Increased risk of postpartum hemorrhage in women with endometriosis and adenomyosis: a prospective cohort study

Introduction: A growing body of evidence suggests that women with endometriosis and adenomyosis are at an increased risk of complications during pregnancy and childbirth. Many of these complications are associated with increased blood loss. This study aims to evaluate and quantify the risk of postpartum hemorrhage in women with these conditions.

We conducted a prospective cohort study of women with endometriosis and adenomyosis, analyzing their peripartal blood loss. Matching was performed for age and mode of conception. We defined postpartum hemorrhage as blood loss of ≥1000 mL, regardless of mode of delivery, according to the ACOG definition.

In our study, we examined 82 women with endometriosis and adenomyosis and 82 women without. A total of 11 women in the study group experienced postpartum hemorrhage, which is significantly higher than the rate in the control group (13% vs 1%). The unadjusted odds ratio for postpartum hemorrhage in the EM group was 8.74 (CI:2.01-82.00). The p-value was 0.002. In the adjusted analysis, participants with EM had a significantly increased risk of PPH compared to those without EM (OR:7.56, 95% CI:1.39-83.70, p=0.018), while gravidity and parity had no significant effect on the risk of PPH in our cohort.

Our study found that women with endometriosis and adenomyosis were significantly more likely to experience postpartum hemorrhage than women without these conditions. These findings should be interpreted with caution, given the small sample size and wide confidence intervals. However, they suggest that women with endometriosis and adenomyosis may benefit from giving birth at hospitals with experience in managing postpartum hemorrhage.

Endometriosis (EM) is a common gynecological condition, affecting approximately one in five premenopausal women (). Concomitant adenomyosis (AM) is present in up to 90% of cases (). The influence of EM and AM on pregnancy and its outcome remains to be elucidated, but a growing body of evidence suggests that pregnant women with EM and AM may experience complications during late pregnancy and childbirth (). In early pregnancy, EM has been linked to an increased risk of miscarriage and ectopic pregnancy. Later in pregnancy, an increased risk of preterm birth and premature rupture of the membranes, in addition to an increased risk of having a low-birthweight infant or developing hypertensive pregnancy disorders (including preeclampsia), has been described. Women with EM/AM are also at an increased risk of placental disorders, including placenta previa (PP) (–). There is evidence that women with EM may experience increased blood loss during cesarean delivery (CD) (). An indirect marker of postpartum hemorrhage (PPH), namely, an increased rate of postpartum hysterectomy, has also been observed in women with EM (). However, evidence on PPH in women with EM/AM is limited and contradictory (). PPH is the leading cause of maternal morbidity and mortality (). To improve clinical management, risk stratification is crucial. Therefore, we conducted the following prospective cohort study to assess the risk of PPH in women with EM/AM compared to those without the diagnosis. We hypothesized that women with EM and AM have a significantly increased risk of postpartum hemorrhage compared with women without these conditions.

The study methods are described in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (). Study design This prospective cohort study involved following a group of pregnant women with EM/AM during childbirth and comparing them with a control group without these conditions. We present an exploratory secondary analysis from an ongoing parent study. Peripartum blood loss was defined as a secondary outcome in the study protocol. The study received ethical approval from the Charité Ethics Committee (EA1/294/21). Cohort From January 2022, pregnant women with a history of EM or AM were recruited at the Department of Obstetrics, Charité – Universitätsmedizin Berlin. We followed the definition of EM proposed by Keckstein et al. as an inflammatory disease characterized by the presence of endometrium-like epithelium, with or without accompanying stromal cells outside the endometrium and myometrium. AM was defined accordingly as the presence of ectopic endometrial tissue with glands and stromal cells infiltrating the myometrium (). EM was classified using the revised American Society for Reproductive Medicine (rASRM) score for pelvic EM (). The #ENZIAN classification was used to describe all forms of EM and AM, with special regard to deep infiltrating EM (DIE) (). The diagnosis was self-reported. The implemented questionnaire was reviewed in a preliminary study by our group (). The questionnaires collected information on patients’ medical histories, and participants were motivated to present clinical records and surgery reports to substantiate self-reported data. Nevertheless, we acknowledge that self-reported data my lead to misclassification and may substantially affect the findings. Clinical data concerning pregnancy and childbirth were extracted from the clinical software ViewPoint, version 6. Inclusion criteria All participants were at least 18 years of age and able to give informed consent. They were included in the study before giving birth. Exclusion criteria Women with a history of cesarean delivery (CD) or other cavity-opening operations were excluded. The study excluded cases of multiple pregnancies, severe maternal diseases, and fetal malformations. Control group For each pregnant woman in the EM group, we found a matched individual based on age and mode of conception. The control pool consisted of all women without EM/AM who gave birth between 2019 and 2023 at Charité. From this pool, we randomly assigned one matching individual to each case. Measurement of blood loss We documented the cumulative blood loss during delivery. PPH was defined as blood loss of at least 1000 mL during childbirth, regardless of the mode of delivery, according to ACOG guidelines (14). Blood loss was assessed using routine clinical methods. In our clinic, a quantitative blood collection bag is used to objectively quantify patients’ blood loss. The bag is used when visual blood loss exceeds the “normal” limit. For vaginal and operative vaginal deliveries, it is applied when blood loss exceeds 250 mL. During a cesarean section, we use a surgical suction device. For extensive blood loss from various sources (e.g., the blood collection bag and surgical swabs), we use the gravity method. These measurement methods are standardized for all deliveries, and staff are trained in PPH management. Transfusion criteria are strict, and blood transfusion is only considered in symptomatic patients with a Hb<7 g/dL. Bias The Charité obstetrics department is a level one perinatal clinic and a tertiary care center. Accordingly, it treats more pregnant women with high-risk pregnancies than other centers. Although tools to measure blood loss are part of the clinical routine, estimates are prone to underestimation (15). We furthermore acknowledge that our clinical routine in estimating blood loss may introduce ascertainment bias. As the recruitment period for the control group overlaps but is not identical to that of the recruitment period of the EM group (2019–2023 vs. 2022–2024, respectively), a time-related bias is possible. Statistical methods We compared pregnancy histories between the study groups. For categorical outcomes, we used Pearson’s chi-square test (X2) when each group included at least five cases for the variable. If any group had fewer than five cases, Fisher’s exact test was applied, and odds ratios (ORs) and 95% confidence interval (CIs) were calculated. To compare parity and gravidity in the study groups, we performed a non-parametrical Wilcoxon-rank-sum-test (WRST). To assess the association between PPH and the exposure variables, we performed univariable and multivariable Firth’s penalized logistic regressions and calculated ORs with 95% CIs. The multivariable model included gravidity (primigravida vs. non-primigravida), parity (primipara vs. non-primipara), and fibroid and EM status (yes vs. no). To assess potential multicollinearity among the predictors (EM, parity, and gravidity), we calculated the variance inflation factor (VIF) and accepted values below a threshold of five. We further divided the study group by EM and fibroid statuses and performed an adjusted penalized logistic regression for each possible combination. To compare the absolute blood loss in the study groups, we performed the WRST, calculated interquartile ranges (IQR) and medians, and visualized the results in a boxplot. We further stratified PPH risk in women with EM by mode of delivery and calculated the risk for PPH for EM subgroups (AM, DIE, and AM+DIE). To compare hemoglobin (Hb) values, we used a two-sided t-test. All analyses were conducted using R (version 4.4.1).

In our study, we included 82 women with EM and 82 women without EM. A total of 11 births in the EM group resulted in PPH (≥1000 mL blood loss), compared with 1 birth in the control group (13% vs. 1%) (Table 1). The odds ratio (OR) for PPH in the EM group was 12.55 (95% confidence interval (CI): 2.35–232.23). The p-value was 0.017. Table 1 | EM/AM status and PPH | Primigravida, n = 75 (%) | Non-primigravida, n = 89 (%) | Primipara, n = 115 (%) | Non-primipara, n = 49 (%) | |---|---|---|---|---| | EM | 44 (59) | 38 (43) | 68 (59) | 14 (29) | | No EM | 31 (41) | 47 (57) | 47 (41) | 35 (71) | | PPH (≥1000 ml) | 9 (12) | 3 (3) | 11 (10) | 1 (2) | Stratification of participants into primigravida and primipara vs. non- primigravida and non-primipara according to their EM status and the occurrence of PPH. Study group selection Applying the inclusion criteria, 138 patients were initially eligible for the EM group. During pre-evaluation telephone screening, we excluded 10 patients who planned delivery outside Charité, 8 patients who delivered before providing consent, 3 dropouts, 1 patient who had an induced abortion, 1 patient with a second-trimester abortion, 1 patient with a stillbirth, and 7 patients who met exclusion criteria. The remaining 107 participants completed questionnaires, which led to further exclusion of 13 patients who reported exclusion criteria. An additional 11 patients delivered outside Charité, and 1 patient completed the questionnaire but never handed in her consent. Finally, 82 participants with EM were included in the study (see Figure 1). Figure 1 Cohort description The median age of women at the time of delivery was 34 years in both groups, and 23 (28%) pregnancies in each group were achieved via IVF/ICSI. In the EM group, 43 (52%) women were primigravida compared with 31 (38%) in the control group. Primipara accounted for 68 (83%) in the EM group and 47 (57%) in the control group. In the EM group, 19 patients (23%) reported fibroids, whereas 3 patients (4%) in the control group had diagnosed fibroids. In the EM group, 1 patient was obese (body mass index (BMI) over 30) (1%) compared with 9 patients in the control group (11%). In the EM group, labor was induced in 19 cases (23%) compared with 21 labor inductions in the control group (26%) (see Table 2). Table 2 | Characteristics | EM | Controls | |---|---|---| | Age (min.–max.) | 34 y (21–47 y) | 34 y (21–47 y) | | n = 82 (%) | n = 82 (%) | | | IVF/ICSI | 23 (28) | 23 (28) | | Primigravida | 43 (52) | 31 (38) | | Primipara | 68 (83) | 47 (57) | | Fibroids | 19 (23) | 3 (4) | | Obesity (BMI > 30) | 1 (1) | 9 (11) | | Labor induction | 19 (23) | 21 (26) | Characteristics of study participants in the cohort and control groups according to risk factors for PPH. When comparing the distribution of the number of pregnancies and births between the study groups, statistically significant differences were observed (Gravida: p = 0.007; Para: p < 0.001). To account for these differences, we further included both variables as covariates in the adjusted analysis (see Table 3). Table 3 | Pregnancies and Births | EM, median (min.–max.) | Controls, median (min.–max.) | P-value | |---|---|---|---| | Gravida | 1 (1 – 7) | 2 (1 – 8) | 0.007* | | Para | 1 (1 – 2) | 1 (1 – 6) | <0.001* | Absolute number of pregnancies and births in cohort and control groups. *Asymptotic significance (Wilcoxon rank sum test). Women with EM and AM A total of 67 participants with EM had already undergone surgery due to their diagnosis prior to the index pregnancy (82%). Only 25 participants stated that they were connected to an EM center (30%). A total of 34 participants reported DIE (41%), and 38 participants declared that they were affected by AM (46%). In all, 45 pregnant women with EM provided a classification according to rASRM, and 56 according to #ENIZIAN () (see Table 4). Table 4 | Classification | n = 82 (%) | |---|---| | DIE | 34 (41) | | AM | 38 (46) | | #ENZIAN | n = 56 (%) | | Peritoneum | 31 (53) | | Endometrioma | 23 (41) | | DIE | 20 (36) | | AM | 23 (41) | | rASRM | n = 45 (%) | | Stadium I | 19 (42) | | Stadium II | 9 (20) | | Stadium III | 5 (11) | | Stadium IV | 12 (27) | | Without classification | 15 (18) | EM classification of participants according to rASRM and #ENZIAN. Previous pregnancies Seven participants in the EM group had an ectopic pregnancy compared to one participant in the control group (18% vs. 2%, OR: 10.37, 95% CI:1.24–486.09, p = 0.020). There was one stillbirth in the EM group (3%). A miscarriage was reported by 23 participants in the EM group and 25 in the control group (58% vs. 49%, X2: 0.35, p = 0.553), and three pregnant women with EM reported a history of termination of pregnancy (TOP) compared to five in the control group (8% vs. 10%, p = 1.000) (see Table 5). Table 5 | Pregnancy outcome | EM, n = 40 (%) | Controls, n = 51 (%) | OR/X2 | 95%CI | P-value | |---|---|---|---|---|---| | Ectopic pregnancy | 7 (18) | 1 (2) | OR: 10.37 | 1.24 – 486.09 | 0.020* | | Intrauterine death | 1 (3) | – | – | – | – | | Miscarriage | 23 (58) | 25 (49) | X2: 0.35 | – | 0.553 | | Termination of pregnancy | 3 (8) | 5 (10) | OR: 0.75 | 0.11 – 4.14 | 1 | | n. s. | – | 4 (8) | - | – | – | Comparison of previous pregnancies in the cohort and control groups. Mode of delivery In all, 35 women with EM and 55 without gave birth spontaneously (43% vs. 67%). A total of 14 participants from the EM group and 6 from the control group gave birth by vacuum extraction (VE) (17% vs. 7%). A CD was performed in 33 pregnant women with EM and 21 pregnant women from the control group (40% vs. 26%), including 13 vs. 8 primary (16% vs. 10%) and 20 vs. 13 emergency CDs (24% vs. 16%). To compare outcomes within birth mode groups, we stratified the analysis by birth mode (see Table 6). Table 6 | Mode of birth | OR (EM vs. no EM) | 95% CI | P-value | |---|---|---|---| | Vaginal birth | 4.74 | 0.25–699.71 | 0.303 | | Vacuum extraction | 1.67 | 0.08–255.90 | 0.755 | | Primary CD | 2.37 | 0.34–27.51 | 0.399 | | Emergency CD | 9.58 | 0.94–1301.59 | 0.058 | Risk for PPH stratified by birth mode. Placental site distribution in women with PPH Of all 82 participants with EM, 35 had a placenta located at the posterior uterine wall (43%), 33 had a placenta located at the anterior uterine wall (40%), 7 had a fundal placenta (9%), and 7 had a placenta located at a side wall (9%). Of all 11 participants with EM and PPH, 8 had a placenta located at the posterior uterine wall (73%), 2 had a placenta at the anterior uterine wall (18%), and 1 had a fundal placenta (9%). In the control-group, one case of PPH was recorded with a placenta located at the anterior uterine wall. PPH in women with EM and AM In 11 women with EM, the cumulative blood loss during delivery was between 1000 mL and 1500 mL (13% vs. 1%, OR: 8.74, 95% CI: 2.01–82.00, p = 0.002). Adjusted analysis of risk factors As pregnancy and birth rates differed between groups, we performed Firth’s penalized logistic regression and adjusted for gravidity and parity. In the adjusted analysis, participants with EM had a significantly increased risk of PPH compared to those without EM (OR: 7.56, 95% CI: 1.39–83.70, p = 0.018). In contrast, primigravida-status was not a significant risk factor for PPH (OR: 0.56, 95% CI: 0.52–6.87, p = 0.369), nor was primipara status (OR: 1.05, 95% CI: 0.17–5.84, p = 0.953). As all VIF values were below 5, no concerning multicollinearity was detected in the model (see Table 7). Table 7 | Characteristics | PPH (% from group) | OR | 95% CI | P-value | |---|---|---|---|---| | EM, unadjusted, n=82 | 11 (13) | 8.74 | 2.01 – 82.00 | 0.002* | | EM, adjusted, n=82 | 11 (13) | 7.56 | 1.39 – 83.70 | 0.018* | | Primigravida, n=75 | 9 (12) | 0.56 | 0.52 – 6.87 | 0.369 | | Primipara, n=115 | 11 (10) | 1.05 | 0.17 – 5.84 | 0.953 | Risk for PPH adjusted for gravidity and parity. *significant at p < 0.05. As all VIF values were below 5, they indicated no concerning multicollinearity in the model. We further evaluated potential modification of the PPH risk by EM and fibroid status, using participants without EM or fibroids as the reference group. Due to the low number of events, these analyses are clearly exploratory and not robust. When EM and fibroids coexisted, participants appeared to have the highest risk for PPH, with an OR of 58.02 (95% CI: 6.06–7733.00, p < 0.001). Women with EM but no fibroids had a lower but still increased risk for PPH, with an OR of 17.91 (95% CI: 2.05–2367.00, p = 0.005) (see Table 8). To substantiate our data, future research is needed. Table 8 | EM and fibroid status | PPH (% from group) | OR | 95% CI | P-value | |---|---|---|---|---| | No EM nor fibroid, n=79 | 0 (0) | Reference | || | EM and fibroid, n=19 | 5 (26) | 58.02 | 6.06–7733.00 | <0.001* | | EM no fibroid, n=63 | 6 (19) | 17.91 | 2.05–2367.00 | 0.005* | Risk for PPH adjusted for fibroids. *significant at p < 0.05. Risk for PPH stratified by birth mode We further evaluated the effect of EM and AM on the risk of PPH, and stratified by birth mode. We acknowledge that the low event count may affect model stability. There was a non-significant tendency for a higher risk for PPH in emergency CDs in women with EM, with an OR of 9.58 (95% CI: 0.94–1301.59, p = 0.058). In all other birth modes, the ORs for EM were greater than 1 but showed no significance or trend: the OR for PPH with EM in vaginal births was 4.74 (95% CI: 0.25–699.7, p = 0.303), for VEs the OR was 1.67 (95% CI: 0.08–255.90, p = 0.755), and for primary CDs the OR was 2.37 (95% CI: 0.34–27.51, p = 0.399) (see Table 6). Risk of PPH by EM subgroup When divided into EM subgroups, no significant risk could be calculated for any subgroup. Within the 82 participants with EM, 20 had an AM diagnosis, 16 had DIE, 19 had both, and 27 had EM without AM or DIE. In the AM-only-group (n = 20), two cases of PPH occurred (10%). Compared to the EM-only group, the OR for PPH in the AM-only group was 0.95 (10% vs. 11%, 95% CI: 0.15–5.39, p = 0.950). In the DIE-only-group (n = 16), three cases of PPH were recorded (19%), and the OR was 1.82 (95% CI: 0.34–9.74, p = 0.473). In the group of participants with both AM and DIE (n = 19), three births were complicated by PPH (16%). Compared to the EM-only group, the OR was 1.49 (95% CI: 0.28–7.84, p = 0.630). None of these findings were statistically significant (see Table 9). Table 9 | EM, n = 82 | PPH (% from group) | OR | 95% CI | P-value | |---|---|---|---|---| | EM, only n = 27 | 3 (11) | Reference | || | AM, n = 20 | 2 (10) | 0.95 | 0.15–5.39 | 0.950 | | DIE, n = 16 | 3 (19) | 1.82 | 0.34–9.74 | 0.473 | | AM+DIE, n = 19 | 3 (16) | 1.49 | 0.28–7.84 | 0.630 | Risk for PPH stratified by EM, AM, and DIE. Absolute blood loss The median blood loss in the EM group was 400 mL (IQR: 250–500mL) compared to 300 mL in the control group (IQR: 300–500mL). The p-value was 0.092, which indicates a tendency but no significant difference in median blood loss (see Table 10). In visualization, the EM group shows a greater range of blood loss and more cases of PPH (see Figure 2). Table 10 | EM status | Blood loss, median (mL) | Blood loss, IQR (mL) | P-value | |---|---|---|---| | EM, n = 82 | 400 | 300 – 500 | 0.092 | | Controls, n = 82 | 300 | 250 – 500 | 0.092 | Absolute blood loss in the cohort and control groups in mL. Figure 2 Hb levels in women with PPH After delivery, women with PPH had a significantly lower Hb level than women in the control group. The mean was 8.7 g/dL compared to 11.0/dL in the control group (standard deviation (SD): 1.51; range: 6.6–10.7 g/dL). The p-value was < 0.001. The mean Hb level in women with EM without PPH and in the control group did not differ significantly (p-value = 0.120). The mean was 10.5 g/dL (SD: 1.67; range: 6.6–15.5 g/dL) vs. 11.0 g/dl (SD: 1.60; range: 7–14.8). A total of 10 participants with EM and 3 participants without EM had no documented Hb value (12% vs. 4%). To calculate the Hb levels, we used only the available data; therefore, these results should be interpreted with caution. Birth mode in women with PPH Women with PPH gave birth via CD in nine cases: four primary and five emergency CDs. The reasons for primary CDs were fetal breech presentation (n = 2), vasa previa (n = 1), and PP (n = 1). Causes of increased blood loss were uterine atony, placenta accreta with placental bed bleeding, myometrial hypervascularization, and intraoperative tears. In four cases, non-reassuring fetal status (NRFS) was the indication for emergency CD, and one was performed due to protracted labor. Notably, in the group of NRFS, one uterine rupture during labor was detected and one spontaneous intra-abdominal hemorrhage occurred. In both cases, an emergency CD was performed, and both mother and child survived in good conditions. In the context of vaginal delivery, two women experienced PPH. One was due to uterine atony following VE after prolonged labor, and one was due to placental remnants causing increased blood loss. Notably, 8 out of 11 women presented with a placenta located on the posterior uterine or lower posterior uterine wall. One had placenta previa of the posterior uterine wall (details see Table 11). Table 11 | Patient number | Age | G/P | Mode of conception | Placenta localization | EM/AM classification | Weeks of gestation | Mode of delivery | Cause for the CD of VE | Cause for the bleeding | Uterotonics | Surgical procedures | Blood loss | Hb ante partum | Hb post-partum | |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| | 1 | 36 | 1/1 | IVF/ICSI | Lower posterior uterine segment | #ENZIAN Oo/2 | 37+0 | Primary CD | Vasa previa | Placenta bed bleeding, atony | Sulprostone | Celox ® tamponade intrauterine | 1000 mL | n. a. | 10,6 | | 2 | 36 | 2/1, 1x EU | Spontaneous | Posterior uterine segment | Adenomyosis | 39+5 | Primary CD | Mobile fetal presentation | Myometrial hypervascularization | Carbetocin, tranexamic acid | Celox® tamponade intrauterine, topical hemostatic sponge | 1500 mL | 12,1 | 9,6 | | 3 | 48 | 1/1 | IVF/ICSI | Posterior uterine segment | rASRM IV, adenomyosis, recto cervical EM, #ENZIAN P3, Oo/1, AB 2-3, C2, Peritoneum | 39+0 | Primary CD | Placenta previa | Placenta bed bleeding, atony | Oxytocin, tranexamic acid | Ligation | 1300 mL | 11,6 | 7,1 | | 4 | 32 | 1/1 | Spontaneous | Posterior uterine segment | rASRM I, Endometrioma uterus myomatosus | 38+6 | Prim CD | Breech presentation | Stony | Carbetocin, tranexamic acid | - | 1300 mL | 11,0 | 9,8 | | 5 | 37 | 1/1 | Spontaneous | Fundus | ENZIAN B1, rASRM II, uterus myomatosus | 36+4 | Secondary CD | FGR and NRFS | Placenta adherence | Carbetocinn, tranexamic acid | Manual placental removal, ligation | 1000 mL | 12,2 | 10,3 | | 6 | 30 | 1/1 | Stimulation of ovulation | Posterior uterine segment | rASRM IV, adenomyosis, uterus myomatosus | 24+1 | Secondary CD | NRFS | Spontaneous hematoperitoneum | Carbetocin, tranexamic acid | Ligation | 1200 mL | 10,5 | 6,9 | | 7 | 35 | 2/1, partial mole pregnancy (2xcurettage) | IVF/ICSI | Anterior uterine segment | #ENZIAN: P1, uterus myomatosus | 39+2 | Secondary CD | Prolonged labor | Atony | Carbetocin | Topical hemostatic sponge | 1000 mL | 13,5 | 10,6 | | 8 | 32 | 1/1 | Spontaneous | Posterior uterine segment | Rectal EM | 41+1 | Secondary CD | NRFS, chorion-amnionitis | Myometrial hypervascularization, intraoperative tear | Carbetocin, tranexamic acid | Ligation and hemostatic powder | 1500 mL | 11,7 | 7,7 | | 9 | 41 | 2/2, 1x vacuum extraction | Spontaneous | Posterior uterine segment | #ENZIAN P1, adenomyosis, uterus myomatosus | 38+2 | Secondary CD | NRFS | Uterine rupture | Carbetocin, Tranexamic acid | Uterine reconstruction | 1500 mL | 10,7 | 7,4 | | 10 | 32 | 1/1 | Spontaneous | Anterior uterine segment | #ENZIAN (s) P1, O2/0, T2/0, B0/2 | 41+4 | Vacuum extraction | Prolonged labor | Atony | Misoprostol rectal | Atony | 1200 mL | 13,7 | 6,1 | | 11 | 39 | 1/1 | IVF/ICSI | Posterior uterine segment | Adenomyosis, rASRM IV | 38+0 | Spontaneous delivery | - | Placental remnants | Oxytocin and tranexamic acid | Manual placental removal | 1100 mL | n. a. | 9,0 | Detailed characteristics of women with PPH. Management of PPH The management of PPH included manual placental removal, surgical ligation, and uterine repair. We further used intrauterine Celox® tamponade and the application of topical hemostatic sponges. Moreover, the patients received tranexamic acid, misoprostol, carbetocin, and sulprostone. None of the women with PPH received red blood cell transfusion (details see Table 11).

Principal findings The rate of PPH in the EM/AM group was significantly higher than in the control group (13% versus 1%). The odds ratio for postpartum hemorrhage in the EM group was 8.74 (CI: 2.01–82.00). The p-value was 0.002. In the adjusted analysis, participants with EM had a significantly increased risk of PPH compared to those without EM (OR: 7.56, 95% CI: 1.39–83.70, p = 0.018), while gravidity and parity had no significant effect on the risk of PPH in our cohort. We excluded women who had undergone previous cesarean sections (CD) or other operations that opened the uterine cavity, performed matching of age and mode of conception, and adjusted for gravidity, parity, and fibroid status in order to eliminate major risk factors for PPH during delivery. Mechanisms of increased blood loss in women with EM/AM We assessed the risk of PPH in women with EM and AM regardless of mode of delivery, according to the ACOG definition as a blood loss of at least 1000 mL during childbirth (14). Despite this, we analyzed the mode of delivery in relation to the risk of PPH (see Table 6). The results should be interpreted with caution due to the low event count. Nevertheless, the highest risk of PPH was detected in the emergency CD group. We consider as partly causative the known risk factors for PPH, including prolonged and protracted labor resulting in unscheduled CD (16, 17). These factors, in combination with EM- and AM-associated pathophysiological components contributing to increased blood loss during CD, may explain the high OR. In our study, mode of delivery may be considered both a risk factor and a confounder. The following sections aim to frame hypotheses to explain the pathophysiology of increased risk of PPH in women with EM and AM: Hormones and the arrest of labor The literature describes the risk of PPH as particularly high in cases of vaginal operative birth and emergency CD due to their association with prolonged labor (16, 17). Oxytocin receptor expression The contractility of the uterus is mediated by oxytocin (OT) (18, 19). OT receptor (OTR) levels increase with gestational age and the onset of labor. However, when OT is used to induce and support labor, OTR levels decrease and the risk of PPH increases (20, 21). During pregnancy, OTRs are expressed more abundantly in the fundus than in the lower uterine segment (22). Consequently, the contractility of the lower uterine segment is weaker than that of the corpus uteri after birth. If the placenta is then located in the lower part of the uterus, bleeding from the placenta may be observed due to uterine atony. Myometrial contractility Uterine motility is disturbed and described as hypermobility in women with EM/AM (23). Altered uterine mobility can lead to two consequences. First, the adenomyotic uterus may be less able to produce expulsive contractions, prolonging labor and increasing the risk of PPH. Second, postpartum uterine hypermobility may interfere with myometrial contractions to stop bleeding from the placental bed, increasing the risk of uterine atony. Additionally, architectural changes to the uterus in the advanced stages of the disease, such as abnormal fixation due to posterior uterine adhesions, thickening of the myometrium, and endometriotic lesions within it, may intensify the difficulty of achieving purposeful contractions (, 24). Placenta localization in women with EM/AM In our cohort, we found that 8 of 11 women with PPH had a placenta located at the posterior uterine wall. One woman presented with posterior placental implantation, and one with a placenta at the lower uterine wall and vasa previa. This is the first evidence that placentation and its localization may be influenced by EM/AM. An increased risk of PP in women with EM/AM has already been reported (, 25), specifically an association between PPH from the posterior uterine wall and posterior extrauterine adhesions, which may be induced by AM and DIE (26). The increased vascularization of adenomyotic lesions, which are more prevalent in the posterior compartment in association with DIE, may provide a niche for placental growth. Additionally, extrauterine adhesions may rupture and cause bleeding during CD if they are located outside the uterine cavity; therefore, exteriorization of the uterus should be avoided in women with AM/DIE. Architectonical and inflammatory changes of soft tissue in women with EM and AM One of our patients experienced spontaneous hemoperitoneum during pregnancy and delivered her baby at 24 weeks and 1 day of gestation via emergency cesarean section. Spontaneous hematoperitoneum in pregnancy may be triggered by extrauterine EM lesions in association with decidualization (27). The constant inflammatory environment in EM can lead to the formation of fibrotic tissue around EM lesions (28). These environmental conditions favor the formation of adhesions that, in the context of pregnancy, may rupture spontaneously during contractions or trauma. We also observed one case of spontaneous uterine rupture during labor. While a hysterectomy is often required in such emergency situations, the mother and child in our case were in good condition after delivery, and we were able to repair the uterus. A tragic case described in the literature illustrates the underlying pathophysiology: a hysterectomy was performed due to a spontaneous uterine rupture during delivery, and a pathological examination of the uterus was conducted. On the side of the rupture, a complete absence of myometrial smooth muscle cells was observed, along with the presence of AM (29). The force of myometrial contractions during labor can cause the uterus to rupture in areas where there are adenomyotic changes to the myometrial wall. Abnormal vascularization of the myometrium in women with EM and AM In addition to the destabilizing effect of AM on the uterine architecture, the presence of endometrial-like tissue in the myometrium is associated with hypervascularization. Injury and repair mechanisms within the myometrium induce angiogenic factors, favoring myometrial hypervascularization and the development of unstable vessels. These changes have been described in the literature as the cause of abnormal uterine bleeding during menstruation in women with AM (30). During pregnancy and childbirth, uterine hypervascularization can lead to increased blood loss following miscarriage and in term pregnancies from the placental bed. We also observe increased bleeding from the uterine incision and uterine tears during CD. EM and concomitant AM in our cohort In our cohort, AM was present in only 46% of patients, whereas a higher percentage would be expected. The majority of uterine factors discussed are directly associated with AM rather than ectopic EM. As only 30% of patients were seen in specialist EM units, the prevalence of AM may be underestimated in this group. Strength and limitations This topic is clinically relevant in obstetrics and clinical medicine. Understanding the links between EM/AM and PPH improves antenatal risk stratification and peripartum management for mothers with EM/AM. This prospective study supports internal validity and standardized clinical assessment. Adjusted and unadjusted analyses of our primary endpoint showed an increased risk of PPH, suggesting a real difference despite the small number of patients. Nevertheless, we acknowledge limitations related to the low event count, possible residual confounding, and potential exposure misclassification. The multivariable analysis may be unstable, is exploratory, and the wide CIs calculated are explained by the small sample size. Matching was performed for age and mode of conception, as these were the greatest potential confounders in our cohort. To minimize the time period for control selection, matching for more variables was not feasible. We therefore performed a statistical analysis to adjust for other potential confounders, such as parity and mode of delivery. We acknowledge that our work is prone to selection bias and diagnostic misclassification, given that the history of EM/AM is self-reported. Temporal bias arising from the different recruitment periods of cases and controls may also have influenced our results; however, standard obstetric procedures within our clinic remained unchanged throughout the entire study period. Clinical implications Our work may result in an increased awareness of PPH risk in primiparous women with EM/AM. To recognize placental disorders, specialized sonography during pregnancy can be performed. Furthermore, giving birth in a medical center with a blood bank and the capability to manage severe bleeding complications can reduce morbidity and mortality in women with severe PPH.

In our study, women with EM/AM were found to be at significantly greater risk of postpartum hemorrhage than those without these conditions. Notably, the majority of the women with PPH in the EM/AM group were primipara. However, these findings should be interpreted with caution given the relatively small number of events and wide confidence intervals. Nevertheless, they suggest that women with EM and AM may benefit from delivering at centers with experience in managing postpartum hemorrhage. Further research is needed to create more robust evidence. Statements Data availability statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Ethics statement The studies involving humans were approved by Ethikkommission Charité - Universitätsmedizin Berlin. 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. Author contributions TG: Conceptualization, Project administration, Writing – original draft, Writing – review & editing. GE: Conceptualization, Formal analysis, Methodology, Visualization, Writing – review & editing. WH: Supervision, Writing – review & editing. SM: Supervision, Writing – review & editing. Funding The author(s) declared that financial support was not received for this work and/or its publication. Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Generative AI statement The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

1 ChaggarPTellumTThanatsisNDe BraudLVSettyTJurkovicD. Prevalence of deep and ovarian endometriosis in women attending a general gynecology clinic: prospective cohort study. Ultrasound. Obstetr. Gynecol. (2023) 61:632–41. doi: 10.1002/uog.26175 2 KunzGBeilDHuppertPNoeMKisslerSLeyendeckerG. Adenomyosis in endometriosis--prevalence and impact on fertility. Evidence from magnetic resonance imaging. Hum Reprod. (2005) 20:2309–16. doi: 10.1093/humrep/dei021 3 ViganoPCortiLBerlandaN. Beyond infertility: obstetrical and postpartum complications associated with endometriosis and adenomyosis. Fertil. Steril. (2015) 104:802–12. doi: 10.1016/j.fertnstert.2015.08.030 4 SaraswatLAyansinaDTCooperKGBhattacharyaSMiligkosDHorneAWet al. Pregnancy outcomes in women with endometriosis: a national record linkage study. Bjog. (2017) 124:444–52. doi: 10.1111/1471-0528.13920 5 ZulloFSpagnoloESacconeGAcunzoMXodoSCeccaroniMet al. Endometriosis and obstetrics complications: a systematic review and meta-analysis. Fertil. Steril. (2017) 108:667–72. doi: 10.1016/j.fertnstert.2017.07.019 6 GruberTMOrtliebLHenrichWMechsnerS. Women with endometriosis-who is at risk for complications associated with pregnancy and childbirth? A retrospective case-control study. J Clin Med. (2024) 13. doi: 10.3390/jcm13020414 7 MiuraMUshidaTImaiKWangJMoriyamaYNakano-KobayashiTet al. Adverse effects of endometriosis on pregnancy: a case-control study. BMC Preg. Childb. (2019) 19:373. doi: 10.1186/s12884-019-2514-1 8 ExacoustosCLauriolaILazzeriLDe FeliceGZupiE. Complications during pregnancy and delivery in women with untreated rectovaginal deep infiltrating endometriosis. Fertil. Steril. (2016) 106:1129–35. doi: 10.1016/j.fertnstert.2016.06.024 9 MatsuzakiSNagaseYUedaYLeeMMatsuzakiSMaedaMet al. The association of endometriosis with placenta previa and postpartum hemorrhage: a systematic review and meta-analysis. Am J Obstet. Gynecol. MFM. (2021) 3:100417. doi: 10.1016/j.ajogmf.2021.100417 10 NearyCNaheedSMcLernonDJBlackM. Predicting risk of postpartum haemorrhage: a systematic review. Bjog. (2020) 128:46–53. doi: 10.1111/1471-0528.16379 11 Von ElmEAltmanDGEggerMPocockSJGøtzschePCVandenbrouckeJP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. (2014) 12:1495–9. doi: 10.1136/bmj.39335.541782.ad 12 KecksteinJSaridoganEUlrichUASillemMOppeltPSchweppeKWet al. The #Enzian classification: A comprehensive non-invasive and surgical description system for endometriosis. Acta Obstet. Gynecol. Scand. (2021) 100:1165–75. doi: 10.1093/humrep/deab130.330 13 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil. Steril. (1997) 67:817–21. doi: 10.1016/s0015-0282(97)81391-x 14 Committee on Bulletins-Obstetrics. Practice bulletin no. 183: Postpartum hemorrhage. Obstet. Gynecol. (2017) 130:e168-e186. doi: 10.47363/jccem/2023(2)134 15 Al KadriHMAl AnaziBKTamimHM. Visual estimation versus gravimetric measurement of postpartum blood loss: a prospective cohort study. Arch Gynecol. Obstet. (2011) 283:1207–13. doi: 10.1007/s00404-010-1522-1 16 Deneux-TharauxCBonnetMPTortJ. Épidémiologie de l’hémorragie du post-partum [Epidemiology of post-partum haemorrhage]. J Gynecol Obstet Biol Reprod (Paris). (2014) 43(10):936–50. doi: 10.1016/j.jgyn.2014.09.023 17 HouLHellersteinSVitonisAZouLRuanYWangXet al. Cross sectional study of mode of delivery and maternal and perinatal outcomes in mainland China. PloS One. (2017) 12:e0171779. doi: 10.1371/journal.pone.0171779 18 MaggiMDel CarloPFantoniGGianniniSTorrisiCCasparisDet al. Human myometrium during pregnancy contains and responds to V1 vasopressin receptors as well as oxytocin receptors. J Clin Endocrinol Metab. (1990) 70:1142–54. doi: 10.1210/jcem-70-4-1142 19 HuangMLiXGuoPYuZXuYWeiZ. The abnormal expression of oxytocin receptors in the uterine junctional zone in women with endometriosis. Reprod Biol Endocrinol. (2017) 15:1. doi: 10.1186/s12958-016-0220-7 20 FuchsARFuchsFHussleinPSoloffMS. Oxytocin receptors in the human uterus during pregnancy and parturition. Am J Obstet. Gynecol. (1984) 150:734–41. doi: 10.1016/0002-9378(84)90677-x 21 BelghitiJKayemGDupontCRudigozRCBouvier-ColleMHDeneux-TharauxC. Oxytocin during labour and risk of severe postpartum haemorrhage: a population-based, cohort-nested case-control study. BMJ Open. (2011) 1:e000514. doi: 10.1136/bmjopen-2011-000514 22 BlanksAMVatishMAllenMJLaddsGDe WitNCSlaterDMet al. Paracrine oxytocin and estradiol demonstrate a spatial increase in human intrauterine tissues with labor. J Clin Endocrinol Metab. (2003) 88:3392–400. doi: 10.1210/jc.2002-021212 23 LeyendeckerGBilgicyildirimAInackerMStalfTHuppertPMallGet al. Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study. Arch Gynecol. Obstet. (2015) 291:917–32. doi: 10.1007/s00404-014-3437-8 24 CampoSCampoVBenagianoG. Adenomyosis and infertility. Reprod BioMed Online. (2012) 24:35–46. doi: 10.1155/2012/786132 25 Gómez-PereiraEBurgosJMendozaRPérez-RuizIOlasoFGarcíaDet al. Endometriosis increases the risk of placenta previa in both IVF pregnancies and the general obstetric population. Reprod Sci. (2023) 30(3):854–864. doi: 10.1007/s43032-022-01054-2 26 NagaseYMatsuzakiSEndoMHaraTOkadaAMimuraKet al. Placenta previa with posterior extrauterine adhesion: clinical features and management practice. BMC Surg. (2021) 21:10. doi: 10.1186/s12893-020-01027-9 27 LierMCIMalikRFKetJCFLambalkCBBrosensIAMijatovicV. Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - a systematic review of the recent literature. Eur J Obstet. Gynecol. Reprod Biol. (2017) 219:57–65. doi: 10.1007/978-90-368-2994-6_35 28 LinYHChenYHChangHYAuHKTzengCRHuangYH. Chronic niche inflammation in endometriosis-associated infertility: current understanding and future therapeutic strategies. Int J Mol Sci. (2018) 19. doi: 10.3390/ijms19082385 29 PhillipsLBrownHWilliamsA. Uterine rupture of an unscarred gravid uterus at term attributed to adenomyosis. BMJ Case Rep. (2023) 16. doi: 10.1136/bcr-2023-257145 30 HarmsenMJWongCFCMijatovicVGriffioenAWGroenmanFHehenkampWJKet al. Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review. Hum Reprod Update. (2019) 25:647–71. doi: 10.1093/humupd/dmz024 Summary

adenomyosis, endometriosis, PPH, pregnancy, risk factors Citation Gruber TM, Ebeling G, Henrich W and Mechsner S (2026) Increased risk of postpartum hemorrhage in women with endometriosis and adenomyosis: a prospective cohort study. Front. Endocrinol. 17:1718224. doi: 10.3389/fendo.2026.1718224 Received 03 October 2025 Revised 20 May 2026 Accepted 28 May 2026 Published 30 June 2026 Volume 17 - 2026 Edited by Angelo Marino, Andros Clinica Day Surgery, Italy Reviewed by Berlin Pandapotan Pardede, Universitas Gadjah Mada, Indonesia Rodrigo Orozco Fernandez, Hospital Quirónsalud Málaga, Spain Updates Copyright © 2026 Gruber, Ebeling, Henrich and Mechsner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Teresa Mira Gruber, [email protected]; Wolfgang Henrich, [email protected] Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.