{"paper_id":"1e957e97-73f2-40ef-82af-7e2c20e99a54","body_text":"Endometriosis and Adverse Pregnancy Outcomes, controversies debates | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endometriosis and Adverse Pregnancy Outcomes, controversies debates Fatemeh Shahmoradi, Ladan Haghighi, Marziyeh Noori, Roya Derakhshan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2290558/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The association between endometriosis and outcome of pregnancy is one of the interesting topics. Patients' pain is alleviated with pregnancy, but it seems that endometriosis causes adverse outcomes in pregnancy. The main accused is systemic chronic inflammation caused by higher level of cytokines, growth factors and angiogenic factors. In this retrospective cohort study, the case group included 125 women with endometriosis who referred to Hazrat-e- Rasool hospital in 2015–2019, and the control group included 125 women without endometriosis who went to the hospital for delivery in 2015–2019. Data on pregnancy, delivery and newborns of the endometriosis and control group was extracted from the hospital information system and the questionnaires were completed. The average age of patients was 32.74 ± 4.10 and 31.7 ± 5.53 years in endometriosis and control group respectively. In terms of pregnancy complications, placenta previa, placenta accreta, placenta abruption pre-eclampsia, GDM and postpartum hemorrhage remarkably increase in the endometriosis group compared to the control group (P < 0.05). In bowel endometriosis SGA was significantly higher than patients without bowel endometriosi. (P < 0.05). Conservative or surgical treatment of rectal endometriosis had no significant effect on pregnancy outcome (P > 0.05). As well as the presence of adenomyosis made pregnancy outcomes significantly unfavorable compared to people without adenomyosis. (P < 0.05). NICU admission rate was notably higher in infants of endometriosis group compared to controls (40.7% vs. 24.8%, P-value 0.009). Infant mortality rate had no significant difference in both groups (P = 0.12). Our findings showed that endometriosis and adenomyosis are related to bad obstetric consequences. Endometriosis deep endometriosis Obstetric complications Introduction Endometriosis is a debilitating disease .Endometriosis prevalence is 10–15% in reproductive age and 30–50% in women with infertility [ 1 – 4 ].The peak of prevalence is reproductive age. Endometriosis represents by three main features including, superficial peritoneal lesions, ovarian endometrioma, and deep endometriosis. Common epigenetic changes in endometriosis and adverse pregnancy outcomes are known. Main complaint of endometriosis are dysmenorrhea, dyspareunia, dyschezia, chronic pelvic pain and infertility. Adenomyosis is related to endometriosis and presented by infertility, menometrorrhagia and pain [ 5 , 6 ]. In recent decades, document of relation between endometriosis and increased risk of obstetrical complications such as preterm birth, hypertensive disorders of pregnancy, Gestational diabetes mellitus (GDM), small for gestational age (SGA), placenta previa, placental abruption, placenta accrete, and postpartum hemorrhage (PPH) is noted [ 7 – 12 ]. Meanwhile, deep endometriosis has attracted the attention of a large number of researchers. A considerable relationship between rectovaginal endometriosis and placenta previa has been found [ 13 ], There is still no evidence that severe endometriosis is more associated with poor obstetric outcomes. Also, there is no evidence of the effect of endometriosis surgery on reducing obstetric complications or aggravating complications during pregnancy [ 14 , 15 ]. On the other hand, due to infertility caused by endometriosis, many patients need assisted reproductive methods for fertility and these patients are at increased risk of obstetrics’ complications of pregnancy [ 16 , 17 ]. The underlying pathogenesis of bad obstetric consequences in endometriosis is poorly understood. Common epigenetic changes in endometriosis and poor consequences of pregnancy may be responsible for obstetric complications in endometriosis patients [ 18 ]. Since the effect of endometriosis on the results of pregnancy can be debited, this study aimed to clarify the relationship between endometriosis, deep endometriosis, adenomyosis, surgical treatment and poor maternal consequences. Methods We designed our retrospective cohort to compare neonatal and maternal complications between women with endometriosis and control group (women without endometriosis who were referred to Endometriosis and prenatal clinic of Rasool –e-Akram Hospital in 2015–2019. This research was approved by the Ethics committee of Iran University of Medical Sciences (approval number: IR.IUMS.FMD.REC.1398.422). Our investigation included 125 patients diagnosed with endometriosis (endometriosis group) and 125patients without endometriosis (control group). Diagnosis of endometriosis was based on laparoscopy with histological confirmation or clinical and sonographic sign and symptom of endometriosis before pregnancy. The control group also included all women who referred to prenatal clinic for delivery in this duration and they did not have history of endometriosis based on clinical and imaging sign and symptoms of endometriosis. Exclusion criteria were included: gestational age less than 22 weeks, fetal malformations, twin pregnancies, insufficient medical records, pregnancy with ART, underlying diseases such as endocrine diseases, Hypothyroidism, diabetes, cardiac diseases, hypertension, neurology and psychological disorders, and autoimmune diseases. We adjusted for maternal age to prevent the effect of increasing pregnancy complications with increasing age of the mother. Pregnancy, childbirth and neonatal questionnaires were completed for both groups and other information extracted from medical records. Maternal and neonatal characteristics were manually extracted from electronic medical record system. Also, data of endometriosis were captured from the patients’ medical records. The maternal outcomes consist of gestational age, delivery mode (cesarean section, normal vaginal delivery), obstetrical complications such as abortion, ectopic pregnancy, preterm delivery (< 37 weeks), gestational diabetes mellitus (GDM), preeclampsia and gestational hypertension, postpartum hemorrhage (PPH) described as bleeding more than 500 ml after delivery, placenta previa, placental abruption, placenta acreta and small for gestational age (SGA). Neonatal characteristics, neonatal intensive care unit (NICU) admission, and mortality also were recorded. Statistical analysis: For the analysis, obstetrics and neonatal characteristics were compared using the chi-squared test for the categorical variables and the unpaired t-test or Mann- Whitney U tests for the continuous variables according to normal or non-normal distributions. The t-test or Wilcoxon signed-rank test was used to compare dependent variables between different times. Logistic regression analysis was used to investigate the relationship between endometriosis and adverse obstetric outcome (pregnancy, delivery and neonatal). The odds ratio (OR) and 95% confidence interval (CI) will be calculated after adjusting a number of intervening variables such as age, etc. The level of significance was set at 0.05, and all results were expressed as absolute and percent frequencies for qualitative variables, or as the mean ± SE for quantitative variables. All data were analyzed with SPSS version 24 software (SPSS Inc., Chicago, IL). Results All patients had superficial peritoneal lesions and ovarian endometrioma.68 patients had rectal endometriotic nodule.Rectal endometriotic nodule were treated either medically or surgically by discoid or segmental resection or shaving technique. Patients who underwent IVF were excluded from the study. A total of 250 patients (125 patients in each group) were analyzed. Table 1 demonstrates the maternal characteristics in the endometriosis and control groups. The patients in endometriosis group had higher BMI than control group before pregnancy (24.2 ± 3 vs. 23.4 ± 3.09 kg/m 2 , p = 0.042). The average age of patients was 32.74 ± 4.10 and 31.7 ± 5.53 years in endometriosis and control group respectively. No remarkable differences were observed in age. Table 1 Obstetric Characteristics in the Endometriosis and Control groups Maternal Characteristics Endometriosis (N = 125) Control (N = 125) P-value Age 32.74 ± 4.10 31.70 ± 5.53 0.94 BMI 24.28 ± 3 23.49 ± 3.09 0.042 Number of pregnancy 1.57 ± 0.6 2.3 ± 1.2 0.001 Number of delivery 1.2 ± 0.4 3.37 ± 2.29 0.001 Data are presented as mean ± standard deviation, BMI: Body Mass Index. There were significant differences in number of pregnancies (1.57 ± 0.6 vs. 2.3 ± 1.2, p < 0.001) and number of deliveries (1.2 ± 0.4 vs. 2.29 ± 3.37, p = 0.001) between the endometriosis and control groups, respectively. There was statistically notable difference regarding, preterm delivery, placenta previa, placenta accreta, placental abruption, preeclampsia, gestational hypertension, GDM, postpartum hemorrhage in endometriosis group in comparison with control group. There were no significant differences between endometriosis and control group concerning in threatened abortion (Table 2 ). Table 2 Obstetrics Outcomes in the Endometriosis and Control groups Out come Control group endometriosis group Pvalue preterm delivery < 37w 2.4% 3 16.8% 21 0.034 Threaten abortion 2.4% 3 4.8% 6 0.313 postpartum hemorrhage 1.6% 2 28% 35 0.001 placenta previa 0% 0 3.2% 4 0.043 placenta accrete 0% 0 4.8% 6 0.013 SGA 4% 5 8% 10 0.22 preeclampsia/Hypertension 7.2% 9 23.2% 29 0.001 Eeclampsia 0.8% 1 0.8% 1 0.99 placenta abruption 0% 0 20% 25 0.001 GDM 3.2% 4 10.4% 13 0.024 CS 71.2% 89 46.4% 58 0.4 still birth 1.6% 2 0 0 0.097 bowel perforation 0% 0 0% 0 - Hemoperitoneum 0% 0 0% 0 - Data are presented as n (%).CS, cesarean section Among endometriosis group, 68 patients (54.4%) had rectal endometriosis. There is a significant difference between the group of patients with rectal endometriosis and the group of patients without rectal endometriosis in terms of SGA (p value < 0.05) (Table 3 ). There was no significant difference between patients with rectal endometriosis treated surgically (n = 42) and medically (n = 26) in terms of pregnancy outcomes (P value > 0.05) (Table 4 ). Table 3 Outcome of pregnancy in patients with and without rectal endometriosis and patients without rectal endometriosis Outcome Without Bowel Endometriosis Bowel endometriosis Pvalue preterm delivery < 37w 19.3% 11 14.7% 10 0.494 postpartum hemorrhage 21.1% 12 33.8% 23 0.113 placenta previa 1.8% 1 4.4% 3 0.392 placenta accrete 5.3% 3 4.4% 3 0.839 SGA 1.8% 1 13.23% 9 0.039 preeclampsia/Hypertension 26.3% 15 20.6% 14 0.45 placenta abruption 17.5% 10 22.1% 15 0.53 GDM 5.3% 3 14.7% 10 0.085 CS 43.9% 25 48.5% 33 0.54 Still birth 0 0 0 0 - Table 4 Pregnancy outcome in rectal endometriosis with surgical and medical treatment Outcome Bowel endometriosis treated medically Bowel endometriosis treated surgically P value preterm delivery < 37w 11.5% 3 16.7% 7 0.68 Postpartum Hemorrage 23.1% 6 40.5% 17 0.085 Placenta previa 3.8% 1 4.8% 2 0.684 Placenta accrete 7.7% 2 2.4% 1 0.57 SGA 7.7% 2 16.7% 7 0.052 Preeclampsia/Hypertension 23.1% 6 19% 8 0.699 Placenta abruption 7.7% 2 31% 13 0.054 GDM 11.5% 3 16.7% 7 0.181 CS 46.2% 12 50% 21 0.825 Still birth 0 0 0 0 - In rectal endometriosis group, pregnancy outcomes include preterm delivery, postpartum hemorrhage (PPH), placenta previa, accrete and abruption, preeclampsia, SGA, gestational diabetes increased with a significant difference (p value < 0.05) compared to control group. Also, the rate of cesarean section in control group was significantly higher than rectal endometriosis group (P value < 0.05) (Table 5 ). In endometriosis group there is a significant difference between the group of patients with adenomyosis and the group without it in terms of pregnancy outcomes such as postpartum hemorrhage (PPH), placenta previa and placenta accreta (p value < 0.05) (Table 6 ). Table 5 Obstetrics Outcomes in rectal Endometriosis and Control groups Outcome Control group (n = 125) Patients with bowel endometriosis (n = 68) Pvalue % n % N preterm delivery < 37w 2.4% 3 14.7% 10 0.008 Postpartum hemorrage 1.6% 2 33.8% 23 0.001 Placenta previa 0% 0 4.4% 3 0.043 Placenta accrete 0% 0 4.4% 3 0.043 SGA 4% 5 13.2% 9 0.23 Preeclampsia/Hypoertension 7.2% 9 20.6% 14 0.048 Placenta abrubtion 0% 0 22.1% 15 0.001 Gestational Diabet 3.2% 4 14.7% 10 0.009 CS 71.2% 89 48.5% 33 0.001 Still birth 0.8% 1 0% 0 0.31 Table 6 Pregnancy outcome in endometriosis patients with and without adenomyosis Outcome Endometriosis without adenomyosis (n = 71) Endometriosis with adenomyosis (n = 54) P value preterm delivery < 37w 19.7% 14 13% 7 0.317 postpartum hemorrage 15.5% 11 44.4% 24 0.001 placenta previa 0% 0 7.4% 4 0.019 placenta accrete 1.4% 1 9.3% 5 0.039 SGA 7.7% 2 16.7% 7 0.052 preeclampsia/Hypertension 21.1% 15 25.9% 14 0.52 placenta abrubtion 19.7% 14 20.4% 11 0.928 Gestational Diabet 7% 5 14.8% 8 0.158 CS 40.8% 29 53.7% 29 0.126 Still birth 0% 0 0% 0 - Neonatal consequences are shown in Table 7 . NICU admission was remarkably higher in neonate of endometriosis group in comparison with control group (40.7% vs 24.8%, P-Value 0.009). Although, no statistically significant differences were seen in mortality rate of neonate (0. 8% vs 4%, respectively. P-Value: 0.12). Table 7 Neonatal complication in endometriosis and control groups Neonatal outcomes Endometriosis Control P-value NICU admission, n (%) 46 (40.7%) 31 (24.8%) 0.009 Mortality, n (%) 1 (0.8%) 5 (4%) 0.126 Data are presented as n (%). NICU Neonatal Intensive Care Unit. Author Contributions Fatemeh Shahmoradi and Ladan Haghighi wrote the manuscript and contributed in conceptualization of the work, Marziyeh Noori, Roya Derakhshan and Neda Hashemi Collected samples; Samaneh Rokhgireh provided ideas and critically edited the entire composition of the manuscript Discussion This investigation designed to evaluate the effects of different phenotypes of endometriosis on obstetrics and neonatal outcomes and to demonstrate whether pre-pregnancy endometriosis managment, including surgical or medical treatment, affect perinatal outcomes. On the other, some studies have found that endometriosis did not affect pregnancy outcomes. Previous studies are heterogenous and the existing data are controversial. The underlying mechanisms relating endometriosis and pregnancy complications remain largely unclear. However, several published papers have suggested that chronic Inflammation due to cyclooxygenase-2, interleukin-8, prostaglandin E2, adhesions and vascularized environment due to angiogenesis could lead to various complications during pregnancy [ 16 , 19 , 20 ]. As well as in women with endometriosis functional and structural abnormalities in the junctional zone have been found in MRI-scans and biopsies [ 21 ], which means that endometriosis is related to adenomyosis. [ 22 ] [ 23 , 24 ]. Also, genetic and epigenetic factors are involved in causing adverse pregnancy consequences in endometriosis patients. Epigenetic factors lead to resistance to progesterone through DNA methylation. On the other hand, resistance to progesterone leads to implantation disorder by causing gene dysregulation [ 25 , 26 ]. The most important finding of our study showed that endometriosis could be considered as an independent risk factor for increase in obstetrical complications. The risk of placenta previa, placental abruption preeclampsia, preterm delivery, GDM and postpartum hemorrhage in the endometriosis group was higher compared to the control group. Adenomyosis leads to an increased risk of premature rupture of membrane and premature delivery. Incomplete remodeling of the spiral vessels in the junctional zone cause deep implantation of the placenta and obstetric complications such as placental abruption, preterm delivery, second trimester miscarriage, preeclampsia, fetal growth restriction. Hyperestrogenism by vicious cycle of hyperperistalsis, thickening, and disruption in the junctional zone, result in uterine contractility disorder, providing a background for autotraumatization and tissue injury and repair [ 27 ]. The findings of our study showed that placenta previa, placenta accrete and postpartum hemorrhage are significantly increased in patients with adenomyosis. An interesting hypothesis regarding the relationship between endometriosis and preterm delivery is the possible role of inflammation due to the presence of cytokines and growth factors [ 28 ]. In endometriosis group 54.4%of patients represented with rectal endometriosis. Risk of SGA was significantly higher in rectal involvement. Other adverse outcomes were not associated with rectal endometriosis. Despite the fact that in our study, the rate of preterm delivery in endometriosis group was significantly higher than control group, the SGA rate in both group was not significantly different, indicating no growth restriction. In the endometriosis group, patients with rectal endometriosis had higher rate of SGA, which raises the possibility that deep endometriosis is responsible for this complication. A meta-analysis of 12 studies shows a borderline association between endometriosis and low birth weight, similar to our result in rectal endometriosis [ 29 ]. Our findings are consistent with previous studies that found an association between endometriosis and other placental complication such as placenta previa [ 30 – 32 ]. In our study, the risk of placenta previa was significantly higher in the group of endometriosis patients compared to the control group and also in patients with adenomyosis. Our finding did not show a significant difference in terms of placenta previa in the group with rectal involvement, Although, out of 4 cases of placenta previa in the endometriosis group, 4 cases had rectal nodules. The small sample size of our study may explain the lack of significant correlation. Also, rectal endometriosis surgery or medical treatment did not change the risk of placenta previa. In Versilini's study, the incidence of placenta previa was 7.6% in rectovaginal endometriosis, 2.1% in endometrioma and peritoneal endometriosis, and 2.4% in peritoneal endometriosis. The risk of placental anomaly in women with rectovaginal endometriosis was 6 times higher. [ 33 ]. Maggiore et al. demonstrated strong association between deep endometriosis and placenta previa [ 34 ]. In our study placenta accrete significantly increased in endometriosis group. Out of 6 patients with placenta accreta, 2 had a history of previous cesarean section and the rest were primigravida. This issue indicates that the cause of placenta accreta has not previous history of caesarean section. Our findings haven’t demonstrated association between rectal endometriosis and increased risk of placenta accreta. But the risk of placenta accreta in patients with adenomyosis was significantly higher than in those without adenomyosis. A meta-analysis of Forty-eight studies demonstrated strong relationship between endometriosis and placenta accrete [ 35 ]. Limited evidence from a few studies also indicated that surgical excision of endometriosis may not reduce the risk of adverse pregnancy outcomes [ 15 ]. In our study there was no significant difference between the group of patients with rectal endometriosis with surgical treatment and non-surgical treatment in terms of adverse pregnancy outcomes.In the study of Nirgianakis et al., similar to our study, the rate of cesarean section, placenta previa, gestational hypertension, and IUGR did not increase with laparoscopic surgery for rectal endometriosis nodules. It is possible that the increased risk of cesarean section after endometriosis rectal nodule surgery in some studies is due to obstetric decision making for cesarean section, not clinical necessity of cesarean section [ 36 ]. In Anni Tuominen et al. study in 2021, there was no difference in the live-birth rate, clinical pregnancy rate and adverse pregnancy outcome in rectovaginal endometriosis treated either conservatively or operatively [ 37 ]. In the Lapointe et al study in 2022, pregnancy complications regardless of the surgical technique of rectal endometriosis occurred in half of the pregnancies, and no increase in complications after surgery was reported [ 38 ]. In our study, NICU admission rate was significantly higher in neonate of endometriosis group compared with control group. Although the rate of neonate mortality was not different in two groups. According to a similar study there was not any difference in neonatal outcome between vaginal delivery and caesarean section. [ 39 ] One neonatal mortality occurred after emergency caesarean section for fetal distress in a woman with rectal endometriosis. The 5-minute Apgar score and arterial PH were 0 and 7.07 respectively. Our hospital is a tertiary referral center for endometriosis especially, severe endometriosis so we had all phenotypes of endometriosis patients in our study. The limitations of our study include the small sample size of study and the retrospective nature of the study causes probability of missing data, memory, and selection biases; therefore, large epidemiological studies in different populations (e.g., races, and regions) are needed to clarify the magnitude of these risks in order to define the appropriate level of proactive management of pregnant women with endometriosis. Conclusion Women with endometriosis are at elevated risk for important adverse maternal outcomes. An increase in pregnancy complications after deep endometriosis surgery was not seen and the reported complications are due to endometriosis itself. From a clinical view, women with endometriosis should benefit from increased surveillance during pregnancy to prevent neonatal and maternal complications. Due to the increase in delivery complications such as increased cesarean section and postpartum hemorrhage in endometriosis patients, adequate preparation during delivery such as uterotonic agents and blood products should be considered. Declarations Acknowledgments We thank all the participating patients for their generous contributions to this study. Ethics approval and consent to participate Ethics approval was obtained from the Iran University of Medical Sciences (approval number: IR.IUMS.FMD.REC.1398.422). Competing interests The authors declare that they have no competing interests. Author Contributions Fatemeh Shahmoradi and Ladan Haghighi wrote the manuscript and contributed in conceptualization of the work, Marziyeh Noori, Roya Derakhshan and Neda Hashemi Collected samples; Samaneh Rokhgireh provided ideas and critically edited the entire composition of the manuscript Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and /or publication of this article. References von Theobald P, Cottenet J, Iacobelli S, Quantin C (2016) Epidemiology of Endometriosis in France: A Large, Nation-Wide Study Based on Hospital Discharge Data. 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