Pregnancy Outcomes and Obstetrical Complications of Twin Pregnancies with Endometriosis: A Single-Center Cohort Study

Endometriosis, defined as the presence of endometrial tissue outside of the uterus, is a chronic, estrogen-dependent inflammatory disorder. 1 It is a common gynecologic condition that occurs in approximately 10%–20% of women of reproductive age and up to 50% of women with infertility. 2 3 Pregnancy has beneficial effects on endometriosis due to various pregnancy related metabolic, hormonal, immunologic, and angiogenetic changes. 4 However, according to a report by Leeners, et al., 5 during pregnancy, 15%–50% of lesions disappeared completely, 34%–64.7% regressed, 25% remained stable, and 8.8%–39% progressed. Additionally, in women with endometriosis, the risk of first trimester miscarriage and ectopic pregnancy were increased, and there was a possible increased risk of obstetrical complications of singleton pregnancies with endometriosis, such as preterm birth, preeclampsia, placenta previa, peripartum hemorrhage, and small for gestational age (SGA). 4 6 7 8 9 10 However, limited studies are available on twin pregnancies with endometriosis-related pregnancy outcomes and obstetrical complications. Therefore, this study aimed to compare the pregnancy outcomes and obstetrical complications in twin pregnancies with or without endometriosis at a single institution.

A total of 1714 twin pregnancies met the study protocol ( Fig. 1 ), and the endometriosis group comprised 127 (7.4%) patients. Baseline characteristics of patients with or without endometriosis were compared and presented in Table 1 . Maternal BMI was significantly lower in the endometriosis group ( p <0.001). However, there were no significant differences in maternal age, pre-pregnancy medical history, parity, mode of conception, and chorionicity. Pregnancy outcomes and obstetric complications were compared and presented in Table 2 . There were no significant differences in pregnancy outcomes, including the gestational age at delivery ( p =0.835) and rate of delivery before 37 weeks ( p =0.579). However, one obstetrical complication showed significantly higher rates in the endometriosis group: SGA<10% ( p =0.029). Table 3 shows the results of the univariable logistic regression analyses: SGA<10% (crude OR, 1.694; 95% CI, 1.067–2.690; p =0.025) was higher in the endometriosis group. After adjusting for BMI, patients with endometriosis showed marginal significance in obstetrical complications, including SGA (adjusted OR, 1.568; 95% CI, 0.984–2.499; p =0.059) and postpartum hemorrhage (adjusted OR, 1.632; 95% CI, 0.972–2.737 ; p =0.064). Tables 4 and 5 show subgroup analysis between the surgical history only without visible endometriosis lesion group and the visible endometriosis lesion with or without surgical history during Cesarean section group. Age was younger in the surgical history without visible lesion group. However, other demographic characteristics as well as obstetrical outcomes and complications showed no significant differences between the groups.

Compared with singleton pregnancy, twin pregnancies are widely known to significantly increase the risk of preeclampsia, preterm labor, placenta previa, and postpartum hemorrhage. Therefore, twin pregnancy alone was considered a confounding factor for the analysis of pregnancy outcomes in endometriosis and resulted in limited data for twin pregnancy outcomes with endometriosis. The present study, which was the largest cohort study of twin pregnancies with endometriosis, suggested that the endometriosis was not related to adverse effects, such as preeclampsia, preterm labor, placenta previa, postpartum hemorrhage, and SGA. There were several possible mechanisms for preterm delivery in endometriosis in singleton pregnancy. Increased levels of prostaglandins and cytokines, indicating the presence of inflammatory markers, have been found in peritoneal fluid. 13 Significantly increased levels of prostaglandin E 2 , cyclooxygenase 2, and various cytokines have been found in endometriotic tissue than in normal endometrium. 14 These increased inflammatory markers may stimulate myometrial contractions and cervical ripening, leading to preterm labor. The eutopic endometrium in the patients with endometriosis also showed aberrant expression of integrins and HOX-genes, which may affect endometrial receptivity and subsequent placentation. 14 15 The junctional zone also showed abnormal molecular and functional levels, such as progesterone resistance, which lead to the impairment of endometrial growth, maturation and decidualization, conversion of the uterine spiral arteries into uteroplacental vessels, and deep placentation. 16 17 18 Defective spiral artery remodeling in the placental bed was classified as 1) partial remodeling, 2) absent remodeling, and 3) absent remodeling with obstructive lesions according to the histological severity. 16 17 Partial remodeling in the placental bed was associated with preterm birth, PROM, and IUGR in the absence of maternal hypertension, and absent remodeling was a typical feature of preeclampsia: trophoblasts failed to invade into the myometrial segment of spiral arteries. This led to failure of deep placentation, and restricted blood flow to the placenta also resulted in inadequate uteroplacental perfusion. 19 Absent remodeling with obstructive lesions in the placental bed was shown in chronic hypertensive patients with superimposed preeclampsia. 16 17 Abnormal placentation may cause increased risks of antepartum hemorrhage and placental complications. Moreover, the normal frequency and amplitude of uterine contractions are altered in women with endometriosis, and this uterine dysperistalsis changes embryo transportation and implantation and increases the risk of placenta previa. 20 21 In vitro fertilization procedures due to endometriosis-related infertility are also related to the risk of placenta previa in singleton pregnancy. 22 However, in our study, there were no statistical differences in the rate of preeclampsia, preterm labor, placenta previa, postpartum hemorrhage, and SGA in twin pregnancies with or without endometriosis. It is well-known that endometriosis is a hormone-responsive disease, and an anti-estrogenic environment suppresses disease progression. Therefore, the possibility of elevated levels of steroid hormones in twin pregnancies overcomes the negative effect of endometriosis in preeclampsia, preterm labor, placenta previa, postpartum hemorrhage, and SGA compared with singleton pregnancy. In our study, patients with twin pregnancy with endometriosis had a lower BMI compared to those without endometriosis, which correlated with a previous study by Stephansson, et al. 23 on singleton pregnancy with endometriosis. In a crude univariable analysis, SGA was the only significant obstetrical complication in twin pregnancies with endometriosis. Due to a lower maternal BMI related to SGA, SGA was excluded as obstetrical complications in twin pregnancies with endometriosis after adjusting for BMI, but showed marginal significance (adjusted OR, 1.568; 95% CI, 0.984–2.499; p =0.059, respectively). In twin pregnancies, the birthweight was closely paralleled with those of singletons until 28 to 30 weeks’ gestation. After that, twin birthweights progressively lagged. 11 It resulted from accelerated placental maturation and relative placental insufficiency. Similarly to singleton pregnancy, SGA in twin pregnancies with endometriosis seemed to be related to the possibility of defective spiral artery remodeling. Postpartum hemorrhage also showed marginal significance (adjusted OR, 1.632; 95% CI, 0.972–2.734; p =0.064). The most common cause of postpartum hemorrhage is uterine atony, accounting for approximately 70% of cases. 24 Multiple gestation and estimated fetal weight >4000 g are considered as medium risk factors for postpartum hemorrhage due to uterine overdistension. 24 Additionally, in the endometriosis group, postpartum hemorrhage resulted from the stretching and tearing of endometriosis-related adhesions during Cesarean delivery, and decidualized endometriosis tissue in the pelvic cavity was usually friable and showed easy touch bleeding. These factors resulted in marginal significance of postpartum hemorrhage in twin endometriosis. Further large-scale studies are needed to re-analyze these two factors. A major strength of our study was the inclusion of a large cohort of twin patients. Furthermore, this was the first comparative study on twin pregnancy with or without endometriosis. However, our study had some limitations. First, the diverse characteristics of endometriosis, including the location, stage, and cyst size (in cases of ovarian endometriosis), were not compared. Due to the small sample size of twin pregnancies with endometriosis, the definitive conclusion of obstetric outcomes in twin pregnancy with endometriosis was difficult to determine. Second, since the data in our study were collected retrospectively, an inherent bias was present. Patients with a history of gynecologic surgery, such as myomectomy or ovarian cystectomy, had a possibility of combined pelvic endometriosis. However, the exact surgical findings were not identified in all patients, which may have resulted in selection bias. Third, we did not evaluate the rates of first trimester pregnancy loss. Many clinicians and patients have been interested in the possibility of implantation failure and early pregnancy loss in the first trimester with endometriosis. However, the study data were retrospectively obtained from the twin delivery registry of our hospital; therefore, accurate data related to early pregnancy loss could not be obtained. Additionally, twin pregnancy alone had a higher risk of early pregnancy loss compared to singleton pregnancies. Finally, generalization of these results may be limited since our data were drawn from a single maternity center in Seoul, South Korea, and power analysis was not used. Further prospective studies should be performed to overcome these important limitations. In conclusion, our study suggests that endometriosis was not related to adverse effects on pregnancy outcomes and obstetrical complications. Endometriosis alone was related to infertility; therefore, the possibility of requiring assisted reproductive technology and subsequent twin pregnancies increased. Our data can be used to provide adequate intrapartum management plans for twin pregnancies with endometriosis. Additional large-scaled multicenter studies are required to confirm our results.

We performed a retrospective review of patients who delivered twins at CHA Gangnam Medical Center between January 2011 and July 2022. Inclusion criteria were as follows: 1) twin Cesarean deliveries at ≥24 weeks of gestational age and 2) intrauterine fetal death (IUFD) of one or both fetuses after 14 weeks of pregnancy. During antenatal ultrasound examinations, the presence of typical ovarian endometrioma was evaluated. The endometriosis group included patients who underwent surgical treatment before pregnancy and had histological confirmation, including visual or histological confirmation during Cesarean section. Exclusion criteria were as follows: patients with 1) monochorionic monoamniotic twins; 2) previous cervical conization; 3) associated uterine anomalies, such as didelphys, septate, unicornuate, and bicornuate uterus; 4) unknown chorionicity or mode of pregnancy; 5) initial ≥triplet pregnancy, which was reduced to twin pregnancy at the time of delivery due to missed abortion or selective abortion of fetus(es) before 14 weeks due to these cases were higher in endometriosis group; and 6) twin vaginal delivery due to possibility of invisible pelvic endometriosis lesions. All twin pregnancies were managed according to the standardized institutional protocol. During the first trimester, we confirmed the gestational age, chorionicity, and adnexal lesions by using transvaginal ultrasonography. If the patient first visited the clinic after late second trimester and the chorionicity was unclear, we confirmed the chorionicity using pathological examination of the placenta. However, some emergency cases were excluded from the study due to missing placenta pathology. The study protocol was approved by the Institutional Review Board (IRB) of CHA Gangnam Medical Center (GCI-2022-11-001). Data were anonymized and de-identified before analysis; therefore, informed consent was not required, and the IRB agreed for the study to be conducted without informed consent from patients. The requirement for informed consent was waived by the IRB of CHA Gangnam Medical Center due to the retrospective nature of this study. All procedures for patients were conducted in accordance with the approved protocol at CHA Gangnam Medical Center. The following data were extracted from the patients’ medical records: maternal age at delivery, body mass index (BMI) at delivery, pre-pregnancy history of hypertension or diabetes mellitus, parity, mode of conception, chorionicity, gestational age at delivery, delivery mode, birth weight of newborns, and obstetric complications, such as preterm labor, premature rupture of membranes (PROM), preeclampsia, gestational diabetes (GDM), placenta previa (complete/incomplete/low lying), incompetent internal OS of the cervix (IIOC), IUFD after the second trimester, SGA (defined as neonatal birth weight in the <10th percentile for gestational age), 11 placenta abruption, postpartum hemorrhage (defined as cumulative blood loss ≥1000 mL, or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process), 12 peripartum transfusion, and peripartum intensive care unit admission. The sum of birth weights of twins and weight differences were calculated in patients without IUFD. Statistical analyses were performed using SPSS 26.00 (IBM Corp., Armonk, NY, USA). Descriptive data are expressed as mean±standard deviation and median, range. Chi-square and Fisher’s exact tests were used to analyze categorical variables. Quantitative variables were compared using the Mann-Whitney U test according to the Shapiro-Wilk test for normal distribution. Logistic regression was used to calculate the odds ratio (OR), presented with 95% confidence intervals (CI), to evaluate the association between endometriosis and pregnancy outcomes and obstetrical complications, before and after adjustment for BMI. Variables with a p -value<0.05, identified using univariable analysis, were subjected to multiple logistic regression. A p -value<0.05 was considered statistically significant.