *, Shayma Ahmed 1, Fawzia Alyafei 1, Noora AlHumaidi 1, Nada Alaaraj 1, Noor Hamed 1, Shaymaa Elsayed 2 and Ahmed Elawwa 2 1 Department of Pediatrics, Hamad Medical Center, Doha, Qatar. 2 Alexandria University Children’s Hospital, Alexandria, Egypt. GSC Advanced Research and Reviews, 2025, 25(03), 001–014 Publication history: Received on 25 October 2025; revised on 28 November 2025; accepted on 01 December 2025 Article DOI: https://doi.org/10.30574/gscarr.2025.25.3.0370 Abstract Background: Neonatal hyperthyroidism and thyrotoxicosis, though rare, represent critical endocrine emergencies associated with significant cardiovascular, metabolic, and neurodevelopmental risks. Most cases result from transplacental passage of thyroid-stimulating receptor antibodies (TRAb) in mothers with Graves’ disease, whereas a minority arise from activating TSHR or GNAS mutations. Early identification, correct etiological classification, and timely treatment are essential to prevent morbidity. Objectives: To synthesize current evidence on the prevalence, clinical characteristics, etiologic differentiation, and therapeutic strategies for neonatal hyperthyroidism, with emphasis on distinguishing transient from permanent disease and highlighting optimal treatment dosing, duration, and outcomes. Methods: A structured literature review (2000–2025) was performed using PubMed, Scopus, and Google Scholar. Inclusion criteria were neonatal hyperthyroidism cases with documented biochemical diagnosis, etiology (maternal TRAb or genetic), treatment details, and clinical outcomes. Case reports, case series, prospective cohorts, and reviews were included. Data extracted included prevalence, onset timing, hormone levels, TRAb status, TSHR/GNAS mutation status, methimazole and propranolol dosing, adjunctive therapies, treatment duration, and shortand long-term outcomes. Results: Across 35 eligible studies, neonatal hyperthyroidism occurred in approximately 1 in 50,000 births in the general population and 1–5% of infants born to mothers with Graves’ disease. Transient antibody-mediated hyperthyroidism predominated, typically presenting in the first 1–2 weeks of life. Clinical manifestations included tachycardia, irritability, feeding difficulty, poor weight gain, goiter, cholestasis, and, in severe cases, heart failure and craniosynostosis. Biochemical markers consistently demonstrated elevated FT4/T3 with suppressed TSH, with positive TRAb confirming autoimmune etiology. Permanent hyperthyroidism from TSHR/GNAS activation was rare but led to persistent hormone excess beyond antibody clearance. Methimazole (MMI) emerged as the preferred therapy, used at 0.25–1.0 mg/kg/day in divided doses, achieving biochemical control within days and typically continued for 2–10 weeks until TRAb clearance. Propranolol (~2 mg/kg/day) provided adrenergic symptom control, particularly tachycardia and irritability. In severe or unstable cases, iodine (Lugol/SSKI) and glucocorticoids were used to rapidly reduce hormone release and T4-to-T3 conversion. Importantly, transient hypothyroidism developed in some infants following treatment, necessitating dose adjustment or temporary levothyroxine. Most treated neonates achieved complete recovery with normal growth and neurodevelopment, whereas permanent cases required prolonged antithyroid therapy with potential progression to definitive treatment later in childhood. GSC Advanced Research and Reviews, 2025, 25(03), 001–014 2 Conclusions: Neonatal hyperthyroidism requires proactive screening in at-risk infants, prompt initiation of methimazole-based therapy, and structured follow-up to monitor biochemical response, growth, and neurodevelopment. Differentiating transient antibody-mediated disease from genetic forms enables optimized treatment duration and long-term management planning. Keywords: Neonatal hyperthyroidism; Graves’ disease; TRAb-mediated thyrotoxicosis; TSH receptor mutation; Methimazole therapy; Neurodevelopmental outcomes 1. Introduction Thyroid hormones, particularly thyroxine (T4) and triiodothyronine (T3), play a pivotal role in the perinatal period for fetal and neonatal growth, metabolism, and neurodevelopment. In the fetus and newborn, adequate thyroid hormone levels are essential for brain maturation, myelination, energy homeostasis and linear growth. (1) In the perinatal period, the fetal thyroid gland begins to function at around 10–12 weeks of gestation and becomes increasingly active by 20–25 weeks, so that by term the fetus is largely dependent on its own thyroid hormone production, as well as maternal hormone contributions. (2) In the neonate, thyroxine contributes to metabolic rate, thermogenesis, cardiac output, and maturation of multiple organ systems. Its action on bone maturation, nervous system development, and even pulmonary function underscores the sensitivity of the newborn to derangements of thyroid hormone levels. (3) In this context, while much attention has focused on neonatal hypothyroidism, the consequences of excess thyroid hormone (neonatal hyperthyroidism or thyrotoxicosis) are less common but potentially serious. The presence of thyrotoxicosis in the neonate may accelerate metabolism, increase cardiac workload, impair growth, and risk long-term neurodevelopmental sequelae. (4) Excess thyroxine in the neonatal period therefore presents a unique endocrine challenge: the immature neonatal systems must accommodate increased hormone action in the context of still-developing organ systems, immature regulatory feedback loops, and potential vulnerability to cardiovascular, skeletal, and neuro-cognitive damage. (5) The pathophysiology of neonatal hyperthyroidism includes transplacental passage of maternal thyroid-stimulating antibodies, de-novo activating mutations of the TSH receptor, iatrogenic or iodine-related exposures, and other rare causes. These mechanisms differ from the usual adult hyperthyroid state and have implications for diagnosis and management. (6) Clinically, neonatal thyrotoxicosis may present with non-specific signs such as tachycardia, irritability, weight loss or poor weight gain, goiter, hepatosplenomegaly, craniosynostosis, and may be easily misdiagnosed or missed if not anticipated. (7) The prevalence of neonatal hyperthyroidism is low (estimates ~1:50,000 to 1:4000 births) but the condition may be transient or permanent, and distinguishing between these states can be confusing. Moreover, the rarity and varied clinical presentation mean delays in diagnosis may adversely affect outcome. (8) Given these aspects — the essential role of thyroid hormones in the perinatal period, the varied etiologies of excess hormone, the challenging presentation in neonates, and the risk of adverse outcomes — it is timely to review the current evidence on neonatal hyperthyroidism/thyrotoxicosis: its mechanisms, diagnosis, prevalence, clinical profiles and therapeutic interventions. Therefore, this mini-review aims to synthesize the published literature from 2000–2025 to inform clinicians caring for neonates at risk of thyroid hormone excess. (9) Objectives This review aimed to synthesize contemporary evidence on neonatal hyperthyroidism and thyrotoxicosis with the following objectives: • To determine prevalence, timing of onset, and clinical characteristics of neonatal hyperthyroidism, particularly among infants born to mothers with Graves’ disease. • To differentiate transient TRAb-mediated neonatal hyperthyroidism from permanent congenital forms associated with TSHR and GNAS mutations, based on clinical features, biochemical profiles, and disease course. GSC Advanced Research and Reviews, 2025, 25(03), 001–014 3 • To evaluate therapeutic strategies and outcomes, including methimazole dosing, adjunctive β-blocker and iodine use, time to biochemical control, and risk of iatrogenic hypothyroidism or relapse. • To appraise the quality of available evidence using structured bias assessment and GRADE standards, identifying strengths, limitations, and implications for clinical practice. 2. Methods 2.1. Search Strategy A structured literature review was conducted covering January 2000 to December 2025 using PubMed, Scopus, and Google Scholar. Search terms included: “neonatal hyperthyroidism,” “neonatal thyrotoxicosis,” “Graves’ disease newborn,” “TRAb neonate,” “TSHR mutation,” “congenital hyperthyroidism,” “methimazole neonatal dosing,” “β-blocker neonatal thyrotoxicosis.” Boolean combinations applied: (neonate OR newborn) AND (hyperthyroidism OR thyrotoxicosis) AND (Graves OR TRAb OR TSHR mutation OR GNAS) AND (treatment OR dosing OR methimazole). 2.2. Inclusion Criteria • Neonates (birth–60 days) with biochemical hyperthyroidism • Studies reporting clinical features, etiology, treatment, or outcomes • Cohorts, case series, case reports, guidelines, or expert reviews • TRAb-mediated and genetic (TSHR/GNAS) etiologies • English-language publications 2.3. Exclusion Criteria • Fetal-only thyroid disease without neonatal follow-up • Maternal hyperthyroidism reports without neonatal data • Animal/in vitro studies • Editorials/commentaries without clinical data 2.4. Data Extraction Two reviewers independently extracted: • Prevalence and epidemiological data • Age at onset and clinical features • TRAb titers, FT4/T3, and TSH levels • Genetic vs antibody-mediated etiology • Treatment regimens (drug type, dose, duration) • Outcomes: time to control, relapse, hypothyroidism, neurodevelopment • Study design, setting, and size 2.5. Quality Assessment Risk of bias was evaluated using Cochrane-aligned criteria (study design, selection bias, follow-up completeness, outcome objectivity). Evidence certainly was graded using the GRADE framework, considering observational predominance, small sample sizes, and consistency of biochemical outcomes. A forest-style quality plot and summary tables were produced. GSC Advanced Research and Reviews, 2025, 25(03), 001–014 4 Figure 1 PRISMA Flow Diagram for Study Selection This PRISMA flow diagram outlines the structured literature screening process for this review on neonatal hyperthyroidism. From 533 initially identified records, removal of duplicates and stepwise eligibility assessment led to 35 studies being included. This ensures that the review is based on rigorously selected, clinically meaningful evidence focusing on neonatal thyrotoxicosis epidemiology, mechanisms, treatment, and outcomes. 3. Results The included studies describe the epidemiology, clinical presentation, and management outcomes of neonatal hyperthyroidism, with a predominance of transient TRAb-mediated cases in infants born to mothers with Graves’ disease. Although rare in the general population, the condition occurs in up to 1–5% of at-risk pregnancies, typically presenting in the first weeks of life with tachycardia, irritability, feeding difficulty, and poor weight gain. Diagnosis across reports relied on elevated FT4/T3 with suppressed TSH and maternal–infant TRAb assessment. The results further distinguish transient immune-mediated disease from rare permanent genetic forms, outline methimazole-based therapeutic strategies, and evaluate study quality using structured risk-of-bias and GRADE frameworks. Table 1 summarizes contemporary evidence on neonatal hyperthyroidism and thyrotoxicosis, demonstrating that although the condition remains rare in the general population (~1 in 50,000 births), it is significantly more frequent among infants born to mothers with Graves’ disease (GD), particularly when maternal thyroid-stimulating receptor antibodies (TRAb) are elevated. Across studies, reported prevalence in at-risk GD pregnancies ranges from 1–5%, with variability linked to maternal TRAb levels, prior radioiodine therapy, and antenatal thyroid status. The clinical spectrum is broad, spanning asymptomatic biochemical hyperthyroidism to severe presentations with tachycardia, irritability, poor feeding, weight loss, goiter, cholestasis, heart failure, and craniosynostosis, emphasizing the diagnostic challenge in this age group. Biochemically, consistently elevated T4/T3 with suppressed TSH remains the cornerstone of diagnosis, supported by maternal and neonatal TRAb measurement to distinguish transient maternal antibody– mediated hyperthyroidism from rare permanent forms caused by TSH-receptor–activating mutations. Overall, the data reinforces the need for systematic neonatal monitoring when mothers have current or past GD, and the importance of integrating biochemical, clinical, and immunologic findings for timely recognition and management. GSC Advanced Research and Reviews, 2025, 25(03), 001–014 5 Table 1 Prevalence and presentations of thyroid hormone excess in neonates and diagnostic criteria Study (Year) Population Prevalence Common Presentations Diagnostic Biochemical Criteria Segni 2019 (Endotext review) Literature review of neonatal hyperthyroidism/thyrotoxicosis ~1 in 50,000 births overall; higher among infants of mothers with Graves’ disease (GD) Tachycardia, irritability, goiter, failure to thrive; may include craniosynostosis & heart failure ↑FT4/TT4, ↑T3, suppressed TSH; maternal/infant TRAb positive (10) Song 2024 (retrospective case-series) 19 neonates with hyperthyroidism (China, 2012– 2021) Case series Goiter ~84%, tachycardia ~95%, weight loss ~47% ↑T4/T3, suppressed TSH, median diagnosis at ~18.5 days (11) Jankovski 2024 (review) Infants of mothers with GD treated with radioiodine Fetal/neonatal thyrotoxicosis in up to 3–5% of such pregnancies Irritability, tachycardia, poor feeding, goiter TRAb positive mother/infant; ↑T3/T4, suppressed TSH (12) Besançon/Polak 2014 (prospective cohort) 68 infants born to mothers with Graves' disease Risk tied to maternal TRAb level Variable—mild to severe hyperthyroidism, tachycardia, irritability ↑FT4/TT4, suppressed TSH; TRAb useful for prediction (13) van der Kaay et al. 2016 (Pediatrics algorithm) Evidence-based GD-pregnancy neonatal protocol Neonatal hyperthyroidism ~1–5% in GD pregnancies Tachycardia, heart failure, irritability Maternal TRAb guides risk; neonatal ↑T4/T3 with low TSH (14) Abeillon-du Payrat 2014 (Eur J Endocrinol) 47 TRAb-positive pregnancies Predictive TRAb thresholds for neonatal disease Fetal tachycardia/goiter; neonatal thyrotoxicosis TRAb ≥ assay cutoff; ↑FT4/TT4, suppressed TSH (15) Pyrżak et al. 2022 (Frontiers Endocrinol follow-up) Infants of GD mothers; long-term follow-up Neonatal hyperthyroidism rare; possible delayed hypothyroidism Tachycardia, irritability; possible late hypothyroidism Serial TFTs; ↑T4/T3 initially; later TSH variability (16) Illouz et al. 2018 (review) Autoimmune GD pregnancy outcomes ~1–2% neonatal hyperthyroidism; ~1 in 50,000 births overall Fetal tachycardia/goiter; neonatal thyrotoxicosis ↑FT4/TT4, ↓TSH; TRAb positive (17) Kurtoğlu et al. 2017 (review) Updated neonatal thyrotoxicosis guidance GD in pregnancy ~0.1–0.2%; neonatal hyperthyroidism 1–10% depending on TRAb Tachycardia, cardiac failure, irritability, cholestasis ↑FT4/TT4/±↑T3; suppressed TSH; maternal/cord TRAb (18) Luz et al. 2020 (Portuguese 15year series) Infants of GD mothers 0.1–2.7% neonatal Variable; some asymptomatic early ↑T4/T3, suppressed TSH; structured GSC Advanced Research and Reviews, 2025, 25(03), 001–014 6 hyperthyroidism reported follow-up needed (19) Spanish cohort 2021 (tertiary endocrine unit) Infants of mothers with GD ~0.1–2.7% neonatal thyroid dysfunction Asymptomatic to overt thyrotoxicosis Maternal TRAb risk; neonatal ↑T4/T3, ↓TSH (20) AAP NeoReviews 2024 Expert neonatal guideline review Neonatal thyrotoxicosis ~1–5% in GD pregnancies Tachycardia, irritability, heart failure; mimic sepsis ↑FT4/TT4, suppressed TSH; correlate with maternal TRAb (21) Mamat 2022 (ASEAN endocrine series) Neonates of hyperthyroid mothers Uncommon; variable duration Irritability, tachycardia, weight loss ↑FT4, ↓TSH; prolonged observation for resolution (22) Kayaş et al. 2022 (TSHR mutation case) Non-autoimmune congenital hyperthyroidism Extremely rare (permanent form) Persistent hyperthyroidism, poor weight gain ↑FT4/T3, suppressed TSH; negative TRAb; TSHR mutation (23) Table 2 Differentiation of transient vs permanent hyperthyroidism in neonates Feature Transient neonatal hyperthyroidism Permanent neonatal hyperthyroidism Etiology Transplacental stimulating TSH-receptor antibodies (TRAb/TSI) from mothers with Graves’ disease; risk & severity track maternal/cord TRAb titres; resolves as antibodies clear (24,25,26,27). Germline activating TSHR mutations (sporadic/familial non-autoimmune hyperthyroidism) or mosaic GNAS mutations (McCune–Albright); antibody-negative; intrinsic autonomy (28,29,30,31,32). Time course Onset days–2 weeks; typical duration 2–3 months (up to 4–6 months) depending on TRAb potency & clearance (24,33,34). Persistent beyond neonatal period unless treated; often lifelong surveillance/therapy (28,29,30). Laboratory findings ↑FT4/TT4 (±↑T3) with suppressed TSH; maternal/cord/neonatal TRAb positive; progressive normalization as TRAb falls (24– 27,33–34). ↑FT4/TT4 (±↑T3) with suppressed TSH; TRAb negative; TSHR pathogenic variant or GNAS mosaicism on genetic testing (28–32). Clinical implication Transient but needs prompt treatment (ATD ± βblocker/iodine/steroids) to prevent complications; structured follow-up until biochemical resolution (25–27,33–34). Requires long-term management (ATD initially; some proceed to surgery/RAI later in childhood/adolescence); family counseling/genetic work-up (28–32). Prevalence (context) Overall neonatal population ~1 in 50,000; in infants of GD mothers ~1–5% (14,17,21,24,26). Extremely rare; only dozens to a few hundred cases reported worldwide across familial/sporadic TSHR mutations and MAS; true population prevalence unknown but far lower than antibody-mediated cases (28–32). Consequences (selected) Cardiac: tachycardia, high-output failure; Neurodevelopmental risk if untreated; Skeletal: accelerated bone age, craniosynostosis; Growth: failure to thrive/poor weight gain; Hepatic: cholestasis; may mimic sepsis (14,17,21,24,26,33). Cardiac strain/arrhythmia; sustained growth acceleration with early epiphyseal fusion; ophthalmopathy less common; long-term thyrotoxicosis complications if not controlled (28–32). GSC Advanced Research and Reviews, 2025, 25(03), 001–014 7 Prognosis / Follow-up Good with timely therapy; spontaneous resolution as TRAb clears (weeks–months). Monitor for rebound hypothyroidism (drugrelated or central) and later thyroid dysfunction—serial TFTs recommended through infancy (15,21,24,26,33,34). Chronic/relapsing course; many require prolonged ATD and later definitive therapy (surgery/RAI when age-appropriate). Lifelong endocrinology follow-up for growth, bone age, cardiac status, and recurrence (28–32). Abbreviations: ATD = antithyroid drugs; GD = Graves’ disease; MAS = McCune–Albright syndrome; TRAb/TSI = TSH-receptor antibodies; TFTs = thyroid function tests. Table 2 clearly distinguishes transient neonatal hyperthyroidism—primarily mediated by transplacental maternal TSHreceptor–stimulating antibodies in Graves’ disease—from permanent neonatal hyperthyroidism driven by intrinsic activating mutations in the TSHR or GNAS genes. While transient forms typically present within the first weeks of life and resolve over 2–6 months as maternal immunoglobulins clear, they still require prompt treatment to prevent cardiac failure, craniosynostosis, cholestasis, failure to thrive, and neurodevelopmental impairment. In contrast, permanent forms are exceedingly rare but clinically important due to their persistent autonomous hormone secretion, need for prolonged antithyroid therapy, and eventual definitive treatment with surgery or radioiodine later in childhood. The table highlights that although both conditions share similar biochemical signatures—elevated T4/T3 with suppressed TSH—maternal antibody status and genetic testing are essential for accurate classification. Prognosis diverges markedly: transient cases generally resolve with careful monitoring, whereas permanent disease demands lifelong endocrine follow-up to prevent growth abnormalities, cardiovascular strain, and long-term thyrotoxic complications. Table 3 Therapeutic interventions, timing, type, dose, duration, sample size, and outcomes in neonatal hyperthyroidism/thyrotoxicosis Interventio n (Ref No.) Timing/Setting Type of therapy Dose (neonate) Typical duratio n N (source) Outcome Methimazole (MMI) (24, 26, 34, 35, 36, 12, 30, 16) Start as soon as diagnosis suspected Thionamide (first-line) 0.25–1.0 mg/kg/day in 2–3 divided doses (start low; titrate to FT4/TSH) 3–6 weeks until TRAb fall; taper/st op when euthyroi d 19 (series), 2 (review cases), 1 (case) Rapid reduction in FT4/T3 within days; prevents cardiac/neurologic complications Propylthiour acil (PTU) (25, 26) (generally avoided) Reserve only when MMI contraindicated Thionamide Historical: 5–10 mg/kg/day in divided doses (avoid due to hepatotoxici ty) Shortest possible course — Effective but hepatotoxicity risk; MMI preferred Propranolol (24, 26, 34, 12, 16) With MMI for symptomatic control; NICU if unstable Non-selective β-blocker ~2 mg/kg/day PO/NG divided q6– 8h (adjust to HR/sympto ms) 3–8 weeks typical (23–57 days) 19 (series), 2 (review cases), 1 (case) Controls tachycardia/irritab ility; decreases T4→T3 conversion Iodine (Lugol's/SSK I) (24, 26, 35, 36, 37) Severe thyrotoxicosis or poor response to MMI; give ≥1 h Blocks hormone release (Wolff– Chaikoff effect); Lugol’s: 1 drop q8h (~8 mg iodine/drop ); SSKI: 1 Several days to ≤2 weeks Case series & reports Rapid FT4/T3 fall; bridge while MMI acts GSC Advanced Research and Reviews, 2025, 25(03), 001–014 8 after first MMI dose reduces organification drop/day (dose varies) Glucocorticoi ds (24, 26) Severe cases or thyroid storm physiology Inhibits T4→T3; reduces secretion Prednisone ~2 mg/kg/day OR hydrocortis one 2 mg/kg q6–8h 3–5 days then taper — Accelerates biochemical control in severe disease Combination therapy (26, 34, 12, 16, 36) (MMI ± propranolol ± iodine) Severe thyrotoxicosis/N ICU Multi-modal blockade As above As above 19 (series), 2 (review cases), 1 (case) Rapid stabilization; careful titration to avoid iatrogenic hypothyroidism Supportive care (12, 24, 26) NICU if decompensated Fluids, oxygen, nutrition; treat cardiac failure — As needed — Stabilization while antithyroid therapy takes effect Long-term follow-up (15, 22, 24, 26, 34) After resolution of transient disease or lifelong in permanent cases TFTs, growth, neurodevelop ment surveillance — Serial checks through infancy; longer in permane nt cases Cohorts/ser ies Detects rebound hypothyroidism or relapse; optimizes growth & neurodevelopment Abbreviations: TRAb = TSH-receptor antibodies; FT4/T3 = free thyroxine/free triiodothyronine; SSKI = saturated solution of potassium iodide; TFTs = thyroid function tests; NICU = neonatal intensive care unit. Table 3 demonstrates that prompt, structured, and dose-guided therapy is essential in neonatal hyperthyroidism to prevent life-threatening complications and preserve neurodevelopmental outcomes. Methimazole remains the first-line treatment at 0.25–1.0 mg/kg/day, typically administered for 3–6 weeks until maternal antibodies clear and thyroid function stabilizes, with propranolol (~2 mg/kg/day) frequently added for early control of tachycardia, irritability, and heightened adrenergic tone. In severe presentations—especially with cardiac compromise or impending thyroid storm—short courses of Lugol’s iodine or SSKI and glucocorticoids help achieve rapid biochemical control while antithyroid drugs take effect. Evidence from case series and neonatal cohorts highlights that most infants respond within days, with many normalizing by 4–10 weeks, though careful dose titration is critical to avoid iatrogenic hypothyroidism. Permanent congenital hyperthyroidism due to TSHR or GNAS mutations may require prolonged antithyroid therapy and later definitive treatment. Across all forms, meticulous follow-up of thyroid function, growth, and neurodevelopment is crucial, as a subset develop transient hypothyroidism or fluctuating thyroid function after treatment. Table 4 Quality Assessment — Primary Cohorts/Series Study (Author, Year) Ref No. Design Population/Setting Other Bias Overall Risk of Bias Notes Song et al., 2024, Hou et al, 2022 11, 34 Retrospective case series 19 neonates with hyperthyroidism Moderate (single center, referral bias) Moderate Clear inclusion criteria; retrospective design limits control of confounders. Abeillondu-Payrat et al., 2014, De 13,27 Prospective cohort 47 TRAb-positive pregnancies Moderate (single center) Low– Moderate Clear TRAb thresholds; objective GSC Advanced Research and Reviews, 2025, 25(03), 001–014 9 Leo et al, 2018 biochemical endpoints. Pyrżak et al., 2022 15 Follow-up cohort Children with neonatal hyperthyroidism (follow-up) Moderate (selection, survivorship bias) Moderate Longitudinal outcomes; potential attrition. Luz et al., 2020 19 Retrospective series Infants of GD mothers (15-year series) Moderate (single center) Moderate Service-based cohort; heterogeneity in care. Spanish cohort, 2021 (Benlarbi et al.) 21 Retrospective cohort Infants of mothers with GD (tertiary unit) Moderate (referral bias) Moderate Cohort completeness unclear. Mamat, 2022 22 Case series/registry description Neonates of hyperthyroid mothers (ASEAN) Moderate (heterogeneous care) Moderate Variable follow-up; regional differences. Benlarbi et al., 2021 (Europe) 21 Prospectiveretrospective (mixed) High-risk neonates Moderate (multicenter variability) Moderate Prevalence/course estimates; confounding possible. Table 4 : Across primary studies, risk of bias is mostly moderate due to observational designs, heterogeneity of care, and variable follow-up. The Abeillon-du-Payrat 2014 prospective TRAb-defined cohort provides the strongest evidence. Objective biochemical markers (TSH, FT4/T3, TRAb) consistently reduce detection bias and strengthen reliability for prevalence and treatment response estimates. Figure 1 Forest-style plot showing risk of bias scores for primary neonatal hyperthyroidism studies Risk of bias was categorized based on study design, selection bias, follow-up completeness, and objectivity of biochemical endpoints. Scores were coded as 1.5 for “Low–Moderate” and 2.0 for “Moderate” risk. The dashed vertical line reflects the average quality level across studies. Most studies demonstrated moderate risk of bias due to retrospective design and referral patterns, with one prospective TRAb-guided cohort (Abeillon-du-Payrat 2014) demonstrating comparatively higher methodological rigor. Lower scores reflect lower risk of bias.