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. Author manuscript; available in PMC: 2025 Oct 1.
Published in final edited form as: Cancer Prev Res (Phila). 2025 Apr 1;18(4):209–221. doi: 10.1158/1940-6207.CAPR-24-0330

Reproductive and Hormonal Factors and Thyroid Cancer Risk: Pooled Analysis of Prospective Cohort Studies in the Asia Cohort Consortium

Sayada Zartasha Kazmi 1,*, Aesun Shin 1,2,3,4,**, Sarah K Abe 5, Rashedul Islam 5,6, Shafiur Rahman 5,7, Eiko Saito 8, Sooyoung Cho 1,4, Ryoko Katagiri 9,10, Melissa A Merritt 11, Ji-Yeob Choi 12, Xiao-Ou Shu 13, Norie Sawada 9, Akiko Tamakoshi 14, Ritsu Sakata 15, Atsushi Hozawa 16, Seiki Kanemura 16, Jeongseon Kim 17, Yumi Sugawara 16, Sue K Park 1,2,3, Hui Cai 13, Shoichiro Tsugane 9,18, Takashi Kimura 14, Habibul Ahsan 19, Paolo Boffetta 20,21, Kee Seng Chia 22, Keitaro Matsuo 23,24, You-Lin Qiao 25, Nathaniel Rothman 26, Wei Zheng 13, Manami Inoue 6, Daehee Kang 1,3
PMCID: PMC11961320  NIHMSID: NIHMS2053097  PMID: 39846314

Abstract

Given the female predominance of thyroid cancer (TC), particularly in the reproductive age range, female sex hormones have been proposed as an aetiology; however, previous epidemiological studies have shown conflicting results. We conducted a pooled analysis using individual data from 9 prospective cohorts in the Asia Cohort Consortium, to explore the association between 10 female reproductive and hormonal factors and TC risk. Using Cox proportional hazards models, cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated and then pooled using a random-effects model. Analyses were stratified by country, birth years, smoking status, body mass index, and TC risk based on age of diagnosis was also examined. Among 259,649 women followed for a mean 17.2 years, 1,353 incident TC cases were identified, 88% (n=1,140) being papillary TC. Older age at first delivery (≥26 vs 21–25 years) was associated with increased TC risk (p-trend=0.003, HR=1.16, 95% CI:1.03–1.31), particularly when diagnosed later in life (≥55 vs <55 years) [p-trend=0.003; HR=1.19, 95% CI:1.02–1.39]. Among younger birth cohorts, women with more number of deliveries showed an increased TC risk [p-trend=0.0001, HR=2.40, 95% CI:1.12–5.18 (≥5 vs 1–2 children)], and there was no substantial trend in older cohorts. Distinct patterns were observed for the number of deliveries and TC risk across countries, with a significant positive association for Korea [p-trend=0.0008, HR=1.89, 95% CI:1.21–2.94 (≥5 vs 1–2 children)], and non-significant inverse associations for China and Japan. Contextual and macrosocial changes in reproductive factors in Asian countries may influence thyroid cancer risk.

Keywords: pooled analysis of prospective studies, thyroid cancer incidence, reproductive factors, Asia cohort consortium, birth years, country-specific

INTRODUCTION

Thyroid cancer is the most common endocrine cancer,1 with an increasing incidence in developed countries,2 and the disease is projected to become the fourth leading type of cancer worldwide.3 It remains debatable whether this rise is due to increased diagnostic testing, access to healthcare or other genetic, dietary, and environmental influences.4,5 However, global efforts to address the impact of overdiagnosis have led to a decline in incidence rates, indicating the mitigating harmful effects of increased diagnostic scrutiny.5,6

Thyroid cancer incidence varies by geography, age, and sex, with Asia having the highest incidence and thyroid cancer occurring most frequently in young adults aged 30 to 50 years.3,7 Uniquely, despite being a non-reproductive cancer, thyroid cancer exhibits a strong female tendency, with women having a three times higher incidence rate than men.3 While radiation exposure, diet, and nutritional factors are known risk factors for thyroid cancer, there is no conclusive evidence that they contribute to the significant gender disparities.8 Thyroid cancer incidence rises dramatically in females during their early reproductive years, peaking between the ages of 40 and 49.9 Fluctuations in female sex hormones during the menstrual cycle and pregnancy are suggested to contribute to this trend of age-specific incidence, with estrogen playing a crucial role in thyroid function and tumor development.10 Therefore, reproductive, and hormonal factors may serve as potential risk factors for thyroid cancer, reflecting lifetime estrogen exposure.

Considering reproductive and hormonal factors as potential risk factors to account for gender disparity, a major effort has focused on examining their association with thyroid cancer. However, the results of previous studies vary considerably. Factors like early menarche, late menopause, childbirth, and higher parity, which contribute to a longer reproductive life span, have been correlated with developing thyroid cancer in females. However, some studies, pooled analyses, systematic reviews and meta-analyses reported either no or weak associations.11–15 Apart from this, the impact of exogenous sex hormones, such as oral contraceptives (OC) and post-menopausal hormonal treatment, on thyroid cancer risk remains inconclusive. Several studies suggest protective effects, while findings from other studies reveal conflicting results.11,13,16

These inconsistent associations could be attributed to the limited power of most studies and heterogeneous study designs. Most previous studies have case-control study designs and are vulnerable to biases, and there seems to be a paucity in population-based prospective studies specifically examining reproductive-aged women, with only few studies from Asian countries.17–24 Furthermore, the reproductive patterns for Western and Asian females show differences in the onset of menarche and menopause, essentially shifting the reproductive age, which warrants the need to investigate the role of reproductive factors in Asian women on the risk of thyroid cancer.

Accordingly, our primary objective was to explore the association between reproductive and hormonal factors with thyroid cancer risk among females in an Asian population, both overall and for the most common histological subtype, papillary thyroid cancer. We also considered whether the association differed by smoking status and body mass index (BMI), taking into account the observed reduced thyroid cancer risk among individuals who smoke25,26 and the consistent link between greater adiposity and increased thyroid cancer risk.27 Furthermore, this study was able to examine the effects of birth year, country, and age of thyroid cancer diagnosis on the relationship between reproductive factors and thyroid cancer across China, Korea and Japan, considering the birth-cohort and age-cohort effects on thyroid cancer incidence in females28 and the significant macrosocial changes occurring in many Asian countries.

MATERIALS AND METHODS

We conducted a pooled analysis of individual data from prospective cohort studies participating in the Asia Cohort Consortium (ACC), containing information on female reproductive factors and thyroid cancer follow-up.

The ACC is a collaborative effort of 44 cohort studies from 10 countries across Asia, to share resources for conducting large-scale epidemiological studies on a variety of health-related topics, involving approximately 1 million participants. These cohorts provide baseline data on various risk factors and demographics collected through questionnaires, anthropometric measurements or tests, and follow-up of new cancer cases and deaths. The collected data is harmonized by the ACC’s coordinating center. Details on the ACC are provided in previous publications. 29,30

The Reproductive Factor Working Group (WG) was established within the ACC in 2020 to standardize protocols for assessing, harmonizing, and processing reproductive factor variables thus ensuring data comparability across participating studies.31 Specifically, the WG is a group of researchers from various countries in Asia who have established a standardized set of reproductive factor variables that are common across all participating studies. Details in Supplementary Methods 1. At the time of data harmonization, 13 cohorts within the ACC had reproductive factor variables available, as follows: Shanghai Women’s Health Study (SWHS), Japan Collaborative Cohort Study (JACC), Japan Public Health Center-based prospective Study 1 (JPHC1), Japan Public Health Center-based prospective Study 2 (JPHC2), Miyagi Cohort (Miyagi), Ohsaki National Health Insurance Cohort Study (Ohsaki), Life Span Study Cohort (LSS), Takayama Study (Takayama), 3-Prefecture Miyagi Cohort (3 Pref Miyagi), Korean Multi-center Cancer Cohort Study (KMCC), Korean National Cancer Center Cohort (KNCC), The Namwon Study (Namwon), Singapore Chinese Health Study (SCHS).

Among the 13 cohorts identified by the WG, 10 cohorts (7 from Japan - JPHC1, JPHC2, JACC, Miyagi, Ohsaki, LSS, 3pref. Miyagi; 1 from China - SWHS and 2 from South Korea - KMCC, KNCC) agreed to participate in the current study (n=507,487). We excluded 217,780 individuals based on the exclusion criteria: males (n=195,055) and individuals with missing information on gender at baseline (n=5). Also excluded were women with missing data on age at baseline (n=2,416), parity status/number of deliveries at baseline (n=18,925), those who had a prior thyroid cancer diagnosis at baseline (n=24), and those for whom information on diagnosis or follow-up was missing or invalid (n=1,355). After these exclusions, a total of 289,707 females with 1,015 thyroid cancer cases remained (Figure 1 and Supplementary Table 1).

Figure 1.

Figure 1

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Flowchart of cohort participation and study flowchart of participant inclusion and exclusion in the Asia Cohort Consortium.

For cohort characteristics by reproductive variables, the LSS cohort did not have data on pregnancy and number of children/deliveries, but only on age at first pregnancy/delivery (which may have referred to pregnancy that was not full-term). Therefore, women were classified as parous if they reported their age at first pregnancy (Supplementary Methods 1); thus, in the LSS cohort the proportion of parous women was likely underestimated. The following cohorts did not have information for the following variables: Breastfeeding status – SWHS, JACC, LSS, 3 pref Miyagi; OC use – SWHS, JPHC1, JPHC2, JACC, LSS, 3 pref Miyagi; HRT use – JPHC1, JPHC2, LSS, 3 pref Miyagi; Hysterectomy status – SWHS, JPHC1, JPHC2, JACC, Miyagi, Ohsaki, LSS, 3 pref Miyagi.

Considering LSS cohort had considerable reproductive variables and histology data missing, we decided to exclude it from the main analyses.

Ten reproductive and hormonal variables examined at baseline were included in this study: age at menarche (<13, 13–14, 15–16, ≥17 years), parity status (nulliparous, parous women who had ≥1 deliveries/children), number of children (1, 2, 3, 4, ≥5 children), age at first delivery/pregnancy (≤20, 21–25, ≥26 years), breastfeeding (never, ever), menopausal status (premenopausal ≤44 and postmenopausal ≥54 years), age at menopause (<45, 45–49, 50–54, ≥55 years), OC (never, ever) and hormone replacement therapy (HRT) use (no, yes), and hysterectomy status (no, yes). The ACC WG undertook an extensive process of harmonizing and deriving these variables, reaching consensus through considerable discussion to ensure the current categories were consistent across studies (Supplementary Methods 1).

Incident primary thyroid cancer cases were identified by linkage to local cancer registries of participating cohorts and were defined using the International Classification of Diseases (ICD) 10th revision code C73. Histological thyroid cancer subtypes were defined based on the ICD for Oncology, third edition (ICD-O-3). Information on histological thyroid cancer subtypes was available from all cohorts except LSS.

Smoking status (never, ever), alcohol drinking status (never, ever), BMI (<18.5, 18.5–22.9, 23–24.9, ≥25 kg/m2) at baseline were considered potential confounding variables.

Statistical analysis

Descriptive statistics were used to summarize the baseline characteristics of each participating cohort. The mean and standard deviation (SD) were calculated for age at baseline and follow-up duration for the total study population and for each participating cohort. We examined the associations of reproductive and hormonal factors with the risk of thyroid cancer incidence overall, and for the most common histologic subtype papillary thyroid cancer, among females in the ACC participating cohorts.

Hazard ratios (HRs) and 95% confidence intervals (CIs) of thyroid cancer incidence were calculated using Cox proportional hazards regression models by different reproductive factors for each cohort. Age was used as the time scale, such that person-time was accrued from age at baseline to the date of thyroid cancer incidence, death, or end of follow-up, whichever occurred first. The proportional hazard assumption was tested by examining the Schoenfeld residuals. Cox models were adjusted for potential covariates including smoking status, alcohol drinking status and BMI. Linear trends across categories of reproductive variables and thyroid cancer were tested and p-value for trend reported. Pooling was done by combining cohort-specific HRs for each reproductive variable by using a random-effects model. Heterogeneity across cohorts was assessed by Cochran’s Q-test and quantified with the I2 statistic, where an I2 statistic of 50% and a Cochran’s Q-test p-value <0.1 indicated substantial heterogeneity.

Analyses stratified by smoking status (never, ever), BMI (<23, ≥23 kg/m2), birth years and country (China, Japan, Korea) were conducted. Significance of interaction term was examined by the likelihood ratio test and reported as a p-value for interaction. BMI was categorized as <23kg/m2 and ≥23 kg/m2 following the World Health Organization guidelines.32 For stratified analyses by birth years, participants were grouped as those born before and after 1940s, and additionally as those born in the 1920s or earlier, 1930s, 1940s and 1950s or later.

To evaluate the association between reproductive variables and thyroid cancer based on age of diagnosis, a cutoff of age 55 years was implemented to delineate two separate age groups. Age at diagnosis cutoff at 55 years was chosen as it coincides with postmenopausal state. Additionally, this considers the age cohort effects on thyroid cancer incidence in females in three East Asian countries28 and it aligns with the mean age at diagnosis of cases in our study, which was 60.2 (12.5) years. Cox models were employed to examine thyroid cancer risk among cases diagnosed before age 55, with follow-up censored at age 55 years. The same approach was applied to those diagnosed after age 55.

Analyses were performed using SAS 9.4 software (SAS Inc., Cary, NC); Statistical Analysis System (RRID:SCR_008567) and STATA software (StataCorp LP, College Station, TX, USA); Stata (RRID:SCR_012763).

Ethics approval

The current study was approved by the ACC executive committee, the ethical committee of the National Cancer Center Japan, and the institutional review board of Seoul National University Hospital (E-2303–037-1410). This study was performed in accordance with the Declaration of Helsinki. Each participating cohort received approval from its respective relevant institutional review board and obtained informed consent from their participants based on their approved protocol. SWHS, KMCC, and KNCC obtained informed consent. For JACC written informed consent was obtained from all participants, in other cohorts (JPHC1, JPHC2, Miyagi, 3 pref Miyagi, Ohsaki, LSS), the return of a completed questionnaire was considered as consent for study participation.

Data availability

The data underlying this article were obtained from the Asia Cohort Consortium (ACC). Researchers can apply for access to these data through the ACC Coordinating Center (https://www.asiacohort.org/CC/index.html) after obtaining ethics approval from an Institutional Review Board. Further information is available from the corresponding author upon request.

RESULTS

Baseline characteristics of cohorts that agreed to participate in the current study are shown in Table 1.

Table 1.

Baseline Characteristics of cohorts who agreed to participate in this study

Cohorts
SWHS JPHC1 JPHC2 JACC Miyagi Ohsaki LSS 3pref. Miyagi KMCC KNCC
Characteristics
Number of women after preset exclusion, N 　 74,930 21,465 27,715 45,659 22,837 22,191 30,058 16,524 11,423 16,905
Enrolment (years),
Start-end 		1996–2000 1990–1992 1993–1995 1988–1990 1990 1996 1963–1992 1984 1993–2005 2002–2015
Age at baseline (years), Mean (SD) 52.6 (9.1) 49.6 (5.9) 54.3 (8.8) 57.4 (9.9) 52.2 (7.4) 60.5 (10.0) 52.1 (15.1) 57.4 (11.3) 54.0 (14.2) 49.8 (9.0)
Follow-up duration (years), Mean (SD) 17.3 (3.1) 21.5 (3.8) 18.3 (3.5) 16.3 (5.6) 22.1 (5.5) 10.9 (4.2) 23.4 (10.3) 11.7 (4.9) 14.5 (4.5) 9.0 (3.4)
Birth years, N (%) a
1920s or earlier 2,640 (4) 0 6,370 (23) 20,349 (45) 3,903 (17) 8,403 (38) 19,572 (65) 9,578 (58) 901 (8) 13 (0)
1930s 19,852 (26) 11,109 (52) 9,196 (33) 14,503 (32) 9,358 (41) 7,854 (35) 6,081 (20) 5,161 (31) 2,534 (22) 297 (2)
1940s 19,738 (26) 10,356 (48) 9,003 (32) 10,684 (23) 8,452 (37) 3,988 (18) 4,405 (15) 1,785 (11) 2,290 (20) 2,965 (18)
1950s and above 32,700 (44) 0 3,146 (11) 123 (0) 1,124 (5) 1,946 (9) 0 0 3,143 (28) 13,630 (81)
Ever smokers at baseline, N (%) a 2,113 (3) 1,602 (7) 2,125 (8) 2,606 (6) 1,873 (8) 1,860 (8) 4,410 (15) 1,435 (9) 965 (8) 1,241 (7)
Ever alcohol drinkers at baseline, N (%) a 1,678 (2) 4,938 (23) 6,021 (22) 10,704 (23) 5,544 (24) 5,050 (23) 7,831 (26) 4,296 (26) 2,305 (20) 7,724 (46)
BMI at baseline (kg/m 2 ), Mean (SD) 24.0 (3.4) 23.6 (3.1) 23.4 (3.2) 22.9 (3.6) 23.7 (3.1) 23.8 (3.4) 22.2 (17.0) 23.4 (3.6) 23.9 (3.4) 23.1 (3.0)
TC cases, N (%) b 306 (20) 108 (7) 77 (5) 89 (6) 167 (11) 57 (4) 166 (11) 27 (2) 101 (7) 421 (28)
Age at baseline of TC cases (years), Mean (SD) 49.0 (7.7) 48.1 (6.0) 52.5 (9.0) 55.4 (7.9) 52.2 (6.7) 59.5 (8.3) 52.0 (14.9) 58.0 (9.3) 49.4 (11.6) 48.6 (8.8)
Age at diagnosis of TC cases (years), Mean (SD) 59.0 (7.8) 58.2 (9.1) 63.3 (11.1) 60.7 (8.2) 64.1 (9.3) 65.8 (8.6) 76.8 (17.0) 62.6 (9.7) 59.2 (10.8) 52.0 (8.9)
Age at menarche, N
<13 years 4,683 1,891 2,483 2,860 1,771 483 1,322 888 136 1,185
13–14 years 27,385 9,040 11,115 17,942 10,913 14,137 16,862 6,354 1,906 6,938
15–16 years 29,548 7,500 9,046 16,661 7,137 5,024 8,243 6,345 3,703 6,102
≥17 years 13,314 3,034 5,071 8,196 3,016 2,547 3,631 2,937 5,678 2,680
Parity status, N
Nulliparous 2,506 1,186 1,609 1,773 567 742 8,802 1,609 532 571
Parous 72,424 20,279 26,106 43,886 22,270 21,449 21,256 14,915 10,891 16,334
Number of children/deliveries, N
No child 2,506 1,186 1,609 1,773 567 742 NA 1,609 532 571
 1–2 children 56,689 8,975 11,189 20,319 11,050 9,176 NA 6,595 2,525 12,234
 3–4 children 12,515 9,254 10,883 19,865 10,323 10,026 NA 5,644 4,111 3,777
 1 child 40,792 1,614 2,125 3,440 1,679 1,635 NA 1,659 543 2,269
 2 children 15,897 7,361 9,064 16,879 9,371 7,541 NA 4,936 1,982 9,965
 3 children 7,870 6,545 7,367 14,589 7,883 7,087 NA 3,847 2,079 3,040
 4 children 4,645 2,709 3,516 5,276 2,440 2,939 NA 1,797 2,032 737
≥5 children 3,220 1,854 3,703 3,702 897 2,247 NA 2,676 3,888 323
Missing 0 196 331 0 0 0 30,058 0 367 0
Age at first delivery/pregnancy, N
≤ 20 years 8,530 1,680 1,887 2234 1,641 1,848 4761 1,526 2,172 360
21–25 years 22,908 10,777 14,579 23721 14,785 14,574 11772 8,954 6,062 5,846
≥ 26 years 40,981 7,360 8,586 15,032 5,689 4,266 4,723 4,049 2,006 9,603
Missing 2,511 1,648 2,663 4,672 722 1,503 8,802 1,995 1,183 1,096
Breastfeeding status, N
Never NA 2,841 2,900 NA 4,013 3,040 NA NA 431 2,441
Ever NA 17,085 22,527 NA 17,570 18,008 NA NA 9,444 12,505
Missing 74,930 1,539 2,288 45,659 1,254 1,143 30,058 16,524 1,548 1,959
Postmenopausal status, N
No 37,102 9,603 8,971 11,575 8,791 3,832 11,913 4,407 289 5,987
Yes 37,824 11,813 18,699 33,933 13,808 18,279 16,066 11,751 8,554 8,828
Missing 4 49 45 151 238 80 2,079 366 2,580 2,090
Age at menopause, N
<45 years 6,266 1,851 2,629 4,241 2,040 1,957 2,446 1,181 1,562 1,294
45–49 years 16,414 4,262 5,936 10,320 3,668 4,384 5,081 2,673 2,001 2,612
50–54 years 13,232 5,046 8,564 14,985 4,695 6,538 5,421 3,150 2,429 3,906
≥55 years 1,440 301 941 1,656 453 861 562 325 550 748
Missing 37,578 10,005 9,645 14,457 11,981 8,451 16,548 9,195 4,881 8,345
OCP use, N
Never NA NA NA NA 21,637 19,140 NA NA 7,496 12,085
Ever NA NA NA NA 732 949 NA NA 3,573 3,100
Missing 74,930 21,465 27,715 45,659 468 2,102 30,058 16,524 354 1,720
HRT Use, N
No 72,279 NA NA 37,313 19,113 18,404 NA NA 10,359 5,838
Yes 2,651 NA NA 1,975 1,446 1,652 NA NA 1,064 2,864
Missing 0 21,465 27,715 6,371 2,278 2,135 30,058 16,524 0 8,203
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a

– % calculated from total participants of each cohort.

b

– % calculated from total thyroid cancer cases (n=1,519) to indicate % cases of each cohort

TC – Thyroid cancer, BMI – Body Mass Index, SD – standard deviation, NA – not applicable, OCP – oral contraceptive, HRT – hormone replacement treatment, SWHS: Shanghai Women’s Health Study, JPHC1: Japan Public Health Center-based prospective Study 1, JPHC2: Japan Public Health Center-based prospective Study 2, JACC: Japan Collaborative Cohort Study, Miyagi: Miyagi Cohort, 3pref. Miyagi: 3-Prefecture Miyagi Cohort, Ohsaki: Ohsaki National Health Insurance Cohort Study, LSS: Life Span Study Cohort, KMCC: Korean Multi-center Cancer Cohort Study, KNCC: Korean National Cancer Centre Cohort

The LSS cohort had considerable missing data on the Number of children/deliveries, Breastfeeding status, OCP and HRT use and was not included for pooled analyses

After exclusion of the LSS cohort, the final study population comprised a total of 259,649 females and 1,353 thyroid cancer cases. Table 2 presents pooled HRs and 95% CIs for the association between reproductive and hormonal factors and overall thyroid cancer risk. In Supplementary Figures 1-4 forest plots demonstrating pooled HRs generated from cohort-specific HRs for each reproductive variable have been presented. A sensitivity analysis excluding the LSS cohort revealed no substantial changes in overall results.

Table 2:

Pooled relative risks for reproductive factors & incident thyroid cancer risk, Overall

Reproductive characteristic a Number of women Person-years Number of TC cases HR b (95% CI) Heterogeneity c
 p trend HR d (95% CI) Heterogeneity c
 p trend
I2 (%) p I2 (%) p
Age at menarche
<13 years 17,702 322,273 108 1.05 (0.81–1.35) 0 0.87 0.80 1.04 (0.80–1.34) 0 0.88 0.81
13–14 years 122,592 2,112,142 656 1.00 (0.84–1.18) 0 0.66 0.99 (0.84–1.17) 0 0.63
15–16 years 99,309 1,711,937 510 1.00 (0.85–1.18) 25 0.23 1.00 (0.85–1.18) 27 0.21
≥17 years 50,104 827,222 245 reference reference
Parity status
Nulliparous 19,897 335,142 93 reference reference
Parous 269,810 4,638,432 1,426 1.00 (0.75–1.33) 55 0.02* 0.97 (0.73–1.30) 55 0.03*
Number of children/deliveries
1–2 children 138,752 2,304,354 822 reference 0.65 reference
3–4 children 86,398 1,437,278 398 1.08 (0.94–1.23) 56 0.02* 1.05 (0.92–1.20) 52 0.03* 0.72
≥5 children 22,510 335,943 80 1.19 (0.90–1.56) 46 0.06 1.15 (0.87–1.51) 44 0.07
1 child 55,756 951,569 320 reference reference
2 children 82,996 1,352,785 502 0.94 (0.77–1.13) 0 0.97 0.92 (0.76–1.11) 0 0.98
3 children 60,307 1,014,650 283 1.01 (0.81–1.26) 21 0.27 0.93 0.96 (0.77–1.21) 16 0.31 0.84
4 children 26,091 422,627 115 1.22 (0.92–1.61) 41 0.10 1.15 (0.87–1.52) 39 0.12
≥ 5 children 22,510 335,943 80 1.13 (0.80–1.60) 38 0.12 1.07 (0.75–1.51) 37 0.13
Age at first delivery (among parous)
≤ 20 years 26,639 459,570 100 1.07 (0.84–1.37) 26 0.21 1.09 (0.85–1.39) 24 0.23
21–25 years 133,978 2,322,477 631 reference 0.005* reference 0.003*
≥ 26 years 102,295 1,745,501 662 1.14 (1.02–1.27) 9 0.36 1.16 (1.03–1.31) 9 0.36
Breastfeeding status
Never 15,666 263,613 110 reference reference
Ever 97,139 1,607,394 727 1.17 (0.96–1.44) 0 0.88 1.15 (0.97–1.36) 0 0.88
Postmenopausal status
No 102,470 1,975,458 639 reference reference
Yes 179,555 2,879,776 796 1.20 (1.00–1.44) 20 0.26 1.19 (0.99–1.42) 21 0.26
Age at menopause
<45 years 25,467 417,630 128 reference reference
45–49 years 57,351 945,648 246 1.00 (0.79–1.26) 0 0.91 1.00 (0.79–1.26) 0 0.91
50–54 years 67,966 1,098,554 296 1.05 (0.83–1.32) 0 0.92 0.28 1.04 (0.82–1.31) 0 0.92 0.28
≥55 years 7,837 116,223 43 1.33 (0.89–1.98) 0 0.95 1.30 (0.87–1.93) 0 0.95
Oral contraceptive use
Never 60,358 902,138 570 reference reference
Ever 8,354 109,753 111 0.97 (0.79–1.20) 48 0.12 0.95 (0.79–1.14) 57 0.07
Hormone replacement therapy
No 163,306 2,690,336 792 reference reference
Yes 11,652 171,179 111 1.06 (0.85–1.32) 0 0.89 1.05 (0.84–1.32) 0 0.89
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a

– The LSS cohort was not included for pooled analyses

Cohort(s) SWHS, JACC, 3pref. Miyagi did not contribute to Breastfeeding status, SWHS, JPHC1, JPHC2, JACC, 3pref Miyagi did not contribute to Oral contraceptive use, JPHC1, JPHC2, 3pref. Miyagi did not contribute to Hormone replacement therapy

b

– Unadjusted Cox proportional hazard model with age as time-scale, Values indicated in bold/* show statistically significant values (p <0.0.5)

c

– Cochran’s Q test p-value (<0.1) provides evidence of heterogeneity. I2 of 0–40% indicates low heterogeneity, 30–60% moderate, 50–90% substantial and 75–100% considerable heterogeneity.

d

– Adjusted Cox proportional hazard model for smoking status, alcohol drinking status and BMI, Values indicated in bold/* show statistically significant values (p <0.0.5)

Abbreviations: TC– Thyroid cancer, HR– Hazards Ratio, CI– confidence interval, SWHS: Shanghai Women’s Health Study, JPHC1: Japan Public Health Center-based prospective Study 1, JPHC2: Japan Public Health Center-based prospective Study 2, JACC: Japan Collaborative Cohort Study, Miyagi: Miyagi Cohort, 3pref. Miyagi: 3-Prefecture Miyagi Cohort, Ohsaki: Ohsaki National Health Insurance Cohort Study, LSS: Life Span Study Cohort, KMCC: Korean Multi-center Cancer Cohort Study, KNCC: Korean National Cancer Centre Cohort

Older age at first delivery/pregnancy was significantly associated with an increased risk of thyroid cancer. Compared to 21–25 years (reference), the HRs (95% CIs) for ≥26 years and ≤20 years were 1.16 (1.03–1.31) and 1.09 (0.85–1.39) respectively (p-trend 0.003). Figure 2 shows the forest plot for the pooled HRs and CIs for age at first delivery and thyroid cancer risk.

Figure 2.

Figure 2

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Forest plot for the pooled hazard ratios (HRs) and 95% confidence intervals (CIs) generated by combining cohort-specific HRs for the association between age at first delivery and thyroid cancer risk, overall

Non-significant positive associations were seen for a higher number of children/deliveries, ever breastfeeding, being menopausal and later age at menopause. Age at menarche, parity status, OC and HRT use were not associated with the risk of thyroid cancer.

Among thyroid cancer cases, 1,294 cases had histological data available, of which 88% (n=1,140) were papillary thyroid cancer, while the medullary, follicular and anaplastic types were 1% (n=7), 3% (n=37) and 1% (n=11) respectively (Supplementary Table 2). Similar associations between reproductive factors and thyroid cancer risk were seen for the papillary subtype as for overall thyroid cancer pooled analysis (Table 3). For reproductive factors with more than three categories, additional analyses were conducted by merging categories. No significant differences were observed (Supplementary Table 3).

Table 3:

Pooled relative risks for reproductive factors & incident thyroid cancer risk, Papillary type

Reproductive characteristic a Number of women Person-years Number of papillary TC cases HR b (95% CI) p-trend HR c (95% CI) p-trend
Age at menarche
<13 years 16,340 763 89 1.03 (0.79–1.34) 0.98 1.03 (0.79–1.33) 0.94
13–14 years 105,642 3,489 473 0.96 (0.79–1.14) 0.95 (0.79–1.13)
15–16 years 90,989 2,513 391 0.97 (0.81–1.16) 0.96 (0.81–1.15)
≥17 years 46,435 1,082 187 reference reference
Parity status
Nulliparous 11,085 177,215 40 reference reference
Parous 248,351 4,091,901 1,100 1.12 (0.89–1.69) 1.18 (0.85–1.62)
Number of children/deliveries
1–2 children 138,641 2,303,256 711 reference 0.53 reference
3–4 children 86,331 1,436,325 331 1.07 (0.93–1.24) 1.05 (0.91–1.22) 0.61
≥5 children 22,488 335,650 58 1.03 (0.76–1.39) 1.03 (0.76–1.39)
1 child 55,709 951,103 273 reference reference
2 children 82,932 1,352,153 438 0.94 (0.71–1.01) 0.92 (0.69–0.99)
3 children 60,259 1,014,027 235 0.99 (0.73–1.11) 0.77 0.97 (0.71–1.08) 0.88
4 children 26,072 422,298 96 1.07 (0.82–1.40) 1.03 (0.79–1.35)
≥ 5 children 22,488 335,650 58 0.91 (0.65–1.27) 0.89 (0.64–1.25)
Age at first delivery (among parous)
≤ 20 years 21,863 348,238 61 1.08 (0.83–1.39) 1.07 (0.83–1.38)
21–25 years 122,119 2,012,167 469 reference 0.07 reference 0.05
≥ 26 years 16,284 268,736 75 1.11 (0.96–1.26) 1.11 (0.98–1.25)
Breastfeeding status
Never 15,657 263,527 101 reference reference
Ever 97,050 1,605,981 638 1.19 (0.96–1.47) 1.18 (0.95–1.45)
Postmenopausal status
No 90,498 1,611,951 507 reference reference
Yes 163,360 2,585,834 580 1.18 (0.98–1.42) 1.17 (0.97–1.41)
Age at menopause
<45 years 23,000 368,672 94 reference reference
45–49 years 52,237 847,499 182 1.10 (0.85–1.42) 1.10 (0.85–1.41)
50–54 years 62,499 999,499 224 1.16 (0.90–1.51) 0.19 1.14 (0.88–1.48) 0.2
≥55 years 7,267 107,235 30 1.29 (0.83–1.98) 1.26 (0.81–1.93)
Oral contraceptive use
Never 60,296 901,198 508 reference reference
Ever 8,340 109,383 97 0.97 (0.77–1.21) 0.97 (0.77–1.22)
Hormone replacement therapy
No 163,168 2,688,486 654 reference reference
Yes 11,642 171,044 101 1.12 (0.89–1.41) 1.11 (0.89–1.40)
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a

– Cohort LSS was not included for pooled analyses. No histological information was available for the LSS and 3pref Miyagi cohorts. Cohort(s) SWHS, JACC did not contribute to Breastfeeding status, SWHS, JPHC1, JPHC2, JACC did not contribute to Oral contraceptive use, JPHC1, JPHC2 did not contribute to Hormone replacement therapy.

b

– Unadjusted Cox proportional hazard model with age as time-scale,

c

– Adjusted Cox proportional hazard model for smoking status, alcohol drinking status and BMI

Abbreviations: TC– Thyroid cancer, HR– Hazards Ratio, CI– confidence interval, SWHS: Shanghai Women’s Health Study, JPHC1: Japan Public Health Center-based prospective Study 1, JPHC2: Japan Public Health Center-based prospective Study 2, JACC: Japan Collaborative Cohort Study, Miyagi: Miyagi Cohort, 3pref. Miyagi: 3-Prefecture Miyagi Cohort, Ohsaki: Ohsaki National Health Insurance Cohort Study, LSS: Life Span Study Cohort, KMCC: Korean Multi-center Cancer Cohort Study, KNCC: Korean National Cancer Centre Cohort

The stratified analyses by country and birth years have been shown in Figure 3. Stratified analyses by countries unveiled significant interactions for the association between number of children/deliveries and thyroid cancer risk (p-interaction 0.002). Korea showed a significant positive association, while China and Japan showed non-significant inverse associations. The HRs (95% CIs) for 3–4 and ≥5 children (vs 1–2 children) were 1.46 (1.18–1.80) and 1.89 (1.21–2.94) respectively (p-trend 0.0008) for Korea, 0.84 (0.51–1.39) and 0.66 (0.23–1.88) respectively (p-trend 0.32) for China, and 0.87 (0.72–1.04) and 0.88 (0.62–1.26) respectively (p-trend 0.22) for Japan (see Supplementary Table 4).

Figure 3.

Figure 3

Open in a new tab

Forest plot of stratified analyses between reproductive factors and thyroid cancer risk by country and birth years in the Asia Cohort Consortium.

The Pooled Hazard Ratios (HRs) with 95% Confidence intervals (CIs) were generated by combining cohort-specific HRs. Models were adjusted for smoking status, alcohol drinking status and Body mass index.

a Significant (p-value <0.05) trend across categories of the reproductive factor. b Significant (p-value <0.05) for interaction indicating a modifying effect on the association between the reproductive factor and thyroid cancer risk. c The model included all 9 cohorts. d The model for Breastfeeding included 6 cohorts, that for Oral contraceptive use included 5 cohorts and that for hormone replacement therapy included 6 cohorts. Detailed results are in Supplementary Table 4.

Birth years significantly modified the association between number of children/deliveries and thyroid cancer (p-interaction <0.05). When stratified by those born before and after the 1940s, no significant trend was observed across categories for women born before the 1940s. However, among women born later than the 1940s, having a greater number of children was associated with an increasing trend of thyroid cancer risk (p-trend 0.03). Details are provided in Supplementary Table 4. On grouping women born in 1920s or earlier, 1930s, 1940s and later than 1950s, a significant trend of increasing thyroid cancer risk with greater number of children/deliveries was observed for women born in 1950s or later (p-trend 0.0001) (Supplementary Figure 5)

The risk of thyroid cancer differed with earlier (<55 years) or later (≥55 years) age at diagnosis for the following reproductive factors: age at first delivery, parity status, and postmenopausal status (Supplementary Figure 6). Older age at first delivery (≥26 vs 21–25 years) significantly increased thyroid cancer risk if diagnosed at a later age [p-trend 0.003; HR 1.19, 95% CI:1.02–1.39], this association was weaker for diagnosis at an earlier age. Parous women diagnosed at an earlier age had a significantly increased risk (HR 1.75, 95% CI:1.11–2.76), while those diagnosed at a later age had non-significantly reduced thyroid cancer risk (HR 0.74, 95% CI:0.50–1.08). The association between being menopausal and thyroid cancer showed clear contrast, with a significantly reduced risk for earlier age at diagnosis (HR 0.70, 95% CI:0.51–0.96) and increased risk if diagnosed ≥55 years (HR 1.79, 95% CI 1.42–2.24).

No significant associations were observed for stratified analyses by BMI and smoking status (Supplementary Figure 7).

DISCUSSION

In this pooled analysis of 259,649 ACC female participants enrolled in 9 prospective cohort studies from three Asian countries, a range of reproductive and hormonal factors were examined in relation to thyroid cancer risk. Older age at first delivery was found to be significantly associated with an increased risk of thyroid cancer. Other factors, such as number of children/deliveries and breastfeeding showed non-significant positive associations, while age at menarche, OC and HRT use were not associated with thyroid cancer risk. Similar associations were seen for overall and papillary thyroid cancer.

Our study’s finding of increased thyroid cancer risk with older age at first delivery/pregnancy is consistent with previous studies from USA,33 Italy,34 China18 and also with a pooled analysis of 14 case-control studies from North America, Europe, and Asia15 which reported similar findings. However, some studies have shown reduced or no association with thyroid cancer risk.16,17,22 The underlying mechanisms for the association between older age at delivery and thyroid cancer risk are not well understood but may be related to longer hormonal exposure, including estrogen, which can influence thyroid cell growth.10,35,36 Other factors like delayed childbearing37 or obesity may also play a role.

We also observed that older age at first delivery/pregnancy significantly increased thyroid cancer risk, especially among women diagnosed later in life. Notably, this association was prominent in Korean cohorts, while no substantial associations were found for China and Japan. Furthermore, when stratified by birth year, there was absence of significant associations.

The global trend toward delayed childbearing, particularly in Asia, 37 further complicates this relationship. As the median age of women at first childbirth rises from 26.8 to 33.2 years, 38 this phenomenon presents a challenge for healthcare providers, given the higher thyroid cancer risk associated with older pregnancies, as more women opt for childbirth at more advanced ages. Our findings indicate that advanced maternal age at first delivery may contribute to increased thyroid cancer risk, and this risk may vary depending on country-specific influences.

Although our study and some previous meta-analyses,13,14,39 indicate a positive relationship between parity number and thyroid cancer risk, this association was non-significant and varied across countries in our analysis. Specifically, a positive association was observed in Korean cohorts, while inverse associations were found in China and Japan. The relationship between the number of deliveries and thyroid cancer risk also differed by birth year, with a stronger positive association observed among younger women, particularly those born after the 1950s. These findings suggest that country-specific factors, such as cultural practices, environmental exposures or changes in dietary patterns, 40 changes in reproductive patterns such as decline in fertility rates or older age at first delivery, 41,42 and healthcare access, may influence the observed associations. The differing patterns across countries highlight the need for caution in interpreting these results, considering potential country-specific influences.

We also observed non-significant increased risk of thyroid cancer with having more than four children, which aligns with findings from a Korean study. 43 The increased risk may be related to hormonal changes during pregnancy, including elevated estrogen and human chorionic gonadotropin levels, which have been suggested to have stimulating effects on thyroid tumors. 44

While ever breastfeeding showed non-significant positive associations for thyroid cancer in this study, previous studies and meta-analyses have mostly documented reduced risk or no association.13,16,23,45 More research is required to better comprehend the underlying mechanisms.

Our study and a previous large study from Korea21 showed no significant association between age at menarche and thyroid cancer risk, consistent with findings from other large prospective studies from USA33 and China22, pooled analyses of 14 case-control studies, and meta-analyses of 24 prospective studies.12,15

This study, in line with previous research, found no association between OC and HRT use and thyroid cancer risk. Two meta-analyses, including cohorts and case-control studies from Western countries and worldwide also support lack of association.13,16 However, conclusions relating to OC and HRT use should be made with caution for this study considering limited cohort contributions to the risk analyses.

Evidence suggests that BMI is a major lifestyle-related factor influencing thyroid cancer development in both Eastern and Western populations.30,46,47 However, variations in the strength and direction of the association and the specific thyroid cancer subtypes affected may exist. These differences in interactions could be attributed to variations in BMI prevalence and childbearing trends. The exact mechanisms by which BMI may increase the risk of thyroid cancer in women with certain reproductive factors are not fully understood. In this study, in addition to adjusting our models for BMI, smoking, and alcohol consumption to account for lifestyle factors potentially influencing thyroid cancer risk, BMI was found to modify the association between age at first delivery and thyroid cancer risk, particularly in Asian women, and this interaction may differ in Western women. Nevertheless, the relationship between BMI, reproductive factors, and thyroid cancer risk remains an active area of research and further investigations are needed to fully elucidate these complexities.

In light of recent developments, the management of thyroid cancer is shifting towards a more parsimonious approach. According to the Global Cancer Observatory, thyroid cancer ranks third among women aged 25–45, following breast and cervical cancer. Considering this, it becomes imperative to conduct more rigorous research to determine the potential role of hormone status as a risk factor. This is especially crucial for women, with the aim of minimizing risks and maximizing patient benefits.

This study has several strengths: a substantial sample size, prospective study design, and plausibly the first pooled analyses exploring associations between reproductive factors and thyroid cancer risk in Asian women. Pooling data from several cohorts increased statistical power for subgroup analyses. Use of prospective studies minimized recall and selection biases. Standardized categorizations of reproductive, hormonal variables and other covariates minimized potential sources of heterogeneity between studies. Stratified analyses by country provided an additional layer of information to stratified analyses by birth year, enabling the examination of cross-country differences in the association between reproductive factors and thyroid cancer risk. These findings underscore the importance of considering both individual reproductive history and broader demographic trends in understanding thyroid cancer risk.

This study has some limitations: limited assessment of exposure changes during follow-up due to baseline measurement of reproductive and hormonal variables, inability to adjust for radiation exposure, diagnostic tools, iodine intake, history of benign thyroid disease and family history of thyroid cancer due to data unavailability across studies. Confounding cannot be completely ruled out; however, it is likely minimal as unadjusted and adjusted models yielded similar results. Small number of ever smokers within each study (cases = 4 to 72) may have affected stratified analyses by smoking status. Stratification by BMI used baseline information; BMI during early adulthood or before pregnancy may be more relevant for assessing potential interaction with reproductive factors.48–50 Generalizability of findings may be limited to the Chinese, Japanese, and Korean populations. Our study spans a wide age range, including individuals born before 1920 to after 1950, which allowed us to explore long-term trends in thyroid cancer risk. However, this broad range introduces variability due to advancements in diagnostic technologies and changes in lifestyle habits over time. While we conducted stratified analyses by birth cohort to account for these temporal differences, the evolving nature of healthcare and societal norms may affect the generalizability of our findings to more recent populations. Advanced diagnostic technologies, particularly after 2000, may lead to differences in the characteristics and incidence of thyroid cancer diagnoses in more recent years.

Conclusion

To our knowledge, this is the first study that conducted a large, pooled analysis to explore the relationship between reproductive factors and thyroid cancer risk in Asian women. Findings revealed a significantly increased risk of thyroid cancer for older age at first delivery, posing a challenge as more women delay pregnancy. The associations of other reproductive and hormonal factors with thyroid cancer risk were generally weak or none. Study findings from stratified analyses underscore the importance of considering country-specific, birth year-specific and thyroid cancer age of diagnosis analyses, highlighting the need for a comprehensive approach. Overall, this fills a knowledge gap and offers valuable insights into the association between reproductive factors and thyroid cancer risk in Asian women.

Supplementary Material

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Prevention Relevance Statement:

This analysis of prospective cohort studies across three Asian countries highlights that older age at first birth is linked to increased thyroid cancer risk. As women delay motherhood, understanding these trends is vital for public health strategies addressing reproductive factors influencing thyroid cancer risk in these populations.

ACKNOWLEDGMENTS

Funding:

The ACC cohorts participating in the pooled analysis were supported by the following grants:

Shanghai Women’s Health Study - US National Cancer Institute [R37 CA070867 and UM1 CA182910: W. Zheng]; Japan Public Health Center-Based Prospective Study 1 and 2 - National Cancer Center Research and Development Fund (since 2011) [23-A-31(toku), 26-A-4 and 2020-A-4: S. Tsugane; 2020-J-4, 2023-J-04: N. Sawada] and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010): S. Tsugane; Japan Collaborative Cohort Study - National Cancer Center Research and Development Fund, A grant-in-aid for cancer research: M. Innoue, and Ministry of Health, Labour and Welfare, Japan (grant for health services and grant for comprehensive research on cardiovascular and life-style related diseases), and Ministry of Education, Culture, Sports, Science and Technology, Japan (grant for the scientific research): A. Tamakoshi; Miyagi Cohort Study - National Cancer Center Research and Development Fund: M. Inoue; Ohsaki National Health Insurance Cohort Study - National Cancer Center Research and Development Fund: M. Inoue; Life Span Study Cohort - The Japanese Ministry of Health, Labour and Welfare and the US Department of Energy: R. Sakata; 3 Prefecture Miyagi Study - National Cancer Center Research and Development Fund: M. Inoue; Korea Multi-Center Cancer Cohort Study - National Research Foundation of Korea (NRF) grant (funded by the Korea government (MSIP) [2016R1A2B4014552; RS-2024-00345260: S. K. Park] and National R&D Program for Cancer Control (through the National Cancer Center(NCC) funded by the Ministry of Health & Welfare, Republic of Korea) [HA21C0140: S. K. Park]; Korea National Cancer Center Cohort - National Cancer Center Research Grant [2210990, 24H1080: J. Kim);

ACC Coordinating Center - National Cancer Center Japan Research and Development Fund [(30-A-15, 2021-A-16) 2024-A-14: M. Inoue].

This work was supported by the grant from the National Research Foundation of Korea (NRF) [No: 2022R1A2C1004608: A. Shin].

Abbreviations:

ACC

Asia Cohort Consortium

BMI

Body mass index

CIs

Confidence intervals

HRs

Hazard ratios

HRT

Hormone replacement therapy

ICD

International Classification of Diseases

ICD-O-3

ICD for Oncology, third edition

JACC

Japan Collaborative Cohort Study

JPHC1

Japan Public Health Center-based prospective Study 1

JPHC2

Japan Public Health Center-based prospective Study 2

KMCC

Korean Multi-center Cancer Cohort Study

KNCC

Korean National Cancer Center Cohort

LSS

Life Span Study Cohort

Miyagi

, Miyagi Cohort

Namwon

The Namwon Study

Ohsaki

Ohsaki National Health Insurance Cohort Study

OC

Oral contraceptives

SCHS

Singapore Chinese Health Study

SWHS

Shanghai Women’s Health Study

Takayama

Takayama Study

WG

Working Group

3 Pref Miyagi

3-Prefecture Miyagi Cohort

Footnotes

The authors declare no potential conflicts of interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS2053097-supplement-1.docx (35.5KB, docx)
2
NIHMS2053097-supplement-2.docx (30.6KB, docx)
3
NIHMS2053097-supplement-3.docx (29.9KB, docx)
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NIHMS2053097-supplement-4.docx (29.8KB, docx)
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NIHMS2053097-supplement-5.docx (45.1KB, docx)
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NIHMS2053097-supplement-6.pdf (169.7KB, pdf)
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NIHMS2053097-supplement-7.pdf (178.6KB, pdf)
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NIHMS2053097-supplement-8.pdf (153.6KB, pdf)
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NIHMS2053097-supplement-9.pdf (93.3KB, pdf)
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NIHMS2053097-supplement-10.pdf (100KB, pdf)
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NIHMS2053097-supplement-11.pdf (92.3KB, pdf)
12
NIHMS2053097-supplement-12.pdf (106.1KB, pdf)

Data Availability Statement

The data underlying this article were obtained from the Asia Cohort Consortium (ACC). Researchers can apply for access to these data through the ACC Coordinating Center (https://www.asiacohort.org/CC/index.html) after obtaining ethics approval from an Institutional Review Board. Further information is available from the corresponding author upon request.

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