Pregnancy after Endometriosis: Maternal and Neonatal Outcomes according to the Location of the Disease

► endometriosis ► pregnancy ► deep endometriosis ► endometrioma ► neonatal outcomes ► maternal outcomes

Objective To systematically evaluate pregnancy and labor course, obstetrical com- plications, and maternal and neonatal outcomes in women with endometriosis, stratifying according to the speci fic location of the disease. Study Design We retrospectively analyzed our prospectively maintained obstetrical database from January 2011 to August 2014 to identify all women with a previous histological diagnosis of endometriosis who delivered at our institution (cases). We divided the cases according to the speci fic location of the disease (deep in filtrating endometriosis, ovarian endometriosis, and peritoneal endometriosis). As controls, we identified all unaffected women who delivered in the year 2013. To avoid the confounding effect of parity, we limited our analysis to nulliparous women.

A total of 118 nulliparous women with endometriosis and 1,690 nulliparous controls were identi fied. Women with endometriosis were signi ficantly older, had a lower body mass index, and had a higher incidence of assisted reproductive technol- ogy. The duration of pregnancy was signi ficantly shorter among women with endo- metriosis. A higher incidence of placenta previa (3.4 vs. 0.5%; p ¼ 0.006), hypertension (11 vs. 5.9%; p ¼ 0.04), cesarean section (41.5 vs. 24.2%; p < 0.0001), and vacuum delivery (10.1 vs. 2.9%; p ¼ 0.006) was found in women with endometriosis. Neonatal outcomes were similar between groups. The incidence of placenta previa in patients with deep endometriosis was 11.7 versus 0.5% among controls ( p < 0.0001), whereas in women with ovarian and peritoneal endometriosis, it was similar to the controls. Copyright © 2019 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI https://doi.org/ 10.1055/s-0039-1692130. ISSN 0735-1631. Original Article S91 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Endometriosis is a common gynecological disease that is defined as the presence of endometrial tissue in ectopic locations; it typically affects women in their fertile age. Three different forms of the disease have been historically described according to the invasiveness and site of the implants: peritoneal disease, ovarian endometriomas, and deep in filtrating endometriosis. 1 It has been hypothesized that the different anatomical locations may re flect diverse pathogenetic mechanisms and different clinical course. 1 Regardless of the location of the disease, the estimated prevalence of endometriosis has been concerningly described to be up to 11% in the general female population, 2 but it dramatically increases among infertile women. 3 Although it has been clearly demonstrated that endometrio- sis reduces fertility, 4–7 pregnancy among women affected by this disease is becoming increasingly common, thanks to assisted reproductive technology (ART) 8 and complex surgi- cal eradicative procedures. 9–17 Despite the rising rates of pregnant women with a previous diagnosis of endometriosis (and in many cases also previous surgical procedures for this condition), information regarding the possible effect of the disease on obstetrical and neonatal outcomes is still scant. Initial reports described an apparently increased risk of preterm birth among women with endometriosis. 18–21 An intriguing hypothesis linking endometriotic process and preterm delivery regards the possible role of in flammation, with cross-reactions among cytokines, hormones and growth factors.22 A recent interesting review of the available literature has concluded that complications of endometriosis during pregnancy are rare and that pregnant women affected by this disease can be reassured on the course of the gestation. 23 However, a nonnegligible increase in the like- lihood of placenta accrete, preterm birth, and aesarean delivery has been described. 23–26 Unfortunately, most of the available evidence relies either on population-based studies, which used codes of the diag- noses for both the mother and the newborn at the time of discharge from the hospital, or on small retrospective collec - tions of data with conflicting results. Moreover, attention has been given almost exclusively to pregnancy and maternal outcomes, whereas scant data are available on the neonates. At the Department of Obstetrics and Gynecology of the University of Insubria, we have been maintaining for years a detailed prospective collection of perinatal data (regarding both the mother and the newborn) on women who deliver at our institution. With the aid of this valuable tool, we designed this study to systematically evaluate pregnancy and labor course, obstetrical complications, and maternal and neonatal outcomes in women with endometriosis, stra- tifying according to the speci fic location of the disease.

The obstetrical database of the Department of Obstetrics and Gynecology of the University of Insubria was queried from January 2011 to August 2014 to identify all women with a previous diagnosis of endometriosis who delivered at our institution (cases). This database is a research quality dataset that is designed and approved for both research and internal- audit purposes, is updated on a regular basis by trained residents, and has thorough and accurate information regarding a patient ’s history, course of pregnancy, possible obstetrical complications, details of delivery and peripartum period, and neonatal outcomes. To avoid the possible confounding effect deriving from the inclusion of multiparous women, we focused only on nulli- parous women with histologically proven endometriosis. The ascertainment of the diagnosis of endometriosis and the anatomical localization of the disease was conducted as follows: the obstetrical database contains details of medical history of endometriosis, including the site of the lesions and the treatment received (whether surgical only or surgical þ pharmacological). For patients previously operated at our institution, a manual search of the operative charts of the patients was performed to con firm the diagnosis, the anato- mical site of the disease, the treatment performed, and the rAFS (revised American Fertility Society) score. Patients operated elsewhere were contacted by phone and were asked to provide the operative charts to obtain details of their disease and of the procedures performed. In case of uncertainty or missing histological diagnosis, and/or inaccu- rate description of the anatomical localization of disease, patients were excluded from the study. The cases of women with endometriosis were then divided according to the site of the lesions in the following manner: (1) deep in filtrating endometriosis (with or with- out ovarian and peritoneal localizations), (2) ovarian endo- metriomas (with or without peritoneal endometriosis), and (3) peritoneal endometriosis only (i.e., patients with only super ficial localizations on the peritoneum and no other types of lesions). The control group was represented by all nulliparous women who delivered during the year 2013 but who did not have any history of suspected or con firmed endometriosis. Institutional Review Board approval was obtained for the prospective collection of data, their retrospective analysis, and collection of follow- up information. Our analysis focused on the identi fication of maternal and fetal/neonatal outcomes during pregnancy, in the intrapar- tum period, and in the postpartum period, comparing all cases of women affected by endometriosis versus controls

Women with endometriosis have a higher incidence of vacuum delivery, cesarean section, and placenta previa com pared with unaffected women. The higher risk of placenta previa is attributable exclusively to women with deep endometriosis. Neonatal outcomes are unaffected by the presence of the disease. American Journal of Perinatology Vol. 36 Suppl. S2/2019 Pregnancy after Endometriosis Uccella et al.S92 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. and then stratifying according to the site of the disease. To correct for the possible confounding effect of ART, we also performed a subanalysis including only those patients who conceived spontaneously. Statistical Analysis Statistical analysis was performed using GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego, CA). Incidence of binomial variables was analyzed for statis- tical signi ficance using the Fisher exact test. Regarding continuous variables, normality testing (D'Agostino and Pearson test) was performed to determine whether data were sampled from a Gaussian distribution. The Student t- test and Mann –Whitney U test were used to compare con- tinuous parametric and nonparametric variables, respec - tively. A p-value of <0.05 was considered statistically significant.

A total of 118 nulliparous women were affected by endome- triosis delivered at our institution during the study period and were included in this analysis, and 1,690 patients were selected as controls. The characteristics of the cases (women with endometriosis) and controls (unaffected women) are shown in ►Table 1 . Women with previously histologically proven endometriosis were signi ficantly older, had a lower body mass index (BMI), and had a higher incidence of ART compared with controls. The duration of pregnancy was significantly shorter among women with endometriosis (p ¼ 0.0002), although the difference was only 5 days (39 weeks and 4 days among controls vs. 38 weeks and 6 days among cases). Eighteen (15.3%) and 9 (7.6%) patients in the endometriosis group and 194 (11.5%) and 70 (4.1%) in the control group delivered before 37 ( p ¼ 0.24) and 34 (p ¼ 0.09) weeks of gestation, respectively. The relative risk of delivering before 34 weeks of gestation was 1.81 (95% con fidence interval: 0.95 –3.43) in the endometriosis group compared with the controls. A higher incidence of placenta previa (3.4 vs. 0.5% p ¼ 0.006) and hypertension (11 vs. 5.9%; p ¼ 0.04) was found in women affected by endo- metriosis compared with controls. ►Table 2 reports the maternal and neonatal outcomes at delivery in cases and controls. Women with endometriosis had a lower incidence of spontaneous labor and a higher risk of cesarean section and vaginal vacuum delivery compared with controls. Neonatal outcomes in terms of birthweight, Apgar score at 5 minutes, umbilical artery pH at birth, incidence of pH < 7, and neonatal intensive care unit (NICU) admissions were similar between groups. ►Table 3 reports the comparison between the 64 patients with ovarian endometriosis and the controls. Patients in the ovarian endometriosis group were signi fi- cantly older and had a lower BMI, a lower median gesta- tional age at delivery, a lower incidence of spontaneous onset of labor, and a higher rate of cesarean section as well as a vacuum delivery compared with controls. The incidence of placenta previa and the neonatal outcomes were similar between groups. ►Table 4 reports the comparison between the 20 women with peritoneal endometriosis and the controls. The age and BMI of the patients were comparable between the two groups. The incidence of vacuum delivery and cesarean section were signi ficantly higher, whereas the likelihood of Table 1 Characteristics of the cases affected by endometriosis (study group) versus unaffected controls (control group) Parameter Study group Control group p-Value No. of patients 118 1,690 Age 34 (22 –45) 31 (15 –48) <0.0001 /C21 35 years (%) 50 (42.4) 434 (25.7) 0.001 BMI (kg/m 2) 24.71 (19.69 –32.42) 26.4 (17.59 –48.87) 0.049 Assisted reproductive technique (%) 17 (14.4) 100 (5.9) 0.001 Multiple fetal gestations (%) 6 (5.1) 65 (3.9) 0.46 Gestational age at delivery 38.9 (29.9 –42) 39.6 (23.3 –42.1) <0.001 Maternal weight at delivery (kg) 70 (45.5 –98) 72 (47 –146) 0.08 Smoking habit (%) 9 (7.6) 97 (5.7) 0.41 Preexisting medical comorbidities (%) 1 (0.8) 12 (0.7) 0.59 Hypertension/preeclampsia (%) 13 (11) 99 (5.9) 0.04 GDM (%) 6 (5.1) 127 (7.5) 0.46 Placenta previa (%) 4 (3.4) 8 (0.5) 0.006 IUGR (%) 6 (5.1) 51 (3) 0.27 Abbreviations: BMI, body mass index; GDM, gestational diabetes mellitus; IUGR, intrauterine growth restriction. Note: Bold characters highlight statistically signi ficant findings. American Journal of Perinatology Vol. 36 Suppl. S2/2019 Pregnancy after Endometriosis Uccella et al. S93 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. vaginal delivery was signi ficantly lower in patients with peritoneal endometriosis compared with controls; the neo- natal outcomes were similar between groups. ►Table 5 shows the comparison between the 34 women with deep endometriosis compared with controls. The patients in the deep endometriosis group had a lower gestational age at birth and a higher incidence of cesarean section, as well as a higher likelihood of hypertensive dis- orders of pregnancy. The incidence of placenta previa in the group of patients with deep endometriosis was 11.7 versus 0.5% among controls ( p < 0.0001). The birthweight, Apgar score at 5 minutes, umbilical artery pH at birth, incidence of pH < 7, and NICU admissions were similar between groups. These results did not change after exclusion of patients who obtained pregnancy with assisted reproductive techniques.

This study demonstrates that women who deliver after a previous histological diagnosis of endometriosis are leaner, are older, and have a lower likelihood of spontaneous onset of labor and a higher incidence of cesarean section and vacuum delivery compared with patients without endome- triosis. We also reported a higher rate of hypertensive disorders of pregnancy and placenta previa in women affected by the disease. The observed increase in the inci- dence of placenta previa is attributable exclusively to the group of women affected by deep in filtrating endometriosis. It is interesting to note that neonatal outcomes are not affected by the presence and location of endometriosis. Another interesting finding of our study is the observed tendency (although not signi ficant) toward a higher rate of preterm delivery < 34 weeks of gestation among women with endometriosis. Even though patients with the disease have a signi ficantly shorter duration of pregnancy, the clinical signi ficance of this shortening appears limited (only 5 days in median) and therefore should not be regarded as a major issue in the everyday clinical practice. Previous studies have already shown an association between endometriosis and some unfavorable pregnancy outcomes. 18–26 However, two interesting and comprehen- sive reviews by Leone Roberti Maggiore et al have high- lighted that the risk of complications associated with endometriosis during pregnancy is low. 23,24 While the avail- able literature suggests that there is an increased risk of placenta previa, particularly in patients with deep endome- triosis, pregnant women with endometriosis should be in general reassured regarding the course of their gestation. Few studies, however, have focused on the possible simila- rities and differences among the different types and loca- tions of endometriosis. 27 Moreover, while a discrete number of papers have focused on women ’s health, the literature is devoid of information on the impact of endometriosis on the course of labor and on neonatal outcomes. Thanks to our systematic and thorough collection of data, we were able to Table 2 Delivery outcomes: patients with endometriosis versus control group Parameter Study group Control group p-Value No. of patients 118 1,690 Spontaneous labor (%) 56 (47.5) 997 (58.9) 0.015 Labor induction (%) 34 (31.4) 452 (26.7) 0.67 Failed induction (%) 10 (8.5) 86 (5.1) 0.13 Epidural analgesia in labor (%) a 34/89 (38.2) 659/1,469 (44.8) 0.23 Vaginal delivery (%) 69 (58.5) 1,281 (75.8) <0.0001 Vacuum delivery (%) 7 (10.1) 37 (2.9) 0.006 CS (%) 49 (41.5) 409 (24.2) <0.0001 CS in labor (%) 20 (16.9) 188 (11.1) 0.07 Blood transfusion (%) 3 (2.5) 36 (2.1) 0.74 EBL (mL) 375 (50 –3,850) 300 (50 –3,000) 0.23 Postpartum hemorrhage (%) 21 (17.8) 413 (24.4) 0.051 Postpartum urinary retention (%) 1 (0.9) 48 (2.8) 0.37 Postpartum hospital stay (days) 3 (1 –8) 3 (0 –15) 0.32 Neonatal weight at birth (grams) 3,105 (1,250 –4,090) 3,120 (400 –5,030) 0.19 Apgar at 5 min 10 (4 –10) 10 (0 –10) 0.91 NICU admissions (%) 7 (5.9) 94 (5.6) 0.68 Umbilical artery pH at birth 7.29 (6.97 –7.48) 7.27 (6.67 –7.45) 0.69 Abbreviations: CS, cesarean section; EBL, estimated blood loss; NICU, neonatal intensive care unit. Note: Bold characters highlight statistically signi ficant findings. aThe percentage is calculated on the total number of women who entered labor. American Journal of Perinatology Vol. 36 Suppl. S2/2019 Pregnancy after Endometriosis Uccella et al.S94 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. provide consistent results and explore the aspects that have been less investigated. The higher incidence of cesarean section observed in our study is maintained also after the exclusion of women who underwent ART. The possible explanations for this observa- tion are dif ficult to find. While the older age and the higher incidence of placenta previa may obviously play a role, it may be hypothesized that the possible coexistence of adenomyosis could be responsible for altered uterine con- tractility both during and before labor. However, these assumptions should be investigated and proven with spe- cific and personalized research. On the other hand, we observed that there is no detrimental impact of endome- triosis on the newborn ’s health, even in case of deep endometriosis. It is interesting to note that different subtypes of endo- metriosis are associated with different pregnancy out- comes. In general, our findings suggest that peritoneal endometriosis should be regarded as the mildest expression of the disease even when considering the course of preg- nancy. On the other hand, it is well known that deep infiltrating endometriosis is the most severe form of the disease, with the worst symptoms and the highest tech- nical dif ficulty when surgical treatment is to be accom- plished. When dealing with pregnancy, deep endometriosis appears as the subtype of disease associated with the poorest outcomes in comparison with ovarian and perito- neal endometriosis. We acknowledge several limitations of our study. First, the retrospective design may be the source of possible selection, detection and reporting bias. However, we emphasize that our systematic collection of data considerably reduces these possible drawbacks. Another possible limitation of our series is that we did not stratify according to the radicality of the surgery performed for endometriosis, particularly for deep endometriosis. However, it is commonly accepted that the complete removal of the disease during surgical procedures is associated not only with a higher risk of complications but also with a signi ficant improvement in terms of fertility rates. 9–11,13 Moreover, it is our policy to completely remove Table 3 Adnexal endometriosis versus control group Parameter Adnexal endome triosis Control group p-Value No. of patients 64 1,690 Gestational week at delivery 38.9 (30 –41.9) 39.6 (range 23.3 –42.1) 0.016 Age 34 (26 –44) 31 (15 –48) <0.0001 Spontaneous labor (%) 28 (43.7) 997 (58.9) 0.02 Vaginal delivery (%) 40 (62.5) 1,281 (75.7) 0.02 Vacuum delivery (%) 4 (10) 37 (2.9) 0.03 CS (%) 24 (37.5) 409 (24.3) 0.02 CS in labor (%) 8 (33.3) 188 (45.9) 0.29 BMI 24.2 (19.7 –27.9) 26.4 (17.5 –48.8) 0.002 Smoking habit (%) 7 (10.9) 97 (5.7) 0.09 Hypertension/preeclampsia (%) 7 (10.9) 99 (5.9) 0.10 GDM (%) 2 (3.1) 127 (7.5) 0.32 Placenta previa 0 8 (0.5) 1.00 EBL (mL) 375 (100 –2,000) 300 (50 –3,000) 0.18 Postpartum hemorrhage (%) 10 (15.6) 413 (24.4) 0.13 Blood transfusion (%) 2 (4.6) 36 (2.1) 0.64 Postpartum urinary retention 0 48 (2.8) 0.41 Postpartum hospital stay (days) 3 (2 –7) 3 (0 –15) 0.47 Neonatal weight at birth 3,100 (1,350 –3,960) 3,120 (400 –5,030) 0.18 Apgar at 5 minutes 10 (5 –10) 10 (0 –10) 0.66 NICU admissions (%) 3 (4.7) 94 (5.6) 0.76 IUGR (%) 3 (4.6) 51 (3) 0.44 Analgesia (%) 22/40 (55) 659/1,281 (51.4) 0.74 Umbilical artery pH at birth 7.3 (6.97 –7.46) 7.27 (6.67 –7.45) 0.18 Abbreviations: BMI, body mass index; CS, cesarean section; EBL, estimated blood loss; GDM, gestational diabetes mellitus; NICU, neonatal intensiv e care unit; IUGR, intrauterine growth restriction. Note: Bold characters highlight statistically signi ficant findings. American Journal of Perinatology Vol. 36 Suppl. S2/2019 Pregnancy after Endometriosis Uccella et al. S95 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Table 4 Peritoneal endometriosis versus control group Parameter Peritoneal endometriosis Control group p-Value No. of patients 20 1,690 Gestational age at delivery 38.8 (29.9 –42) 39.6 (23.3 –42.1) 0.16 Multiple fetal gestations (%) 1 (5) 65 (3.9) 0.54 A g e( y e a r s ) 3 3 . 5( 2 6 –39) 31 (15 –48) 1.00 Spontaneous labor (%) 9 (45) 997 (58.9) 0.25 Vaginal delivery (%) 10 (50) 1,281 (75.8) 0.02 Vacuum delivery (%) 3 (30) 37 (2.9) 0.003 CS (%) 10 (50) 409 (24.2) 0.02 CS in labor (%) 6 (60) 188 (45.9) 0.52 BMI 24.62 (20.8 –28.4) 26.4 (17.5 –48.8) 0.5 Smoking habit (%) 2 (10) 97 (5.7) 0.32 Hypertension/preeclampsia (%) 1 (5) 99 (5.9) 1.00 GDM (%) 1 (5) 127 (7.5) 1.00 Placenta previa (%) 0 8 (0.5) 1.00 Estimated blood loss (mL) 350 (50 –900) 300 (50 –3,000) 0.76 Postpartum hemorrhage (%) 5 (25) 413 (24.4) 1.00 Blood transfusion 0 36 (2.1) 1.00 Postpartum urinary retention (%) 1 (5) 48 (2.8) 0.44 Postpartum hospital stay (days) 3 (2 –4) 3 (0 –15) 0.41 Neonatal weight (grams) 3,150 (1,250 –4,090) 3,120 (400 –5,030) 0.82 Apgar at 5 min 10 (7 –10) 10 (0 –10) 0.24 NICU admissions (%) 1 (5) 94 (5.6) 1.00 IUGR (%) 1 (5) 51 (3) 0.46 Epidural analgesia in labor (%) 5 (50) 659/1,281 (51.4) 1.00 Umbilical artery pH at birth 7.31 (7.11 –7.48) 7.27 (6.67 –7.45) 0.02 Abbreviations: BMI, body mass index; CS, cesarean section; GDM, gesta tional diabetes mellitus; NICU, neonatal intensive care unit; IUGR, intrauterine growth restriction. Note: Bold characters highlight statistically signi ficant findings. Table 5 Deep endometriosis versus control group Parameter Deep endometriosis Control group p-Value No. of patients 34 1,690 Gestational age at delivery 38.6 (30 –41.6) 39.6 (23.3 –42.1) 0.002 A g e( y e a r s ) 3 3 . 5( 2 2 –45) 31 (15 –48) 0.09 Spontaneous labor (%) 15 (44.1) 997 (58.9) 0.11 Vaginal delivery (%) 19 (55.8) 1,281 (75.7) 0.013 Vacuum delivery (%) 0 37 (2.9) 1.000 CS (%) 15 (44.2) 409 (24.3) 0.013 CS in labor (%) 6 (40) 188 (45.9) 1.000 BMI 27 (23.5 –32.4) 26.4 (17.5 –48.8) 0.54 Smoking habit (%) 0 97 (5.7) 0.25 Hypertension/preeclampsia (%) 5 (14.7) 99 (5.9) 0.03 GDM (%) 2 (5.8) 127 (7.5) 0.19 American Journal of Perinatology Vol. 36 Suppl. S2/2019 Pregnancy after Endometriosis Uccella et al.S96 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the disease when surgery is indicated. As a consequence, we assume that almost all the patients included in this study had optimal removal of endometriosis at the time of surgery before the onset of pregnancy. In conclusion, our analysis provides useful data on an appropriate and moderately optimistic counseling to preg- nant women previously operated for endometriosis. Our findings show that although patients with deep endome- triosis have a considerably higher risk of placenta previa ( /C24 1 out of 10), the overall outcomes of pregnancy and in parti- cular the neonatal outcomes are in line with those of unaffected women. Funding None. Conflict of Interest None declared.

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Surg Endosc 2012;26(07): 2029–2045 Table 5 (Continued ) Parameter Deep endometriosis Control group p-Value Placenta previa (%) 4 (11.7) 8 (0.5) <0.0001 Estimated blood loss (mL) 400 (50 –3,850) 300 (50 –3,000) 0.84 Postpartum hemorrhage (%) 6 (17.6) 413 (24.4) 0.42 Blood transfusion (%) 1 (2.9) 36 (2.1) 0.52 Episiotomy Postpartum urinary retention 0 48 (2.8) 1.00 Postpartum hospital stay (days) 3 (1 –8) 3 (0 –15) 0.003 Neonatal weight at birth (grams) 3,080 (1,530 –3,760) 3,120 (400 –5,030) 0.42 Apgar at 5 min 10 (4 –10) 10 (0 –10) 0.23 NICU admissions (%) 3 (8.8) 94 () 0.42 IUGR (%) 2 (5,8) 51 (3) 0.28 Epidural analgesia in labor (%) 7/19 (36.8) 659/1,281 (51.4) 1.00 Umbilical artery pH at birth 7.26 (7.01 –7.49) 7.27 (6.67 –7.45) 0.66 Abbreviations: BMI, body mass index; CS, cesarean section; GDM, gesta tional diabetes mellitus; NICU, neonatal intensive care unit; IUGR, intrauterine growth restriction. Note: Bold characters highlight statistically signi ficant findings. 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