Systemic inflammation indices measured shortly before delivery are not associated with preterm birth in pregnant women with endometriosis

The Ethical Committee of Wuxi Maternity and Child Health Care Hospital, Jiangnan University, Wuxi, China approved this retrospective study (approval numbers: 2024- 06–1024-54). The Ethical Committee waived the patient’s consent form due to the data collected from the hospital database. This study was performed in accordance with the Medical Association Declaration of Helsinki. Between January 2022 and December 2024, a total of 31,687 women delivered at our hospital. Among them, 75 women were incidentally identified with endometriosis during cesarean section and included in this study. The clinical symptoms of endometriosis were not recorded. The diagnosis of endometriosis was confirmed histologically by the presence of endometrial glands, endometrial stroma, or hemosiderin-laden macrophages in surgically excised tissue. None of these women had a history of chronic inflammatory diseases, such as rheumatoid arthritis and other autoimmune diseases. Of these 75 pregnant women with endometriosis, 32 (42.6%) were incidentally identified with endometriomas, and 43 (57.4%) were incidentally identified with peritoneal endometriosis. Women who delivered vaginally were not included, as medical history records (including endometriosis status) were incomplete or not available. During the same study period, 31,687 delivered at our hospital, of whom 14,079 had cesarean sections. Of these, 1601 (11.4%) had a preterm birth after excluding the 75 pregnant women with endometriosis. Preterm birth was defined as a spontaneously delivered liveborn before 37 weeks of gestation. Among the 75 women incidentally identified with endometriosis, two pregnancies were conceived by in vitro fertilization (IVF), none of the women was a smoker, and one woman had a previous preterm birth. For women with endometriosis, data from peripheral blood tests performed within 5 days before delivery were retrospectively collected, with a median interval of 2 days (interquartile range, IQR: 1 day) between sampling and delivery, along with maternal age, pre-pregnancy body mass index (BMI), pregnancy history (gravidity and parity), and pregnancy outcomes from the hospital’s electronic database. Results of group B Streptococcus (GBS) testing at 35 weeks of gestation were also collected. Additionally, peripheral blood tests performed within 5 days before delivery were also randomly collected from 177 women with cesarean section and no complications during the same study period for comparison. GDM was defined as peripheral blood glucose levels greater than 5.1mmol/L at 0 h of 75 g-oral glucose tolerance test (OGTT, fasting glucose levels), and/or greater than 10.0 mmol/L at 1 h of 75 g-OGTT, and/or greater than 8.5 mmol/L at 2 h of 75 g-OGTT, between 24 and 28 weeks of gestational age, following the IADPSG guideline [ 21 ]. Preeclampsia was defined as when maternal systolic blood pressure was ≥ 140 mmHg and/or diastolic blood pressure was ≥ 90 mmHg on two occasions between 6 h with or without proteinuria (> 300 mg in 24 h), and/or impaired liver function, and/or lower platelet count, after 20 weeks of gestation, followed by international guidelines [ 22 ]. The systemic immune-inflammation index (SII) was calculated as platelet count × neutrophil/lymphocyte count (10^9/L). The systemic inflammation response index (SIRI) was calculated by neutrophil count × monocyte count/lymphocyte count (10^9/L). The neutrophil-to-lymphocyte ratio (NLR) was calculated by neutrophil/lymphocyte count (10^9/L). Pan-immune inflammation value (PIV) was calculated by neutrophil count × monocyte count × platelet count/lymphocyte count (10^9/L). A sensitivity analysis (detectable-effect analysis) was performed to assess the study power using an online power calculation ( https://www.stat.ubc.ca/~rollin/stats/ssize/ ). Data in Tables 1 and 2 were expressed as mean and standard deviation (SD), or number and percentage. Normality of data was tested using GraphPad Prism (version 10). Because outliers were present, potentially skewing the mean, data in Tables 3 and 4 were expressed as median and 95% confidence interval (CI). Median and interquartile range, and the Mann-Whitney U test for non-parametric data, or one-way ANOVA (non-parametric tests) were performed for statistical analysis using Prism GraphPad (version 10). Given that the number of preterm births was small ( n  = 15), multivariable adjustment was restricted a priori to two key covariates, parity and BMI, which are known to influence both maternal characteristics and the risk of preterm delivery. This strategy was chosen to minimize model overfitting while addressing potential confounding. A p-value  < 0.05 was defined as statistically significant. Table 1 Demographics of the study cohort ( n  = 75) Age at diagnosis (years, mean/SD) 32 ± 4 BMI (Kg/m 2 , mean/SD) 22.64 ± 3.15 Gravidity (n, %)  1 34/75 (45%)  ≥ 2 41/75 (55%) Parity (excluding current pregnancy) (n, %)  0 49/75 (65%)  ≥ 1 26/75 (35%) Complications of pregnancy (n, %) Preterm birth 15 (20%) GDM 22 (29%) Preeclampsia 5 (6.7%) Gravidity includes all pregnancies, including the current pregnancy. Parity refers to the number of previous pregnancies reaching ≥ 20 weeks of gestation and excludes the current pregnancy. Percentages are based on the total study cohort ( n  = 75) Table 2 Comparison of pregnancy complications between women with endometriosis and the general obstetric population who delivered by Cesarean section at our hospital Women with endometriosis ( n  = 75) General obstetric populations without a diagnosis of endometriosis who had a cesarean section ( n  = 14,079) P value (Chi-square test) Preterm birth (n, %) 15 (20%) 1601 (11.4%) 0.019 GDM (n, %) 22 (29%) 3343 (24%) 0.257 Preeclampsia (n, %) 5 (6.7) 793 (5.6%) Not performed. Percentages are based on the total study cohorts ( n  = 75 or n  = 14,079). The analysis for the incidence of preeclampsia was not performed due to the small number of cases of preeclampsia in the study cohort, and was only for descriptive purposes 12 Table 3 The comparison of systemic inflammation indices between pregnant women diagnosed with endometriosis who had preterm birth and those who had term delivery Preterm birth ( n  = 15) Without preterm birth ( n  = 60) P value Whole white cell counts (10^9/L, median/95% CI) 8.75 (8.22, 10.69) 8.01 (6.33, 9.78) 0.091 Neutrophil (10^9/L, median/95% CI) 7.2 (5.83, 8.05) 5.8 (5.34, 6.47) 0.107 Monocyte (10^9/L, median/95% CI) 0.53 (0.38, 0.73) 0.49 (0.45, 0.56) 0.706 Lymphocyte (10^9/L, median/95% CI) 1.6 (1.14, 2.23) 1.4 (1.23, 1.66) 0.311 Platelet (10^9/L, median/95% CI) 169 (127, 205) 192 (177, 205) 0.336 Table 4. The comparison of systemic inflammation indices between pregnant women diagnosed with endometriosis who had preterm birth and those who had term delivery Preterm birth ( n  = 15) Without preterm birth ( n  = 60) Healthy pregnancies with cesarean section ( n  = 177) P value (one-way ANOVA) SII (mean/95% CI) 898 (629, 1168) 871 (759, 984) 915 (806, 1025) 0.691 SIRI (mean/95% CI) 2.27 (1.89, 3.58) 2.41 (2.01, 2.82) 2.67 (2.39, 2.95) 0.333 NLR (mean/95% CI) 5.32 (3.44, 7.19) 4.66 (4.04, 5.28) 4.52 (3.91, 5.14) 0.535 PIV (mean/95% CI) 482 (323, 642) 462 (377, 547) 555 (498, 613) 0.100 All systemic inflammation indices are calculated from complete blood count parameters and are presented as unitless values Demographics of the study cohort ( n  = 75) Gravidity includes all pregnancies, including the current pregnancy. Parity refers to the number of previous pregnancies reaching ≥ 20 weeks of gestation and excludes the current pregnancy. Percentages are based on the total study cohort ( n  = 75) Comparison of pregnancy complications between women with endometriosis and the general obstetric population who delivered by Cesarean section at our hospital Percentages are based on the total study cohorts ( n  = 75 or n  = 14,079). The analysis for the incidence of preeclampsia was not performed due to the small number of cases of preeclampsia in the study cohort, and was only for descriptive purposes 12 The comparison of systemic inflammation indices between pregnant women diagnosed with endometriosis who had preterm birth and those who had term delivery The comparison of systemic inflammation indices between pregnant women diagnosed with endometriosis who had preterm birth and those who had term delivery All systemic inflammation indices are calculated from complete blood count parameters and are presented as unitless values

The clinical demographics and pregnancy outcomes for women incidentally identified with endometriosis are summarised in Table 1 . The mean maternal age at delivery was 32 ± 4 years. Among the 75 women with endometriosis, 49 (65%) were primiparous. Preterm birth occurred in 15 women (20%), including two who had a very preterm birth (< 32 weeks of gestation). In addition, 22 women (29%) were diagnosed with GDM, and 5 women (6.7%) were diagnosed with preeclampsia. There was no difference in BMI between women incidentally identified with endometriosis who had preterm birth and those who delivered at term (22.15 ± 2.8 vs. 22.72 ± 3.2 Kg/m 2 , p  = 0.653). We then compared the incidence of pregnancy complications between women incidentally identified with endometriosis ( n  = 75) and the general obstetric population who underwent cesarean sections at our hospital during the same period ( n  = 14,079) (Table 2 ). The incidence of preterm birth was significantly higher in women incidentally identified with endometriosis than in the general obstetric population with cesarean Sect. (20% vs. 11.4%, p  = 0.019). However, the incidence of GDM did not differ significantly between the two groups ( p  = 0.257). To explore the potential mechanisms underlying the increased risk of developing preterm birth, we compared peripheral blood cell counts measured within 5 days before delivery between women incidentally identified with endometriosis who had preterm birth and those who had term delivery. As shown in Table 3; Fig. 1 , there were no significant differences in total white blood cell count, neutrophils, monocytes, lymphocytes, or platelets between the two groups (all p  > 0.091). Likewise, systemic inflammation indices, including SII, SIRI, NLR, and PIV, did not differ significantly between the two groups (Table 3 ; Fig. 2 , all p  > 0.333). In a sensitivity analysis, with 15 pregnancies with preterm birth among 75 women incidentally identified with endometriosis, our study had approximately 80% power to detect odds ratios of ≥ 2.24 per 1-standard deviation (SD) increase in a systemic inflammation index, suggesting smaller associations could not be reliably excluded. We further compared the systemic inflammation indices across three groups: women with endometriosis and preterm birth, women with endometriosis and term delivery, and women without complications undergoing cesarean section. There were no significant differences in systemic inflammation indices among the three groups (Table 3 ; Fig. 2 , all p  > 0.1002, One-way ANOVA non-parametric tests). Fig. 1 The comparison of complete counts ( A while blood cells, neutrophil, monocytes, and lymphocytes; B platelets) between preterm and term delivery in women with endometriosis Fig. 2 The comparison of SII, SIRI, NLR, and PPIV among women with and without endometriosis The comparison of complete counts ( A while blood cells, neutrophil, monocytes, and lymphocytes; B platelets) between preterm and term delivery in women with endometriosis The comparison of SII, SIRI, NLR, and PPIV among women with and without endometriosis We also evaluated whether the subtypes of endometriosis are associated with preterm birth or systemic inflammation indices. Among the 15 women with endometriosis and preterm birth, seven (46%) were diagnosed with endometriomas, and the remaining eight (54%) were diagnosed with peritoneal endometriosis. There were no statistical differences in systemic inflammation indices between women with endometriomas who had preterm birth and those who had term delivery (all p  > 0.291). Additionally, there were also no statistical differences in systemic inflammation indices between women with peritoneal endometriosis who had preterm birth and those who did not (all p  > 0.194). In the multivariable logistic regression model including parity and BMI, none of the covariates were significantly associated with preterm birth. For example, SIRI was associated with lower odds of preterm birth (OR 0.26, 95% CI 0.03–2.23, p  = 0.22), while NLR showed a non-significant trend towards higher odds (OR 2.41, 95% CI 0.73–7.99, p  = 0.15). Other variables showed odds ratios close to 1 with confidence intervals crossing unity. Finally, for women with endometriosis who delivered at term ( n  = 60), 5 (8.3%) tested positive for Group B Streptococcus (GBS). Among women with endometriosis who had preterm birth ( n  = 15), eight women tested negative for GBS, and seven women did not perform the GBS test before delivery.

In this retrospective study, we confirmed a higher incidence of preterm birth among women incidentally identified with endometriosis. However, systemic inflammatory indices did not differ significantly between those women with and without preterm birth, after adjusting for parity and BMI. Additionally, women with preterm birth tested negative for GBS, where data were available. In China, the average incidence of preterm birth is reported to be 6.09%, with a range of 5.4% to 7.04% [ 23 ]. Consistent with recent evidence identifying endometriosis as a risk factor for preterm birth [ 5 – 8 ], our study found a significantly higher incidence in women incidentally identified with endometriosis compared to the general obstetric population with cesarean Sect. (20% vs. 11.4%). However, differences in maternal characteristics and indications for cesarean delivery may still limit direct comparability. Endometriosis is characterized by elevated levels of pro-inflammatory cytokines and altered immune responses in ectopic endometrial lesions, which may affect the uterine environment during pregnancy and contribute to preterm birth [ 24 ]. Previous studies have reported increased systemic inflammatory indices at the time of endometriosis diagnosis [ 18 ], leading to the hypothesis that systemic inflammation may contribute to preterm birth. However, in our study, no significant differences were observed in peripheral white blood cell, neutrophil, monocyte, or lymphocyte counts between women incidentally identified with endometriosis who experienced preterm birth and those who delivered at term. Similarly, systemic inflammatory indices, including SII, SIRI, NLR, and PIV, were also not significantly different between the two groups. These findings suggest that systemic inflammation, as assessed by peripheral blood counts shortly before delivery, may not be associated with preterm birth in women with endometriosis. Although preterm birth is often considered an inflammation-related complication, our data indicate that systemic inflammation indices alone may not capture relevant inflammatory changes in this context. Furthermore, while GBS infection is a recognized risk factor for preterm birth [ 25 ], none of the eight women with preterm birth in our study tested positive for GBS, where data were available, suggesting it may not be a major contributing factor to preterm birth in our cohort. Chronic inflammation and associated alterations in the uterine and placental environment, such as imbalances in pro- and anti-inflammatory signaling, remain potential mechanisms underlying preterm birth in endometriosis. In addition to the potential limitation of statistical power on analysis, our results showing the lack of association with systemic inflammatory indices and preterm birth do not exclude the role of inflammation entirely. Rather, they may also suggest that systemic inflammation indices may not reflect localized immune activity at the maternal-foetal interface. Endometriosis is well-known to alter the uterine microenvironment, potentially affecting cytokine expression, immune cell profiles (such as uterine NK cells and macrophages), and decidualization processes [ 24 ]. These local immune environmental changes may contribute to the development of preterm births in women with endometriosis. Therefore, future studies with a large sample size should better focus on characterizing local inflammatory pathways and immune cell dynamics in the endometrium or placenta to understand the mechanistic link between endometriosis and preterm birth. This study has several limitations. First, the number of women incidentally identified with endometriosis who had preterm birth was relatively small, potentially limiting statistical power. Our sensitivity analysis indicates that only odds ratios ≥ 2.2 per 1 SD increase in systemic inflammation indices could be reliably detected, suggesting that subtler associations between systemic inflammation indices and preterm birth in our study cohort cannot be ruled out. The potential reasons for the lower number of women with endometriosis were (1) endometriosis was incidentally identified during a cesarean section and then confirmed by histology. It resulted in a certain number of women with endometriosis who had vagianl delivery not being diagnosed; (2) Pregnancy can temporarily improve the symptoms of endometriosis, such as pelvic pain, partially due to the suppression of menstruation and the reduction of new lesion formation [ 26 ]. It can result in many asymptomatic women going undiagnosed. This also may cause a selection bias, and our findings need to be further confirmed in future studies. Second, the time point for analysis of systemic inflammation indices was only performed within five days before delivery, which may not etiologically reflect systemic inflammation conditions across gestation. This is because multiple factors, such as labour stress, the use of steroids, and potential infection, could influence the systemic inflammation indices. The severity of endometriosis may also influence the systemic inflammation indices. However, these data were not available. Future studies to investigate the temporal changes in systemic inflammation in those women with endometriosis should be conducted. Third, endometriosis was incidentally identified during cesarean section and confirmed histologically, which excluded women who delivered vaginally and may have led to underdiagnosis of asymptomatic cases. Fourth, due to the small sample size, confounders, such as IVF, that may be associated with preterm birth, were not included. We also do not have placental histology data. The GBS test was not performed for all women with preterm birth. Fifth, this was a retrospective study, which may induce information bias, selection bias, and confounding. Sixth, due to the small number of preterms, the multivariable model was limited to parity and BMI. While this approach reduces the risk of model overfitting, it may not fully account for residual confounding by other maternal characteristics. Finally, we did not assess specific subtypes of lymphocytes or other immune cell subsets that may be relevant to the pathogenesis of preterm birth. In this study, we classified endometriosis into endometriomas and peritoneal endometriosis. It is common that endometriomas represent a more severe and advanced stage of endometriosis compared to peritoneal endometriosis. This could result in a difference in systemic inflammation indices between the two subtypes. Analysis with a small sample size, we found that there were no statistical differences in systemic inflammation indices between women with different subtypes of endometriosis. Although we did not investigate the potential pathway linking endometriosis-related inflammation to preterm birth in this study. However, ongoing research in our group is examining immune cell changes in local lesions of endometriosis, including the underlying mechanisms, such as whether chemokine decoy receptor D6 and NLRP3 [ 27 ], toll-like receptors (TLR) [ 28 ], and progesterone receptor imbalance [ 29 ] are associated with an increased risk of preterm birth in women with endometriosis [ 30 ]. Additionally, longitudinal measurements of multiple inflammatory markers, including inflammatory cytokines, during pregnancy, and assessment of placental immune responses are necessary. Increasing evidence suggests the role of systemic inflammation indices in the prediction of complications of pregnancy. However, long-term prospective studies are needed to confirm their role in routine clinical practice as routine clinical screening tools, including diagnostic, prognostic, predictive, and holistic value in the future. In conclusion, our study demonstrates that systemic inflammation indices, as measured shortly before delivery, did not have an association with preterm birth in women incidentally identified with endometriosis. However, localized uterine inflammation and systemic inflammation changes earlier in gestation were not evaluated. Given the small sample size and lack of temporal changes in systemic inflammation indices, our findings should be cautiously interpreted and considered hypothesis-generating. Further studies with larger cohorts and longitudinal assessment of systemic and local inflammation are required to confirm our findings.

Endometriosis, characterized by the presence of endometrial-like tissue outside the uterus, affects approximately 10 to 15% of women of reproductive age [ 1 ]. It is a chronic inflammatory condition typically associated with pelvic pain and menorrhagia [ 2 ]. Despite its prevalence, endometriosis is often under-recognized, and many cases remain undiagnosed or misdiagnosed due to its varied and non-specific symptoms. This resulted in a diagnostic delay averaging 7 to 10 years [ 3 ]. Such delays can significantly affect women’s physical and psychological well-being as well as their reproductive outcomes. Inflammation is a recognized contributor to pregnancy complications such as miscarriage, preeclampsia, and preterm birth [ 4 ]. Recent evidence has indicated that women with endometriosis have a significantly increased risk of preterm birth, placental abruption, and preeclampsia [ 5 – 8 ]. However, the underlying mechanisms remain poorly understood. Endometriosis, a condition of chronic inflammation, is characterized by elevated levels of pro-inflammatory cytokines (e.g., interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α)), and altered immune cell activity in the peritoneal and endometrial environments [ 9 ], which may contribute to an abnormal uterine immune milieu that predisposes to adverse pregnancy outcomes. Recently, systemic inflammation indices, like the systemic immune-inflammation index (SII), the systemic inflammation response index (SIRI), the neutrophil to lymphocyte ratio (NLR), and the pan-immune inflammation value (PIV), are derived from routine peripheral blood counts and increasingly used to assess systemic inflammatory status in various obstetric and gynaecological conditions, such as preeclampsia [ 4 , 10 – 13 ], cesarean scar pregnancy (CSP) [ 14 ], gestational diabetes mellitus (GDM), andmiscarriage [ 15 ], as early predictive biomarkers. While prospective studies are needed to confirm their role in the prediction of pregnancy complications. Among these, NLR is widely recognized as a systemic marker of inflammation in response to various infectious and non-infectious diseases [ 16 , 17 ], as neutrophil counts typically reflect the body’s inflammation response. Our previous research also showed elevated systemic inflammation indices in women with endometriosis [ 18 ], supporting the hypothesis that the chronic and local inflammation associated with endometriosis may elicit systemic immune responses. It is well known that inflammation is a major factor in causing preterm birth, with most preterm births linked to inflammatory processes triggered by infection, uterine stress, or other factors [ 19 ]. In fact, elevated NLR has been associated with spontaneous preterm birth in the general obstetric population [ 20 ]. Thus, it is reasonable to raise the question that systemic inflammation may mediate the increased risk of preterm birth in women with endometriosis. Based on this background, we hypothesize that systemic inflammation processes play a role in the pathway linking endometriosis to preterm birth, and that systemic inflammation indices are associated with preterm birth in pregnant women with endometriosis. The aim of this study was to investigate the association between systemic inflammation indices and preterm birth in women with endometriosis who delivered by cesarean section in a three-year period. Clarifying this relationship may help identify biomarkers for early risk stratification and improve the management of pregnancies complicated by endometriosis.