Abstract
Background
The purpose of the present study was to examine the association of female reproductive factor, including age at first birth (AFB), age at last birth (ALB), number of pregnancies, and live births with prevalence of arthritis in the female population of the American.
Methods
The present study analyzed cross-sectional data from a sample of females of National Health and Nutrition Examination Survey (NHANES) years 1999 through 2018. After adjusting for potential confounding factors, we used weighted multivariable logistic regression analysis, restricted cubic spline (RCS) model, and subgroup analysis to evaluate the association of AFB, ALB, number of live births, and pregnancies with prevalence of arthritis.
Results
A total of 15,842 female individuals were included in our analysis. The RCS showed that the U-shaped were found between AFB, and number of pregnancies with prevalence of arthritis. The above U-shaped correlation was also found for AFB and osteoarthritis (OA), rheumatoid arthritis (RA), and other arthritis, for ALB and OA. Among, number of pregnancies and OA, and RA were associated in a J-shape. However, ALB, and number of live births is negatively correlated with prevalence of arthritis. In addition, the association of ALB with OA, and other type arthritis, number of pregnancies with other arthritis, number of live births with RA, and other type arthritis showed linear negative correlation. In contrast, a positive linear correlation existed between number of live births and RA.
Conclusions
This study provides evidence that women with younger or later AFB have higher odds of arthritis (OA and RA) in later life. When screening for arthritis and devising preventive strategies, reproductive factors need to be taken into consideration.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12978-025-02095-x.
Keywords: Arthritis, Cross-sectional study, Female reproductive factor, Osteoarthritis, Rheumatoid arthritis
Introduction
As one of the most prevalent musculoskeletal conditions, arthritis results in joint pain, swelling, functional impairment, disability, and a loss of quality of life [1]. In the United States, around 22.7% of adults report having medically diagnosed arthritis, with rheumatoid arthritis (RA) and osteoarthritis (OA) being the two most common types [2]. At present, the pathogenic mechanism is not completely clear, genetic factors, environmental factors, immune factors and other factors may play an important role in its occurrence and development [3]. Epidemiological surveys shown that there are significant gender differences in the occurrence of arthritis, and the incidence is higher and more serious in females, particularly after menopausal age [4]. Therefore, there may be a role for reproductive and hormonal factors in the development of arthritis [5].
At present, there are few studies on the relationship between reproductive factors and arthritis, and the conclusions are inconsistent. The risk of RA in women was found to be inversely related to their age at delivery of the first child in a Danish cohort study. Additionally, nulliparity and a history of pregnancy loss were not associated with an increased risk of RA, but when compared with women who had just one child, women with two or three children had a lower risk of the disease [6]. Peschken CA et al. found that greater parity significantly reduced the odds of RA and an early AFB increased the odds, and the postpartum period has been confirmed as a high-risk period for the onset of RA in this North American native population [7]. Additionally, consistent with the Danish study, Shaw et al. also found that the risk of hip and/or knee OA and overall OA is reduced by 19% and 20% respectively for each additional year of AFB [8]. Currently, a clear association between female reproductive factor with risk of arthritis (OA, and RA) has not been clearly defined in American population and remains an issue of controversy. Thus, the purpose of the research was to investigate the association of female reproductive factor with risk of arthritis, using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2018, and provide new ideas on how to prevent diabetes at an early stage.
Material and methods
Study population
The NHANES is a series of national continuous cross-sectional study of representative sample of the US noninstitutionalized civilian resident population, utilizing a complex, stratified, multi-stage, probability cluster design [9]. In this study, we analyzed NHANES data from ten two-year cycles (1999–2018). A sample of 49,209 females between the ages of 20 and 85 years of age were included in the study. Then, we excluded female participants with missing female reproductive factor (AFB, ALB, number of pregnancies, and live births) questionnaires (n = 13,746) data and information on arthritis questionnaires (n = 19,603). Ultimately, a total of 15,842 female individuals were included in our analysis (Fig. 1). The National Center for Health Statistics (NCHS) ethics review board approved our study protocol and the written informed consent was obtained from all participants before participating in the study [10]. A complete description of the survey design, methodology, and data can be found on the NHANES website. (https://www.cdc.gov/nchs/nhanes/).
Fig. 1.
Study flow chart. Abbreviations: NHANES, National Health and Nutrition Examination Surveys
Reproductive factors
Self-administered questionnaires were used to determine reproductive factors in the study. Women participants recalled their AFB, ALB, number of pregnancies, number of live births, age at menopause, menopause status, whether to use oral contraceptives, whether to use female hormones, whether to have a hysterectomy, whether to remove both ovaries, and fertile lifespan at the time of the survey. Based on the age at menopause minus the age at menarche, a fertile lifespan was calculated. As a reminder, AFB refers to the first live birth, pregnancy loss (ectopic pregnancies, miscarriages, previous stillbirths) or stillbirths were not included in the analysis. The NHANES website has more information on reproductive factors (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx).
Definition of OA and RA
There were 2 continuous medical condition questions that were asked to determine whether the participant had OA or RA. First, “Doctor ever said you had arthritis?” Second, “Which type of arthritis?” We classified respondents who answered only “Osteoarthritis or degenerative arthritis” as OA, while respondents who answered only “Rheumatoid Arthritis” as RA. When participants answered that the result was neither of these two types of arthritis, it was defined as another type of arthritis.
Covariates
The following covariates were downloaded from the NHANES database: age, sex (female/male), education level (less than high school/high school/more than high school), the complications of hypertension, race/ethnicity (Mexican American/Other Hispanic/Non-Hispanic White/Non-Hispanic Black/Other race), family poverty income ratio (PIR), the complications of diabetes mellitus (DM), body mass index (BMI), smoker (no/former/now), marital status (having a partner/no partner/unmarried), drinker (no/former/mild/moderate/heavy), waist circumference, work activity, recreational activity, mean energy intake, fast glucose (FBG), albumin (Alb), sodium, potassium, total cholesterol (TC), phosphorus, serum creatinine (Scr), high-density lipoprotein-cholesterol (HDL-C), triglyceride (TC), calcium (Ca), uric acid (UA), blood urea nitrogen (BUN), alkaline phosphatase (Alk), and hemoglobin (Hb). Details of all variables are available online at https://www.cdc.gov/nchs/nhanes/.
Statistical analysis
An analysis of all the data was conducted using the SPSS version 24.0 (SPSS Inc., Chicago, IL, USA), and R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). P-value < 0.05 was regarded as statistically significant. Continuous variables expressed as the mean (standard deviation, SD) were analyzed by t-test. Additionally, the chi-square test was used to analyze categorical variables that were presented as percentages (%) to demonstrate the demographic and hematological characteristics with arthritis and non-arthritis. The weighted multivariable logistic regression was used to investigate the association of female reproductive factor with risk of arthritis. We built three models: model 1, which adjusted for age and sex; model 2, which adjusted for sex, race/ethnicity, age, family PIR, smoking status, educational level, drinking status, marital status, the complication of hypertension, and DM; and model 3, which adjusted for all of the potential confounding factors listed in Table 1.
Table 1.
Demographic characteristics of the study participants
| Variables | Overall (n = 15,842) | Non-Arthritis (n = 10,093) | Arthritis (n = 5,749) | P-value |
|---|---|---|---|---|
| Age, years | 52.38 ± 0.19 | 47.43 ± 0.21 | 61.52 ± 0.23 | < 0.001 |
| Race, % | < 0.001 | |||
| Mexican American | 3101 (19.6%) | 2318 (14.6%) | 783 (4.9%) | |
| Other Hispanic | 1412 (8.9%) | 936 (5.9%) | 476 (3.0%) | |
| Non-Hispanic White | 6903 (43.6%) | 3916 (24.7%) | 2987 (18.9%) | |
| Non-Hispanic Black | 3233 (20.4%) | 2050 (12.9%) | 1183 (7.5%) | |
| Other race | 1193 (7.5%) | 873 (5.5%) | 320 (2.0%) | |
| Family PIR | 2.81 ± 0.03 | 2.86 ± 0.04 | 2.72 ± 0.04 | < 0.001 |
| Education level, % | < 0.001 | |||
| Less than high school | 4763 (30.1%) | 2899 (18.3%) | 1864 (11.8%) | |
| High school | 1540 (9.7%) | 925 (5.8%) | 615 (3.9%) | |
| More than high school | 9539 (60.2%) | 6269 (39.6%) | 3270 (20.6%) | |
| Marital status, % | < 0.001 | |||
| Having a partner | 9398 (59.3%) | 6524 (41.2%) | 2874 (18.1%) | |
| No partner | 5302 (33.5%) | 2692 (17.0%) | 2610 (16.5%) | |
| Unmarried | 1142 (7.2%) | 877 (5.5%) | 265 (1.7%) | |
| Hypertension, % | < 0.001 | |||
| No | 8231 (52.0%) | 6381 (40.3%) | 1850 (11.7%) | |
| Yes | 7611 (48.0%) | 3712 (23.4%) | 3899 (24.6%) | |
| DM, % | < 0.001 | |||
| No | 12,796 (80.8%) | 8678 (54.8%) | 4118 (26.0%) | |
| Yes | 3046 (19.2%) | 1415 (8.9%) | 1631 (10.3%) | |
| Smoker, % | < 0.001 | |||
| No | 9892 (62.4%) | 6677 (42.1%) | 3215 (20.3%) | |
| Former | 3185 (20.1%) | 1697 (10.7%) | 1488 (9.4%) | |
| Now | 2765 (17.5%) | 1719 (10.9%) | 1046 (6.6%) | |
| Alcohol user, % | < 0.001 | |||
| No | 3585 (22.6%) | 2240 (14.1%) | 1345 (8.5%) | |
| Former | 2989 (18.9%) | 1647 (10.4%) | 1342 (8.5%) | |
| Mild | 4507 (28.4%) | 2785 (17.6%) | 1722 (10.9%) | |
| Moderate | 2647 (16.7%) | 1838 (11.6%) | 809 (5.1%) | |
| Heavy | 2114 (13.3%) | 1583 (10.0%) | 531 (3.4%) | |
| Work activity, % | < 0.001 | |||
| No | 9317 (58.8%) | 5787 (36.5%) | 3530 (22.3%) | |
| Yes | 6525 (41.2%) | 4306 (27.2%) | 2219 (14.0%) | |
| Recreational activity, % | < 0.001 | |||
| No | 10,663 (67.3%) | 6520 (41.2%) | 4143 (26.2%) | |
| Yes | 5179 (32.7%) | 3573 (22.6%) | 1606 (10.1%) | |
| Menopause status, % | < 0.001 | |||
| No | 3112 (19.6%) | 2786 (17.6%) | 326 (2.1%) | |
| Yes | 12,730 (80.4%) | 7307 (46.1%) | 5423 (34.2%) | |
| Oral contraceptive use, % | < 0.001 | |||
| No | 5467 (34.5%) | 3214 (20.3%) | 2253 (14.2%) | |
| Yes | 10,375 (65.5%) | 6879 (43.4%) | 3496 (22.1%) | |
| Use female hormones, % | < 0.001 | |||
| No | 12,059 (76.1%) | 8416 (53.1%) | 3643 (23.0%) | |
| Yes | 3783 (23.9%) | 1677 (10.6%) | 2106 (13.3%) | |
| Had a hysterectomy, % | < 0.001 | |||
| No | 11,358 (71.7%) | 8101 (51.1%) | 3257 (20.6%) | |
| Yes | 4484 (28.3%) | 1992 (12.6%) | 2492 (15.7%) | |
| Both ovaries removed, % | < 0.001 | |||
| No | 13,120 (82.8%) | 8943 (56.5%) | 4177 (26.4%) | |
| Yes | 2722 (17.2%) | 1150 (11.4%) | 1572 (9.9%) | |
| BMI, kg/m2 | 29.34 ± 0.09 | 28.58 ± 0.10 | 30.75 ± 0.13 | < 0.001 |
| Waist circumference, cm | 97.40 ± 0.21 | 95.18 ± 0.24 | 101.49 ± 0.28 | < 0.001 |
| Hb, g/dL | 13.47 ± 0.02 | 13.41 ± 0.02 | 13.56 ± 0.03 | < 0.001 |
| Mean energy | 1756.33 ± 6.96 | 1790.74 ± 9.09 | 1692.90 ± 9.97 | < 0.001 |
| Intake (kcal/day) | ||||
| FBG, mg/dL | 104.23 ± 0.31 | 101.21 ± 0.29 | 109.79 ± 0.52 | < 0.001 |
| Alk, U/L | 71.20 ± 0.33 | 69.29 ± 0.37 | 74.71 ± 0.49 | < 0.001 |
| Total protein, g/dL | 7.10 ± 0.01 | 7.12 ± 0.01 | 7.06 ± 0.01 | < 0.001 |
| Sodium, mmol/L | 139.20 ± 0.07 | 139.16 ± 0.07 | 139.27 ± 0.08 | 0.079 |
| Phosphorus, mmol/L | 3.78 ± 0.01 | 3.77 ± 0.01 | 3.80 ± 0.01 | 0.004 |
| Calcium, mg/dL | 9.39 ± 0.01 | 9.36 ± 0.01 | 9.44 ± 0.01 | < 0.001 |
| Potassium, mg/dL | 3.98 ± 0.01 | 3.96 ± 0.01 | 4.01 ± 0.01 | < 0.001 |
| TC, mg/dL | 202.06 ± 0.52 | 199.73 ± 0.57 | 206.36 ± 0.83 | < 0.001 |
| TG, mg/dL | 125.64 ± 0.93 | 119.27 ± 1.13 | 137.40 ± 1.61 | < 0.001 |
| HDL, mg/dL | 58.11 ± 0.25 | 58.12 ± 0.28 | 58.09 ± 0.37 | 0.953 |
| BUN, mg/dL | 13.34 ± 0.08 | 12.42 ± 0.08 | 15.04 ± 0.10 | < 0.001 |
| Scr, mg/dL | 0.78 ± 0.00 | 0.75 ± 0.00 | 0.84 ± 0.01 | < 0.001 |
| UA, mg/dL | 4.84 ± 0.01 | 4.66 ± 0.01 | 5.18 ± 0.02 | < 0.001 |
| eGFR, ml/min/1.73m2 | 90.92 ± 0.32 | 96.37 ± 0.32 | 80.87 ± 0.41 | < 0.001 |
| AFB, years | 22.60 ± 0.09 | 22.90 ± 0.10 | 22.04 ± 0.11 | < 0.001 |
| ALB, years | 29.18 ± 0.08 | 29.24 ± 0.09 | 29.08 ± 0.13 | 0.235 |
| Number of live births, times | 2.86 ± 0.02 | 2.75 ± 0.02 | 3.06 ± 0.03 | < 0.001 |
| Number of pregnancies, times | 3.60 ± 0.02 | 3.48 ± 0.02 | 3.84 ± 0.04 | < 0.001 |
| Age at menarche, years | 12.74 ± 0.02 | 12.78 ± 0.02 | 12.67 ± 0.03 | 0.003 |
| Age at menopause, years | 42.07 ± 0.13 | 41.09 ± 0.15 | 43.86 ± 0.18 | < 0.001 |
| Fertile lifespan, years | 29.33 ± 0.13 | 28.32 ± 0.15 | 31.19 ± 0.18 | < 0.001 |
Abbreviations: DM diabetes mellitus, BMI body mass index, CHD coronary heart disease, CHF congestive heart failure, Hb hemoglobin, FBG fast glucose, Alk Alkaline phosphatase, BUN blood urea nitrogen, UA uric acid, Scr serum creatinine, TC total cholesterol, TG triglycerides, HDL-cholesterol high density lipoprotein-cholesterol, eGFR estimated glomerular filtration rate, AFB age at first birth, ALB age at last birth
Data are presented as mean ± SD or n (%)
Results
Baseline characteristics
The baseline characteristics of the participants in the study are shown in Table 1. In total, 3,778 people were included and arthritis was present in 36.3% of this population. In addition to the levels of sodium, and HDL, and ALB, there were significant differences in baseline parameters between the arthritis and non-arthritis groups. Participants in the arthritis group were older and had higher level of BMI, waist circumference, Hb, FBG, Alk, phosphorus, calcium, potassium, TC, TG, BUN, Scr, and UA than those in the non-arthritis group.
Association of female reproductive factor with arthritis
The RCS showed that U-shaped were found between AFB, and number of pregnancies with arthritis (P for nonlinear < 0.05; Fig. 2A, and C). However, non-linear association was not detected in this association (P for nonlinear > 0.05), which demonstrated that ALB, and number of live births is negatively correlated with the prevalence of arthritis (Fig. 2B, and D). Tables 2 and 3 also shown the results of multivariate logistic regression analyses for the association of AFB, ALB, and number of pregnancies, and live births with risk of arthritis. Compared to female individuals with AFB of ≤ 23 years old (reference group), the fully adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in women with arthritis in 24–26, 27–29, 30–32, 33–35, ≥ 36 years were 0.88 (0.79, 0.99), 0.99 (0.86, 1.14), 0.95 (0.78, 1.16), 0.81 (0.62, 1.08), and 1.02 (0.71, 1.46), respectively. In addition, after controlling for underlying cofounders, compared to female individuals with ALB of ≤ 23 years old (reference group), the fully adjusted the ORs with 95% CIs for arthritis were 0.94 (0.84, 1.05), 0.84 (0.75, 0.94), 0.81 (0.72, 0.93), and 0.65 (0.53, 0.78) for 25–29, 0–34, 35–39, and ≥ 40 years (Table 2). Finally, after adjusting for interfering factors, in the fully adjusted model, the ORs with 95% CIs for association of number of pregnancies, and live births with arthritis across 3, 4 and ≥ 5 times were (0.91 (0.82, 1.02), 0.98 (0.88, 1.09), 1.03 (0.93, 1.14)) and (0.99 (0.90, 1.09), 0.96 (0.86, 1.08), and 0.96 (0.85, 1.08)), respectively, compared with ≤ 2 times (Table 3).
Fig. 2.
Restricted cubic spline curve for the association of female reproductive factor with the prevalence of arthritis. A Age at first birth and arthritis; (B) Age at last birth and arthritis; (C) number of pregnancies; (D) number of live births and arthritis. Abbreviations: OR, odd ratio; CI, confidence interval
Table 2.
Associations of AFB, and ALB with the risk of arthritis
| Model 1 | Model 2 | Model 3 | ||||
|---|---|---|---|---|---|---|
| OR (95%CI) | P for trend | OR (95%CI) | P for trend | OR (95%CI) | P for trend | |
| AFB (years) | < 0.001 | 0.051 | 0.229 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 24–26 | 0.56 (0.43, 0.74)*** | 0.69 (0.53, 0.91)* | 0.81 (0.79, 0.99)* | |||
| 27–29 | 0.61 (0.51, 0.74)*** | 0.77 (0.64, 0.94)* | 0.88 (0.62, 1.08) | |||
| 30–32 | 0.68 (0.48, 0.86)*** | 0.81 (0.73, 0.96)* | 0.95 (0.78, 1.16) | |||
| 33–35 | 0.70 (0.64, 0.79)*** | 0.83 (0.74, 0.97)* | 0.99 (0.86, 1.14) | |||
| ≥ 36 | 0.71 (0.62, 0.81)*** | 0.85 (0.58, 1.17) | 1.03 (0.71, 1.47) | |||
| ALB (years) | < 0.001 | 0.281 | 0.457 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 25–29 | 0.82 (0.74, 0.91)*** | 0.90 (0.81, 1.00) | 0.94 (0.84, 1.05) | |||
| 30–34 | 0.67 (0.60, 0.75)*** | 0.76 (0.68, 0.85)*** | 0.84 (0.75, 0.94)** | |||
| 35–39 | 0.62 (0.55, 0.70)*** | 0.70 (0.62, 0.79)*** | 0.81 (0.72, 0.93** | |||
| ≥ 40 | 0.48 (0.40, 0.58)*** | 0.52 (0.43, 0.63)*** | 0.65 (0.53, 0.78)*** | |||
Abbreviations: AFB age at first birth, ALB age at last birth, OR odds ratio, CI confidence interval
Model 1: age and race/ethnicity
Model 2: model 1 variables plus education level, marital status, family poverty-income ratio, hypertension, diabetes mellitus, smoker, alcohol user
Model 3 was adjusted for model 2 variables plus body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, mean energy intake, hemoglobin, fast glucose, alkaline phosphatase, total protein, sodium, phosphorus, calcium, potassium, menopause status, oral contraceptive use, use female hormones, had a hysterectomy, both ovaries removed, blood urea nitrogen, uric acid, serum creatinine, estimated glomerular filtration rate, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, age at menarche, age at menopause, and fertile lifespan
*P < 0.05, **P < 0.01, ***P < 0.001
Table 3.
Associations of number of pregnancies, and live births with the risk of arthritis
| Model 1 | Model 2 | Model 3 | ||||
|---|---|---|---|---|---|---|
| OR (95%CI) | P for trend | OR (95%CI) | P for trend | OR (95%CI) | P for trend | |
| Number of | 0.005 | 0.546 | 0.847 | |||
| Pregnancies, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 1.01 (0.92, 1.12) | 0.96 (0.86, 1.07) | 0.91 (0.82, 1.02) | |||
| 4 | 1.01 (0.90, 1.12) | 1.00 (0.90, 1.10) | 0.98 (0.88, 1.09) | |||
| ≥ 5 | 1.16 (1.05, 1.28) | 1.04 (0.94, 1.15) | 1.03 (0.93, 1.14) | |||
| Number of | 0.135 | 0.407 | 0.354 | |||
| Live births, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 1.03 (0.94, 1.13) | 0.99 (0.91, 1.10) | 0.99 (0.90, 1.09) | |||
| 4 | 1.06 (0.95, 1.19) | 0.98 (0.88, 1.10) | 0.96 (0.86, 1.08) | |||
| ≥ 5 | 1.08 (0.96, 1.21) | 0.94 (0.84, 1.06) | 0.96 (0.85, 1.08) | |||
Abbreviations: OR odds ratio, CI confidence interval
Model 1: age and race/ethnicity
Model 2: model 1 variables plus education level, marital status, family poverty-income ratio, hypertension, diabetes mellitus, smoker, alcohol user
Model 3 was adjusted for model 2 variables plus body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, mean energy intake, hemoglobin, fast glucose, alkaline phosphatase, total protein, sodium, phosphorus, calcium, potassium, menopause status, oral contraceptive use, use female hormones, had a hysterectomy, both ovaries removed, blood urea nitrogen, uric acid, serum creatinine, estimated glomerular filtration rate, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, age at menarche, age at menopause, and fertile lifespan
*P < 0.05, **P < 0.01, ***P < 0.001
Association of female reproductive factor with OA, RA, and other arthritis
The RCS model showed a nonlinear U-shaped association of AFB with OA, RA, and other arthritis (P for non-linearity < 0.05, Fig. 3A, B, and C). ALB was found to be U-shaped in relation to the prevalence of OA (P for non-linearity < 0.05), but linearly negative in relation to RA, and other arthritis (P for non-linearity > 0.05; Fig. 4A, B, and C). There was a negative linear correlation between number of pregnancies and other arthritis (P for non-linearity < 0.05; Fig. 5C), but a J-shaped correlation with OA, and RA (P for non-linearity < 0.05; Fig. 5A, and B). A negative linear correlation existed between number of live births and OA, and other arthritis (Fig. 6A, and C), but it was positively related to RA (Fig. 6B). Separate multivariate logistic regression analyses were conducted to examine the association of female reproductive factor with OA, RA, and other arthritis (Tables 4, 5, and 6).
Fig. 3.
Restricted cubic spline curve for the association of age at first birth with the prevalence of osteoarthritis, rheumatoid arthritis, and other arthritis. Abbreviations: OR, odd ratio; CI, confidence interval
Fig. 4.
Restricted cubic spline curve for the association of age at last birth with the prevalence of osteoarthritis, rheumatoid arthritis, and other arthritis. Abbreviations: OR, odd ratio; CI, confidence interval
Fig. 5.
Restricted cubic spline curve for the association of number of pregnancies with the prevalence of osteoarthritis, rheumatoid arthritis, and other arthritis. Abbreviations: OR, odd ratio; CI, confidence interval
Fig. 6.
Restricted cubic spline curve for the association of number of live births with the prevalence of osteoarthritis, rheumatoid arthritis, and other arthritis. Abbreviations: OR, odd ratio; CI, confidence interval
Table 4.
Associations of AFB, ALB, numbers of pregnancies, and number of live births with the risk of osteoarthritis
| Model 1 | Model 2 | Model 3 | ||||
|---|---|---|---|---|---|---|
| OR (95%CI) | P for trend | OR (95%CI) | P for trend | OR (95%CI) | P for trend | |
| AFB (years) | 0.044 | 0.056 | 0.693 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 24–26 | 0.85 (0.74, 0.97)* | 0.83 (0.72, 0.95)* | 0.90 (0.78, 1.04) | |||
| 27–29 | 0.89 (0.70, 1.13) | 0.91 (0.76, 1.08) | 0.96 (0.60, 1.24) | |||
| 30–32 | 0.92 (0.77, 1.09) | 0.90 (0.71, 1.15) | 1.06 (0.88, 1.26) | |||
| 33–35 | 0.95 (0.73, 1.17) | 0.96 (0.73, 1.18) | 1.11 (0.86, 1.42) | |||
| ≥ 36 | 0.97 (0.62, 1.52) | 0.98 (0.63, 1.54) | 1.20 (0.76, 1.88) | |||
| ALB (years) | 0.678 | 0.952 | 0.219 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 25–29 | 0.90 (0.78, 1.03) | 0.90 (0.78, 1.03) | 0.95 (0.82, 1.09) | |||
| 30–34 | 0.62 (0.49, 0.79)*** | 0.69 (0.54, 0.87)*** | 0.83 (0.72, 0.96) | |||
| 35–39 | 0.72 (0.61, 0.84)*** | 0.75 (0.65, 0.87)*** | 0.89 (0.76, 1.05) | |||
| ≥ 40 | 0.73 (0.63, 0.84)*** | 0.76 (0.65, 0.89)*** | 0.90 (0.69, 1.12) | |||
| Number of | 0.602 | 0.912 | 0.919 | |||
| Pregnancies, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 0.92 (0.80, 1.06) | 0.93 (0.80, 1.07) | 0.89 (0.77, 1.03) | |||
| 4 | 0.99 (0.87, 1.13) | 1.03 (0.90, 1.17) | 1.00 (0.88, 1.15) | |||
| ≥ 5 | 1.02 (0.90, 1.17) | 1.04 (0.91, 1.18) | 1.02 (0.89, 1.17) | |||
| Number of | < 0.001 | 0.018 | 0.024 | |||
| Live births, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 0.95 (0.85, 1.07) | 0.97 (0.86, 1.09) | 0.96 (0.86, 1.09) | |||
| 4 | 0.87 (0.76, 1.01) | 0.90 (0.78, 1.05) | 0.90 (0.78, 1.04) | |||
| ≥ 5 | 0.76 (0.66, 0.88)*** | 0.84 (0.72, 0.98)* | 0.85 (0.72, 0.99)* | |||
Abbreviations: AFB age at first birth, ALB age at last birth, OR odds ratio, CI confidence interval
Model 1: age and race/ethnicity
Model 2: model 1 variables plus education level, marital status, family poverty-income ratio, hypertension, diabetes mellitus, smoker, alcohol user
Model 3 was adjusted for model 2 variables plus body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, mean energy intake, hemoglobin, fast glucose, alkaline phosphatase, total protein, sodium, phosphorus, calcium, potassium, menopause status, oral contraceptive use, use female hormones, had a hysterectomy, both ovaries removed, blood urea nitrogen, uric acid, serum creatinine, estimated glomerular filtration rate, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, age at menarche, age at menopause, and fertile lifespan
*P < 0.05, **P < 0.01, ***P < 0.001
Table 5.
Associations of AFB, ALB, number of pregnancies, and number of live birth with the risk of rheumatoid arthritis
| Model 1 | Model 2 | Model 3 | ||||
|---|---|---|---|---|---|---|
| OR (95%CI) | P for trend | OR (95%CI) | P for trend | OR (95%CI) | P for trend | |
| AFB (years) | < 0.001 | 0.296 | 0.999 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 24–26 | 0.66 (0.46, 0.90)*** | 0.86 (0.71, 1.05) | 0.90 (0.74, 1.09) | |||
| 27–29 | 0.74 (0.62, 0.94)* | 0.96 (0.76, 1.23) | 0.92 (0.46, 1.83) | |||
| 30–32 | 0.79 (0.63, 1.00)* | 0.98 (0.78, 1.19) | 0.94 (0.65, 1.35) | |||
| 33–35 | 0.82 (0.52, 1.28) | 1.03 (0.65, 1.62) | 1.06 (0.83, 1.35) | |||
| ≥ 36 | 0.85 (0.58, 1.28) | 1.12 (0.71, 1.63) | 1.14 (0.72, 1.81) | |||
| ALB (years) | 0.003 | 0.530 | 0.839 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 25–29 | 0.93 (0.78, 1.11) | 0.99 (0.85, 1.21) | 0.99 (0.86, 1.22) | |||
| 30–34 | 0.88 (0.74, 1.05) | 0.98 (0.82, 1.18) | 0.98 (0.84, 1.22) | |||
| 35–39 | 0.85 (0.72, 1.07) | 0.95 (0.78, 1.17) | 0.97 (0.82, 1.24) | |||
| ≥ 40 | 0.75 (0.56, 1.02) | 0.77 (0.57, 1.05) | 0.84 (0.61, 1.14) | |||
| Number of | 0.018 | 0.477 | 0.666 | |||
| Pregnancies, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 0.93 (0.78, 1.11) | 0.91 (0.76, 1.09) | 0.90 (0.75, 1.07) | |||
| 4 | 1.03 (0.86, 1.23) | 0.97 (0.81, 1.17) | 0.94 (0.78, 1.13) | |||
| ≥ 5 | 1.18 (1.00, 1.39)* | 1.04 (0.88, 1.22) | 1.02 (0.86, 1.20) | |||
| Number of | < 0.001 | 0.065 | 0.104 | |||
| Live births, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 1.03 (0.88, 1.21) | 1.01 (0.85, 1.16) | 1.02 (0.83, 1.14) | |||
| 4 | 1.20 (1.00, 1.44)* | 1.09 (0.90, 1.30) | 1.06 (0.88, 1.27) | |||
| ≥ 5 | 1.40 (1.17, 1.66)*** | 1.18 (0.98, 1.41) | 1.16 (0.97, 1.39) | |||
Abbreviations: AFB age at first birth, ALB age at last birth, OR odds ratio, CI confidence interval
Model 1: age and race/ethnicity
Model 2: model 1 variables plus education level, marital status, family poverty-income ratio, hypertension, diabetes mellitus, smoker, alcohol user
Model 3 was adjusted for model 2 variables plus body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, mean energy intake, hemoglobin, fast glucose, alkaline phosphatase, total protein, sodium, phosphorus, calcium, potassium, menopause status, oral contraceptive use, use female hormones, had a hysterectomy, both ovaries removed, blood urea nitrogen, uric acid, serum creatinine, estimated glomerular filtration rate, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, age at menarche, age at menopause, and fertile lifespan
*P < 0.05, **P < 0.01, ***P < 0.001
Table 6.
Associations of AFB, ALB, number of pregnancies, and number of live births with the risk of other arthritis
| Model 1 | Model 2 | Model 3 | ||||
|---|---|---|---|---|---|---|
| OR (95%CI) | P for trend | OR (95%CI) | P for trend | OR (95%CI) | P for trend | |
| AFB (years) | 0.016 | 0.352 | 0.813 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 24–26 | 0.53 (0.31, 0.89) | 0.65 (0.38, 1.10) | 0.73 (0.43, 1.24) | |||
| 27–29 | 0.71 (0.55, 0.93) | 0.80 (0.61, 1.04) | 0.84 (0.64, 1.10) | |||
| 30–32 | 0.75 (0.54, 1.03) | 0.88 (0.63, 1.22) | 0.95 (0.68, 1.33) | |||
| 33–35 | 0.82 (0.45, 1.52) | 1.00 (0.54, 1.85) | 1.08 (0.58, 2.00) | |||
| ≥ 36 | 1.16 (0.56, 2.37) | 1.37 (0.67, 2.83) | 1.52 (0.73, 3.16) | |||
| ALB (years) | 0.286 | 0.828 | 0.488 | |||
| ≤ 23 | 1.00 | 1.00 | 1.00 | |||
| 25–29 | 0.78 (0.62, 0.99)* | 0.85 (0.67, 1.07) | 0.85 (0.67, 1.07) | |||
| 30–34 | 0.70 (0.55, 0.89)** | 0.78 (0.61, 1.00)* | 0.79 (0.62, 1.01) | |||
| 35–39 | 0.64 (0.48, 0.84)** | 0.71 (0.53, 0.94)* | 0.74 (0.55, 1.00)* | |||
| ≥ 40 | 0.57 (0.36, 0.91)** | 0.61 (0.38, 0.98)* | 0.68 (0.42, 1.09) | |||
| Number of | 0.536 | 0.114 | 0.071 | |||
| Pregnancies, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 0.98 (0.81, 1.22) | 0.99 (0.73, 1.24) | 0.99 (0.79, 1.28) | |||
| 4 | 0.91 (0.72, 1.15) | 0.89 (0.70, 1.12) | 0.87 (0.69, 1.11) | |||
| ≥ 5 | 0.87 (0.69, 1.10) | 0.78 (0.61, 0.99)* | 0.76 (0.60, 0.97)* | |||
| Number of | 0.516 | 0.103 | 0.084 | |||
| Live births, times | ||||||
| ≤ 2 | 1.00 | 1.00 | 1.00 | |||
| 3 | 0.99 (0.80, 1.21) | 0.95 (0.78, 1.17) | 0.93 (0.75, 1.15) | |||
| 4 | 0.98 (0.79, 1.21) | 0.92 (0.71, 1.19) | 0.90 (0.70, 1.17) | |||
| ≥ 5 | 0.89 (0.67, 1.17) | 0.78 (0.59, 1.03) | 0.77 (0.58, 1.03) | |||
Abbreviations: AFB age at first birth, ALB age at last birth, OR odds ratio, CI confidence interval
Model 1: age and race/ethnicity
Model 2: model 1 variables plus education level, marital status, family poverty-income ratio, hypertension, diabetes mellitus, smoker, alcohol user
Model 3 was adjusted for model 2 variables plus body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, mean energy intake, hemoglobin, fast glucose, alkaline phosphatase, total protein, sodium, phosphorus, calcium, potassium, menopause status, oral contraceptive use, use female hormones, had a hysterectomy, both ovaries removed, blood urea nitrogen, uric acid, serum creatinine, estimated glomerular filtration rate, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, age at menarche, age at menopause, and fertile lifespan
*P < 0.05, **P < 0.01, ***P < 0.001
Subgroup analyses
Subgroup analyses were carried out based on age (< 45 or ≥ 45 years), menopause status (no or yes), race/ethnicity (Non-Hispanic Black, Other Hispanic, Mexican American, Other Race, and Non-Hispanic White), age at menarche (< 12, 12–13, and > 13 years), ever used female hormone therapy (no or yes), and fertile lifespan (< 28, 28–35, and > 35 years) to find the association of AFB, ALB, number of live births, and pregnancies with prevalence of arthritis (Supplementary Table 1, 2, 3, and 4; Supplementary Fig. 1, 2, 3, and 4).
Discussion
Pregnancy and childbirth are physiological processes unique to women, during which there are a series of changes, such as venous stasis, edema, hypercoagulability, increased insulin levels and lipid levels. Additionally, results of epidemiologic studies of various reproductive factors and arthritis are inconsistent. Therefore, an analysis of NHANES data from 1999 to 2018 years was performed on a large cross-sectional sample of women > 20 years of age in this study. We observed a U-shaped association of the AFB, and number of pregnancies with prevalence of arthritis. However, the arthritis risk and ALB, and numbers of live births were negatively linearly related. In addition, the above U-shaped curve correlation has also been found in AFB and OA, RA, and other arthritis, in ALB and OA, in number of pregnancies and OA, and RA.
A woman's physiology changes fundamentally during pregnancy, and her body's metabolic requirements increase as a result [11]. Biological changes may occur as a result of women giving birth at a young age and/or giving birth to numerous children, which can lead to drastic physiological changes as a woman ages, increasing her risk of chronic diseases and poor physical functioning. For example, pregnancy may interfere with bone mineral density and an increase in the risk of osteoporosis in the future, especially in women who give birth to their first child when they are adolescents [12]. A temporal relationship has been established between bone mineral density and arthritis [13]. Therefore, we speculated women who give birth as adolescents may increase the risk of osteoporosis that can lead to arthritis. Multiple studies have shown that pregnancy may also affect a woman's long-term glucose homeostasis, and multiparity may be associated with DM in later life [14–16]. In addition, an early maternal age at first birth has been related to a higher risk of diabetes-related death [15]. The DM is also associated with an increased risk of arthritis [17, 18]. Additionally, Pirkle CM et al. also found that when women give birth at a young age, they are at a much higher risk of developing chronic diseases and physical limitations in their old age than women who do not give birth at a young age [19]. These results explain the U-shaped relationship between risk of arthritis and AFB. There is currently no literature on the association of ALB with arthritis, and more exploratory studies may be needed in the future. There are several possible reasons for the negative linear association between arthritis risk and ALB. Lower-income women are more likely to start childbearing earlier, have more children, and face greater risks during childbirth [20]. Most of these people who marry and have children late are intellectuals, so they pay more attention to their health and have regular physical examinations. In addition, people who have children later in life are likely to have higher incomes and better health care at the time of birth. Women often develop RA during postpartum and perimenopausal periods, when sex steroid hormone levels are changing [21–24]. Parikh NI et al. also shown parity has also been related to cardiovascular disease (stroke, heart failure, and coronary heart disease) in later life [25]. These diseases mentioned above are associated with the development of arthritis, including OA, and RA [26, 27]. People with these underlying conditions are more likely to develop arthritis. This is consistent with the findings of our study that the RA risk and numbers of live births were positive linearly related. Wise BL and his team have shown that there is a correlation between parity in women and incident knee OA, particularly among mothers with more than four children [28]. In addition, Kim SM also revealed that the odds of OA in the back, knees, and hips increase with parity and radiographic knee OA increases independently with parity [29]. Wei S and his colleague revealed that in this population-based sample of older women, parity is independently associated with lower cartilage volume, primarily in the patella compartment, as well as higher cartilage defects in the tibia compartment [30]. This is consistent with our findings. We also found that the number of pregnancies was positively correlated with the incidence of OA. However, Ren L et al. founded that parity was related to decreased risk of RA through meta-analysis [31]. Additionally, Guthrie KA et al. found a significantly lower risk of RA in parous women in the Seattle, Washington area [32]. The above findings may explain the arthritis risk and numbers of live births were negatively linearly related. However, other studies have shown that birth time, age at birth, and number of children are not associated with RA risk [32, 33]. Therefore, more prospective clinical studies are needed to explore the association of number of pregnancies, and live births and risk of arthritis, including OA, and RA. However, there are a number of limitations that need to be considered when interpreting this study. Firstly, there are a lot of self-reported data in this study, such as reproductive health and physical activity, that may reduce the reliability of the results, since a large number of self-reported data are included. Secondly, there were also no data available on lifestyle earlier in life, such as alcohol drinking, BMI around pregnancy, and smoking status, which might be related to arthritis risk in the future. Thirdly, due to the cross-sectional design of the study, it was not possible to elucidate cause-and-effect relationships between the variables. Finally, Additionally, since the data were collected from multiple cross-sectional studies, the design of the questionnaires was not the same across the cycles; therefore, non-measurable bias would be included during the merging of the data. The validity of these findings will therefore require further investigation.
Conclusion
Our result demonstrated that the early or later AFB related to the risk of OA and RA in later life for women. There is a need for additional research to elucidate the potential mechanisms underlying the link between reproductive factors and the history of arthritis (OA and RA).
Supplementary Information
Supplementary Material 1: Supplementary Figure 1. Restricted cubic spline curve for the association of age at first birth with the prevalence of arthritis.The association of age at first birth with arthritis stratified by age;The association of age at first birth with arthritis stratified by menopause status;The association of age at first birth with arthritis stratified by hysterectomy;The association of age at first birth with arthritis stratified by female hormone;The association of age at first birth with arthritis stratified by age at menarche;The association of age at first birth with arthritis stratified by age at fertile lifespan. Supplementary Figure 2. Restricted cubic spline curve for the association of age at last birth with the prevalence of arthritis.The association of age at last birth with arthritis stratified by age;The association of age at last birth with arthritis stratified by menopause status;The association of age at last birth with arthritis stratified by hysterectomy;The association of age at last birth with arthritis stratified by female hormone;The association of age at last birth with arthritis stratified by age at menarche;The association of age at last birth with arthritis stratified by age at fertile lifespan. Supplementary Figure 3. Restricted cubic spline curve for the association of number of pregnancies with the prevalence of arthritis.The association of number of pregnancies with arthritis stratified by age;The association of number of pregnancies with arthritis stratified by menopause status;The association of number of pregnancies with arthritis stratified by hysterectomy;The association of number of pregnancies with arthritis stratified by female hormone;The association of number of pregnancies with arthritis stratified by age at menarche;The association of number of pregnancies with arthritis stratified by age at fertile lifespan. Supplementary Figure 4. Restricted cubic spline curve for the association of number of live births with the prevalence of arthritis.The association of number of live births with arthritis stratified by age;The association of number of live births with arthritis stratified by menopause status;The association of number of live births with arthritis stratified by hysterectomy;The association of number of live births with arthritis stratified by female hormone;The association of number of live births with arthritis stratified by age at menarche;The association of number of live births with arthritis stratified by age at fertile lifespan. Supplementary Table 1. Subgroups analysis for the associations of AFB with the risk of arthritis. Supplementary Table 2. Subgroups analysis for the associations of ALB with the risk of arthritis. Supplementary Table 3. Subgroup analysis for associations between number of pregnancies and the risk of arthritis. Supplementary Table 4. Subgroup analysis for associations between number of live births and the risk of arthritis.
Acknowledgements
My sincere thanks go out to all the volunteers that participated in the NHANES.
Authors’ contributions
Jiajia Wang participated in data collection and drafting and editing of the paper. Yiting Ge participated in data analysis and revision of the paper. Jingbo Xu, Lin He, and Chunjiang Liu were responsibility for the data analysis. Yuefei Wang contributed to the data interpretation and revision of the manuscript. All authors saw and approved the final version and no other person made a substantial contribution to the paper.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The survey data are publicly available on the Internet for data users and researchers throughout the world https://www.cdc.gov/nchs/nhanes/.
Declarations
Ethics approval and consent to participate
All NHANES participants provided written informed consent and the National Center for Health Statistics obtained institutional review board approval prior to data collection. Because NHANES data are de-identified and publicly available, the analysis presented here was exempt from Institutional Review Board review.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jiajia Wang and Yiting Ge contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1: Supplementary Figure 1. Restricted cubic spline curve for the association of age at first birth with the prevalence of arthritis.The association of age at first birth with arthritis stratified by age;The association of age at first birth with arthritis stratified by menopause status;The association of age at first birth with arthritis stratified by hysterectomy;The association of age at first birth with arthritis stratified by female hormone;The association of age at first birth with arthritis stratified by age at menarche;The association of age at first birth with arthritis stratified by age at fertile lifespan. Supplementary Figure 2. Restricted cubic spline curve for the association of age at last birth with the prevalence of arthritis.The association of age at last birth with arthritis stratified by age;The association of age at last birth with arthritis stratified by menopause status;The association of age at last birth with arthritis stratified by hysterectomy;The association of age at last birth with arthritis stratified by female hormone;The association of age at last birth with arthritis stratified by age at menarche;The association of age at last birth with arthritis stratified by age at fertile lifespan. Supplementary Figure 3. Restricted cubic spline curve for the association of number of pregnancies with the prevalence of arthritis.The association of number of pregnancies with arthritis stratified by age;The association of number of pregnancies with arthritis stratified by menopause status;The association of number of pregnancies with arthritis stratified by hysterectomy;The association of number of pregnancies with arthritis stratified by female hormone;The association of number of pregnancies with arthritis stratified by age at menarche;The association of number of pregnancies with arthritis stratified by age at fertile lifespan. Supplementary Figure 4. Restricted cubic spline curve for the association of number of live births with the prevalence of arthritis.The association of number of live births with arthritis stratified by age;The association of number of live births with arthritis stratified by menopause status;The association of number of live births with arthritis stratified by hysterectomy;The association of number of live births with arthritis stratified by female hormone;The association of number of live births with arthritis stratified by age at menarche;The association of number of live births with arthritis stratified by age at fertile lifespan. Supplementary Table 1. Subgroups analysis for the associations of AFB with the risk of arthritis. Supplementary Table 2. Subgroups analysis for the associations of ALB with the risk of arthritis. Supplementary Table 3. Subgroup analysis for associations between number of pregnancies and the risk of arthritis. Supplementary Table 4. Subgroup analysis for associations between number of live births and the risk of arthritis.
Data Availability Statement
The survey data are publicly available on the Internet for data users and researchers throughout the world https://www.cdc.gov/nchs/nhanes/.