Pelvic inflammatory disease (PID) is a polymicrobial infection that generally occurs in the women’s genital tract and often leads to the impairment of the endometrium, oviduct, and ovaries (1). The clinical manifestations of PID include long-term infertility, extrauterine pregnancies, and chronic pelvic pain (2). The cause of PID is associated with many factors, including race, age, and smoking status (3). Young people and African or Caucasian people are especially prone to PID (4). A study has estimated that 4 to 12% of women of reproductive age have PID worldwide (5). However, few studies on the epidemiological trends of PID among different areas of the world have been conducted due to challenges with the invasiveness and sensitivity of screening methods (6). In the United States, approximately 0.5 to 1 million cases of PID develop annually, and the average cost is up to $3,025 per episode for PID therapy (7, 8). At the same time, the majority of PID patients are prone to experience disease recurrence, resulting in additional burdens on society and healthcare systems (9). Hence, it is crucial to examine the risk factors associated with PID to enable early intervention.

Diets enriched with antioxidants (fruit and vegetables), vitamins (vitamins B6, A, C, E), and macronutrients (n-3 fatty acids) improve immune system functioning and eliminate free radical damage, which can help control chronic pelvic pain, including PID (10). Although trace minerals account for only a small part of the diet, they are essential to ensure normal function and health, and the excessive or inadequate consumption of trace elements is detrimental to the inherent metabolic balance of the body (11). Trace elements, including copper, iron, selenium, and zinc, are vital for maintaining metabolic balance, especially in cell function, DNA repair, and antioxidant defense (12). Previous studies have indicated that dietary trace minerals have powerful regulatory effects on the oxidative activation of protein kinase C, prostaglandin synthesis, and Ca²⁺ receptors which, in turn, increase chronic pain intensity (13). A study has revealed that copper is closely related to inflammatory responses in many chronic diseases, such as metabolic disorders and cancer (14). Additional studies have illustrated that the intake of dietary copper and selenium is linked to many diseases including gynecological tumors and metabolic syndrome (15–17). Meanwhile, dietary intake of iron and zinc was found to be negatively correlated with fibromyalgia, characterized by widespread muscle soreness, and other chronic symptoms such as fatigue, anxiety, and depression (18). However, the relationship between dietary trace elements and PID is not fully understood.

To this end, using data from the NHANES, the current study aimed to determine if dietary trace elements and PID were correlated after controlling for covariates.

PID is a chronic and recurrent disease that significantly impacts the well-being of patients, causing considerable suffering. Until now, few studies have been done on the dietary recommendations for women with PID. This is the first research to our knowledge to investigate the link between PID and dietary trace minerals. Based on the large sample size of the NHANES, dietary copper intake was shown to exhibit a significant negative linear relationship with PID; however, no difference was found in the correlation between other trace minerals (iron, selenium, and zinc) and PID. In addition, we found that age and BMI may have meaningful interactions between copper intake and PID. In the younger age subgroup, the relationship exhibited a curved pattern; however, in the older age subgroup, it showed a straight line. Similarly, a curved relationship was observed in the overweight subgroup.

Currently, dietary iron intake is mainly focused on pregnancy and anemia among women (25, 26). However, it has been shown that dietary iron intake exhibited no relationship with non-pregnancy diseases such as gynecological cancers (15). In our study, dietary iron intake was not significantly different between the PID and non-PID groups, as supported by insignificant results from logistic regression analysis. Selenium is now recognized as an important trace nutrient with anti-inflammatory function (27). Compared with the control group, in men, selenium supplementation improved inflammatory parameters (28). No significant link was found between selenium in the diet and PID in this study, which may be explained by sex differences and disease-specific factors. Zinc deficiency is closely related to an increased risk to pregnancy health because of its vital role in some enzymatic reactions (29), and bone mineral density is associated with zinc intake in a positive manner (30). However, in the present study, univariate analysis of dietary zinc intake and PID showed no significant relationship, suggesting avenues for future research. Compared to non-pregnant women, the urine levels of trace element silicon in pregnant women were higher, which might be accounted for by the differences in the gastrointestinal tract, kidney excretion, and metabolism in pregnant women (31). The trace elements metabolism also changed between gestational weeks (32). Consequently, as a non-pregnancy disease, PID might not be easily susceptible to changes in common trace elements.

Copper performs an integral function in the secretion of inflammatory products and is linked to many inflammatory diseases by regulating the nuclear factor kappa-B and mitogen-activated protein kinase pathways (14). Another study has shown that copper is capable of activating nicotinamide adenine dinucleotide phosphate hydrogen in mitochondria, thus mediating metabolic and epigenetic processes toward the inflammatory state (33). The dietary copper intake was demonstrated to be correlated with inflammatory disorders and serum estradiol levels in women (34, 35). Adequate copper intake is vital to maintain the antioxidant capacity of the body (36). Although, to our knowledge, no study has been conducted on dietary copper intake and PID, evidence has shown that using non-hormonal copper-containing intrauterine devices could effectively decrease pelvic pain, which highlights the importance of the copper mechanism in PID (37). Our data showed a consistent negative linear correlation between copper intake and PID, which remained stable across different models. Our findings imply that copper intake can aid in the fight against PID, which may contribute to its regulatory role in inflammation. However, a key consideration is that excessive copper intake may be harmful to health. Therefore, future research is needed to determine the specific turning points of copper intake that are effective in preventing and managing PID.

Age and body weight were independently associated with pelvic disease, especially in older and obese women (38). In our study, age and BMI covariates were identified as interaction terms between copper intake and PID. In the younger age group, it appears that adequate copper intake (>1.19 mg/day), which exceeds the RDA, may have a protective effect against PID. However, in the older age group, the relationship between copper intake and PID is assumed to be linear from the beginning of copper intake. According to a disease burden analysis, women younger than 25 years old had a higher rate of PID than older women (39). Young women may be more susceptible to the modulatory effects of high estrogen and progesterone levels, which in turn makes them less susceptible to the influence of copper intake. Among the different BMI subgroups, only the overweight participants showed a significant non-linear relationship between copper intake and PID, while no significant correlations were found in other BMI subgroups. Although there was an initially positive correlation between copper intake and PID in the underweight subgroup, this relationship disappeared in the subsequent multivariate RCS, which could be due to the presence of confounding variables. Before reaching a copper intake of 0.85 mg/day (close to the RDA), the link between copper intake and PID in the overweight subgroup (≥30.0 kg/m²) was flat and decreased rapidly when the RDA of copper was reached. A retrospective study has shown that obese PID patients were identified to be associated with an unfavorable clinical course (9). Thus, adequate copper intake may become even more important for older and overweight women with PID. Poultry was considered a valuable food for its abundance of minerals (specifically iron, zinc, and copper) and moderate energy (40). Therefore, intake of a certain amount of meat rich in copper may be beneficial for women with PID. However, the trace minerals consumed are not equivalent to the actual uptake of minerals, and the absorption efficiency may also be a critical factor. Before being absorbed, dietary copper (Cu²⁺) was first reduced to cuprous copper, then absorbed by the intestinal epithelial cells, and finally transported to the liver for processing and activation (41). Thus, people with gastrointestinal disease or liver diseases may present a low absorption efficiency of dietary copper. Furthermore, copper imbalance was associated with liver pathological features, including oxidative stress and mitochondrial dysfunction, which in turn affect the copper absorption efficiency (42). Hence, future studies on dietary copper absorption efficiency and PID will be required to apply our findings to real-world situations.

To our knowledge, our research is the first to investigate whether PID is linked to dietary trace minerals. A significant negative relationship between PID and dietary copper intake was identified, though not in iron, selenium, and zinc. Additionally, multiple linear regression was used to verify the solid relationship between dietary copper intake and PID after adjusting for several covariates. Our study may have important implications regarding the setting of recommended dietary copper intake for women with PID. However, there were several limitations to this research. To begin with, this was a cross-sectional study; therefore, no causal relationship could be determined based on the accurate dietary trace intake recommendation for women with PID. Second, the diagnostic nature of the PID questionnaire inevitably introduced some degree of selection bias. Thirdly, although efforts were made to incorporate related confounding factors, we were unable to address all confounders. Finally, sampling errors inherent in the NHANES data cannot be ruled out. Given these limitations, large prospective cohort studies are necessary to validate the link between dietary copper intake and determine the recommended intake of dietary trace minerals for women with PID.

Overall, our study suggested that decreased dietary copper intakes are linked to PID. However, no significant link was found for other dietary trace minerals (iron, selenium, and zinc). To confirm our findings, more large-scale prospective investigations are needed.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by National Center for Health Statistics Ethics Review Board gave approval for the project (https://www.cdc.gov/nchs/nhanes/irba98.htm). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

PH: Writing – original draft. SM: Conceptualization, Writing – original draft. HL: Data curation, Conceptualization, Writing – review & editing. XY: Data curation, Formal analysis, Software, Writing – review & editing. XZ: Conceptualization, Data curation, Supervision, Writing – review & editing. QZ: Supervision, Funding acquisition, Writing – review & editing.