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Highlights
• High parity raises T2DM risk after adjusting for lifestyle and socioeconomic factors.
• The risk is higher in Asian, obese, and abdominally obese women.
• Visceral adiposity, socioeconomic factors, and metainflammation are key mediators.
• Women with normal BMI and waist circumference show no increase in T2DM risk.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a prevalent global disease and a significant cause of morbidity and mortality. According to the 2021 Diabetes Atlas released by the International Diabetes Federation (IDF), approximately 530 million adults between the ages of 20 and 79 currently live with diabetes worldwide, with an estimated 17 million more cases in men than women [1]. However, it has been reported that compared to men, women have higher incidences of diabetes-related mortality and complications such as hypertension, dyslipidemia, and cardiovascular diseases [2]. In addition, most of these complications tend to have a worse prognosis in women than men; thus, healthcare professionals need to pay special attention to preventing and managing diabetes in women.
Women experience hormonal fluctuations throughout their lives, such as during menstruation, pregnancy, childbirth, and menopause; these fluctuations can potentially influence the onset of diabetes and complications [3]. During pregnancy, physiological increases occur in insulin secretion and resistance [4]. Pregnancy is also a period of rapid fat accumulation, which can significantly impact the development of postpartum diabetes and metabolic syndrome [5]. The association between parity and T2DM was first reported in the 1950s [6] and has been of research interest ever since. Most studies have reported a positive association, but some have claimed no association or even suggested a protective effect of childbirth, causing confusion and controversy [7]. Notably, most studies have focused solely on the relationship of parity with T2DM risk and need more adjustment for factors such as lifestyle habits, socio-economic status (SES), and genetic factors associated with T2DM [8]. Furthermore, to the best of our knowledge, no studies have examined whether the association between T2DM and parity is influenced by race or body composition, as well as whether there are any protective factors that could mitigate this risk relationship. Therefore, in this study, we used the large-scale UK Biobank cohort to more comprehensively investigate the relationship between parity and T2DM risk, including various considerations such as race, SES, body composition, and genetic factors. We further conducted mediation analysis on metabolic, inflammatory, and socio-economic variables to identify potential mediators in the parity-T2DM risk relationship.
METHODS
Study population and study design
This study is based on data from the UK Biobank, a large prospective cohort of over 500,000 individuals from diverse racial backgrounds aged between 40 and 69 at baseline, registered between 2006 and 2010 in England, Wales, and Scotland. A wide range of information, including lifestyle habits, environment, reproductive factors, medical history, and blood, urine, and saliva samples, were obtained for further analysis [9]. The UK Biobank received ethical approval from the National Research Ethics Committee, and all participants provided written informed consent [10]. For this study, we utilized data from female participants (n=242,159) in the UK Biobank who met the following criteria: had available information on blood glucose levels and birth history and had not received a prior diagnosis of diabetes. We excluded participants who were diagnosed with T2DM at the time of registration (n=21,533), those missing parity data (n=511), and those missing the blood test data necessary for diagnosing T2DM (n=40,531).
Variable measurement
Information on lifestyle habits and medical history was collected at the time of registration in the UK Biobank through self-administered touchscreen questionnaires and personal interviews. During the interviews, trained staff measured participant height, weight, and waist circumference (WC) using standardized procedures [11]. Smoking status was categorized into nonsmoker, former, and current smoker. Physical activity was divided into two groups: those who reported engaging in moderate activity for at least 5 days a week, which were classified as exercising, and those who did not meet this criterion, which were considered not exercising. Eating habits were defined based on the recommendations for cardiometabolic health [12]. A diet pattern was considered poor if participants did not fulfill more than half of the recommendations assessed by a food frequency questionnaire. Body mass index (BMI) was calculated as weight in kilograms divided by height in square meters (kg/m²). Obesity and abdominal obesity status were based on World Health Organization classifications and the IDF consensus report, and race-specific criteria were applied to reduce errors that may arise due to racial differences (Supplementary Table 1) [13,14]. The Townsend deprivation index (TDI) measures material deprivation and socio-economic disadvantage based on four factors: unemployment rate, car ownership rate, homeownership rate, and household overcrowding. A higher score indicates a greater level of deprivation [11]. Income was obtained through a questionnaire that assessed pre-tax income and was categorized into five groups: <£18,000, £18,000–£30,999, £31,000–£51,999, £52,000–£100,000, and ≥£100,000 [15]. Depressive symptoms were assessed using a self-reported frequency of depressive mood over the past 2 weeks, and participants were categorized on frequency from low to very high [16]. Detailed descriptions of the biological sampling procedures can be found in previous publications or papers related to this study [17].
Polygenic risk scores
To generate a polygenic risk score (PRS) for T2DM, we utilized a Bayesian polygenic prediction method, PRS-continuous shrinkage [18], which infers the posterior mean effect size of each variant using linkage disequilibrium (LD) reference panel and genome-wide association study summary statistics. Here, the 1000 Genomes Project phase 3 data was used as the external LD reference panel, and summary statistics derived from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium [19] were used to infer the posterior single nucleotide polymorphism effect sizes. Individual PRSs were computed from beta coefficients as the weighted sum of the risk alleles by applying PLINK version 1.90 (https://zzz.bwh.harvard.edu/plink) [20]. More details are given in the Supplementary Methods.
Reproductive factors
Female participants provided self-reported responses regarding reproductive factors through a questionnaire. This questionnaire included age at menarche, parity, age at first childbirth, history of hysterectomy, menopausal status, and use of hormone replacement therapy [21]. Parity was categorized into six groups: nulliparous, 1, 2, 3, 4, and 5 or more childbirths.
Definition of T2DM and gestational diabetes
We utilized the International Classification of Diseases 10th Revision (ICD-10) and self-reported information to determine whether individuals had T2DM at enrollment. The occurrence of newly diagnosed T2DM during the follow-up period was identified through hospitalization records, which were coded using ICD-10 diagnostic codes. Information regarding gestational diabetes mellitus (GDM) was obtained using the same methodology (Supplementary Table 2).
Statistical analyses
We performed t-tests and chi-square tests to examine the differences in baseline characteristics between groups. Continuous variables are reported as mean±standard deviation and categorical variables as percentages. Parity was analyzed as both a continuous and a categorical variable. Multivariable adjusted Cox proportional hazard regression models were constructed to assess the association between parity and the risk of developing T2DM; the results are reported as hazard ratio (HR) with 95% confidence interval (CI). To account for potential confounders or mediators, the Cox models were stratified by age, sex, race, BMI, WC, and SES.
We further conducted a causal mediation analysis using the R package mediation to assess the mediating effects of metabolic and inflammatory factors, including WC, BMI, triglyceride, glycosylated hemoglobin (HbA1c), high-sensitivity C-reactive protein (hs-CRP), TDI, depressive symptoms, and income level. We employed a quasi-Bayesian method with 1,000 simulations to estimate variance for each analysis. Statistical analyses were conducted using PLINK version 1.9 and R version 3.9.0 (R Foundation for Statistical Computing, Vienna, Austria). The significance level was set at P<0.05, with values below that threshold considered statistically significant.
RESULTS
Baseline characteristics of the study population
Our study included 242,159 female participants without a history of T2DM, stratified into six groups according to parity. The baseline clinical characteristics are shown in Table 1. The mean age of participants was 56.8 years, 60.4% were postmenopausal, and 95.4% were Caucasian. The mean BMI was 26.8 kg/m2, mean WC was 84.1 cm and mean HbA1c level was 5.4%. Only 8.9% of participants were current smokers, and 67.3% engaged in moderate to vigorous physical activity. Regarding economic status, 24.1% were in the low-income group, with an annual income below £18,000.
Among the participant population, 45,568 (18.8%) had no history of childbirth, while 106,624 (44.0%) had borne two children, the largest parity group. Only 3,612 (1.5%) had given birth to five or more children. As the number of children increased, both the average age and the proportion of non-Caucasian participants also increased; moreover, other variables such as WC, body fat, BMI, blood pressure, HbA1c, blood glucose level, and the number of applicable metabolic syndrome criteria also increased. The TDI, income, and depressive mood all showed a J-shaped pattern, with the most favorable outcomes observed in women with two children and deteriorating patterns in those with five or more children.
Association between parity and risk of T2DM
During a median follow-up period of 8.9 years, 4,045 (1.7%) participants were newly diagnosed with T2DM. Cox regression analysis, summarized in Table 2, revealed the absolute risk rate to be highest in women with five or more children, at 5.03 per 1,000 person-years (95% CI, 4.28 to 5.87), and lowest in nulliparous women, at 1.61 per 1,000 person-years (95% CI, 1.48 to 1.73). Regarding relative risk, each additional child showed a 16% increased risk of T2DM occurrence. However, the risk was not increased in women with two children compared to those with no history of childbirth. Adjusting for age, physical factors, lifestyle habits, social factors, and reproductive factors attenuated the association, but there remained an increased risk of developing T2DM among multiparous women.
After excluding 315 women with a history of GDM, the risk of developing T2DM remained consistent with the previous findings. Among women who had given birth to five or more children, who exhibited the highest risk, the HR was 3.16 (95% CI, 2.66 to 3.76) (Supplementary Table 3).
Subgroup analysis and mediation analysis
Fig. 1 shows the results of the subgroup analysis investigating the relationship between parity and T2DM risk with consideration of race, BMI, and WC. Concerning race, the Asian population demonstrated the strongest association (Supplementary Table 4). Having four or more children is related to a significantly increased risk of T2DM among women with higher BMI, specifically those who were overweight or obese (Supplementary Table 5); however, no such association was observed in the standard BMI group. Meanwhile, among individuals with abdominal obesity, having four or more children was associated with a substantial increase in T2DM risk, but in the absence of abdominal obesity, no such increase was observed (Supplementary Table 6).
We conducted a mediation analysis to examine the involvement of several potential mediators. WC, BMI, HbA1c, hsCRP, triglyceride levels, depressive mood, income, and TDI were all found to significantly mediate the relationship between parity and T2DM risk, with WC having the highest mediated proportion of 49%, followed by BMI at 38% (Table 3).
Association of genetic risk, parity, and risk of T2DM
Women in each parity category were further stratified based on a PRS for T2DM into low, intermediate, and high genetic risk groups. This risk stratification analysis revealed a sequential increase in T2DM risk with increasing parity and genetic risk (Supplementary Table 7). The highest risk was identified in women who had given birth to five or more children and harbored a high genetic risk for T2DM, with a HR of 8.56. Adjusting the primary T2DM-parity association for PRS revealed that genetic factors do not influence the risk of developing T2DM based on parity (Supplementary Table 8). In other words, no significant differences were observed among the low, intermediate, and high genetic risk groups.
DISCUSSION
This large prospective study aimed to investigate the association between parity and the risk of developing T2DM in a population of 241,159 middle-aged women without a history of T2DM in the UK Biobank. It also examined the impact of race, body composition, and SES on that association. The analysis revealed that while women with two children do not exhibit an increased risk of T2DM compared to nulliparous women, as the parity level increases to three or more children, the risk of developing T2DM increases significantly. After adjusting for lifestyle, body composition, and socio-economic variables, this risk remained, though somewhat reduced. In subgroup analysis, there were prominent associations between parity and T2DM risk in Asian individuals and women with obesity and abdominal obesity; however, particularly noteworthy was multiparous women with normal BMI and WC did not show a significant increase in T2DM risk. This finding suggests that maintaining an ideal weight and WC in multiparous women may protect against the parity-T2DM risk relationship. We also discovered that genetic factors do not significantly impact the relationship. Finally, mediation analysis highlighted abdominal obesity as a prominent mediator of the association between parity and T2DM.
Women undergo various physiological changes during pregnancy and childbirth, including increased insulin resistance, dyslipidemia, fat accumulation, hormonal fluctuations, inflammatory responses [22]. High parity may result in repeated exposure to pregnancy-related insulin resistance, which exacerbates β-cell exhaustion and thereby increases the risk of T2DM [23]. Along with the increasing insulin resistance during pregnancy, changes in lipid metabolism play a crucial role in postpartum weight retention and glucose metabolism. Specialists anticipate that prolonged or repeated exposure to pregnancy-related weight changes could have long-term negative effects on lipid metabolism [8]. Hypertriglyceridemia, which can worsen during pregnancy, facilitates fat accumulation in muscle, pancreas, and liver, thereby impairing insulin action [24]. High-density lipoprotein cholesterol (HDL-C) levels increase during mid-pregnancy but decline below the reference range in the third trimester, and these lower levels tend to persist postpartum [4]. Low HDL-C levels also contribute to increased inflammation and oxidative stress, further exacerbating insulin resistance. Studies in mouse models have reported an association between multiparity and increased maternal obesity risk [25], and several human studies have also found positive associations between multiparity, weight gain, BMI, and WC [26,27]. In general, postpartum weight retention of approximately 1.5 to 3.0 kg has been observed after 12 months of follow-up [28].
Regarding other metabolic changes, one study reported that women who have experienced pregnancy and childbirth show approximately 22% lower estrogen levels than those who have not. Decreased estrogen exposure can contribute to disorders in lipid metabolism, hyperglycemia, and the development of metabolic syndrome [29]. Additionally, pregnancy induces a systemic inflammatory state, with increased levels of pro- and anti-inflammatory cytokines such as interferon-γ and tumor necrosis factor-α [30]. Studies examining parity and inflammation have also found that women with a history of childbirth, regardless of the number of births, have increased levels of hs-CRP; this increased systemic inflammatory response also contributes to insulin resistance [31]. Finally, a meta-analysis of 62,095 women in 15 observational studies investigating parity and metabolic syndrome determined that greater parity increases the risk of developing metabolic syndrome [29].
T2DM results from insulin resistance, leading to increased insulin secretion from the pancreatic β-cells and eventual dysfunction. During a normal pregnancy, insulin resistance occurs as a physiological change in the maternal body that ensures a sustained supply of glucose to the fetus by maintaining higher blood glucose levels in the maternal circulation [19]. Given this, the relationship between T2DM and parity has been the subject of numerous studies, but their findings have not been consistent. Several studies on Asian populations have demonstrated an association between parity and T2DM risk [6]. A prospective cohort study based on the Singapore Chinese Health Study found that even after adjusting for lifestyle, reproductive factors, health factors, BMI, and other variables, women with a history of childbirth had a significantly increased risk of T2DM compared to nulliparous women. The study also found a positive association between parity and HbA1c level, regardless of T2DM diagnosis. Another study that utilized computed tomography to assess visceral fat and considered family history and other diabetes risk factors found that women with six or more children had an increased risk of developing T2DM independent of other factors [32]. Finally, a meta-analysis of eight cohort studies found that parity is an independent risk factor for T2DM, with a dose-response relationship [30]. On the other side of the argument, a paper in 2010 suggested that the relationship between multiparity and T2DM risk may be confounded or mediated by changes in body weight and socio-demographic factors; in particular, the authors observed that multiparity does not seem to promote the development of T2DM in older women without diabetes [7]. However, we should consider that this study was primarily conducted with the elderly population with a mean age of 72.5±5.4, and the sample size was relatively small. Additionally, the study design was cross-sectional, restricting the ability to establish causal relationships.
Our present findings support a progressive increase in the risk of developing T2DM among multiparous women, consistent with most previous findings. A previous meta-analysis determined a J-shaped association between parity and T2DM, with the lowest risk in women with one child; the authors suggested this may be attributed to the fact that such women are more likely to belong to a high-income group [30]. Our findings from the UK Biobank cohort, which indicate no increased risk among women with two children, also highlight a potential influence of SES on the association of T2DM risk with parity. Specifically, mothers giving birth to two children had significantly higher income and lower TDI than other groups, including nulliparous women. Considering the potential confounding factors, further analysis is needed to fully explore the association between T2DM risk in women and parity.
Pregnant women with normal pre-pregnancy weight are recommended to gain an average of 11.5 to 16.0 kg, representing a significant and rapid increase over a short period [33]. Consequently, it is expected that each successive pregnancy will lead to increased fat accumulation in the body [34]. When weight gain during pregnancy exceeds the recommended amount, there is a higher likelihood of excess postpartum weight retention or failure to return to the pre-pregnancy weight even after 1 year [35]. In a 2023 study that followed nulliparous women aged 31 to 36 years for 6 years, women who had given birth were approximately 1 kg heavier and consumed about 833.9 kJ/day more energy while also having lower activity levels [36]. In addition, a study conducted on the Chinese population reported a positive association between parity and obesity risk. It highlighted that the correlation was more robust for central obesity than general obesity [37]. When insulin resistance occurs, the remaining calories accumulate in undesirable areas, such as visceral fat, contributing to the development of abdominal obesity [38]; thus, increased insulin resistance due to pregnancy can lead to abdominal obesity [37].
Our study identified a significant association between parity and T2DM among Asian women, which may be explained by differences in insulin secretion capacity, visceral fat accumulation, and cultural and lifestyle factors related to pregnancy and postpartum care. First, Asians are known to have a lower insulin secretion capacity compared to other ethnic groups [39]. This diminished β-cell function makes them more vulnerable to T2DM, particularly in situations of increased insulin demand, such as during and after pregnancy. Second, despite having a lower BMI compared to Western populations, Asians tend to have higher levels of visceral fat accumulation [40]. Repeated pregnancies may further promote visceral fat accumulation, thereby amplifying insulin resistance and increasing the risk of T2DM [41]. Third, lifestyle changes associated with a more Westernized diet and decreased physical activity have contributed to rising obesity rates and T2DM prevalence in Asian populations [42]. These factors may have a particularly strong impact on Asians, who have a relatively lower insulin secretion capacity, thus worsening insulin resistance and increasing the risk of T2DM after multiple pregnancies. Lastly, cultural practices surrounding postpartum care may also influence T2DM risk. Some studies suggest that Asian women are more likely to retain weight for longer periods postpartum, which can lead to increased weight gain with subsequent pregnancies, particularly visceral fat, thereby increasing the risk of T2DM [43]. Inadequate weight recovery between pregnancies may further exacerbate this risk.
In our study, women who had two children did not exhibit an increased risk of T2DM compared to nulliparous women. Several factors may contribute to this observation. Previous studies have noted an association between grand multiparity and T2DM risk [7,32], and women with a parity of 1–2 children tend to belong to relatively higher SES groups [30,44]. Consistent with these findings, our data showed that women with two children had the lowest rates of obesity and the smallest WC among all parous women. Additionally, they had higher income levels, and higher SES is associated with better access to healthcare resources, healthier dietary choices, and greater health literacy, all of which can contribute to a reduced risk of T2DM. Furthermore, this group was less likely to report depressive symptoms. Lower levels of stress and depression can lead to healthier lifestyle choices, potentially reducing the risk of T2DM [45,46]. Indeed, the mediation analysis in our study identified central obesity, general obesity, the TDI, and depression as significant mediators in the relationship between parity and T2DM risk.
The strengths of this study are its large-scale prospective design and the adjustment for confounding and mediating variables such as genetic factors, body composition, and SES to comprehensively analyze the relationship between parity and T2DM risk.
This study has several limitations to consider when interpreting the results. Firstly, lifestyle and metabolic data were obtained through self-reported questionnaires at the time of registration in the UK Biobank, potentially not capturing changes after registration, such as postpartum weight changes. Secondly, the participants in the UK Biobank tend to have higher SES and health consciousness, limiting the generalizability to the broader UK population [47]. Third, breastfeeding has been shown to have a protective effect against T2DM by improving postpartum glucose metabolism and insulin sensitivity [48,49]; however, data on breastfeeding were not available in our study, and thus could not be included in the analysis. Lastly, the focus on middle-aged individuals from tertiary hospitals may not represent younger women or patients seen in primary care centers, affecting the generalizability of the findings [50].
In conclusion, we found a positive association between parity and risk of T2DM, particularly in multiparous women. This parity-T2DM risk relationship was especially evident in the Asian population and among women with obesity and abdominal obesity. However, these association was not observed in the standard BMI and standard WC groups which means the parity-T2DM risk relationship is modifiable through weight and body shape control. Our study sheds light on the importance of weight management during and after pregnancy, offering valuable insights for policymakers and healthcare providers to create effective interventions to reduce the risk of T2DM in this particular group of women.
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