Background
Methods
Data source and study setting
Study population
Reproductive factors
Study outcomes and follow-up
Covariates: traditional cardiovascular risk factors
Statistical analyses
Results
Baseline characteristics of the study population
Incident cardiovascular disease (myocardial infarction or ischemic stroke) | P value | AMD or PR (95% CI) | ||
---|---|---|---|---|
No (n = 1,163,480) | Yes (n = 61,067) | |||
Age (years) | 60.8 ± 8.0 | 66.9 ± 8.3 | < 0.0001 | 6.16 (6.10–6.23) |
Income (quartile) | ||||
Q1 (lowest) | 269,311 (23.2) | 13,247 (21.7) | < 0.0001 | 1.00 |
Q2 | 219,661 (18.9) | 10,941 (17.9) | 1.01 (0.99–1.04) | |
Q3 | 289,069 (24.9) | 14,843 (24.3) | 1.04 (1.02–1.07) | |
Q4 (highest) | 385,439 (33.1) | 22,036 (36.1) | 1.15 (1.13–1.18) | |
Smoking status | ||||
Never | 1,121,142 (96.4) | 57,779 (94.6) | < 0.0001 | 1.00 |
Ex-smoker | 11,914 (1.02) | 670 (1.1) | 1.09 (1.01–1.17) | |
Current smoker | 30,424 (2.61) | 2618 (4.3) | 1.62 (1.56–1.68) | |
Alcohol consumption | ||||
None | 1,013,068 (87.1) | 54,967 (90.0) | < 0.0001 | 1.00 |
Mild | 144,190 (12.4) | 5827 (9.5) | 0.75 (0.74–0.78) | |
Heavy | 6222 (0.50) | 273 (0.5) | 0.82 (0.73–0.92) | |
Regular exercise | 219,319 (18.9) | 8764 (14.4) | < 0.0001 | 0.73 (0.72–0.75) |
Body mass index (kg/m2) | 24.1 ± 3.1 | 24.4 ± 3.3 | < 0.0001 | 0.31 (0.28–0.33) |
< 18.5 | 24,611 (2.1) | 1582 (2.6) | 1.37 (1.31–1.44) | |
18.5–23 | 406,916 (35.0) | 18,704 (30.6) | 1.00 | |
23–25 | 309,110 (26.6) | 15,474 (25.3) | 1.08 (1.06–1.11) | |
25–30 | 375,149 (32.2) | 22,075 (36.2) | 1.26 (1.24–1.29) | |
≥ 30 | 47,694 (4.1) | 3232 (5.29) | 1.44 (1.39–1.50) | |
Systolic BP (mmHg) | 125.2 ± 16.1 | 129.9 ± 17.0 | < 0.0001 | 4.71 (4.58–4.85) |
Diastolic BP (mmHg) | 76.8 ± 10.1 | 78.7 ± 10.4 | < 0.0001 | 1.94 (1.86–2.02) |
Fasting glucose (mg/dL) | 99.0 ± 23.0 | 105.3 ± 33.8 | < 0.0001 | 6.30 (6.11–6.49) |
Total cholesterol (mg/dL) | 209.01 ± 43.8 | 210.1 ± 45.1 | < 0.0001 | 0.96 (0.60–1.32) |
Comorbidities | ||||
Hypertension | 491,733 (42.3) | 37,169 (60.9) | < 0.0001 | 2.05 (2.01–2.08) |
Diabetes mellitus | 134,195 (11.5) | 13,492 (22.1) | < 0.0001 | 2.07 (2.03–2.11) |
Dyslipidemia | 376,475 (32.4) | 21,960 (36.0) | < 0.0001 | 1.16 (1.15–1.18) |
Age at menarche (years) | 16.4 ± 1.8 | 16.8 ± 1.8 | < 0.0001 | 0.36 (0.34–0.37) |
≤ 12 | 11,793 (1.0) | 373 (0.6) | < 0.0001 | 0.89 (0.80–0.98) |
13–14 | 146,603 (12.6) | 5251 (8.6) | 1.00 | |
15 | 209,389 (18.0) | 8718 (14.3) | 1.16 (1.12–1.20) | |
16 | 244,831 (21.0) | 12,700 (20.8) | 1.43 (1.38–1.47) | |
≥ 17 | 550,864 (47.4) | 34,025 (55.7) | 1.68 (1.64–1.73) | |
Age at menopause (years) | 50.1 ± 4.0 | 49.6 ± 4.5 | < 0.0001 | 0.48 (0.45–0.51) |
< 40 | 19,301 (1.7) | 1637 (2.7) | < 0.0001 | 1.88 (1.79–1.98) |
40–45 | 115,815 (10.0) | 8154 (13.4) | 1.58 (1.54–1.62) | |
46–50 | 527,997 (45.4) | 28,694 (47.0) | 1.24 (1.22–1.26) | |
51–54 | 434,332 (37.3) | 18,815 (30.8) | 1.00 | |
≥ 55 | 66,035 (5.7) | 3767 (6.2) | 1.30 (1.26–1.34) | |
Reproductive span (years) | 33.6 ± 4.4 | 32.8 ± 4.9 | < 0.0001 | 0.84 (0.80–0.88) |
< 30 | 156,340 (13.4) | 11,567 (18.9) | < 0.0001 | 1.79 (1.74–1.84) |
30–33 | 351,323 (30.2) | 20,109 (32.9) | 1.41 (1.37–1.44) | |
34–36 | 471,279 (40.5) | 21,244 (34.8) | 1.15 (1.13–1.18) | |
37–40 | 161,421 (13.9) | 6737 (11.0) | 1.00 | |
≥ 41 | 23,117 (2.0) | 1410 (2.3) | 1.37 (1.30–1.43) | |
Parity | ||||
Nulliparity | 28,295 (2.4) | 990 (1.6) | < 0.0001 | 1.00 |
1 | 1,062,402 (91.3) | 57,740 (94.6) | 0.92 (0.86–0.99) | |
≥ 2 | 72,783 (6.3) | 2337 (3.8) | 1.52 (1.43–1.62) | |
Duration of breast feeding (months) | ||||
Never | 78,590 (6.8) | 2410 (4.0) | < 0.0001 | 1.00 |
< 6 | 77,652 (6.7) | 2195 (3.6) | 0.92 (0.87–0.98) | |
6–12 | 203,318 (17.5) | 7776 (12.7) | 1.24 (1.18–1.30) | |
≥ 12 | 803,920 (69.1) | 48,686 (79.7) | 1.92 (1.84–2.00) | |
Duration of HRT (years) | ||||
Never | 971,399 (83.5) | 54,552 (89.3) | < 0.0001 | 1.00 |
< 2 | 112,034 (9.6) | 3709 (6.1) | 0.60 (0.58–0.62) | |
2–5 | 45,869 (3.9) | 1537 (2.5) | 0.61 (0.58–0.64) | |
≥ 5 | 34,178 (2.9) | 1269 (2.1) | 0.67 (0.64–0.71) | |
Duration of OC use (years) | ||||
Never | 978,738 (84.1) | 52,483 (85.9) | < 0.0001 | 1.00 |
< 1 | 111,850 (9.6) | 4992 (8.2) | 0.84 (0.82–0.86) | |
≥ 1 | 72,892 (6.3) | 3592 (5.9) | 0.92 (0.89–0.95) |
Associations between age at menarche, age at menopause, and reproductive span with CVD events
Reproductive factors | Subjects (N) | Myocardial infarction | Ischemic stroke | Cardiovascular disease | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Events (n) | IR | Model 1 | Model 2 | Events (n) | IR | Model 1 | Model 2 | Events (n) | IR | Model 1 | Model 2 | ||
Age at menarche (years) | |||||||||||||
≤ 12 | 12,166 | 137 | 1.4 | 0.86 (0.72–1.02) | 0.86 (0.72–1.02) | 252 | 2.5 | 1.15 (1.01–1.31) | 1.16 (1.02–1.31) | 373 | 3.7 | 1.03 (0.93–1.14) | 1.03 (0.93–1.15) |
13–14 | 151,854 | 2267 | 1.8 | 1 (Ref.) | 1 (Ref.) | 3238 | 2.6 | 1 (Ref.) | 1 (Ref.) | 5251 | 4.2 | 1 (Ref.) | 1 (Ref.) |
15 | 218,107 | 3712 | 2.1 | 1.02 (0.97–1.07) | 1.01 (0.96–1.07) | 5418 | 3.0 | 1.01 (0.96–1.05) | 1.00 (0.96–1.04) | 8718 | 4.9 | 1.01 (0.98–1.05) | 1.01 (0.97–1.04) |
16 | 257,531 | 5268 | 2.5 | 1.07 (1.01–1.12) | 1.06 (1.01–1.11) | 8074 | 3.8 | 1.08 (1.03–1.12) | 1.07 (1.03–1.11) | 12,700 | 6.1 | 1.08 (1.04–1.11) | 1.07 (1.03–1.10) |
≥ 17 | 584,889 | 13,797 | 2.9 | 1.08 (1.03–1.13) | 1.06 (1.02–1.11) | 22,014 | 4.6 | 1.11 (1.07–1.15) | 1.09 (1.05–1.13) | 34,025 | 7.2 | 1.10 (1.07–1.13) | 1.08 (1.05–1.12) |
P for trend | < 0.0001 | 0.0002 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | |||||||
Age at menopause (years) | |||||||||||||
< 40 | 20,938 | 686 | 4.0 | 1.41 (1.30–1.52) | 1.40 (1.30–1.52) | 1048 | 6.2 | 1.32 (1.24–1.40) | 1.31 (1.23–1.39) | 1637 | 9.8 | 1.36 (1.29–1.43) | 1.35 (1.28–1.42) |
40–45 | 123,969 | 3372 | 3.3 | 1.24 (1.19–1.30) | 1.24 (1.19–1.29) | 5246 | 5.2 | 1.18 (1.15–1.22) | 1.18 (1.14–1.22) | 8154 | 8.2 | 1.21 (1.18–1.24) | 1.21 (1.17–1.24) |
46–50 | 556,691 | 11,771 | 2.6 | 1.12 (1.09–1.16) | 1.12 (1.09–1.16) | 18,400 | 4.1 | 1.12 (1.09–1.14) | 1.12 (1.09–1.14) | 28,694 | 6.4 | 1.12 (1.10–1.14) | 1.12 (1.10–1.14) |
51–54 | 453,147 | 7833 | 2.1 | 1 (Ref.) | 1 (Ref.) | 11,860 | 3.2 | 1(Ref.) | 1 (Ref.) | 18,815 | 5.1 | 1 (Ref.) | 1 (Ref.) |
≥ 55 | 69,802 | 1519 | 2.6 | 0.99 (0.93–1.04) | 0.98 (0.93–1.04) | 2442 | 4.3 | 1.01(0.97–1.06) | 1.01 (0.97–1.05) | 3767 | 6.7 | 1.00 (0.96–1.03) | 1.00 (0.96–1.03) |
P for trend | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | |||||||
Reproductive span (years)a | |||||||||||||
< 30 | 167,907 | 4735 | 3.5 | 1.33 (1.27–1.39) | 1.32 (1.26–1.38) | 7495 | 5.5 | 1.27 (1.23–1.32) | 1.26 (1.22–1.31) | 11,567 | 8.6 | 1.30 (1.26–1.33) | 1.29 (1.25–1.32) |
30–33 | 371,432 | 8250 | 2.7 | 1.20 (1.16–1.25) | 1.19 (1.15–1.24) | 12,909 | 4.3 | 1.17 (1.14–1.21) | 1.17 (1.13–1.20) | 20,109 | 6.7 | 1.19 (1.16–1.22) | 1.18 (1.15–1.21) |
34–36 | 401,857 | 7444 | 2.2 | 1.12 (1.08–1.17) | 1.12 (1.08–1.16) | 11,298 | 3.4 | 1.10 (1.07–1.14) | 1.10 (1.06–1.13) | 17,877 | 5.5 | 1.11 (1.08–1.14) | 1.11 (1.08–1.13) |
37–40 | 240,950 | 3861 | 1.9 | 1 (Ref.) | 1 (Ref.) | 5842 | 2.9 | 1 (Ref.) | 1 (Ref.) | 9284 | 4.7 | 1 (Ref.) | 1 (Ref.) |
≥ 41 | 42,401 | 891 | 2.6 | 1.03 (0.96–1.11) | 1.03 (0.96–1.11) | 1452 | 4.2 | 1.06 (1.00–1.12) | 1.06 (1.00–1.13) | 2230 | 6.5 | 1.05 (1.00–1.10) | 1.05 (1.00–1.10) |
P for trend | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |