Text box 1. Contributions to the literature
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• A cross-sectional analysis using NHANES 2013-2018 revealed that the blood concentrations of Pb were dose-dependently associated with historical infertility in women, but the concentrations of cadmium (Cd) and mercury (Hg) and mixtures of Pb, Cd, and Hg were comparable between ever-infertile and pregnant women; |
• The blood concentrations of Cd were negatively associated with women’s long-term amenorrhea, and no associations were observed for Pb, Hg, and mixtures of Cd, Pb, and Hg with amenorrhea; |
• Mechanistic studies are required to investigate the effects of single heavy metals and their mixtures on women’ reproductive health. |
Introduction
Materials and methods
Study population
Study sample, variable descriptions, and inclusion
Measurements of blood Pb, Cd, Hg concentrations
Creating a metal mixture value
Women’s infertility history
Women’s recent long-term amenorrhea
Other covariates
Statistical analysis
Results
Exposure to heavy metals and women’s infertility
Study population
Characteristics | Main group sample (ever-infertile vs fertile) | Sub-group sample (ever-infertile vs pregnant) | ||||||
---|---|---|---|---|---|---|---|---|
Total Sample N (%) | Ever-infertile1 N (%) | Fertile2 N (%) | p-Value4 | Total Sample N (%) | Ever-infertile1 N (%) | Pregnant3 N (%) | p-Value4 | |
Total Women | 1999 | 238 (12.8) | 1761 (87.2) | 297 | 238 (81.6) | 59 (18.4) | ||
Age, mean ± SE (years) | 34 ± 0.23 | 37 ± 0.79 | 33 ± 0.22 | < .001 | 35 ± 0.71 | 37 ± 0.70 | 27 ± 0.58 | < .001 |
Race/Ethnicity | 0.85 | 0.26 | ||||||
Hispanic | 518 (18.2) | 62 (17.9) | 456 (18.2) | 78 (18.5) | 62 (17.9) | 16 (21.4) | ||
Non-Hispanic White | 697 (58.4) | 90 (60.5) | 607 (58.1) | 108 (57.8) | 90 (60.5) | 18 (45.8) | ||
Non-Hispanic Black | 426 (13.2) | 47 (13.0) | 379 (13.2) | 61 (14.4) | 47 (13.0) | 14 (20.4) | ||
Other Race Including Multi-Racial | 358 (10.2) | 39 (8.6) | 319 (10.5) | 50 (9.3) | 39 (8.6) | 11 (12.4) | ||
Education Level | 0.53 | 0.73 | ||||||
Less than High School | 297 (10.8) | 36 (11.7) | 261 (10.7) | 46 (15.5) | 36 (11.7) | 10 (14.1) | ||
High School | 397 (19.6) | 50 (22.1) | 347 (19.2) | 62 (20.9) | 50 (22.1) | 12 (17.1) | ||
More than High School | 1305 (69.6) | 152 (66.3) | 1153 (70.1) | 189 (63.6) | 152 (66.3) | 37 (68.8) | ||
Marital Status | < .001 | 0.59 | ||||||
Married / Living with Partner | 1173 (61.3) | 175 (78.1) | 998 (58.9) | 223 (78.6) | 175 (78.1) | 48 (80.6) | ||
Divorced / Widowed / Separated | 243 (10.3) | 29 (8.8) | 214 (10.5) | 31 (8.0) | 29 (8.8) | 2 (4.2) | ||
Never Married | 583 (28.4) | 34 (13.0) | 549 (30.6) | 43 (13.4) | 34 (13.0) | 9 (15.2) | ||
Poverty Income Ratio, mean ± SE | 2.770 ± 0.07 | 2.95 ± 0.14 | 2.75 ± 0.070 | 0.15 | 2.90 ± 0.14 | 2.95 ± 0.14 | 2.72 ± 0.23 | 0.52 |
Covered by Health Insurance | 0.33 | 0.03 | ||||||
Yes | 1601 (83.0) | 187 (80.7) | 1414 (83.3) | 239 (82.6) | 187 (80.7) | 52 (91.0) | ||
No | 398 (17.0) | 51 (19.3) | 347 (16.7) | 58 (17.4) | 51 (19.3) | 7 (9.0) | ||
Body Mass Index (kg/m**2) | 0.007 | 0.16 | ||||||
Underweight (< 18.5) | 39 (2.0) | 4 (1.2) | 35 (2.1) | 5 (1.2) | 4 (1.2) | 1 (1.4) | ||
Normal Weight (18.5–24.9) | 615 (32.1) | 64 (27.8) | 551 (32.7) | 78 (26.2) | 64 (27.8) | 14 (19.2) | ||
Overweight (25.0–29.9) | 471 (24.9) | 38 (18.5) | 433 (25.9) | 53 (21.1) | 38 (18.5) | 15 (32.4) | ||
Obese (> 30) | 874 (50.0) | 132 (52.5) | 742 (39.3) | 161 (51.5) | 132 (52.5) | 29 (47.0) | ||
Ever Smoked | 0.028 | 0.50 | ||||||
Yes | 613 (33.0) | 88 (40.5) | 525 (31.9) | 109 (39.3) | 88 (40.5) | 21 (34.1) | ||
No | 1386 (67.0) | 150 (59.5) | 1236 (68.1) | 188 (60.7) | 150 (59.5) | 38 (65.9) | ||
Ever taken hormone-based contraception? | 0.85 | 0.15 | ||||||
Yes | 1389 (75.7) | 170 (76.3) | 1219 (75.6) | 204 (74.3) | 170 (76.3) | 34 (65.1) | ||
No | 610 (24.3) | 68 (23.7) | 542 (24.4) | 93 (25.7) | 68 (23.7) | 25 (34.9) | ||
At least one period in past 12 months | 0.73 | n/a | ||||||
Yes | 1815 (89.8) | 222 (89.0) | 1593 (89.9) | 281 (91.0) | 222 (89.0) | 59 (100) | ||
No | 183 (10.2) | 16 (11.0) | 167 (10.1) | 16 (9.0) | 16 (11.0) | 0 (0) | ||
Seen a DR b/c unable to become pregnant? | < .001 | < .001 | ||||||
Yes | 166 (9.3) | 136 (60.3) | 30 (1.8) | 137 (49.5) | 136 (60.3) | 1 (1.9) | ||
No | 1833 (90.7) | 102 (39.7) | 1731 (98.2) | 160 (50.5) | 102 (39.7) | 58 (98.1) |
Bivariate results and metal exposures
Main group sample (ever-infertile vs fertile n = 1999) | Sub-group sample (ever-infertile vs pregnant n = 297) | |||||||
---|---|---|---|---|---|---|---|---|
Metal | Total Sample | Ever- infertile1 | Fertile2 | p-Value4 | Total Sample - | Ever- infertile1 | Pregnant3 | p-Value4 |
Lead, median, IQR (ug / dL) | 0.53 (0.34-0.78) | 0.56 (0.42-0.79) | 0.53 (0.38-0.78) | 0.19 | 0.54 (0.36-0.74) | 0.56 (0.42-0.79) | 0.36 (0.26-0.53) | 0.001 |
Log Transformed Lead, Mean, SE | -0.57 ± 0.02 | -0.49 ± 0.04 | -0.58 ± 0.03 | 0.11 | -0.58 ± 0.05 | -0.49 ± 0.04 | -0.99 ± 0.06 | < .001 |
Cadmium, median, IQR (ug / L) | 0.25 (0.16-0.44) | 0.26 (0.15-0.47) | 0.25 (0.60-0.44) | 0.68 | 0.25 (0.14-0.44) | 0.26 (0.15-0.47) | 0.19 (0.11-0.35) | 0.21 |
Log Transformed Cadmium, Mean, SE | -1.25 ± 0.03 | -1.24 ± 0.07 | -1.25 ± 0.03 | 0.91 | -1.30 ± 0.07 | -1.24 ± 0.07 | -1.54 ± 0.10 | 0.07 |
Mercury, median, IQR (ug / L) | 0.61 (0.33-1.26) | 0.60 (0.37-1.15) | 0.61 (0.32-1.27) | 0.72 | 0.59 (0.35-1.16) | 0.60 (0.37-1.15) | 0.55 (0.26-1.14) | 0.051 |
Log Transformed Mercury, Mean, SE | -0.37 ± 0.03 | -0.36 ± 0.08 | -0.37 ± 0.03 | 0.89 | -0.40 ± 0.07 | -0.36 ± 0.08 | -0.58 ± 0.12 | 0.21 |
Weighted Mixed Metal, median, IQR | 3.01 (2.12 – 4.39) | 3.10 (2.27 – 4.31) | 2.10 (2.98 – 4.39) | 0.19 | 2.94 (2.03 – 4.23) | 3.10 (2.27 – 4.31) | 1.39 (2.04 – 2.79) | 0.001 |
Log Transformed Mix, Mean, SE | 1.14 ± 0.02 | 1.21 ± 0.04 | 1.13 ± 0.02 | 0.15 | 1.12 ± 0.04 | 1.21 ± 0.04 | 0.73 ± 0.06 | < .001 |
Multiple logistic regression analysis results
Main group sample (ever infertileb vs fertilec n = 1999) | Sub-group sample (ever-infertileb vs pregnantd n = 297) | ||||||||
---|---|---|---|---|---|---|---|---|---|
Characteristics | Total N (%) or Mean (SD)a | Ever- infertileb n (%) or Mean (SD)a | Crude OR (95% CI) Model 1 | Adj OR (95% CI) Model 2 | Fully Adj OR (95% CI) Model 3 | Ever- infertileb n (%) or Mean (SD)a | Crude OR (95% CI) Model 1 | Adj OR (95% CI) Model 2 | Fully Adj OR (95% CI) Model 3 |
Lead | |||||||||
Log Transformed | -0.52 (0.62) | -0.48 (0.61) | 1.28 (0.97-1.68) | 1.69 (1.01-2.85)* | 1.75 (1.02-3.02)* | -0.48 (0.61) | 5.02 (2.73-9.23)* | 5.19 (2.14-12.59)* | 3.09 (1.22-7.85)* |
Lead quartiles | |||||||||
Q1 (Ref) (\(\le\) 0.40) | 488 (24.41%) | 52 (2.6%) | Ref | Ref | Ref | 52 (17.51%) | Ref | Ref | Ref |
Q2 (0.41 – 0.56) | 492 (24.61%) | 56 (2.8%) | 1.15 (0.70-1.89) | 1.37 (0.67-2.80) | 1.38 (0.68-2.79) | 56 (18.86%) | 3.23 (1.18-8.86)* | 2.88 (0.61-13.55) | 2.52 (0.53-12.09) |
Q3 (0.57 – 0.86) | 513 (25.66%) | 70 (3.5%) | 1.52 (1.00-2.29)* | 1.60 (0.82-3.10) | 1.61 (0.83-3.09) | 70 (23.57%) | 5.32 (2.20-12.88)* | 5.60 (1.67-18.73)* | 3.47 (1.11-10.83)* |
Q4 (> 0.86) | 506 (25.31) | 60 (3.0%) | 1.30 (0.80-2.11) | 1.71 (0.76-3.85) | 1.72 (0.75-3.95) | 60 (20.2%) | 6.71 (2.85-15.81)* | 12.62 (2.48-64.21)* | 5.26 (1.18-23.54)* |
Cadmium | |||||||||
Log Transformed | -1.16 (0.84) | -1.13 (0.84) | 1.01 (0.81-1.26) | 1.01 (0.68-1.52) | 0.94 (0.63-1.41) | -1.13 (0.84) | 1.51 (0.94-2.43) | 2.29 (0.87-6.04) | 1.90 (0.64-5.63) |
Cadmium quartiles | |||||||||
Q1 (Ref) (\(\le\) 0.18) | 469 (23.46%) | 52 (2.6%) | Ref | Ref | Ref | 52 (17.51%) | Ref | Ref | Ref |
Q2 (0.19 – 0.29) | 509 (25.46%) | 67 (3.35%) | 1.08 (0.66-1.77) | 0.65 (0.34-1.25) | 0.67 (0.35-1.27) | 67 (22.56%) | 2.06 (0.81-5.27) | 0.82 (0.16-4.05) | 0.58 (0.10-3.41) |
Q3 (0.30–0.51) | 513 (25.66%) | 53 (2.65%) | 0.87 (0.57-1.32) | 0.71 (0.38-1.33) | 0.70 (0.37-1.31) | 53 (17.85%) | 1.83 (0.76-4.41) | 0.38 (0.05-2.83) | 0.37 (0.04-3.20) |
Q4 (> 0.51) | 508 (25.41%) | 66 (3.3%) | 1.07 (0.64-1.81) | 0.95 (0.41-2.18) | 0.83 (0.36-1.94) | 66 (22.22%) | 2.19 (0.80-6.02) | 1.33 (0.09-19.70) | 0.61 (0.04-9.94) |
Mercury | |||||||||
Log Transformed | -0.29 (0.99) | -0.28 (0.96) | 1.01 (0.85-1.21) | 1.07 (0.80-1.44) | 1.02 (0.76-1.36) | -0.28 (0.96) | 1.35 (0.84-2.17) | 1.37 (0.71-2.67) | 1.38 (0.76-2.51) |
Mercury quartiles | |||||||||
Q1 (Ref) (\(\le\) 0.34) | 491 (24.56%) | 46 (2.3%) | Ref | Ref | Ref | 46 (15.49%) | Ref | Ref | Ref |
Q2 (0.34 – 0.67) | 508 (25.41%) | 72 (3.6%) | 1.69 (0.96-2.97) | 1.70 (0.76-3.81) | 1.59 (0.70-3.61) | 72 (24.24%) | 2.54 (0.90-7.17) | 2.26 (0.47-10.90) | 1.48 (0.43-5.03) |
Q3 (0.68–1.38) | 493 (24.66%) | 63 (3.15%) | 1.43 (0.82-2.49) | 1.54 (0.75-3.18) | 1.49 (0.72-3.08) | 63 (21.21%) | 1.91 (0.62 – 5.90) | 2.53 (0.54-11.78)* | 2.51 (0.60-10.59) |
Q4 (> 1.38) | 507 (25.36%) | 57 (2.85%) | 1.20 (0.66-2.17) | 0.58 (3.66-3.11) | 1.26 (0.51-3.11) | 57 (19.19%) | 1.90 (0.61 – 5.94) | 2.01 (0.40-10.20) | 1.67 (0.33-8.43) |
Weighted mixed metals | |||||||||
Log Transformed | 1.19 (0.60) | 1.22 (0.61) | 1.26 (0.94-1.69) | 1.69 (0.95 -2.99) | 1.00 (0.46—2.19) | 1.22 (0.61) | 4.60 (2.42-8.76)* | 6.21 (2.24-17.20) * | 1.30 (0.09-18.13) |
Weighted Mixed Metals quartiles | |||||||||
Q1 (Ref) (\(\le\) 2.24) | 499 (24.96%) | 53 (2.65%) | Ref | Ref | Ref | 53 (17.85%) | Ref | Ref | Ref |
Q2 (2.24–3.14) | 500 (25.01%) | 65 (3.25%) | 1.34 (0.91-1.99) | 1.58 (0.86-2.91) | 1.47 (0.80-2.71) | 65 (21.89%) | 2.66 (1.33-5.32) * | 1.86 (0.53-6.47) | 0.87 (0.18-4.30) |
Q3 (3.14–4.74) | 500 (25.01%) | 59 (2.95%) | 1.39 (0.90-2.15) | 1.31 (0.65-2.63) | 1.12 (0.56-2.25) | 59 (19.87%) | 9.62 (2.74-33.80) * | 15.87 (3.11-80.91) * | 6.92 (0.72-66.79) |
Q4 (> 4.74) | 500 (25.01%) | 61 (3.05%) | 1.29 (0.82-2.05) | 2.02 (0.89-4.75) | 1.17 (0.44-3.10) | 61 (20.54%) | 4.80 (1.77-13.03) * | 13.22 (2.39-73.17) * | 0.48 (0.01-16.32) |
Women’s historical infertility is not associated with their recent long-term amenorrhea
Amenorrhea | Menstruating | Total | % of women with amenorrhea by infertility status | p-value | |
---|---|---|---|---|---|
Infertile | 9 | 222 | 231 | 3.9% | 0.29 |
Fertile | 94 | 1593 | 1687 | 5.6% | |
Total | 103 | 1815 | 1918 | ||
% of women who are infertile by menstrual status | 8.7% | 12.2% |
Exposure to heavy metals and women’s long-term amenorrhea
Study population
Characteristics | Total Sample N (%) | Long-term amenorrhea1 N (%) | Menstruating2 N (%) | p-Value3 |
---|---|---|---|---|
Total Women | 1919 | 103 (6.4) | 1816 (93.6) | |
Age, mean ± SE (years) | 34 ± 0.2 | 35 ± 0.1 | 33 ± 0.2 | 0.24 |
Race/Ethnicity | 0.03 | |||
Hispanic | 501 (18.4) | 23 (11.9) | 478 (18.8) | |
Non-Hispanic White | 664 (58.0) | 47 (68.5) | 617 (57.3) | |
Non-Hispanic Black | 409 (13.4) | 26 (14.1) | 383 (13.3) | |
Other Race Including Multi-Racial | 345 (10.3) | 7 (5.6) | 338 (10.6) | |
Education Level | 0.65 | |||
Less than High School | 285 (10.7) | 16 (11.8) | 269 (10.6) | |
High School | 382 (19.9) | 27 (23.0) | 355 (19.6) | |
More than High School | 1252 (69.4) | 60 (65.3) | 1192 (69.7) | |
Marital Status | 0.77 | |||
Married / Living with Partner | 1117 (60.8) | 57 (63.5) | 1060 (60.6) | |
Divorced / Widowed / Separated | 228 (10.1) | 13 (10.8) | 215 (10.1) | |
Never Married | 574 (29.1) | 33 (25.7) | 541 (29.3) | |
Covered by Health Insurance | 0.47 | |||
Yes | 1533 (82.5) | 88 (85.7) | 1445 (82.3) | |
No | 386 (17.5) | 15 (14.3) | 371 (17.7) | |
Poverty Income Ratio, mean ± SE | 2.75 ± 0.065 | 2.59 ± 0.189 | 2.77 ± 0.067 | 0.39 |
Body Mass Index (kg/m**2) | 0.88 | |||
Underweight (< 18.5) | 38 (2.1) | 1 (1.2) | 37 (2.1) | |
Normal Weight (18.5–24.9) | 591 (31.8) | 34 (31.9) | 557 (31.8) | |
Overweight (25.0–29.9) | 451 (25.0) | 21 (22.6) | 430 (25.2) | |
Obese (> 30) | 839 (41.1) | 47 (44.4) | 792 (40.9) | |
Ever Smoked | 0.51 | |||
Yes | 580 (32.6) | 34 (35.9) | 546 (32.3) | |
No | 1339 (67.4) | 69 (64.1) | 1270 (67.7) | |
Ever taken hormone-based contraception? | 0.38 | |||
Yes | 1328 (75.4) | 73 (71.3) | 1255 (75.7) | |
No | 591 (24.6) | 30 (28.7) | 561 (24.3) |
Bivariate results and heavy metal exposures
Metal | Total Sample | Long-term amenorrhea1 | Menstruating2 | p-Value3 |
---|---|---|---|---|
Lead, median, IQR (ug / dL) | 0.53 (0.38-0.78) | 0.52 (0.35-0.71) | 0.53 (0.38-0.78) | 0.72 |
Log Transformed Lead, Mean, SE | -0.58 ± 0.02 | -0.62 ± 0.09 | -0.57 ± 0.02 | 0.60 |
Cadmium, median, IQR (ug / L) | 0.25 (0.16-0.44) | 0.23 (0.12-0.41) | 0.26 (0.16-0.44) | 0.99 |
Log Transformed Cadmium, Mean, SE | -1.25 ± 0.03 | -1.37 ± 0.11 | -1.25 ± 0.03 | 0.33 |
Mercury, median, IQR (ug / L) | 0.61 (0.33-1.26) | 0.65 (0.37-1.01) | 0.61 (0.32-1.29) | 0.004 |
Log Transformed Mercury, Mean, SE | -0.37 ± 0.03 | -0.38 ± 0.06 | -0.37 ± 0.03 | 0.84 |
Mixed Metal, median, IQR | 2.97 (2.10 – 4.34) | 2.91 (1.84 – 3.82) | 2.97 (2.10 – 4.37) | 0.74 |
Log Transformed Mix, Mean, SE | 1.13 ± 0.02 | 1.08 ± 0.08 | 1.13 ± 0.02 | 0.57 |
Multiple logistic regression model results
Full sample (Long-term amenorrheaa vs Menstruatingb n = 1919) | |||||
---|---|---|---|---|---|
Characteristics | Total N (%) or Mean (SD)a | Long-term amenorrhea n (%) or Mean (SD) | Crude OR (95% CI) Model 1 | Adj OR (95% CI) Model 2 | Fully Adj OR (95% CI) Model 3 |
Lead | |||||
Log Transformed | -0.53 (0.62) | -0.54 (0.56) | 0.88 (0.53-1.46) | 0.89 (0.53-1.50) | 0.93 (0.54-1.59) |
Quartiles | |||||
Q1 (\(\le\) 0.39) | 460 (23.97%) | 22 (1.15%) | Ref | Ref | Ref |
Q2 (0.40-0.55) | 475 (24.75%) | 27 (1.41%) | 0.99 (0.41—2.35) | 1.02 (0.42—2.50) | 1.04 (0.42-2.54) |
Q3 (0.56-0.83) | 504 (26.26%) | 32 (1.67%) | 1.03 (0.46-2.32) | 1.03 (0.46-2.32) | 1.06 (0.46-2.42) |
Q4 (> 0.83) | 480 (25.01%) | 22 (1.15%) | 0.71 (0.31-1.61) | 0.72 (0.31-1.68) | 0.76 (0.31-1.85) |
Cadmium | |||||
Log Transformed | -1.16 (0.83) | -1.27 (0.94) | 0.84 (0.58-1.22) | 0.73 (0.48-1.09) | 0.72 (0.49-1.08) |
Quartiles | |||||
Q1 (\(\le\) 0.18) | 455 (23.71%) | 38 (1.98%) | Ref | Ref | Ref |
Q2 (0.18-0.28) | 490 (25.53%) | 23 (1.20%) | 0.49 (0.26-0.91)* | 0.47 (0.25-0.87)* | 0.47 (0.25-0.87)* |
Q3 (0.29-0.51) | 488 (25.43%) | 16 (0.83%) | 0.36 (0.16-0.82)* | 0.31 (0.13-0.75)* | 0.31 (0.13-0.76)* |
Q4 (> 0.51) | 486 (25.33%) | 26 (1.35%) | 0.69 (0.34-1.38) | 0.52 (0.23-1.20) | 0.53 (0.24-1.21) |
Mercury | |||||
Log Transformed | -0.29 (0.98) | -0.38 (-1.61) | 0.98 (0.84-1.15) | 1.10 (0.92-1.32) | 1.11 (0.91-1.36) |
Quartiles | |||||
Q1 (\(\le\) 0.34) | 471 (24.54%) | 25 (1.30%) | Ref | Ref | Ref |
Q2 (0.35 – 0.68) | 485 (25.27%) | 30 (1.56%) | 1.60 (0.82-3.13) | 1.68 (0.83-3.42) | 1.70 (0.84-3.44) |
Q3 (0.69 – 1.39) | 480 (25.01%) | 27 (1.41%) | 1.60 (0.81-3.19) | 1.87 (0.92-3.82) | 1.87 (0.92-3.77) |
Q4 (> 1.39) | 483 (25.17%) | 21 (1.09%) | 0.91 (0.53-1.56) | 1.18 (0.65-2.14) | 1.19 (0.63-2.25) |
Weighted mixed metals | |||||
Log Transformed | 1.18 (0.60) | 1.17 (0.56) | 0.86 (0.51 -1.46) | 0.86 (0.50-1.47) | 0.82 (0.35 -1.93) |
Quartiles | |||||
Q1 (\(\le\) 2.21) | 479 (24.96%) | 24 (1.25%) | Ref | Ref | Ref |
Q2 (2.21 – 3.10) | 480 (25.01%) | 25 (1.30%) | 0.71 (0.31-1.63) | 0.71 (0.30-1.67) | 0.74 (0.29 -1.85) |
Q3 (3.10 –4.66) | 480 (25.01%) | 27 (1.41%) | 0.86 (0.39 – 1.90) | 0.86 (0.39-1.92) | 0.93 (0.37-2.34) |
Q4 (> 4.66) | 480 (25.01%) | 27 (1.41%) | 0.83 (0.40-1.74) | 0.85 (0.39-1.84) | 1.04 (0.42-2.58) |