A cohort study on the association between metabolic/inflammatory status and pregnancy complications in PCOS patients after IVF/ICSI treatment.

Metabolic abnormalities and inflammatory responses in PCOS patients undergoing IVF/ICSI treatment may negatively impact pregnancy complications and neonatal outcomes, indicating a higher risk for this population during pregnancy. Therefore, individualized metabolic and inflammatory management for PCOS patients, particularly within the context of IVF/ICSI treatment, could help reduce the incidence of pregnancy complications and improve pregnancy outcomes.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women, characterized by irregular menstrual cycles, anovulation, hyperandrogenism, and ovarian cysts. [ 1 , 2 ] Beyond its impact on fertility, PCOS is closely linked to various metabolic and endocrine disturbances. [ 3 , 4 ] With the rapid development of assisted reproductive technologies, particularly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), increasing numbers of PCOS patients are achieving successful pregnancies. [ 5 ] IVF/ICSI have proven effective in addressing ovulatory dysfunction and significantly enhancing infertility treatment outcomes in these patients. [ 6 ] Nevertheless, despite the success in overcoming infertility, PCOS patients continue to experience metabolic irregularities and increased pregnancy-related risks, which may negatively influence pregnancy outcomes. [ 7 ] The exact mechanisms behind these complications are not yet fully understood. Therefore, investigating the metabolic alterations in PCOS patients undergoing IVF/ICSI, and their influence on pregnancy outcomes: especially the links between insulin resistance, inflammation, and pregnancy complications, is of crucial clinical significance. Metabolic abnormalities in PCOS patients are primarily manifested by insulin resistance, dysregulation of glucose metabolism, lipid metabolism disorders, and chronic low-grade inflammation. [ 8 , 9 ] Studies have shown that insulin resistance often worsens during pregnancy in PCOS patients, leading to an increased risk of pregnancy complications such as diabetes, hypertension, gestational diabetes, and placental dysfunction. [ 10 , 11 ] Furthermore, chronic low-grade inflammation is a common issue during pregnancy in PCOS patients, where inflammatory mediators may influence immune responses and metabolic states, further exacerbating the incidence of pregnancy complications. [ 12 , 13 ] The combined effects of insulin resistance and inflammation may exert a compound influence on pregnancy outcomes, thereby affecting maternal and neonatal health. [ 14 ] Therefore, investigating the dynamic changes in insulin resistance, metabolic alterations, and inflammatory responses during IVF/ICSI treatment in PCOS patients, and their relationships with pregnancy complications, is a critical issue that needs to be addressed. Currently, research on the changes in insulin resistance and metabolic status during IVF/ICSI treatment in PCOS patients remains incomplete. [ 15 ] While previous studies have focused on metabolic abnormalities in PCOS patients and their impact on pregnancy complications, most have not adequately examined the changes in insulin resistance during IVF/ICSI treatment, especially the dynamic alterations in insulin resistance and metabolism across different stages of pregnancy. [ 16 ] Consequently, this study aims to explore the changes in metabolic and inflammatory states at various stages of pregnancy in PCOS patients undergoing IVF/ICSI treatment, analyzing the relationship between these changes and the occurrence of pregnancy complications. This will provide scientific evidence to optimize the management of pregnancy in PCOS patients. In the management of pregnancy in PCOS patients, the assessment of metabolic abnormalities and insulin resistance has become one of the key research areas. [ 17 ] Despite the continuous improvement in the success rates of IVF/ICSI technologies, optimizing treatment protocols and reducing the occurrence of pregnancy complications remain significant challenges in current clinical practice. [ 18 ] Insulin resistance and inflammatory responses may have profound impacts on pregnancy outcomes in PCOS patients. [ 19 ] Therefore, early detection and intervention of these metabolic abnormalities, particularly during IVF/ICSI treatment, are of substantial clinical significance. By investigating the metabolic changes in PCOS patients at different stages of pregnancy, especially the variations in insulin resistance, this study aims to provide more precise intervention strategies to enhance pregnancy management, reduce pregnancy complications, and ensure maternal and neonatal health. Currently, most studies on metabolic changes in PCOS patients have primarily focused on single metabolic indicators or the impact of glucose metabolism abnormalities, with limited comprehensive analysis of the changes in metabolic status during pregnancy and their interaction with inflammatory responses. To address this research gap, the present study aims to systematically analyze the dynamic changes in metabolism, insulin sensitivity, and inflammatory responses in PCOS patients undergoing IVF/ICSI treatment. Through this integrated analysis, the study aims to offer new theoretical perspectives for the management of pregnancy in PCOS patients and provide possible references for optimizing personalized intervention strategies during IVF/ICSI treatment, with the goal of reducing pregnancy complications and improving pregnancy outcomes. In summary, this study seeks to provide new insights into metabolic management during IVF/ICSI treatment in PCOS patients and offer valuable scientific evidence to enhance maternal and neonatal health and reduce the incidence of pregnancy complications.

Conceptualization: Mengmeng Du, Hongshan Ge. Data curation: Mengmeng Du. Formal analysis: Mengmeng Du. Investigation: Hongshan Ge. Methodology: Hongshan Ge. Writing – original draft: Mengmeng Du. Writing – review & editing: Hongshan Ge.

This study enrolled 100 PCOS patients receiving IVF/ICSI treatment at the Reproductive Medicine Center of our hospital between February 2022 and February 2024. The average age of these participants was 28 (27, 31) years. Additionally, 100 pregnant women with natural conception were selected as controls, with a mean age of 29.50 (27.25, 32.75) years (Figure S1, Supplemental Digital Content, https://links.lww.com/MD/O994 ). Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Board of Taizhou People’s Hospital (KY 2023-116-01). PCOS group: participants diagnosed with PCOS based on established criteria [ 20 ] ; aged 20 to 35 years; infertile for at least 1 year; undergoing IVF/ICSI for infertility; and consenting to pregnancy monitoring and delivery at our hospital. Natural pregnancy group: participants aged 20 to 35 years; naturally pregnant without prior treatments; with regular menstrual cycles and normal ovulatory history; and agreeing to complete pregnancy monitoring and delivery at our hospital. Participants were excluded if they had coexisting gynecological conditions (e.g., endometriosis, adenomyosis, recurrent pregnancy loss), other endocrine disorders (e.g., diabetes mellitus, thyroid dysfunction, systemic lupus erythematosus), recent treatment with endocrine or antibiotic medications within the past 3 months, or had undergone surgery in the last 6 months. On days 2 to 3 of the natural menstrual cycle, venous blood was drawn to measure sex hormones, including luteinizing hormone, follicle-stimulating hormone, estrogen, progesterone, testosterone, and prolactin. Liver and kidney function tests: at various stages of pregnancy (early, mid, and late), fasting venous blood was collected to assess lipid profile and kidney function markers: triglycerides (TG), total cholesterol (TC), high-density lipoprotein, low-density lipoprotein (LDL), serum creatinine, blood urea nitrogen, and uric acid. Glucose and insulin measurements: fasting venous blood samples were collected at different pregnancy stages (early, mid, and late) to measure fasting plasma glucose and fasting insulin levels. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as follows: [HOMA-IR = fasting plasma glucose (μU/mL) × fasting insulin (mmol/L)/22.5]. Inflammatory markers: at each stage of pregnancy (early, mid, and late), fasting venous blood was collected to analyze inflammatory markers, including C-reactive protein (CRP) and interleukins IL-2, IL-4, IL-6, IL-8, IL-12, and IL-18. Some pregnant women were unable to provide metabolic and inflammatory marker data at various stages of pregnancy due to miscarriage, resulting in missing data. To address the missing data, multiple imputation was employed. Given that some participants could not provide complete metabolic and inflammatory marker data due to miscarriage, the missing data were handled using regression models. Existing complete data were used as predictor variables to generate corresponding imputed datasets, which were then used to fill in the missing metabolic and inflammatory marker data. Pregnancy outcomes were recorded for both groups of women, including miscarriage rate, preterm birth rate, and the incidence of pregnancy-related complications. The neonatal birth weight was recorded in grams (g). Birth weight was measured immediately after delivery by clinical staff using standardized infant weighing equipment. The Apgar score was used to assess the neonate’s physiological condition at 1 and 5 minutes post-birth. The Apgar score consists of 5 components: heart rate, respiration, muscle tone, reflexes, and skin color. Each component is scored from 0 to 2, with a total score ranging from 0 to 10. Data were analyzed using SPSS 20.0 software. Normality of the data was assessed with the Shapiro–Wilk test. For normally distributed continuous variables, results are presented as mean ± standard deviation ( x ¯ ± s ), and comparisons between groups were made using the independent t test. Non-normally distributed data are expressed as median [interquartile range (Q 25 , Q 75 )], with group differences analyzed by the Mann–Whitney U test. Categorical data are reported as frequencies n (%), and intergroup comparisons were conducted using the Chi-square test. For the metabolic and inflammatory marker data missing due to miscarriage in this study, multiple imputation was used to handle the missing data. Regression models were applied to impute the missing data based on the existing complete data, generating 5 imputed datasets. Each dataset was analyzed independently, and the results were subsequently combined using Rubin rules to enhance the robustness of the analysis. The imputed datasets were used in subsequent statistical analyses to minimize potential bias caused by missing data. Statistical significance was set at P  < .05.

Significant differences were observed between the PCOS-IVF/ICSI and natural pregnancy groups in body mass index, SBP, menstrual cycle, TG, TC, and LDL levels ( P  < .05). The PCOS-IVF/ICSI group showed higher values in body mass index, SBP, menstrual cycle length, TG, TC, and LDL compared to the natural pregnancy group ( P   .05). These results indicate that PCOS patients have distinct metabolic and endocrine profiles compared to women with natural pregnancies, which may be attributed to the unique pathophysiological mechanisms of PCOS (see Table 1 ). Comparison of baseline characteristics between the 2 groups [ x ¯ ± s , M (Q 25 , Q 75 )]. BMI = body mass index, BUN = blood urea nitrogen, HDL = high-density lipoprotein cholesterol, LDL = low-density lipoprotein cholesterol, SCr = creatinine, TC = total cholesterol, TG = triglycerides. The PCOS group exhibited significantly higher levels of luteinizing hormone, follicle-stimulating hormone, estrogen, progesterone, and testosterone compared to the natural pregnancy group ( P  < .01). In contrast, prolactin levels did not show a significant difference between the 2 groups ( P  = .29). These findings suggest that the hormonal imbalances in PCOS patients are likely related to ovarian dysfunction, elevated androgen secretion, and ovulatory disorders characteristic of the condition (see Table 2 ). Comparison of baseline hormone levels between the 2 groups [ x ¯ ± s , M (Q 25 , Q 75 )]. E2 = estrogen, FSH = follicle-stimulating hormone, LH = luteinizing hormone, P = progesterone, PRL = prolactin, T = testosterone. Compared to the natural pregnancy group, the PCOS-IVF/ICSI group exhibited significantly elevated fasting blood glucose, fasting insulin, and HOMA-IR index levels at early, mid, and late pregnancy stages ( P  < .05). These findings indicate a progressive worsening of insulin resistance throughout pregnancy in the PCOS-IVF/ICSI group, likely linked to the underlying metabolic abnormalities characteristic of PCOS (see Table 3 ). Metabolic changes during different stages of pregnancy in the 2 groups [ x ¯ ± s , M (Q 25 , Q 75 )]. FINS = fasting insulin, FPG = fasting plasma glucose, HOMA-IR = homeostasis model assessment of insulin resistance. Compared to the natural pregnancy group, the PCOS-IVF/ICSI group exhibited significantly higher levels of inflammatory markers (CRP, IL-2, IL-4, IL-6, IL-8, IL-12, IL-18) at various pregnancy stages (early, mid, and late). In the early pregnancy stage, CRP, IL-2, IL-4, IL-6, and IL-18 levels were notably higher in the IVF/ICSI group ( P  < .05), whereas no significant differences were observed for IL-8 and IL-12 ( P  = .114 and P  = .319, respectively). During mid-pregnancy, the IVF/ICSI group showed elevated levels of CRP, IL-2, IL-4, IL-6, IL-8, and IL-18 ( P  < .05), but IL-12 did not achieve statistical significance ( P  = .224). In the late stage of pregnancy, significantly higher levels of CRP, IL-2, IL-4, IL-6, IL-8, IL-12, and IL-18 were observed in the IVF/ICSI group ( P  < .05). These findings suggest that inflammatory responses are notably more pronounced in PCOS patients undergoing IVF/ICSI treatment throughout pregnancy, particularly in markers such as CRP, IL-2, IL-4, IL-6, and IL-18 (see Table 4 ). Changes in inflammatory markers during different stages of pregnancy in the 2 groups [ x ¯ ± s , M (Q 25 , Q 75 )]. CRP = C-reactive protein. PCOS patients undergoing IVF/ICSI treatment had significantly higher rates of miscarriage and pregnancy complications compared to the natural pregnancy group ( P  < .05). However, no significant differences were found in the preterm birth rates between the 2 groups ( P  = .12). These findings indicate that IVF/ICSI treatment could potentially elevate the risk of miscarriage and other pregnancy complications in PCOS patients (see Table 5 ). Comparison of pregnancy outcomes between the 2 groups [n (%)]. The neonatal birth weight, 1-minute Apgar score, and 5-minute Apgar score were significantly lower in the PCOS-IVF/ICSI group compared to the natural pregnancy group ( P  < .05). These results indicate that infants born to women undergoing IVF/ICSI treatment tend to have lower birth weight and lower initial Apgar scores compared to those born through natural conception (see Table 6 ). Comparison of birth indicators between the 2 groups.

Metabolic abnormalities and insulin resistance are key factors influencing pregnancy outcomes in PCOS patients, a group typically at higher risk for pregnancy complications. [ 21 ] Although IVF/ICSI offers an opportunity for pregnancy in PCOS patients, there remains a lack of systematic research on the changes in metabolism, inflammation, and the associations between these factors and pregnancy complications in this population after IVF/ICSI treatment. [ 22 , 23 ] This study aims to explore the metabolic/inflammatory status changes during pregnancy in PCOS-IVF/ICSI patients and analyze the relationship between these changes and the occurrence of pregnancy complications, in order to provide more scientifically grounded references for clinical interventions and personalized treatments. The results indicate that the PCOS-IVF/ICSI group displayed significant metabolic disturbances during pregnancy, characterized by markedly elevated fasting blood glucose and insulin levels, as well as a sustained increase in insulin resistance (HOMA-IR index) across all pregnancy stages. These findings align with the typical metabolic abnormalities seen in PCOS patients and suggest that IVF/ICSI treatment may exacerbate these disturbances. [ 24 ] Such metabolic impairments could not only compromise maternal health but also contribute to pregnancy complications by influencing placental function and fetal development. Moreover, the inflammatory response in the PCOS-IVF/ICSI group was notably more pronounced compared to the natural pregnancy group, with higher levels of inflammatory markers like CRP, IL-2, IL-4, and IL-6. This heightened inflammation may play a crucial role in pregnancy outcomes in PCOS patients. [ 25 ] The activation of inflammation could potentially lead to complications such as gestational hypertension and miscarriage, while also affecting fetal growth and development. [ 26 ] Further analysis revealed that the incidence of pregnancy complications in the PCOS-IVF/ICSI group was significantly higher than in the natural pregnancy group, particularly with higher rates of miscarriage and gestational hypertension. This finding is consistent with existing research, which has indicated that PCOS patients, due to insulin resistance and metabolic disturbances, are more susceptible to complications such as hypertension and gestational diabetes during pregnancy. [ 27 ] Additionally, we observed that newborns in the PCOS-IVF/ICSI group had lower birth weights and Apgar scores compared to the natural pregnancy group. This further supports the potential adverse effects of metabolic abnormalities on fetal development and neonatal status. Compared to the natural pregnancy group, the fetuses in the PCOS-IVF/ICSI group may face a higher developmental risk. Although all pregnancies ultimately resulted in successful outcomes, the long-term impact of metabolic disturbances should not be overlooked. [ 28 ] In comparison to existing studies, this research provides a new perspective. While numerous studies have examined the direct impact of metabolic abnormalities in PCOS patients on pregnancy outcomes, [ 29 ] there is limited exploration of the relationship between metabolic status during IVF/ICSI treatment and pregnancy complications. This study is the first to systematically analyze the metabolic changes, inflammatory responses, and their potential impact on neonatal outcomes in PCOS-IVF/ICSI patients, hoping to offer new insights for clinical treatment and management of PCOS patients. We believe that while IVF/ICSI has made significant strides in addressing infertility in PCOS patients, the metabolic challenges these patients face during pregnancy, and their potential effects on pregnancy outcomes, warrant further attention and research. However, several aspects of this study require further exploration. First, due to the small sample size and the single-center design, there may be selection bias, and the generalizability of the results needs to be verified in larger, multicenter studies. Second, while the study focuses on the metabolic changes in PCOS patients, the underlying mechanisms, such as the biological basis of insulin resistance and the relationship between inflammation and placental function, need further investigation. Additionally, while we analyzed pregnancy complications and neonatal outcomes, the long-term effects on maternal health were not fully assessed. Future studies should also examine the metabolic and inflammatory changes in PCOS patients during the later stages of pregnancy and postpartum to provide a more comprehensive understanding. Based on the findings of this study, future research could further expand in the following areas. First, expanding the sample size and conducting multicenter studies will help validate our conclusions and explore the metabolic changes and their impact on pregnancy outcomes in PCOS-IVF/ICSI patients across different regions and contexts. Second, in-depth research into how metabolic abnormalities and inflammation affect fetal development through the placenta will provide stronger theoretical support for clinical interventions. Furthermore, future studies should focus on interventions for pregnancy management in PCOS patients, especially early diagnosis and management of insulin resistance, as well as inflammation control, to reduce the incidence of pregnancy complications and improve maternal and neonatal health. To sum up, this study offers valuable insights into the management of pregnancy in PCOS patients undergoing IVF/ICSI treatment. However, additional research is necessary to explore the connection between metabolic disturbances and pregnancy outcomes more comprehensively. The ultimate aim is to develop more targeted intervention strategies in clinical practice to enhance maternal and neonatal health.