Reproductive Factors and Disease Progression in Differentiated Thyroid Cancer: A Large Retrospective Cohort Study of 1,098 Chinese Women

Reproductive Factors and Disease Progression in Differentiated Thyroid Cancer: A Large Retrospective Cohort Study of 1,098 Chinese Women | 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 Study protocol Reproductive Factors and Disease Progression in Differentiated Thyroid Cancer: A Large Retrospective Cohort Study of 1,098 Chinese Women Leijun He, Yuyao Zhang, Lujing Xiong, Hao Ai, Yongcong Cai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8553244/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background: Differentiated thyroid carcinoma (DTC) shows a marked female predominance, particularly during reproductive years, implicating sex hormones and reproductive factors in its pathogenesis. However, evidence regarding the impact of reproductive variables—such as age at menarche, parity, and pregnancy history—on disease progression remains inconsistent, especially in Chinese women. Large‑scale studies addressing this issue are limited. This study aimed to evaluate the association between reproductive history and clinicopathological aggressiveness in female patients with DTC. Methods: We conducted a single‑center retrospective cohort study of 1,098 female patients with DTC who underwent surgical resection between June 2014 and February 2024. Data on reproductive history and tumor characteristics were collected. Group comparisons were performed using standard statistical tests, and multivariable logistic regression was applied to adjust for confounders and estimate odds ratios (ORs) with 95% confidence intervals (CIs). The study was performed in accordance with the ethical principles of the Declaration of Helsinki and relevant institutional guidelines.The study was approved by the Institutional Review Board of Sichuan Cancer Hospital (SCCHEC‑02‑2025‑148), with informed consent waived. Results: Multivariable analysis identified early (≤11 years) and late menarche (≥15 years) as independent predictors of advanced clinical stage (OR=7.60, 95%CI:2.76–20.92; OR=3.10, 95%CI:1.31–7.35, respectively). Parity demonstrated a dose-response relationship with disease severity, with ≥3 births being the strongest predictor of advanced stage (OR=23.19, 95%CI:11.00–59.64). Nulliparity showed protective effects against advanced staging (OR=0.03, 95%CI:0.01–0.23).Reproductive factors exhibited compartment-specific nodal metastasis patterns: nulliparity associated with central compartment involvement (OR=1.69, 95%CI:1.25–2.28), while ≥5 pregnancies linked to lateral neck metastasis (OR=2.37, 95%CI:1.29–4.36). Parity ≥3 correlated with both local invasion (T3/T4: OR=4.12, 95%CI:2.13–7.97) and metastases in central (OR=3.81, 95%CI:1.67–8.69) and lateral neck compartments (OR=4.24, 95%CI:2.24–8.00). Conclusion: Abnormal menarche timing, multiple pregnancies, and high parity independently predict more advanced and aggressive DTC in Chinese women, with clear dose–response relationships. Incorporating reproductive history into clinical risk stratification may improve identification of high‑risk patients and guide individualized management. differentiated thyroid carcinoma reproductive factors disease progression risk factors retrospective cohort study Figures Figure 1 Figure 2 Figure 3 1. Introduction: Thyroid cancer has emerged as one of the fastest growing malignancies worldwide, with its prevalence rising sharply over the past two decades [ 1 – 3 ] . In China, this trend is particularly striking, as the age-standardized incidence rate nearly tripled from 3.21 to 9.61 per 100,000 between 2005 and 2015, a pace that exceeds the global average [ 4 ] . A notable epidemiological feature of thyroid cancer is its pronounced gender disparity: women are affected approximately three times more often than men [ 5 ] . This difference is most evident during reproductive years (20–49 years), when the female-to-male ratio may reach 4.1:1, suggesting that sex hormones and reproductive factors could play a critical role in the onset and progression of differentiated thyroid carcinoma (DTC) [ 6 – 8 ][ 25 ] . Estrogen is widely recognized as a key factor underlying the gender disparity in thyroid cancer. By binding to estrogen receptors on thyroid cells, estrogen activates oncogenic signaling cascades such as MAPK and PI3K/Akt, which promote cellular proliferation, migration, and invasion [ 11 – 14 ] . In parallel, improvements in nutritional status have led to earlier pubertal onset, thereby extending the cumulative duration of estrogen exposure across the lifespan [ 15 ][ 16 ] . Moreover, many Chinese women born in the 1960s and 1970s—shaped by historical fertility policies—experienced multiple pregnancies, each accompanied by repeated surges in estrogen levels [ 24 ] . Together, these elements create a distinctive reproductive hormone exposure profile in Chinese women, which may contribute to heightened susceptibility to differentiated thyroid carcinoma. . Despite plausible molecular mechanisms linking reproductive factors to thyroid cancer, epidemiological evidence remains inconsistent and fragmented, underscoring the need for further investigation. While several studies have identified early menarche, high parity, and multiple pregnancies as potential risk factors [ 17 – 20 ] , large-scale cohort analyses in European populations, including Norway and Sweden, have failed to confirm these associations [ 21 – 23 ] . Such discrepancies may reflect differences in population characteristics, study design, and approaches to confounder adjustment. Importantly, most prior research has focused on disease etiology, leaving the determinants of disease progression largely unexplored. Although differentiated thyroid carcinoma (DTC) generally carries a favorable prognosis, its clinical behavior is heterogeneous; a subset of patients develops aggressive features such as nodal or distant metastases and extrathyroidal extension, which significantly worsen outcomes. This highlights a critical knowledge gap regarding the influence of reproductive history on tumor aggressiveness, particularly in relation to advanced TNM stage and lymph node burden. To address this critical gap, we conducted a large hospital-based retrospective cohort study of Chinese women who underwent surgical treatment for differentiated thyroid carcinoma (DTC) at a tertiary academic center between 2014 and 2024. The primary objective was to examine the associations between key reproductive factors—including age at menarche, parity, and pregnancy history—and indicators of tumor aggressiveness, specifically advanced clinical stage and lymph node metastasis. 2. Materials and Methods 2.1 General Data 2.1.1 Study Population A retrospective cohort analysis was performed on female patients with differentiated thyroid carcinoma (DTC) who underwent surgical treatment at the Department of Head and Neck Surgery of Sichuan Cancer Hospital between June 2014 and February 2024. Clinical data were extracted from medical records to ensure accuracy and minimize recall bias(Figure 1 ). 2.1.2 Inclusion Criteria (1) Patients admitted for thyroid nodules; (2) Treated in the Department of Head and Neck Surgery at Sichuan Cancer Hospital; (3) Pathological diagnosis of differentiated thyroid carcinoma; (4) Age ≥ 18 years; (5) Female patients. 2.1.3 Exclusion Criteria (1) Missing or incomplete clinical information; (2) No surgical treatment performed; (3) Histopathological diagnosis other than DTC. 2.1.4 Grouping Information Collected reproductive variables included age at menarche, number of pregnancies, and parity. Menarche age ranged from 7 to 19 years (SD = 1.3). National survey data indicate that the mean age of menarche among Chinese female students declined from 12.8 years in 2005 to 12.3 years in 2014 [ 27 ] . For analysis, menarche was categorized as: (1) ≤ 11 years (early), (2) 12–14 years (normal), and (3) ≥ 15 years (late). Pregnancy history ranged from 0 to 9, and parity from 0 to 6. These distributions reflect historical fertility trends in China, where average pregnancies per woman decreased from 5.37 in 1982 to 1.62 in 2015, with current total fertility rates between 1.0 and 1.3 [ 28 – 30 ] . Clinical staging is classified into early-stage (Stages I and II) and advanced-stage (Stages III and IV); TNM staging, tumor size, and local invasion are categorized into a low-risk group (T1-T2) and a medium-high-risk group (T3-T4) [ 31 ] . 2.2 Research Methods A retrospective clinical study was conducted on female patients diagnosed with differentiated thyroid carcinoma (DTC) who underwent surgical treatment in the Department of Head and Neck Surgery at Sichuan Cancer Hospital between June 2014 and February 2024. Clinical data were collected from medical records, including demographic information (age, body mass index [BMI]), reproductive history (age at menarche, pregnancy and delivery history), and tumor characteristics (TNM stage, clinical stage, postoperative pathology, and lymph node metastasis). Associations between reproductive variables (menarche age, number of pregnancies, and parity) and clinicopathological outcomes (lymph node metastasis, clinical stage, tumor size, and local invasion) were analyzed. The objective was to determine whether reproductive history was significantly correlated with disease progression in female patients with DTC. 2.3 Statistical Methods A database was established using Excel 2019 to organize and clean the collected data. Quantitative variables were expressed as mean ± standard deviation, while categorical variables were presented as frequency and percentage. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corporation, Armonk, NY, USA). Group comparisons were conducted using appropriate statistical tests: t-tests for normally distributed quantitative data, Mann–Whitney U tests for non-normally distributed quantitative data, and chi-square or Fisher’s exact tests (when expected frequency < 5) for categorical variables. Multivariable logistic regression models were applied to evaluate associations between reproductive factors (age at menarche, number of pregnancies, and parity) and clinicopathological features of differentiated thyroid carcinoma, including TNM stage, T stage, and lymph node metastasis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate effect sizes. All hypothesis tests were two-tailed, and statistical significance was defined as P < 0.05. 3. Results and Analysis 3.1 Correlation between Age at Menarche and Disease Advancement in Differentiated Thyroid Carcinoma 3.1.1 Correlation between Age of Menarche and Clinical Staging. A univariate rank-sum test revealed significant differences in clinical stage distribution among patients with varying menarcheal ages (χ² = 23.45, P = 0.003) (Table 3-1). Multivariate logistic regression analysis of 981 patients demonstrated that, after adjustment for age and BMI, early menarche (≤11 years) was independently associated with advanced disease stage (III/IV), conferring a 7.60-fold increased risk compared with the reference group (12–14 years) (OR = 7.60, 95% CI: 2.76–20.92, P < 0.001). Similarly, late menarche (≥15 years) was significantly correlated with disease progression, with patients exhibiting a 3.10-fold higher risk of advanced-stage disease relative to the reference group (OR = 3.10, 95% CI: 1.31–7.35, P = 0.010) (Table 3-1). Table 3-1: Impact of Different Menarche Timing on Tumor Staging Age at menarche Clinical Stage χ² P OR （ 95% CI ） P-value Stage I and II Stage III and IV Early Normal(ref) Late 47 (4.93) 714 (74.92) 192 (20.15) 6 (21.43) 12 (42.86) 10 (35.71) 23.45 0.003 7.60（2.76–20.92） 1.00 3.10（1.31–7.35） <0.001 - 0.010 3.1.2 Correlation between Age at Menarche and Lymph Node Metastasis Chi-square analyses revealed no significant differences in the distribution of central compartment lymph node metastasis (χ² = 1.755, P = 0.416) or lateral neck lymph node metastasis (χ² = 0.240, P = 0.887) among patients stratified by age at menarche (Table 3-2). These findings indicate that menarcheal age was not correlated with the occurrence of lymph node metastasis in differentiated thyroid carcinoma (DTC), suggesting that reproductive timing does not influence nodal involvement in this cohort. Table 3-2: Effect of Different Menarche Timing on Lymph Node Metastasis Age at menarche Central Zone Lymph Node Metastasis Lateral Neck Lymph Node Metastasis Yes No Yes No Early Normal Late Total χ² P 29 (4.74) 465 (75.98) 118 (19.28) 612 24 (6.50) 261 (70.73) 84 (22.76) 369 17 (5.86) 213 (73.45) 60 (20.69) 290 36 (5.99) 513 (85.36) 142 (23.63) 601 1.755 0.240 0.416 0.887 3.1.3 Correlation Between Age at Menarche and T Staging T staging in DTC reflects disease advancement by assessing tumor size and local invasion, thereby guiding surgical planning, adjuvant therapy, and follow-up strategies. Chi-square analysis demonstrated no significant differences in T stage distribution among patients stratified by age at menarche (χ² = 2.145, P = 0.342) (Table 3-3). These findings indicate that menarcheal age was not associated with tumor dimensions or local invasiveness in this cohort. Table 3-3: Effect of different menarche timing on tumor size and local invasion Menarche Stage T Stage Total χ² P T1+T2 T3+T4 Early Normal Late Total 48 (5.71) 625 (74.32) 168 (19.98) 841 5 (3.57) 101 (72.14) 34 (24.29) 140 53 (5.40) 726 (74.01) 202 (20.59) 981 2.145 0.342 3.2 Correlation Between Pregnancy Count and Patients Diagnosed with Differentiated Thyroid Carcinoma 3.2.1 Correlation Between Various Pregnancy Counts and Tumor Clinical Staging Univariate analysis revealed a significant association between pregnancy count and clinical stage of DTC (χ² = 40.520, P < 0.001; Table 3-4). Patients with stage III/IV disease had markedly higher rates of 3–4 pregnancies (39.29% vs. 13.35%) and ≥5 pregnancies (28.57% vs. 4.79%). Multivariate logistic regression, adjusted for age, BMI, and menarcheal age, confirmed that 3–4 pregnancies (OR = 5.91, 95% CI: 2.54–13.74, P < 0.001) and ≥5 pregnancies (OR = 18.56, 95% CI: 6.43–53.58, P < 0.001) were independent risk factors for advanced-stage disease, demonstrating a clear dose–response relationship. Conversely, nulliparity was associated with a significantly reduced risk compared with 1–2 births (OR = 0.08, 95% CI: 0.01–0.60, P = 0.014) (Table 3-4). These findings underscore parity as a key reproductive determinant of DTC progression, warranting closer monitoring in patients with three or more pregnancies. Table 3-4: Impact of different numbers of pregnancies on thyroid cancer staging Number of Pregnancies Tumor Stage χ ² P OR(95% CI) P-value Stage I and II Stage III and IV 0 times 1 - 2 times(ref) 3 - 4 times 5 times or more 282 (29.90) 505 (53.55) 120 (12.73) 39 (4.14) 1 (3.57) 8 (28.57) 11 (39.29) 8 (28.57) 40.52 <0.001 0.08（0.01 - 0.60） - 5.91（2.54 - 13.74） 18.56（6.43 - 53.58） 0.014 - <0.001 <0.001 3.2.2 Correlation Between Number of Pregnancies and Lymph Node Metastasis Pregnancy count was significantly associated with lymph node metastasis in DTC. The central compartment showed the highest metastasis rate in nulliparous patients (70.6%, 207/293), compared with 57.4% in the 1–2 pregnancies group, 62.6% in the 3–4 group, and 63.8% in the ≥5 group(Table 3-5). Multivariable analysis confirmed that nulliparity independently increased central metastasis risk relative to 1–2 pregnancies (OR = 1.69, 95% CI: 1.25–2.28, P < 0.001), whereas 3–4 and ≥5 pregnancies were not significant(Table 3-6). In the lateral neck, metastasis rates rose with pregnancy count (31.7% in nulliparous patients, 25.5% in 1–2, 35.1% in 3–4, and 44.7% in ≥5). Adjusted models indicated that only ≥5 pregnancies were significantly associated with lateral metastasis (OR = 2.37, 95% CI: 1.29–4.36, P = 0.0052)(Table 3-6). These findings suggest a compartment-specific pattern: central metastasis risk is elevated in nulliparous women, while lateral metastasis requires very high pregnancy exposure. Table 3-5 Effect of Number of Pregnancies on Lymph Node Metastasis Number of Pregnancies Central Zone Lymph Node Metastasis Lateral Neck Metastasis Yes No Yes No 0 times 1 - 2 times 3 - 4 times 5 times or more Total χ² P 207 (33.82) 293 (47.88) 82 (13.40) 30 (4.90) 612 86 (23.31) 217 (58.81) 49 (13.28) 17 (4.61) 369 93 (32.07) 130 (44.83) 46 (15.86) 21 (7.24) 290 200 (33.28) 380 (63.23) 85 (14.14) 26 (4.33) 601 15.32 9.76 0.002 0.021 Table 3-6 Association Between Pregnancy Count and Lymph Node Metastasis Number of Pregnancies Central Compartment Metastasis OR （ 95% CI ） P-value Lateral Neck Metastasis OR (95% CI) P-value 0 times 1.69 (1.25–2.28) <0.001 1.13 (0.82–1.56) 0.44 1 - 2 times(ref) 1.00 - 1.00 - 3 - 4 times 1.25 (0.84–1.85) 0.27 1.28 (0.84–1.95) 0.25 5 times or more 1.31 (0.72–2.39) 0.38 2.37 (1.29–4.36) 0.0052 3.2.3 Correlation Between Pregnancy Count and T Staging Pregnancy number was significantly associated with tumor T stage (χ² = 16.75, P < 0.001; Table 3-7). Multivariate analysis confirmed that ≥5 pregnancies independently increased the risk of T3/T4 disease (OR = 3.28, 95% CI: 1.73–6.21, P < 0.001), while other groups showed no significant differences compared with 1–2 pregnancies (Table 3-7). These results highlight high parity as a risk factor for local tumor invasiveness in DTC. Table 3-8: Impact of Varying Pregnancy Counts on Tumor Dimensions and Extent of Local Invasion Pregnancy Grading T Stage χ² P OR(95% CI) P-value T1+T2 T3+T4 0 times 1 - 2 times(ref) 3 - 4 times 5 times or more 250 (29.73) 446 (53.03) 114 (13.56) 31 (3.69) 43 (30.71) 64 (45.71) 17 (12.14) 16 (11.43) 16.75 <0.001 0.81（0.53 - 1.23） 1.00 0.95（0.54 - 1.67） 3.28（1.73 - 6.21） 0.32 - 0.86 <0.001 3.3 Correlation between Birth Rate and Incidence of Differentiated Thyroid Carcinoma 3.3.1 Correlation between Parity and Tumor Stage Chi-square analysis revealed a significant correlation between parity and clinical stage in DTC (χ² = 63.58, P < 0.001; Table 3-9). Multivariate logistic regression of 981 patients, adjusted for pregnancy count, demonstrated that ≥3 births were independently associated with progression to advanced stages (III/IV) (OR = 23.19, 95% CI: 11.00–59.64, P < 0.001). Conversely, nulliparous women exhibited a markedly reduced risk compared with those having 1–2 births (OR = 0.03, 95% CI: 0.01–0.23, P < 0.001), suggesting a protective effect of nulliparity against disease advancement (Table 3-9). These findings underscore high parity (≥3 births) as a robust independent risk factor for advanced-stage DTC. Table 3-9: Effect of Different Birth Counts on Thyroid Cancer Tumor Staging Number of births Tumor Staging χ² P OR (95% CI) P-value Stage I and II Stage III and IV 0 times 1 - 2 times(ref) 3 - 4 times and 5 times or more 300 (31.81) 624 (66.17) 29 (2.76) 1 (3.57) 13 (46.43) 14 (42.86) 63.58 <0.001 0.03 (0.01–0.23) 1.00 23.19 (10.56–50.93) <0.001 - <0.001 3.3.2 Correlation between Birth Rate and Lymph Node Metastasis Parity was also significantly correlated with nodal involvement. Central compartment metastasis rates were 69.8% in nulliparous women, 57.5% in the 1–2 births group, and 81.6% in the ≥3 births group (χ² = 22.72, P < 0.001)(Table 3-10). Multivariable regression confirmed that ≥3 births independently increased central metastasis risk (OR = 3.81,95% CI: 1.67–8.69, P = 0.0028)(Table 3-11). For the lateral neck, metastasis rates were 31.6% in nulliparous women, 26.5% in the 1–2 births group, and 60.5% in the ≥3 births group (χ² = 9.01, P = 0.011)(Table 3-10).Adjusted models demonstrated a strong association between ≥3 births and lateral metastasis (OR = 4.24, 95% CI: 2.24 - 8.00, P < 0.001)(Table 3-11).These results highlight parity as a robust predictor of nodal involvement, with both central and lateral compartments significantly affected when ≥3 births are present. Table 3-10 Correlation between Various Parity Levels and Lymph Node Metastasis Lymph Nodes Metastasis Outcome Number of Parities 0 times 1 - 2 times ≥3 times Total χ² P Central Zone Lymph Node Metastasis Yes No 210(69.76) 91(30.23) 366(57.46) 271(42.54) 36(81.58) 7(18.42） 612（62.39） 369（37.61） 22.72 <0.001 Lateral Neck Lymph Node Metastasis Yes No 95(31.56) 206(68.44) 169(26.53) 468(73.47) 26（60.53） 17（39.48） 290（29.56） 691（70.44） 9.01 0.011 Table 3-11 Association Between Parity Count and Lymph Node Metastasis Number of parities Central Compartment Metastasis OR （ 95% CI ） P-value Lateral Neck Metastasis OR (95% CI) P-value 0 times 1.71 (1.28–2.29) <0.001 1.28 (0.95–1.72) 0.11 1 - 2 times(ref) 1.00 - 1.00 - ≥3 times 3.81 (1.67–8.69) 0.0028 4.24 (2.24–8.00) <0.001 3.3.3 Correlation between Pregnancy Count and T Staging Chi-square analysis revealed a significant correlation between parity and tumor T stage, reflecting tumor size and local invasion (χ² = 19.75, P < 0.001; Table 3-13). Multivariate logistic regression, adjusted for age, BMI, and menarcheal age, demonstrated that ≥3 births were independently associated with advanced T3/T4 staging (OR = 4.12, 95% CI: 2.13–7.97, P < 0.001), corresponding to a more than fourfold increased risk compared with the 1–2 birth group (Table 3-12). No significant differences were observed between nulliparous women and the reference cohort. Table 3-12: Effects of different parity levels on tumor size and degree of local invasion Parity Grading T Stage X2 P OR （ (95% CI) ） P-value T1+T2 T3+T4 0 times 257 (30.56) 44 (31.43) 19.75 <0.001 1.19（0.80–1.77） 0.39 1-2 times(ref) 557 (66.23) 80 (57.14) 1 - 3-4 times 27 (3.21) 16 (11.42) 4.12（2.13–7.97） <0.001 4. Results 4.1 Association Between Reproductive Factors and Clinical Stage Multivariate logistic regression analysis revealed that several reproductive factors were significantly associated with advanced clinical stage (III/IV) in DTC patients. As shown in Figure A, early menarche (≤11 years) was strongly linked to advanced disease (OR = 7.60, 95% CI: 2.76–20.92, P < 0.001), and late menarche (≥15 years) also conferred increased risk (OR = 3.10, 95% CI: 1.31–7.35, P = 0.010). Among all variables, high parity (≥3 births) emerged as the strongest predictor (OR = 23.19, 95% CI: 11.00–59.64, P < 0.001), followed by ≥5 pregnancies (OR = 18.56, 95% CI: 6.43–53.58, P < 0.001) and 3–4 pregnancies (OR = 5.91, 95% CI: 2.54–13.74, P < 0.001). Conversely, nulliparity exerted a significant protective effect (OR = 0.03, 95% CI: 0.01–0.23, P < 0.001). These findings demonstrate a clear dose–response relationship between reproductive history and disease progression. 4.2 Association Between Reproductive Factors and Local Invasion As illustrated in Figure B, parity and pregnancy count were independently associated with local tumor invasion (T3/T4 stage). Women with ≥3 births had a significantly elevated risk of local invasion (OR = 4.12, 95% CI: 2.13–7.97, P < 0.001), and ≥5 pregnancies showed similar effects (OR = 3.28, 95% CI: 1.73–6.21, P 0.05). These results suggest that reproductive burden, particularly high parity and multiple pregnancies, is a robust predictor of tumor invasiveness, whereas pubertal timing does not appear to influence local extension. 4.3 Association with lymph node metastasis Compartment-specific effects of reproductive factors on lymph node metastasis were observed, as shown in Figure C. Nulliparity was independently associated with increased central compartment metastasis (OR = 1.69, P < 0.001), while lateral neck metastasis was significantly elevated only in patients with ≥5 pregnancies (OR = 2.37, P = 0.0052). In contrast, parity ≥3 births was strongly associated with both central (OR = 3.81, P = 0.0028) and lateral metastasis (OR = 4.24, P 0.05). These findings indicate that reproductive history influences nodal spread in a compartment- and measure-specific manner: central metastasis risk is elevated in nulliparous and high-parity patients, whereas lateral metastasis is driven by heavy reproductive exposure. 4.4 Dose–response relationship Taken together, reproductive factors demonstrated a consistent dose–response relationship with disease progression. Increasing numbers of pregnancies and births were associated with progressively higher risks of advanced clinical stage, local invasion, and lymph node metastasis. Conversely, nulliparity consistently conferred a protective effect across multiple analyses. 5. Discussion 5.1 Correlation Between Age at Menarche and Differentiated Thyroid Carcinoma Our study demonstrated that both early menarche (≤ 11 years) and late menarche (≥ 15 years) were independently associated with advanced-stage DTC, while no significant associations were observed with lymph node metastasis. These findings suggest that reproductive timing primarily influences overall stage progression rather than nodal dissemination. Prior studies have reported inconsistent results. He et al. [ 27 ] and Xhaard et al. [ 32 ] identified early menarche as a risk factor, whereas Sakoda et al. [ 33 ] and Wang et al. [ 36 ] suggested increased risk or protective effects with later onset. Other investigations, including Galanti et al. [ 35 ] and a meta-analysis by Cao et al. [ 34 ] , found no correlation. Such discrepancies may reflect differences in population genetics, study design, and whether endpoints assessed incidence or progression. Mechanistically, early menarche extends cumulative estrogen exposure, activating ER-mediated pathways such as MAPK/ERK and PI3K/Akt [ 9 ][ 10 ] , while delayed menarche may reflect endocrine dysregulation [ 11 ] . Estrogen also remodels the tumor microenvironment, promoting angiogenesis, immune modulation, and fibroblast activation [ 40 ] , and enhances tumor stemness via lncRNA H19 [ 38 ] or proliferation through suppression of miR-570-3p [ 39 ] . Future studies integrating molecular pathology, including BRAF mutations, are warranted to clarify these associations and improve risk stratification 5.2 Correlation Between Pregnancy Count and Thyroid Carcinoma Our study demonstrated that pregnancy count was strongly correlated with disease progression in DTC, showing a clear dose–response relationship. Women with 3–4 pregnancies and those with ≥ 5 pregnancies had significantly higher risks of advanced-stage disease (OR = 5.91, 95% CI: 2.54–13.74, P < 0.001; OR = 18.56, 95% CI: 6.43–53.58, P < 0.001, respectively). Moreover, increasing pregnancy frequency was positively associated with both central and lateral cervical lymph node metastases, underscoring the role of reproductive history in tumor aggressiveness. These findings are consistent with international reports. Messuti et al. [ 43 ] observed that patients diagnosed with DTC during pregnancy or shortly postpartum had a significantly higher risk of disease persistence or recurrence (OR = 1.1, P = 0.023). Similarly, Moleti et al. [ 44 ] and Preston-Martin et al. [ 45 ] reported that multiple pregnancies were associated with a 3–4.2-fold increased risk of thyroid cancer. Collectively, this evidence suggests that repeated endocrine fluctuations during pregnancy may promote tumor growth through continuous activation of oncogenic signaling pathways such as MAPK and PI3K/Akt. Interestingly, while multiple pregnancies increase aggressiveness and recurrence risk, prior studies have shown no significant impact on long-term survival [ 42 ] . This paradox likely reflects the generally favorable prognosis of DTC, indicating that reproductive factors primarily influence local tumor behavior rather than overall mortality. Based on these findings, we propose that a history of ≥ 3 pregnancies should be considered in risk stratification models, with closer surveillance warranted in this subgroup. Future research should aim to clarify the mechanistic links between pregnancy-related hormonal changes and driver mutations in thyroid cancer progression. 5.3 Correlation Between Pregnancy Count and Differentiated Thyroid Carcinoma Our study identified parity as the reproductive factor most strongly associated with DTC progression. Women with ≥ 3 live births had a markedly increased risk of advanced-stage disease (OR = 23.19, 95% CI: 10.56–50.93, P < 0.001) and locally invasive tumors (T3/T4 stage; OR = 4.12, 95% CI: 2.13–7.97, P < 0.001). A clear dose–response relationship was observed, with central lymph node metastasis rates reaching 81.58% in the 3–4 births group and 100% in the ≥ 5 births group. These findings extend prior research on reproductive factors and thyroid cancer. While some studies, such as those conducted in Scandinavian populations [ 35 ] , reported no significant association, and others failed to establish a dose–response relationship [ 52 ] , our results align with reports emphasizing the impact of completed pregnancies. Previous studies have linked higher parity to increased thyroid cancer risk [ 51 ] and malignant nodule formation [ 47 ] , suggesting that full-term gestation may impart lasting physiological effects beyond pregnancy itself. The underlying mechanisms likely involve profound endocrine and immune remodeling during delivery [ 48 ] . The postpartum and lactation periods, characterized by elevated prolactin and declining estrogen/progesterone [ 49 ] , may exert persistent influences on the thyroid microenvironment. Moreover, the frequent co-expression of estrogen (ERα), progesterone (PR), and prolactin (PRLR) receptors in thyroid cancer tissues [ 50 ] supports the hypothesis that abnormal activation of sex hormone signaling pathways contributes to aggressive tumor phenotypes [ 37 ][ 50 ] . In conclusion, parity is a significant predictor of DTC progression. Women with ≥ 3 births, particularly those with ≥ 5, should be considered at exceptionally high risk, warranting comprehensive preoperative evaluation and intensified postoperative surveillance. Future studies should further clarify the synergistic effects of full-term pregnancies and other carcinogenic drivers in thyroid cancer progression. 6. Conclusion This study demonstrated that abnormal menarche age, multiple pregnancies, and high parity are independent predictors of advanced DTC, with a distinct dose–response relationship. Nulliparity was protective. These reproductive traits should inform clinical risk assessment and management, including enhanced preoperative evaluation and postoperative monitoring. Future multicenter studies should validate these associations and investigate hormonal–genetic interactions to support precision prevention and treatment. Abbreviations DTC (Differentiated Thyroid Carcinoma) OR (Odds Ratio) CI (Confidence Interval) BMI (Body Mass Index) IRB (Institutional Review Board) TNM (Tumor, Node, Metastasis) ER (Estrogen Receptor) PR (Progesterone Receptor) PRLR (Prolactin Receptor) MAPK (Mitogen-Activated Protein Kinase) PI3K/Akt (Phosphoinositide 3-Kinase/Protein Kinase B) lncRNA (Long Non-Coding RNA) miRNA/miR (MicroRNA) Declarations Ethics approval and consent to participate Ethics approval ： This retrospective study involved the analysis of anonymized clinical data and was formally approved by the Institutional Review Board (IRB) of Sichuan Cancer Hospital ( Approval No.: SCCHEC-02-2025-148 ). Consent to participate ： All procedures performed in this study were in strict accordance with the ethical standards of the responsible institutional and national committees on human experimentation and with the principles of the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants included in the study prior to their enrollment. The need for informed consent was waived by the IRB of Sichuan Cancer Hospital due to the retrospective nature of the study. Consent for publication Not Applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This study was supported by the Noncommunicable Chronic Diseases National Science and Technology Major Project (Grant No. 2024ZD0525600) and the Sichuan Clinical Research Center for Cancer. Authors' contributions Lei-Jun He: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing. Yu-Yao Zhang ： Data curation, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing. Lu-Jing Xiong ： Data curation, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing. Hao Ai ： Data curation, Formal analysis, Investigation, Methodology, Software, Validation. Yong-Cong Cai: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. Acknowledgement Not applicable. Declaration of AI and AI-assisted technologies in the writing process ： During the preparation of this work, the authors used ChatGPT (OpenAI) to assist with the language polishing and editing of the cover letter. Since the authors’ native language is Chinese, the tool was employed solely to improve the clarity and fluency of the English text. After using this tool, the authors carefully reviewed and edited the content, and take full responsibility for the final version and the scientific integrity of the manuscript. References Liu S, Semenciw R, Ugnat AM, Mao Y. Increasing thyroid cancer incidence in Canada, 1970-1996: time trends and age-period-cohort effects. Br J Cancer. 2001;85(9):1335-1339. doi:10.1054/bjoc.2001.2061. Kilfoy BA, Zheng T, Holford TR, et al. International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control. 2009;20(5):525-531. doi:10.1007/s10552-008-9260-4 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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BioMed Research International 2015, 2015:103515 Galanti MR, Hansson L, Lund E, Bergström R, Grimelius L, Stalsberg H, Carlsen E, Baron JA, Persson I, Ekbom A: Reproductive history and cigarette smoking as risk factors for thyroid cancer in women: a population-based case-control study. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Co-sponsored by the American Society of Preventive Oncology 1996, 5(6):425-431 Wang M, Gong WW, He QF, Hu RY, Yu M: Menstrual, reproductive, and hormonal factors and thyroid cancer: a hospital-based case-control study in China. BMC Women's Health 2021, 21(1):13 Vannucchi G, De Leo S, Perrino M, et al. Impact of estrogen and progesterone receptor expression on the clinical and molecular features of papillary thyroid cancer. Eur J Endocrinol. 2015;173(1):29-36. doi:10.1530/EJE-15-0054 Li M, Chai HF, Peng F, et al. Estrogen receptor β upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma. Cell Death Dis. 2018;9(11):1120. Published 2018 Nov 2. doi:10.1038/s41419-018-1077-9 Hu X, Ye Q, Lu H, Wu Z, Chen S, Zheng R. Estrogen-mediated DNMT1 and DNMT3A recruitment by EZH2 silences miR-570-3p that contributes to papillary thyroid malignancy through DPP4. Clin Epigenetics. 2024;16(1):81. Published 2024 Jun 18. doi:10.1186/s13148-024-01685-z Hima S, Sreeja S. Modulatory role of 17β-estradiol in the tumor microenvironment of thyroid cancer. IUBMB Life. 2016;68(2):85-96. doi:10.1002/iub.1462 Rossing MA, Voigt LF, Wicklund KG, Daling JR: Reproductive factors and risk of papillary thyroid cancer in women. American Journal of Epidemiology 2000, 151(8):765-772 Moleti M, Sturniolo G, Di Mauro M, Russo M, Vermiglio F: Female Reproductive Factors and Differentiated Thyroid Cancer. Frontiers in Endocrinology 2017, 8:111 Messuti I, Corvisieri S, Bardesono F, Rapini I, Giorcelli J, Pellerito R, Volante M, Orlandi F: Impact of Pregnancy on Prognosis of Differentiated Thyroid Cancer: Clinical and Molecular Features. European Journal of Endocrinology 2014, 170(5):659-666 Moleti M, Trimarchi F, Vermiglio F: Thyroid Physiology in Pregnancy. Endocrine Practice 2014, 20(6):589-596 Preston-Martin S, Bernstein L, Pike MC, Maldonado AA, Henderson BE: Thyroid cancer among young women related to prior thyroid disease and pregnancy history. British Journal of Cancer 1987, 55(2):191-195 Kung AW, Chau MT, Lao TT, Tam SC, Low LC: The effect of Pregnancy on thyroid nodule formation. The Journal of Clinical Endocrinology and Metabolism 2002, 87(3):1010-1014 Wang K, Yang Y, Wu Y, Chen J, Zhang D, Liu C. The association of menstrual and reproductive factors with thyroid nodules in Chinese women older than 40 years of age. Endocrine. 2015;48(2):603-614. doi:10.1007/s12020-014-0342-7 Tang MX, Hu XH, Liu ZZ, Kwak-Kim J, Liao AH. What are the roles of macrophages and monocytes in human pregnancy?. J Reprod Immunol. 2015;112:73-80. doi:10.1016/j.jri.2015.08.001 Parisi F, Fenizia C, Introini A, et al. The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester. Hum Reprod Update. 2023;29(6):699-720. doi:10.1093/humupd/dmad016 Costa P, Catarino AL, Silva F, Sobrinho LG, Bugalho MJ. Expression of prolactin receptor and prolactin in normal and malignant thyroid: a tissue microarray study. Endocr Pathol. 2006;17(4):377-386. doi:10.1007/s12022-006-0009-x Truong T, Orsi L, Dubourdieu D, Rougier Y, Hémon D, Guénel P: Role of goiter and of menstrual and reproductive factors in thyroid cancer: a population-based case-control study in New Caledonia (South Pacific), a very high incidence area. American Journal of Epidemiology 2005;161(11):1056-1065 Zhu J, Zhu X, Tu C, et al. Parity and thyroid cancer risk: a meta-analysis of epidemiological studies. Cancer Medicine 2016;5(4):739-752. doi:10.1002/cam4.604 Additional Declarations No competing interests reported. Supplementary Files datas.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 05 Apr, 2026 Reviews received at journal 05 Apr, 2026 Reviewers agreed at journal 31 Mar, 2026 Reviews received at journal 31 Mar, 2026 Reviewers agreed at journal 31 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers invited by journal 23 Feb, 2026 Editor assigned by journal 11 Feb, 2026 Editor invited by journal 27 Jan, 2026 Submission checks completed at journal 23 Jan, 2026 First submitted to journal 23 Jan, 2026 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8553244","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":595971573,"identity":"e9b29ddf-8958-4f1e-bd47-20b4320f2cc9","order_by":0,"name":"Leijun He","email":"","orcid":"","institution":"University of Electronic Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Leijun","middleName":"","lastName":"He","suffix":""},{"id":595971575,"identity":"98658687-dc3a-4727-81aa-6e2ac304b99c","order_by":1,"name":"Yuyao Zhang","email":"","orcid":"","institution":"Sichuan Taikang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuyao","middleName":"","lastName":"Zhang","suffix":""},{"id":595971576,"identity":"16a5816f-1ac1-4606-ace3-bd6e0a3e7761","order_by":2,"name":"Lujing Xiong","email":"","orcid":"","institution":"Chengdu Seventh People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lujing","middleName":"","lastName":"Xiong","suffix":""},{"id":595971579,"identity":"5c2ab1a8-1da3-4de5-9279-92a44dfa33c1","order_by":3,"name":"Hao Ai","email":"","orcid":"","institution":"Chengdu Medical College","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Ai","suffix":""},{"id":595971580,"identity":"a7887d09-ff9b-40c4-851e-05f04031f352","order_by":4,"name":"Yongcong Cai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYFACxgY46wGI5CNFC7MBiGQjxT42CaK08LcfbpP4uKNWnl+6/Vrlj5o6ezaJHAOGj3tqGfhnN2DVInEmsU1y5pnjhjPnnCm7zXPsMDNIC+OMZ8cZJO4cwKrFgCGxTZq37ViCwY2ctNuMDQfYQFqYeQ4cYzCQSMCuhf8hQkvhz4Y6HsJaJMC21AC1pB9j4G1gloBqqcGpReLGw2bLmW0HDGfOyGGWBvrFgI3nWcHBGQcO8EjcwK6Fvz/94Y2PbXXy/BLpDz+CQoyfPXnjgw8H6uT4Z2DXAgQswOg4DKR5DCB8gQwDYFAd5sGlHgiYPzAw1AFp9gdQi4+DGHV4dIyCUTAKRsEIAwB4Fl3hZPMoFwAAAABJRU5ErkJggg==","orcid":"","institution":"Sichuan Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yongcong","middleName":"","lastName":"Cai","suffix":""}],"badges":[],"createdAt":"2026-01-08 15:38:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8553244/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8553244/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103577517,"identity":"cc436ac7-a49a-47e2-bd35-1e096ac119f2","added_by":"auto","created_at":"2026-02-27 09:28:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77799,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure A.\u003c/strong\u003e Forest plot of reproductive factors associated with advanced clinical stage (III/IV) in differentiated thyroid carcinoma (DTC). Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from multivariate logistic regression models adjusted for age and BMI. Red markers indicate significant risk factors (OR \u0026gt; 1, P \u0026lt; 0.05), blue markers indicate protective factors (OR \u0026lt; 1, P \u0026lt; 0.05), and the vertical dashed line represents the null value (OR = 1).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8553244/v1/70b4445782fd9b207d7464d4.png"},{"id":103577524,"identity":"06330feb-9922-4ee5-b4d8-970e0c8990ed","added_by":"auto","created_at":"2026-02-27 09:28:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60634,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure B.\u003c/strong\u003e Forest plot of reproductive factors associated with local invasion (T3/T4 stage) in differentiated thyroid carcinoma (DTC). Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from multivariate logistic regression models adjusted for age and BMI. Red markers indicate significant risk factors, blue markers indicate protective factors, and gray markers represent non-significant associations (P \u0026gt; 0.05). The vertical dashed line represents the null value (OR = 1).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8553244/v1/bb9c08bea10277d3747ea170.png"},{"id":103577592,"identity":"1673819f-9716-4519-accc-980ed0d07a29","added_by":"auto","created_at":"2026-02-27 09:28:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":98369,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure C. \u003c/strong\u003eForest plot of reproductive factors associated with lymph node metastasis in DTC.Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from crude 2×2 comparisons. Red markers indicate significant risk factors (P \u0026lt; 0.05), gray markers indicate non-significant associations. The vertical dashed line represents the null value (OR = 1).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8553244/v1/d800aec90f20fc0a2ae7d778.png"},{"id":103577632,"identity":"a4bb9b7f-3b39-417f-8b1c-e2d2a4384890","added_by":"auto","created_at":"2026-02-27 09:28:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1930099,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8553244/v1/872b70b3-291a-41df-8909-b0dc4c8d6dc0.pdf"},{"id":103577561,"identity":"5df76a1e-d17f-41cc-9069-cdbceab969f5","added_by":"auto","created_at":"2026-02-27 09:28:29","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":148164,"visible":true,"origin":"","legend":"","description":"","filename":"datas.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8553244/v1/b8538b8b6613e409e8b75908.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reproductive Factors and Disease Progression in Differentiated Thyroid Cancer: A Large Retrospective Cohort Study of 1,098 Chinese Women","fulltext":[{"header":"1. Introduction:","content":"\u003cp\u003eThyroid cancer has emerged as one of the fastest growing malignancies worldwide, with its prevalence rising sharply over the past two decades\u003csup\u003e[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In China, this trend is particularly striking, as the age-standardized incidence rate nearly tripled from 3.21 to 9.61 per 100,000 between 2005 and 2015, a pace that exceeds the global average\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. A notable epidemiological feature of thyroid cancer is its pronounced gender disparity: women are affected approximately three times more often than men\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. This difference is most evident during reproductive years (20\u0026ndash;49 years), when the female-to-male ratio may reach 4.1:1, suggesting that sex hormones and reproductive factors could play a critical role in the onset and progression of differentiated thyroid carcinoma (DTC) \u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eEstrogen is widely recognized as a key factor underlying the gender disparity in thyroid cancer. By binding to estrogen receptors on thyroid cells, estrogen activates oncogenic signaling cascades such as MAPK and PI3K/Akt, which promote cellular proliferation, migration, and invasion \u003csup\u003e[\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In parallel, improvements in nutritional status have led to earlier pubertal onset, thereby extending the cumulative duration of estrogen exposure across the lifespan \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Moreover, many Chinese women born in the 1960s and 1970s\u0026mdash;shaped by historical fertility policies\u0026mdash;experienced multiple pregnancies, each accompanied by repeated surges in estrogen levels \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Together, these elements create a distinctive reproductive hormone exposure profile in Chinese women, which may contribute to heightened susceptibility to differentiated thyroid carcinoma. .\u003c/p\u003e \u003cp\u003eDespite plausible molecular mechanisms linking reproductive factors to thyroid cancer, epidemiological evidence remains inconsistent and fragmented, underscoring the need for further investigation. While several studies have identified early menarche, high parity, and multiple pregnancies as potential risk factors \u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, large-scale cohort analyses in European populations, including Norway and Sweden, have failed to confirm these associations \u003csup\u003e[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Such discrepancies may reflect differences in population characteristics, study design, and approaches to confounder adjustment. Importantly, most prior research has focused on disease etiology, leaving the determinants of disease progression largely unexplored. Although differentiated thyroid carcinoma (DTC) generally carries a favorable prognosis, its clinical behavior is heterogeneous; a subset of patients develops aggressive features such as nodal or distant metastases and extrathyroidal extension, which significantly worsen outcomes. This highlights a critical knowledge gap regarding the influence of reproductive history on tumor aggressiveness, particularly in relation to advanced TNM stage and lymph node burden.\u003c/p\u003e \u003cp\u003eTo address this critical gap, we conducted a large hospital-based retrospective cohort study of Chinese women who underwent surgical treatment for differentiated thyroid carcinoma (DTC) at a tertiary academic center between 2014 and 2024. The primary objective was to examine the associations between key reproductive factors\u0026mdash;including age at menarche, parity, and pregnancy history\u0026mdash;and indicators of tumor aggressiveness, specifically advanced clinical stage and lymph node metastasis.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 General Data\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e2.1.1 Study Population\u003c/h2\u003e \u003cp\u003eA retrospective cohort analysis was performed on female patients with differentiated thyroid carcinoma (DTC) who underwent surgical treatment at the Department of Head and Neck Surgery of Sichuan Cancer Hospital between June 2014 and February 2024. Clinical data were extracted from medical records to ensure accuracy and minimize recall bias(Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.1.2 Inclusion Criteria\u003c/h2\u003e \u003cp\u003e(1) Patients admitted for thyroid nodules; (2) Treated in the Department of Head and Neck Surgery at Sichuan Cancer Hospital; (3) Pathological diagnosis of differentiated thyroid carcinoma; (4) Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (5) Female patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.1.3 Exclusion Criteria\u003c/h2\u003e \u003cp\u003e(1) Missing or incomplete clinical information; (2) No surgical treatment performed; (3) Histopathological diagnosis other than DTC.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.1.4 Grouping Information\u003c/h2\u003e \u003cp\u003eCollected reproductive variables included age at menarche, number of pregnancies, and parity. Menarche age ranged from 7 to 19 years (SD\u0026thinsp;=\u0026thinsp;1.3). National survey data indicate that the mean age of menarche among Chinese female students declined from 12.8 years in 2005 to 12.3 years in 2014 \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. For analysis, menarche was categorized as: (1)\u0026thinsp;\u0026le;\u0026thinsp;11 years (early), (2) 12\u0026ndash;14 years (normal), and (3)\u0026thinsp;\u0026ge;\u0026thinsp;15 years (late). Pregnancy history ranged from 0 to 9, and parity from 0 to 6. These distributions reflect historical fertility trends in China, where average pregnancies per woman decreased from 5.37 in 1982 to 1.62 in 2015, with current total fertility rates between 1.0 and 1.3 \u003csup\u003e[\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Clinical staging is classified into early-stage (Stages I and II) and advanced-stage (Stages III and IV); TNM staging, tumor size, and local invasion are categorized into a low-risk group (T1-T2) and a medium-high-risk group (T3-T4)\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e .\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Research Methods\u003c/h2\u003e \u003cp\u003eA retrospective clinical study was conducted on female patients diagnosed with differentiated thyroid carcinoma (DTC) who underwent surgical treatment in the Department of Head and Neck Surgery at Sichuan Cancer Hospital between June 2014 and February 2024. Clinical data were collected from medical records, including demographic information (age, body mass index [BMI]), reproductive history (age at menarche, pregnancy and delivery history), and tumor characteristics (TNM stage, clinical stage, postoperative pathology, and lymph node metastasis).\u003c/p\u003e \u003cp\u003eAssociations between reproductive variables (menarche age, number of pregnancies, and parity) and clinicopathological outcomes (lymph node metastasis, clinical stage, tumor size, and local invasion) were analyzed. The objective was to determine whether reproductive history was significantly correlated with disease progression in female patients with DTC.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical Methods\u003c/h2\u003e \u003cp\u003eA database was established using Excel 2019 to organize and clean the collected data. Quantitative variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, while categorical variables were presented as frequency and percentage. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corporation, Armonk, NY, USA).\u003c/p\u003e \u003cp\u003eGroup comparisons were conducted using appropriate statistical tests: t-tests for normally distributed quantitative data, Mann\u0026ndash;Whitney U tests for non-normally distributed quantitative data, and chi-square or Fisher\u0026rsquo;s exact tests (when expected frequency\u0026thinsp;\u0026lt;\u0026thinsp;5) for categorical variables.\u003c/p\u003e \u003cp\u003eMultivariable logistic regression models were applied to evaluate associations between reproductive factors (age at menarche, number of pregnancies, and parity) and clinicopathological features of differentiated thyroid carcinoma, including TNM stage, T stage, and lymph node metastasis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate effect sizes. All hypothesis tests were two-tailed, and statistical significance was defined as P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and Analysis","content":"\u003cp\u003e\u003cstrong\u003e3.1\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation between Age at Menarche and Disease Advancement in Differentiated Thyroid Carcinoma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1.1\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation between Age of Menarche and Clinical Staging.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA univariate rank-sum test revealed significant differences in clinical stage distribution among patients with varying menarcheal ages (\u0026chi;\u0026sup2; = 23.45, P = 0.003) (Table 3-1). Multivariate logistic regression analysis of 981 patients demonstrated that, after adjustment for age and BMI, early menarche (\u0026le;11 years) was independently associated with advanced disease stage (III/IV), conferring a 7.60-fold increased risk compared with the reference group (12\u0026ndash;14 years) (OR = 7.60, 95% CI: 2.76\u0026ndash;20.92, P \u0026lt; 0.001). Similarly, late menarche (\u0026ge;15 years) was significantly correlated with disease progression, with patients exhibiting a 3.10-fold higher risk of advanced-stage disease relative to the reference group (OR = 3.10, 95% CI: 1.31\u0026ndash;7.35, P = 0.010) (Table 3-1).\u003c/p\u003e\n\u003cp\u003eTable 3-1: Impact of Different Menarche Timing on Tumor Staging\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"689\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 124px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at menarche\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026chi;\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage I and II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage III and IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003eEarly\u003c/p\u003e\n \u003cp\u003eNormal(ref)\u003c/p\u003e\n \u003cp\u003eLate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e47 (4.93)\u003c/p\u003e\n \u003cp\u003e714 (74.92)\u003c/p\u003e\n \u003cp\u003e192 (20.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (21.43)\u003c/p\u003e\n \u003cp\u003e12 (42.86)\u003c/p\u003e\n \u003cp\u003e10 (35.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e23.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e7.60（2.76\u0026ndash;20.92）\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e3.10（1.31\u0026ndash;7.35）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.1.2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation between Age at Menarche and Lymph Node Metastasis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChi-square analyses revealed no significant differences in the distribution of central compartment lymph node metastasis (\u0026chi;\u0026sup2; = 1.755, P = 0.416) or lateral neck lymph node metastasis (\u0026chi;\u0026sup2; = 0.240, P = 0.887) among patients stratified by age at menarche (Table 3-2). These findings indicate that menarcheal age was not correlated with the occurrence of lymph node metastasis in differentiated thyroid carcinoma (DTC), suggesting that reproductive timing does not influence nodal involvement in this cohort.\u003c/p\u003e\n\u003cp\u003eTable 3-2: Effect of Different Menarche Timing on Lymph Node Metastasis\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Age at menarche\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Central Zone Lymph Node Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Lateral Neck Lymph Node Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;Early\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Normal\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Late\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Total\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026chi;\u0026sup2;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;P\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;29 (4.74)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;465 (75.98)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;118 (19.28)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;24 (6.50)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;261 (70.73)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;84 (22.76)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;17 (5.86)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;213 (73.45)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;60 (20.69)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;36 (5.99)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;513 (85.36)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;142 (23.63)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;601\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u0026nbsp;1.755\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u0026nbsp;0.240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u0026nbsp;0.416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u0026nbsp;0.887\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.1.3\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation Between Age at Menarche and T Staging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eT staging in DTC reflects disease advancement by assessing tumor size and local invasion, thereby guiding surgical planning, adjuvant therapy, and follow-up strategies. Chi-square analysis demonstrated no significant differences in T stage distribution among patients stratified by age at menarche (\u0026chi;\u0026sup2; = 2.145, P = 0.342) (Table 3-3). These findings indicate that menarcheal age was not associated with tumor dimensions or local invasiveness in this cohort.\u003c/p\u003e\n\u003cp\u003eTable 3-3: Effect of different menarche timing on tumor size and local invasion\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Menarche Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;T Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Total\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026chi;\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;T1+T2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;T3+T4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;Early\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Normal\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Late\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Total\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;48 (5.71)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;625 (74.32)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;168 (19.98)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;841\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;5 (3.57)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;101 (72.14)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;34 (24.29)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;53 (5.40)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;726 (74.01)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;202 (20.59)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;981\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;2.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;0.342\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation Between Pregnancy Count and Patients Diagnosed with Differentiated Thyroid Carcinoma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2.1\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation Between Various Pregnancy Counts and Tumor Clinical Staging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate analysis revealed a significant association between pregnancy count and clinical stage of DTC (\u0026chi;\u0026sup2; = 40.520, P \u0026lt; 0.001; Table 3-4). Patients with stage III/IV disease had markedly higher rates of 3\u0026ndash;4 pregnancies (39.29% vs. 13.35%) and \u0026ge;5 pregnancies (28.57% vs. 4.79%). Multivariate logistic regression, adjusted for age, BMI, and menarcheal age, confirmed that 3\u0026ndash;4 pregnancies (OR = 5.91, 95% CI: 2.54\u0026ndash;13.74, P \u0026lt; 0.001) and \u0026ge;5 pregnancies (OR = 18.56, 95% CI: 6.43\u0026ndash;53.58, P \u0026lt; 0.001) were independent risk factors for advanced-stage disease, demonstrating a clear dose\u0026ndash;response relationship. Conversely, nulliparity was associated with a significantly reduced risk compared with 1\u0026ndash;2 births (OR = 0.08, 95% CI: 0.01\u0026ndash;0.60, P = 0.014) (Table 3-4). These findings underscore parity as a key reproductive determinant of DTC progression, warranting closer monitoring in patients with three or more pregnancies.\u003c/p\u003e\n\u003cp\u003eTable 3-4: Impact of different numbers of pregnancies on thyroid cancer staging\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"699\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Pregnancies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026chi;\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage I and II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage III and IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003cp\u003e1 - 2 times(ref)\u003c/p\u003e\n \u003cp\u003e3 - 4 times\u003c/p\u003e\n \u003cp\u003e5 times or more\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e282 (29.90)\u003c/p\u003e\n \u003cp\u003e505 (53.55)\u003c/p\u003e\n \u003cp\u003e120 (12.73)\u003c/p\u003e\n \u003cp\u003e39 (4.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e1 (3.57)\u003c/p\u003e\n \u003cp\u003e8 (28.57)\u003c/p\u003e\n \u003cp\u003e11 (39.29)\u003c/p\u003e\n \u003cp\u003e8 (28.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e40.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0.08（0.01 - 0.60）\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e5.91（2.54 - 13.74）\u003c/p\u003e\n \u003cp\u003e18.56（6.43 - 53.58）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.2.2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation Between Number of Pregnancies and Lymph Node Metastasis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePregnancy count was significantly associated with lymph node metastasis in DTC. The central compartment showed the highest metastasis rate in nulliparous patients (70.6%, 207/293), compared with 57.4% in the 1\u0026ndash;2 pregnancies group, 62.6% in the 3\u0026ndash;4 group, and 63.8% in the \u0026ge;5 group(Table 3-5). Multivariable analysis confirmed that nulliparity independently increased central metastasis risk relative to 1\u0026ndash;2 pregnancies (OR = 1.69, 95% CI: 1.25\u0026ndash;2.28, P \u0026lt; 0.001), whereas 3\u0026ndash;4 and \u0026ge;5 pregnancies were not significant(Table 3-6).\u003c/p\u003e\n\u003cp\u003eIn the lateral neck, metastasis rates rose with pregnancy count (31.7% in nulliparous patients, 25.5% in 1\u0026ndash;2, 35.1% in 3\u0026ndash;4, and 44.7% in \u0026ge;5). Adjusted models indicated that only \u0026ge;5 pregnancies were significantly associated with lateral metastasis (OR = 2.37, 95% CI: 1.29\u0026ndash;4.36, P = 0.0052)(Table 3-6). These findings suggest a compartment-specific pattern: central metastasis risk is elevated in nulliparous women, while lateral metastasis requires very high pregnancy exposure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3-5 Effect of Number of Pregnancies on Lymph Node Metastasis\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"104%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 21px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Pregnancies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCentral Zone Lymph Node Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLateral Neck Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003cp\u003e1 - 2 times\u003c/p\u003e\n \u003cp\u003e3 - 4 times\u003c/p\u003e\n \u003cp\u003e5 times or more\u003c/p\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e\u0026chi;\u0026sup2;\u003c/p\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e207 (33.82)\u003c/p\u003e\n \u003cp\u003e293 (47.88)\u003c/p\u003e\n \u003cp\u003e82 (13.40)\u003c/p\u003e\n \u003cp\u003e30 (4.90)\u003c/p\u003e\n \u003cp\u003e612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e86 (23.31)\u003c/p\u003e\n \u003cp\u003e217 (58.81)\u003c/p\u003e\n \u003cp\u003e49 (13.28)\u003c/p\u003e\n \u003cp\u003e17 (4.61)\u003c/p\u003e\n \u003cp\u003e369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e93 (32.07)\u003c/p\u003e\n \u003cp\u003e130 (44.83)\u003c/p\u003e\n \u003cp\u003e46 (15.86)\u003c/p\u003e\n \u003cp\u003e21 (7.24)\u003c/p\u003e\n \u003cp\u003e290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e200 (33.28)\u003c/p\u003e\n \u003cp\u003e380 (63.23)\u003c/p\u003e\n \u003cp\u003e85 (14.14)\u003c/p\u003e\n \u003cp\u003e26 (4.33)\u003c/p\u003e\n \u003cp\u003e601\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e15.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e9.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 3-6 Association Between Pregnancy Count and Lymph Node Metastasis\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"586\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Pregnancies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCentral Compartment Metastasis\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLateral Neck Metastasis\u003cbr\u003e\u0026nbsp;OR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e1.69 (1.25\u0026ndash;2.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e1.13 (0.82\u0026ndash;1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e1 - 2 times(ref)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e3 - 4 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e1.25 (0.84\u0026ndash;1.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e1.28 (0.84\u0026ndash;1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e5 times or more\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e1.31 (0.72\u0026ndash;2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e2.37 (1.29\u0026ndash;4.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0052\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.2.3\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation Between Pregnancy Count and T Staging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePregnancy number was significantly associated with tumor T stage (\u0026chi;\u0026sup2; = 16.75, P \u0026lt; 0.001; Table 3-7). Multivariate analysis confirmed that \u0026ge;5 pregnancies independently increased the risk of T3/T4 disease (OR = 3.28, 95% CI: 1.73\u0026ndash;6.21, P \u0026lt; 0.001), while other groups showed no significant differences compared with 1\u0026ndash;2 pregnancies (Table 3-7). These results highlight high parity as a risk factor for local tumor invasiveness in DTC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3-8:\u0026nbsp;Impact of Varying Pregnancy Counts on Tumor Dimensions and Extent of Local Invasion\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"568\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePregnancy Grading\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026chi;\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT1+T2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3+T4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003cp\u003e1 - 2 times(ref)\u003c/p\u003e\n \u003cp\u003e3 - 4 times\u003c/p\u003e\n \u003cp\u003e5 times or more\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e250 (29.73)\u003c/p\u003e\n \u003cp\u003e446 (53.03)\u003c/p\u003e\n \u003cp\u003e114 (13.56)\u003c/p\u003e\n \u003cp\u003e31 (3.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e43 (30.71)\u003c/p\u003e\n \u003cp\u003e64 (45.71)\u003c/p\u003e\n \u003cp\u003e17 (12.14)\u003c/p\u003e\n \u003cp\u003e16 (11.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 39px;\"\u003e\n \u003cp\u003e16.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.81（0.53 - 1.23）\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.95（0.54 - 1.67）\u003c/p\u003e\n \u003cp\u003e3.28（1.73 - 6.21）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.3\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation between Birth Rate and Incidence of Differentiated Thyroid Carcinoma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3.1\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation between Parity and Tumor Stage\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChi-square analysis revealed a significant correlation between parity and clinical stage in DTC (\u0026chi;\u0026sup2; = 63.58, P \u0026lt; 0.001; Table 3-9). Multivariate logistic regression of 981 patients, adjusted for pregnancy count, demonstrated that \u0026ge;3 births were independently associated with progression to advanced stages (III/IV) (OR = 23.19, 95% CI: 11.00\u0026ndash;59.64, P \u0026lt; 0.001). Conversely, nulliparous women exhibited a markedly reduced risk compared with those having 1\u0026ndash;2 births (OR = 0.03, 95% CI: 0.01\u0026ndash;0.23, P \u0026lt; 0.001), suggesting a protective effect of nulliparity against disease advancement (Table 3-9). These findings underscore high parity (\u0026ge;3 births) as a robust independent risk factor for advanced-stage DTC.\u003c/p\u003e\n\u003cp\u003eTable 3-9: Effect of Different Birth Counts on Thyroid Cancer Tumor Staging\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"666\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 192px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of births\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 196px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor Staging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026chi;\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage I and II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage III and IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 192px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003cp\u003e1 - 2 times(ref)\u003c/p\u003e\n \u003cp\u003e3 - 4 times and 5 times or more\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e300 (31.81)\u003c/p\u003e\n \u003cp\u003e624 (66.17)\u003c/p\u003e\n \u003cp\u003e29 (2.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e1 (3.57)\u003c/p\u003e\n \u003cp\u003e13 (46.43)\u003c/p\u003e\n \u003cp\u003e14 (42.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 39px;\"\u003e\n \u003cp\u003e63.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e0.03 (0.01\u0026ndash;0.23)\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e23.19 (10.56\u0026ndash;50.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.3.2\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Correlation between Birth Rate and Lymph Node Metastasis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParity was also significantly correlated with nodal involvement. Central compartment metastasis rates were 69.8% in nulliparous women, 57.5% in the 1\u0026ndash;2 births group, and 81.6% in the \u0026ge;3 births group (\u0026chi;\u0026sup2; = 22.72, P \u0026lt; 0.001)(Table 3-10). Multivariable regression confirmed that \u0026ge;3 births independently increased central metastasis risk (OR = 3.81,95% CI: 1.67\u0026ndash;8.69, P = 0.0028)(Table 3-11).\u003c/p\u003e\n\u003cp\u003eFor the lateral neck, metastasis rates were 31.6% in nulliparous women, 26.5% in the 1\u0026ndash;2 births group, and 60.5% in the \u0026ge;3 births group (\u0026chi;\u0026sup2; = 9.01, P = 0.011)(Table 3-10).Adjusted models demonstrated a strong association between \u0026ge;3 births and lateral metastasis (OR = 4.24, 95% CI:\u0026nbsp;2.24 - 8.00, P \u0026lt; 0.001)(Table 3-11).These results highlight parity as a robust predictor of nodal involvement, with both central and lateral compartments significantly affected when \u0026ge;3 births are present.\u003c/p\u003e\n\u003cp\u003eTable 3-10\u0026nbsp;Correlation between Various Parity Levels and Lymph Node Metastasis\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"121%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph Nodes Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Parities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e1 - 2 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026ge;3 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026chi;\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eCentral Zone Lymph Node Metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e210(69.76)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e91(30.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e366(57.46)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e271(42.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e36(81.58)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(18.42）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 16px;\"\u003e\n \u003cp\u003e612（62.39）\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e369（37.61）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7px;\"\u003e\n \u003cp\u003e22.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eLateral Neck Lymph Node Metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e95(31.56)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e206(68.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e169(26.53)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e468(73.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e26（60.53）\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17（39.48）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 16px;\"\u003e\n \u003cp\u003e290（29.56）\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e691（70.44）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7px;\"\u003e\n \u003cp\u003e9.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 55px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 3-11 Association Between Parity Count and Lymph Node Metastasis\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"628\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of parities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCentral Compartment Metastasis\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLateral Neck Metastasis\u003cbr\u003e\u0026nbsp;OR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 194px;\"\u003e\n \u003cp\u003e1.71 (1.28\u0026ndash;2.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e1.28 (0.95\u0026ndash;1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e1 - 2 times(ref)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 194px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026ge;3 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 194px;\"\u003e\n \u003cp\u003e3.81 (1.67\u0026ndash;8.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.0028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e4.24 (2.24\u0026ndash;8.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.3.3\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCorrelation between Pregnancy Count and T Staging\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChi-square analysis revealed a significant correlation between parity and tumor T stage, reflecting tumor size and local invasion (\u0026chi;\u0026sup2; = 19.75, P \u0026lt; 0.001; Table 3-13). Multivariate logistic regression, adjusted for age, BMI, and menarcheal age, demonstrated that \u0026ge;3 births were independently associated with advanced T3/T4 staging (OR = 4.12, 95% CI: 2.13\u0026ndash;7.97, P \u0026lt; 0.001), corresponding to a more than fourfold increased risk compared with the 1\u0026ndash;2 birth group (Table 3-12). No significant differences were observed between nulliparous women and the reference cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3-12: Effects of different parity levels on tumor size and degree of local invasion\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"568\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParity Grading\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eX2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT1+T2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3+T4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e257 (30.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e44 (31.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 47px;\"\u003e\n \u003cp\u003e19.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e1.19（0.80\u0026ndash;1.77）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1-2 times(ref)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e557 (66.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e80 (57.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e3-4 times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e27 (3.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e16 (11.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e4.12（2.13\u0026ndash;7.97）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"4. Results","content":"\u003cp\u003e\u003cstrong\u003e4.1 Association Between Reproductive Factors and Clinical Stage\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariate logistic regression analysis revealed that several reproductive factors were significantly associated with advanced clinical stage (III/IV) in DTC patients. As shown in Figure A, early menarche (\u0026le;11 years) was strongly linked to advanced disease (OR = 7.60, 95% CI: 2.76\u0026ndash;20.92, P \u0026lt; 0.001), and late menarche (\u0026ge;15 years) also conferred increased risk (OR = 3.10, 95% CI: 1.31\u0026ndash;7.35, P = 0.010). Among all variables, high parity (\u0026ge;3 births) emerged as the strongest predictor (OR = 23.19, 95% CI: 11.00\u0026ndash;59.64, P \u0026lt; 0.001), followed by \u0026ge;5 pregnancies (OR = 18.56, 95% CI: 6.43\u0026ndash;53.58, P \u0026lt; 0.001) and 3\u0026ndash;4 pregnancies (OR = 5.91, 95% CI: 2.54\u0026ndash;13.74, P \u0026lt; 0.001). Conversely, nulliparity exerted a significant protective effect (OR = 0.03, 95% CI: 0.01\u0026ndash;0.23, P \u0026lt; 0.001). These findings demonstrate a clear dose\u0026ndash;response relationship between reproductive history and disease progression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2 Association Between Reproductive Factors and Local Invasion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs illustrated in Figure B, parity and pregnancy count were independently associated with local tumor invasion (T3/T4 stage). Women with \u0026ge;3 births had a significantly elevated risk of local invasion (OR = 4.12, 95% CI: 2.13\u0026ndash;7.97, P \u0026lt; 0.001), and \u0026ge;5 pregnancies showed similar effects (OR = 3.28, 95% CI: 1.73\u0026ndash;6.21, P \u0026lt; 0.001). In contrast, nulliparity (OR = 0.81, 95% CI: 0.53\u0026ndash;1.23, P = 0.32) and menarcheal age (\u0026le;11 or \u0026ge;15 years) were not significantly associated with T3/T4 stage (P \u0026gt; 0.05). These results suggest that reproductive burden, particularly high parity and multiple pregnancies, is a robust predictor of tumor invasiveness, whereas pubertal timing does not appear to influence local extension.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.3 Association with lymph node metastasis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompartment-specific effects of reproductive factors on lymph node metastasis were observed, as shown in Figure C. Nulliparity was independently associated with increased central compartment metastasis (OR = 1.69, P \u0026lt; 0.001), while lateral neck metastasis was significantly elevated only in patients with \u0026ge;5 pregnancies (OR = 2.37, P = 0.0052). In contrast, parity \u0026ge;3 births was strongly associated with both central (OR = 3.81, P = 0.0028) and lateral metastasis \u0026nbsp;(OR = 4.24, P \u0026lt; 0.001). Menarcheal age showed no significant correlation with lymph node involvement or T stage (P \u0026gt; 0.05). These findings indicate that reproductive history influences nodal spread in a compartment- and measure-specific manner: central metastasis risk is elevated in nulliparous and high-parity patients, whereas lateral metastasis is driven by heavy reproductive exposure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.4 Dose\u0026ndash;response relationship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTaken together, reproductive factors demonstrated a consistent dose\u0026ndash;response relationship with disease progression. Increasing numbers of pregnancies and births were associated with progressively higher risks of advanced clinical stage, local invasion, and lymph node metastasis. Conversely, nulliparity consistently conferred a protective effect across multiple analyses.\u003c/p\u003e"},{"header":"5. Discussion","content":"\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003e5.1 Correlation Between Age at Menarche and Differentiated Thyroid Carcinoma\u003c/h2\u003e \u003cp\u003eOur study demonstrated that both early menarche (\u0026le;\u0026thinsp;11 years) and late menarche (\u0026ge;\u0026thinsp;15 years) were independently associated with advanced-stage DTC, while no significant associations were observed with lymph node metastasis. These findings suggest that reproductive timing primarily influences overall stage progression rather than nodal dissemination.\u003c/p\u003e \u003cp\u003ePrior studies have reported inconsistent results. He et al. \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e and Xhaard et al. \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e identified early menarche as a risk factor, whereas Sakoda et al. \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e and Wang et al.\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003esuggested increased risk or protective effects with later onset. Other investigations, including Galanti et al.\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003eand a meta-analysis by Cao et al.\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, found no correlation. Such discrepancies may reflect differences in population genetics, study design, and whether endpoints assessed incidence or progression.\u003c/p\u003e \u003cp\u003eMechanistically, early menarche extends cumulative estrogen exposure, activating ER-mediated pathways such as MAPK/ERK and PI3K/Akt \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, while delayed menarche may reflect endocrine dysregulation\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Estrogen also remodels the tumor microenvironment, promoting angiogenesis, immune modulation, and fibroblast activation \u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e, and enhances tumor stemness via lncRNA H19 \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e or proliferation through suppression of miR-570-3p\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. Future studies integrating molecular pathology, including BRAF mutations, are warranted to clarify these associations and improve risk stratification\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec30\" class=\"Section2\"\u003e \u003ch2\u003e5.2 Correlation Between Pregnancy Count and Thyroid Carcinoma\u003c/h2\u003e \u003cp\u003eOur study demonstrated that pregnancy count was strongly correlated with disease progression in DTC, showing a clear dose\u0026ndash;response relationship. Women with 3\u0026ndash;4 pregnancies and those with \u0026ge;\u0026thinsp;5 pregnancies had significantly higher risks of advanced-stage disease (OR\u0026thinsp;=\u0026thinsp;5.91, 95% CI: 2.54\u0026ndash;13.74, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; OR\u0026thinsp;=\u0026thinsp;18.56, 95% CI: 6.43\u0026ndash;53.58, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). Moreover, increasing pregnancy frequency was positively associated with both central and lateral cervical lymph node metastases, underscoring the role of reproductive history in tumor aggressiveness.\u003c/p\u003e \u003cp\u003eThese findings are consistent with international reports. Messuti et al.\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003eobserved that patients diagnosed with DTC during pregnancy or shortly postpartum had a significantly higher risk of disease persistence or recurrence (OR\u0026thinsp;=\u0026thinsp;1.1, P\u0026thinsp;=\u0026thinsp;0.023). Similarly, Moleti et al. \u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e and Preston-Martin et al. \u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e reported that multiple pregnancies were associated with a 3\u0026ndash;4.2-fold increased risk of thyroid cancer. Collectively, this evidence suggests that repeated endocrine fluctuations during pregnancy may promote tumor growth through continuous activation of oncogenic signaling pathways such as MAPK and PI3K/Akt.\u003c/p\u003e \u003cp\u003eInterestingly, while multiple pregnancies increase aggressiveness and recurrence risk, prior studies have shown no significant impact on long-term survival \u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e. This paradox likely reflects the generally favorable prognosis of DTC, indicating that reproductive factors primarily influence local tumor behavior rather than overall mortality. Based on these findings, we propose that a history of \u0026ge;\u0026thinsp;3 pregnancies should be considered in risk stratification models, with closer surveillance warranted in this subgroup. Future research should aim to clarify the mechanistic links between pregnancy-related hormonal changes and driver mutations in thyroid cancer progression.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003e5.3 Correlation Between Pregnancy Count and Differentiated Thyroid Carcinoma\u003c/h2\u003e \u003cp\u003eOur study identified parity as the reproductive factor most strongly associated with DTC progression. Women with \u0026ge;\u0026thinsp;3 live births had a markedly increased risk of advanced-stage disease (OR\u0026thinsp;=\u0026thinsp;23.19, 95% CI: 10.56\u0026ndash;50.93, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and locally invasive tumors (T3/T4 stage; OR\u0026thinsp;=\u0026thinsp;4.12, 95% CI: 2.13\u0026ndash;7.97, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A clear dose\u0026ndash;response relationship was observed, with central lymph node metastasis rates reaching 81.58% in the 3\u0026ndash;4 births group and 100% in the \u0026ge;\u0026thinsp;5 births group.\u003c/p\u003e \u003cp\u003eThese findings extend prior research on reproductive factors and thyroid cancer. While some studies, such as those conducted in Scandinavian populations \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, reported no significant association, and others failed to establish a dose\u0026ndash;response relationship \u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e, our results align with reports emphasizing the impact of completed pregnancies. Previous studies have linked higher parity to increased thyroid cancer risk \u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e and malignant nodule formation\u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e, suggesting that full-term gestation may impart lasting physiological effects beyond pregnancy itself. The underlying mechanisms likely involve profound endocrine and immune remodeling during delivery \u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. The postpartum and lactation periods, characterized by elevated prolactin and declining estrogen/progesterone\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e, may exert persistent influences on the thyroid microenvironment. Moreover, the frequent co-expression of estrogen (ERα), progesterone (PR), and prolactin (PRLR) receptors in thyroid cancer tissues \u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e supports the hypothesis that abnormal activation of sex hormone signaling pathways contributes to aggressive tumor phenotypes\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e][\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn conclusion, parity is a significant predictor of DTC progression. Women with \u0026ge;\u0026thinsp;3 births, particularly those with \u0026ge;\u0026thinsp;5, should be considered at exceptionally high risk, warranting comprehensive preoperative evaluation and intensified postoperative surveillance. Future studies should further clarify the synergistic effects of full-term pregnancies and other carcinogenic drivers in thyroid cancer progression.\u003c/p\u003e \u003c/div\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThis study demonstrated that abnormal menarche age, multiple pregnancies, and high parity are independent predictors of advanced DTC, with a distinct dose\u0026ndash;response relationship. Nulliparity was protective. These reproductive traits should inform clinical risk assessment and management, including enhanced preoperative evaluation and postoperative monitoring. Future multicenter studies should validate these associations and investigate hormonal\u0026ndash;genetic interactions to support precision prevention and treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eDTC (Differentiated Thyroid Carcinoma)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOR\u0026nbsp;(Odds Ratio)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI\u0026nbsp;(Confidence Interval)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI\u0026nbsp;(Body Mass Index)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIRB\u0026nbsp;(Institutional Review Board)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTNM\u0026nbsp;(Tumor, Node, Metastasis)\u003c/p\u003e\n\u003cp\u003eER\u0026nbsp;(Estrogen Receptor)\u003c/p\u003e\n\u003cp\u003ePR\u0026nbsp;(Progesterone Receptor)\u003c/p\u003e\n\u003cp\u003ePRLR\u0026nbsp;(Prolactin Receptor)\u003c/p\u003e\n\u003cp\u003eMAPK\u0026nbsp;(Mitogen-Activated Protein Kinase)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePI3K/Akt\u0026nbsp;(Phosphoinositide 3-Kinase/Protein Kinase B)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003elncRNA\u0026nbsp;(Long Non-Coding RNA)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003emiRNA/miR (MicroRNA)\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThis retrospective study involved the analysis of anonymized clinical data and was formally approved by the Institutional Review Board (IRB) of Sichuan Cancer Hospital (\u003cstrong\u003eApproval No.: SCCHEC-02-2025-148\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e All procedures performed in this study were in strict accordance with the ethical standards of the responsible institutional and national committees on human experimentation and with the principles of the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants included in the study prior to their enrollment. The need for informed consent was waived by the IRB of Sichuan Cancer Hospital due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Noncommunicable Chronic Diseases National Science and Technology Major Project (Grant No. 2024ZD0525600) and the Sichuan Clinical Research Center for Cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLei-Jun He:\u003c/strong\u003e Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYu-Yao Zhang\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eData curation, Formal analysis, Investigation, Methodology, Validation, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLu-Jing Xiong\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eData curation, Formal analysis, Investigation, Methodology, Validation, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHao Ai\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eData curation, Formal analysis, Investigation, Methodology, Software, Validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYong-Cong Cai:\u003c/strong\u003e Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of AI and AI-assisted technologies in the writing process\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the authors used ChatGPT (OpenAI) to assist with the language polishing and editing of the cover letter. Since the authors\u0026rsquo; native language is Chinese, the tool was employed solely to improve the clarity and fluency of the English text. After using this tool, the authors carefully reviewed and edited the content, and take full responsibility for the final version and the scientific integrity of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLiu S, Semenciw R, Ugnat AM, Mao Y. Increasing thyroid cancer incidence in Canada, 1970-1996: time trends and age-period-cohort effects. Br J Cancer. 2001;85(9):1335-1339. doi:10.1054/bjoc.2001.2061.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Kilfoy BA, Zheng T, Holford TR, et al. International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control. 2009;20(5):525-531. doi:10.1007/s10552-008-9260-4\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Hum Reprod Update. 2023;29(6):699-720. doi:10.1093/humupd/dmad016\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Costa P, Catarino AL, Silva F, Sobrinho LG, Bugalho MJ. Expression of prolactin receptor and prolactin in normal and malignant thyroid: a tissue microarray study. Endocr Pathol. 2006;17(4):377-386. doi:10.1007/s12022-006-0009-x\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Truong T, Orsi L, Dubourdieu D, Rougier Y, H\u0026eacute;mon D, Gu\u0026eacute;nel P: Role of goiter and of menstrual and reproductive factors in thyroid cancer: a population-based case-control study in New Caledonia (South Pacific), a very high incidence area. American Journal of Epidemiology 2005;161(11):1056-1065\u003c/li\u003e\n \u003cli\u003e\u0026nbsp; Zhu J, Zhu X, Tu C, et al. Parity and thyroid cancer risk: a meta-analysis of epidemiological studies. Cancer Medicine 2016;5(4):739-752. doi:10.1002/cam4.604\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"differentiated thyroid carcinoma, reproductive factors, disease progression, risk factors, retrospective cohort study","lastPublishedDoi":"10.21203/rs.3.rs-8553244/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8553244/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Differentiated thyroid carcinoma (DTC) shows a marked female predominance, particularly during reproductive years, implicating sex hormones and reproductive factors in its pathogenesis. However, evidence regarding the impact of reproductive variables—such as age at menarche, parity, and pregnancy history—on disease progression remains inconsistent, especially in Chinese women. Large‑scale studies addressing this issue are limited. This study aimed to evaluate the association between reproductive history and clinicopathological aggressiveness in female patients with DTC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a single‑center retrospective cohort study of 1,098 female patients with DTC who underwent surgical resection between June 2014 and February 2024. Data on reproductive history and tumor characteristics were collected. Group comparisons were performed using standard statistical tests, and multivariable logistic regression was applied to adjust for confounders and estimate odds ratios (ORs) with 95% confidence intervals (CIs). The study was performed in accordance with the ethical principles of the Declaration of Helsinki and relevant institutional guidelines.The study was approved by the Institutional Review Board of Sichuan Cancer Hospital (SCCHEC‑02‑2025‑148), with informed consent waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Multivariable analysis identified early (≤11 years) and late menarche (≥15 years) as independent predictors of advanced clinical stage (OR=7.60, 95%CI:2.76–20.92; OR=3.10, 95%CI:1.31–7.35, respectively). Parity demonstrated a dose-response relationship with disease severity, with ≥3 births being the strongest predictor of advanced stage (OR=23.19, 95%CI:11.00–59.64). Nulliparity showed protective effects against advanced staging (OR=0.03, 95%CI:0.01–0.23).Reproductive factors exhibited compartment-specific nodal metastasis patterns: nulliparity associated with central compartment involvement (OR=1.69, 95%CI:1.25–2.28), while ≥5 pregnancies linked to lateral neck metastasis (OR=2.37, 95%CI:1.29–4.36). Parity ≥3 correlated with both local invasion (T3/T4: OR=4.12, 95%CI:2.13–7.97) and metastases in central (OR=3.81, 95%CI:1.67–8.69) and lateral neck compartments (OR=4.24, 95%CI:2.24–8.00).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eAbnormal menarche timing, multiple pregnancies, and high parity independently predict more advanced and aggressive DTC in Chinese women, with clear dose–response relationships. Incorporating reproductive history into clinical risk stratification may improve identification of high‑risk patients and guide individualized management.\u003c/p\u003e","manuscriptTitle":"Reproductive Factors and Disease Progression in Differentiated Thyroid Cancer: A Large Retrospective Cohort Study of 1,098 Chinese Women","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 09:25:39","doi":"10.21203/rs.3.rs-8553244/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-05T20:48:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-05T12:48:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"254319466313317398460167048009634164261","date":"2026-03-31T15:00:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-31T06:21:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276299985232972264808799350036121821392","date":"2026-03-31T06:16:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"15936989452704846876763822419807538045","date":"2026-03-27T19:18:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"112668785327363206290776712286370453011","date":"2026-03-26T06:04:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176892466425057105175678447887774907844","date":"2026-03-20T00:27:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-24T02:18:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-12T02:36:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-27T08:28:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-24T03:29:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2026-01-24T03:22:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"254ebd20-64eb-4f5e-8572-2fb980f4b23c","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-27T09:25:39+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 09:25:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8553244","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8553244","identity":"rs-8553244","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}