This single-center, randomized, open-label trial was approved by the Fujian Provincial Hospital Institutional Review Board (K2022-06-016) and the research ethics board. The trial was registered under ChiCTR2300076803. Recruitment, treatment, and follow-up were conducted from July 2022 to December 2023.

Participants in this clinical trial received compensation for their time and involvement. Compensation was provided to recognize the participants’ contributions and to help offset any expenses associated with their participation. Participants who attend the screening visit will receive compensation for their time and travel expenses. Participants will be compensated for each study visit attended. This includes time spent on medical assessments, laboratory tests, and any other required procedures (¥500-600, US $70-$80). Any out-of-pocket expenses incurred during participation, such as transportation or childcare, may be reimbursed upon submission of receipts. Upon successful completion of all study visits, participants will receive a completion bonus (¥1000, US $150).

Study participants were conveniently recruited from the Fujian Provincial Hospital outpatient practice and prescreened during appointments scheduled for SCH evaluations. Eligibility was confirmed through in-person assessments to ensure compliance with inclusion criteria. Written informed consent was obtained from all participants, and all data were anonymized or deidentified to protect confidentiality.

The inclusion criteria were as follows: pregnant women diagnosed with SCH, as defined by the 2017 American Thyroid Association Guidelines for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum (serum thyrotropin levels above the pregnancy-specific upper reference limit, or ≥4.0 mIU/L, with normal FT4 levels [16]), diagnosis and initiation of LT4 treatment before 8 weeks of gestation, singleton pregnancy, and age ≥18 years. The exclusion criteria were a history of thyroid disease; history of residence in areas with endemic goiter; use of LT4 before pregnancy or medications that affect thyroid function; history of nonthyroidal autoimmune diseases; preexisting cardiovascular, liver, or kidney diseases; or any prepregnancy condition that could interfere with the study. A total of 60 participants were enrolled in the trial.

Participants were randomly assigned in a 1:1 ratio to either the standard or metaverse group using computer-generated randomization. Both groups were managed by the same medical team. Investigators and participants were not masked to treatment allocation. The research team, data manager, and statistician were aware of group assignments during the process of data collection. Data were securely stored in the Fujian Provincial Hospital database, with the first author overseeing data accuracy and integrity. No placebo was used in the study. As predefined guidelines exist for LT4 use, the potential bias introduced by the nonblinded design on the primary outcome was considered minimal.

The research team comprised a chief endocrinologist, an attending endocrinologist, an obstetrician-gynecologist, and a physician specializing in health management, all with extensive experience in thyroid disorder management. Eligible patients were prescribed oral LT4 (Euthyrox, Berlin-Chemie AG, Germany; H20110178, 50 μg × 100 tablets) based on thyroid function test results [16]. Initial dosages ranged from 25 to 50 μg and were adjusted according to pregnancy status [16]. Patients took one tablet daily on an empty stomach in the morning, with thyrotropin and FT4 levels monitored every 14 days for dose adjustments. Once thyrotropin levels were within 0.1-2.5 mIU/L, monitoring was conducted every 4 weeks, with doses adjusted to maintain trimester-specific target ranges [16]. Treatment continued consistently until delivery.

Participants in the standard group attended regular in-person follow-ups to monitor blood pressure, heart rate, weight, thyroid function, medication dosage, and other pregnancy-related indicators. Participants in the metaverse group only visited the hospital for enrollment, blood tests, and required pregnancy assessments. Follow-ups for the metaverse group were conducted through the platform, with medications delivered to their homes. The metaverse platform enabled secure communication between participants and investigators at any time, enhancing adherence to treatment protocols. Technical support was provided, with hardware promptly replaced if issues could not be resolved remotely. Participants used home monitoring devices under investigator guidance, with training provided for platform use. Weekly assessments ensured proficiency. Participants identified as “unfamiliar” received additional training until they could fully engage in medical activities on the platform. The platform supported uploading and recording thyroid function test results and other relevant health data. It also offered lifestyle guidance, psychological counseling, and educational games focused on endocrinology. Immersive experiences using Pico VR glasses (Fujian Huayu Education Technology Co Ltd, China) provided gamified learning and live discussions with physicians. The standard group participated in similar educational activities during weekly in-person sessions.

Adverse pregnancy outcomes were tracked through follow-ups and patient self-reports. Offspring neurobehavioral development was assessed using Gesell Development Scale (GDS) scores at 1 and 3 months of age, evaluating gross motor, fine motor, adaptability, language, and personal-social skills. Maternal mental health was assessed using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) at baseline, during the last trimester, and 6 weeks post partum. Psychological support was offered based on the SAS/SDS results, with interventions delivered via the metaverse platform for the metaverse group and through outpatient sessions for the standard group.

The intervention spanned from pregnancy through 3 months post partum, with participation continuing unless interrupted by withdrawal or loss to follow-up.

The primary outcomes of the study focused on assessing adverse maternal and offspring outcomes. Maternal adverse outcomes included gestational diabetes, gestational hypertension, premature rupture of membranes, amniotic fluid abnormalities, postpartum hemorrhage, and related complications [17]. Offspring adverse outcomes included fetal distress, abortion, stillbirth, preterm birth, neonatal asphyxia, and related complications [13,17]. Secondary outcomes focused on offspring neurobehavioral development and maternal mental health. Neurobehavioral development was considered normal if the developmental quotient on the GDS exceeded 85 [18]. Anxiety was defined as SAS scores greater than 50, and depression was defined as SDS scores greater than 53 [19]. Investigators conducted GDS assessments, while participants completed SAS and SDS questionnaires independently, which were collected immediately after completion.

Based on a significance level of 5%, statistical power of 90%, and an anticipated 5% loss to follow-up, a total of 60 participants (30 per group) was calculated as sufficient for this randomized controlled trial.

Quantitative data were expressed as means and SDs, while categorical data were presented as percentages. Between-group comparisons of normally distributed variables used the independent samples 2-tailed t test or Mann-Whitney U test, while categorical variables were analyzed using Pearson χ² test or Fisher exact test. Analysis of covariance, with baseline thyroid function and initial psychological scores as covariates, was performed to assess postintervention differences in thyroid function and psychological outcomes between groups. Statistical analyses were conducted using SPSS 25.0 (IBM Corp), with a P value <.05 considered statistically significant.

Between July 2022 and July 2023, 87 individuals were screened for eligibility, with 60 participants randomized equally into the standard group (n=30) and the metaverse group (n=30; Figure 1). By December 2023, all participants had completed the trial, including follow-up through 3 months post partum (Figure 2).

The median age of participants was 30 years in both groups, with age ranges of 20-40 years in the standard group and 23-38 years in the metaverse group. The median gestational age at delivery was 39 weeks, ranging from 23 to 40 weeks in the standard group and 36 to 40 weeks in the metaverse group. The median prepregnancy BMI was 22.8 (IQR 15.8-32.7) kg/m² in the standard group and 21.5 (IQR 17.6-30) in the metaverse group. There were 19 (63%) nulliparous participants in the standard group and 18 (60%) in the metaverse group. Three participants in each group had a history of obstetric abnormalities (Table 1).

At baseline, the mean thyrotropin levels were 4.6 (SD 1.4) mIU/L in the standard group and 4.4 (SD 0.9) mIU/L in the metaverse group. After LT4 treatment, the mean thyrotropin level at delivery was 2.0 (SD 0.1) mIU/L in the standard group and 1.9 (SD 0.1) mIU/L in the metaverse group (P=.83). At 6 weeks post partum, the mean thyrotropin levels were 2.7 (SD 0.1) mIU/L in both groups (P=.78).

Maternal adverse outcomes occurred in 43% (13/30) of the standard group and 37% (11/30) of the metaverse group (P=.60). These included gestational diabetes, preeclampsia, premature rupture of membranes, and amniotic fluid abnormalities (Table 2). Offspring baseline characteristics showed no significant differences between the two groups (Table S1 in Multimedia Appendix 1). The median birthweight was 3290 (IQR 1830-3940) g in the standard group and 3315 (IQR 2870-3660) g in the metaverse group (P=.91). Two newborns in the standard group were diagnosed as small for gestational age. Adverse offspring outcomes were significantly lower in the metaverse group (2/30, 7%) compared to the standard group (10/30, 33%; P=.01). These outcomes included preterm birth, fetal distress, neonatal intensive care unit admissions, and neonatal hypoxemia (Table 3).

Neonatal thyroid function showed no significant differences between the groups at birth, 14 days post partum, and 28 days post partum (Tables S2-S4 in Multimedia Appendix 1). The median thyrotropin levels at birth were 7.0 (IQR 3.2-16.2) mIU/L in the standard group and 6.2 (IQR 3.0-16.4) mIU/L in the metaverse group (P=.31). By 14 days post partum, the median thyrotropin level had decreased to 5.3 (IQR 3.5-7.8) mIU/L in the standard group and 5.0 (IQR 3.2-5.7) mIU/L in the metaverse group (P=.26). At 28 days post partum, median thyrotropin levels were 4.8 (IQR 3.2-6.1) mIU/L in the standard group and 4.7 (IQR 3.2-5.4) mIU/L in the metaverse group (P=.68). FT4 levels also showed no significant differences between the groups at any time point (all P>.05).

At 1 month of age, neurobehavioral scores showed no significant differences between the groups across all domains (Table 4). The median scores for the standard group in gross motor, fine motor, adaptability, language, and social-emotional domains were 99 (IQR 85.5-109.8), 100 (IQR 83.3-109), 99 (IQR 86-107.3), 101.25 (IQR 85-106.8), and 101 (IQR 87.8-107), respectively. The corresponding scores for the metaverse group were 100 (IQR 90.8-109), 100.9 (IQR 93-108), 100 (IQR 95-109.0), 102 (IQR 94-107.8), and 100.5 (IQR 92-109), respectively. At 3 months of age, similar results were observed, with neurobehavioral scores remaining comparable between groups (Table 4). The median scores for the standard group were 100 (IQR 88-111) for gross motor, 101 (IQR 89-113.3) for fine motor, 102.8 (IQR 88-112.8) for adaptability, 103.7 (IQR 88.8-111.3) for language, and 104.0 (IQR 90.8-111) for social-emotional domains. Scores for the metaverse group were 102 (IQR 92.8-109.8), 103.0 (IQR 95-112.8), 104 (IQR 96-114), 104.4 (IQR 96-111.0), and 104.9 (IQR 92.8-110), respectively.

Maternal mental health outcomes were assessed via the SAS and SDS. The baseline of the mean SAS scores was 44.1 (SD 8.3) in the standard group and 43.8 (SD 7.9) in the metaverse group. It showed significantly lower scores in the metaverse group compared to the standard group at delivery (SAS: mean 44.9, SD 1.0 vs mean 50.0, SD 1.0; P=.001; SDS: mean 44.7, SD 0.9 vs mean 49.7, SD 0.9; P<.001). This trend persisted at 6 weeks post partum, with the metaverse group continuing to exhibit lower scores (SAS: mean 46.9, SD 1.0 vs mean 51.3, SD 1.0; P=.002; SDS: mean 47.9, SD 1.0 vs mean 51.6, SD 1.0; P=.009).