Endometriosis and adverse maternal, fetal and neonatal outcomes, a systematic review and meta-analysis

Endometriosis is a chronic inflammatory condition characterized by the presence of endometrial glands and stroma outside of the uterine cavity and diagnosed by surgery ( Leyland et al. , 2010 ; Acién and Velasco, 2013 ). It affects 10–15% of reproductive age women ( Missmer and Cramer, 2003 ; Macer and Taylor, 2012 ), and may cause dyspareunia, dysmenorrhea and infertility. As 30–50% of women with endometriosis may have difficulty conceiving ( Macer and Taylor, 2012 ), more women with endometriosis are achieving pregnancy through ART ( Stephansson et al. , 2009 ). Endometriosis may be associated with altered ovulation and oocyte production, increased inflammatory cells in the peritoneal fluid, ovarian endometriomata, and disruption of normal endometrium all of which alter the uterine environment and may compromise normal embryonic development ( Koch et al. , 2012 ; Macer and Taylor, 2012 ; Harb et al. , 2013 ). It is possible that such disturbances in the peri-implantation period may perpetuate throughout the later stages in pregnancy resulting in adverse maternal and fetal outcomes ( Maggiore et al. , 2016 ). There have been many studies in the literature, especially in more recent years, showing an association between endometriosis and certain adverse maternal and fetal outcomes such as preterm birth, pre-eclampsia, placenta praevia and postpartum hemorrhage ( Hadfield et al. , 2009 ; Healy et al. , 2010 ; Kuivasaari-Pirinen et al. , 2012 ; Aris, 2014 ; Stern et al. , 2015 ; Berlac et al. , 2017 ; Glavind et al. , 2017 ; Saraswat et al. , 2017 ; Chen et al. , 2018 ). However, the reported findings are conflicting, as some studies have shown a positive association while others have not. Further, given that many studies include women conceiving with the use of assisted reproduction, the relationship between endometriosis and adverse perinatal outcomes may be confounded by the higher rates of endometriosis among women requiring fertility treatment ( Stephansson et al. , 2009 ; Benaglia et al. , 2016 ). Given the prevalence of endometriosis and the clinical significance of adverse pregnancy outcomes, we conducted a systematic review of the literature to investigate the association between endometriosis and maternal, fetal and neonatal outcomes. In addition to reviewing the outcomes frequently reported in the literature, we also performed an extensive review for less commonly reported but important fetal and neonatal outcomes, such as stillbirth and neonatal death. Where appropriate, we performed a meta-analysis to provide an estimate of the effect for each outcome. To remove the effect of potential confounding with assisted reproduction, we performed a stratified analysis, where possible, to determine the effect of endometriosis on pregnancy outcomes in the subgroup of women with spontaneous conception and the subgroup of women with assisted reproduction.

The methods for this review were developed in accordance with the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines ( Stroup et al. , 2000 ), and registered a priori in the International Prospective Register of Systematic Reviews (PROSPERO registration no. CRD42015013911). Two independent reviewers were available at all stages of the study, including study selection, data extraction and assessment of risk of bias, with a third reviewer available to resolve any discrepancies. The search protocol was developed by an experienced university librarian to identify studies investigating endometriosis and various adverse maternal, fetal and neonatal outcomes ( Supplementary Data ). The electronic bibliographic databases Embase and Medline were searched for publications 1 January 1990–31 December 2017, and reference lists of identified articles were hand-searched for additional studies ( Supplementary Data ). Studies were included if they (i) were prospective or retrospective cohort or case–control studies, (ii) included women >20 weeks gestational age with endometriosis and (iii) included a control group of gravid women without endometriosis. Studies needed to clearly describe case ascertainment for endometriosis and report at least one of the outcomes of interest. The primary outcomes of this study were determined a priori and included maternal (pre-eclampsia, placenta previa, antepartum hemorrhage, placental abruption, malpresentation, labor dystocia, cesarean section, postpartum hemorrhage), fetal and neonatal (preterm birth, preterm premature rupture of membranes, intrauterine growth restriction, neonatal compromise, APGAR and fetal/neonatal death) outcomes. The secondary outcomes were to assess for the presence of any other clinically important adverse pregnancy outcomes reported in the literature. Studies were excluded from the review if the data were not extractable. Abstracts, reviews, letters to the editor, case reports and case series were also excluded. A standardized data extraction form was used to extract information on study design; patient characteristics (age, gravidity, parity, body mass index, race); the diagnosis of endometriosis (mode of diagnosis, severity); use of assisted reproductive technology; and details regarding any reported adverse pregnancy outcomes. Data for adverse outcomes were collected as dichotomous data, and the results were given as odds ratios (OR) with 95% CI. Where appropriate, study results were combined in meta-analysis using a random-effects model for a pooled OR and 95% CI. Where possible, subgroup analyses were performed for women who conceived spontaneously and for women who conceived by assisted reproduction. Forest plots and I 2 statistic were calculated for each study outcome for each group. All analyses were performed using RevMan 5.3. The risk of bias was assessed for each study using the Newcastle–Ottawa Scale (NOS) for the selection of study groups (up to 4 stars/points); comparability of groups (up to 2 stars/points); and, the ascertainment of either the exposure or outcome of interest for case–control or cohort studies, respectively (up to 3 stars/points) ( Wells et al. , 2014 ).

The electronic search strategy identified 3925 records, and 2794 studies were identified following the removal of duplicates. Following title and abstract screen, 117 studies were included for full text review, and 33 studies (sample size, n = 3 280 488) were included in the meta-analysis (Fig. 1 ) ( Kortelahti et al. , 2003 ; Omland et al. , 2005 ; Brosens et al. , 2007 ; Fernando et al. , 2009 ; Hadfield et al. , 2009 ; Healy et al. , 2010 ; Kuivasaari-Pirinen et al. , 2012 ; Takemura et al. , 2013 ; Aris, 2014 ; Conti et al. , 2014 ; Mekaru et al. , 2014 ; Rombauts et al. , 2014 ; Baggio et al. , 2015 ; Lin et al. , 2015 ; Messerlian et al. , 2015 ; Stern et al. , 2013 , 2015 ; Benaglia et al. , 2012 , 2016 ; Exacoustos et al. , 2016 ; Fujii et al. , 2016 ; Guo et al. , 2016 ; Harada et al. , 2016 ; Jacques et al. , 2016 ; Morassutto et al. , 2016 ; Berlac et al. , 2017 ; Glavind et al. , 2017 ; Li et al. , 2017 ; Mannini et al. , 2017 ; Pan et al. , 2017 ; Saraswat et al. , 2017 ; Tzur et al. , 2018 ; Chen et al. , 2018 ). PRISMA diagram for selection of included studies for endometriosis and adverse maternal, fetal and neonatal outcomes—a systematic review and meta-analysis. Of the included studies, thirteen studies ( n = 70 306) only included women who conceived by ART, and two studies ( n = 586) only included women who conceived spontaneously. Five studies ( n = 1 735 474) included women stratified by spontaneous and assisted reproduction. Overall, 12 studies ( n = 1 473 747) did not identify or separate patients according to the method of conception. The remaining one study ( n = 375) had two subsets of analyses whereas one was for women without identification of method of conception and another with documented ART and no-ART (Table I ). Table I Characteristics of included studies for endometriosis and adverse maternal, fetal and neonatal outcomes—a systematic review and meta-analysis. Authors(s) (year) Study design Endometriosis Non-endometriosis Mode of conception Case ascertainment for endometriosis Aris (2014) Retrospective cohort 784 30 284 Combined spontaneous and assisted Surgical/Histological Baggio et al . (2015) Retrospective cohort 30 93 Combined spontaneous and assisted Surgical/Histological Benaglia et al . (2012) Retrospective cohort 61 130 Assisted reproduction Clinical Benaglia et al . (2016) Case–control 239 239 Assisted reproduction Surgical/Histological or clinical Berlac et al. (2017) Retrospective cohort 19331 1 071 920 Combined spontaneous and assisted Existing database codes Brosens et al . (2007) Retrospective cohort 245 274 Assisted reproduction Surgical/Histological or existing record Chen et al. (2018) Retrospective cohort 469 51 733 Combined spontaneous and assisted Existing database codes Conti et al . (2014) Prospective cohort 219 1331 Combined spontaneous and assisted Surgical/Histological Exacoustos et al . (2016) Prospective cohort 41 300 Stratified by spontaneous and assisted Surgical/Histological Fernando et al . (2009) Retrospective cohort 630 1140 Assisted reproduction Clinical or existing record Fuji et al . (2016) Retrospective cohort 92 512 Assisted reproduction Surgical/Histological Glavind et al . (2017) Retrospective cohort 1719 81 074 Stratified by spontaneous and assisted Existing database codes Guo et al . (2016) Retrospective cohort 129 145 Assisted reproduction Surgical/Histological Hadfield et al . (2009) Retrospective cohort 3239 205 640 Stratified by spontaneous and assisted Existing database codes Harada et al . (2016) Prospective cohort 330 8856 Combined spontaneous and assisted Clinical Healy et al . (2010) Retrospective cohort 1265 5465 Assisted reproduction Not described Jacques et al . (2016) Case–control 113 113 Assisted reproduction Existing record in files Kortelahti et al . (2003) Case–control 137 137 Combined spontaneous and assisted Surgical/Histological Kuivasaari-Pirinen et al . (2012) Retrospective cohort 49 26 870 Assisted reproduction Surgical/Histological or clinical Li et al. (2017) Retrospective cohort 75 300 Stratified by spontaneous and assisted Surgical/Histological Lin et al . (2015) Retrospective cohort 249 249 Spontaneous Surgical/Histological Mannini et al . (2017) Retrospective cohort 262 524 Stratified by spontaneous and assisted Surgical/Histological Mekaru et al . (2014) Retrospective cohort 40 48 Spontaneous Surgical/Histological Messerlian et al . (2015) Retrospective cohort 269 16 712 Combined spontaneous and assisted Not described Omland et al . (2005) Retrospective cohort 212 274 Assisted reproduction Surgical/Histological Pan et al. (2017) Retrospective cohort 2578 10 312 Combined spontaneous and assisted Surgical/Histological Rombauts et al . (2014) Retrospective cohort 376 4016 Assisted reproduction Clinical Saraswat et al . (2017) Retrospective cohort 4232 6707 Combined spontaneous and assisted Surgical/Histological Stephansson et al . (2009) Retrospective cohort 13090 1 429 585 Stratified by spontaneous and assisted Existing database codes Stern et al . (2013) Retrospective cohort 7937 19 475 Assisted reproduction Not described Stern et al . (2015) Retrospective cohort 996 297 987 Combined spontaneous and assisted Existing database codes Takemura et al . (2013) Case–control 44 261 Assisted reproduction Surgical/Histological or MRI Tzur et al. (2018) Retrospective cohort 35 467 Combined spontaneous and assisted Surgical/Histological Characteristics of included studies for endometriosis and adverse maternal, fetal and neonatal outcomes—a systematic review and meta-analysis. Compared with women without endometriosis, women with endometriosis had higher odds of pre-eclampsia (13 studies; OR = 1.18 [1.01–1.39]), gestational hypertension and/or pre-eclampsia (24 studies; OR = 1.21 [1.05, 1.39]), gestational diabetes (12 studies; OR = 1.26 [1.03–1.55]), gestational cholestasis (1 study; OR = 4.87 [1.85–12.83]), placenta praevia (18 studies; OR = 3.31 [2.37, 4.63]) (Fig. 2 ), antepartum hemorrhage (5 studies; OR = 1.69 [1.38–2.07]), antepartum hospital admissions (1 study; OR = 3.18 [2.60–3.87]), malpresentation (1 study; OR = 1.71 [1.34, 2.18]), labor dystocia (1 study; OR = 1.45 [1.04–2.01]) and cesarean section (20 studies; OR = 1.86 [1.51–2.29]) (Fig. 3 and Table II ). Table II Association between endometriosis and adverse maternal outcomes. Outcome indicator Study population No. of studies Patients with endometriosis Patients without endometriosis I 2 OR [95% CI] Pre-eclampsia Combined spontaneous and assisted 13 39 653 2 857 045 63% 1.18 [1.01, 1.39] Spontaneous only 2 3636 265672 51% 1.21 [0.94, 1.56] Assisted reproduction only 7 1741 7348 59% 0.89 [0.48, 1.67] Gestational hypertension and/or pre-eclampsia Combined spontaneous and assisted 24 48 660 3 225 765 77% 1.21 [1.05, 1.39] Spontaneous only 5 3298 499 289 33% 1.12 [0.90, 1.39] Assisted reproduction only 5 1792 7479 52% 0.79 [0.56, 1.11] Gestational diabetes Combined spontaneous and assisted 12 3275 367 537 31% 1.26 [1.03, 1.55] Spontaneous only 2 209 766 0% 1.30 [0.85, 1.98] Assisted reproduction only 5 881 2444 34% 1.08 [0.73, 1.60] Gestational cholestasis Combined spontaneous and assisted 1 262 524 – 4.87 [1.85, 12.83] Placenta praevia Combined spontaneous and assisted 18 27 395 1 178 425 77% 3.31 [2.37, 4.63] Spontaneous only 3 458 1015 49% 6.83 [2.10, 22.24] Assisted reproduction only 8 1937 6911 70% 3.33 [1.52, 7.30] Antepartum hemorrhage Combined spontaneous and assisted 5 38 055 2 513 814 83% 1.69 [1.38, 2.07] Assisted reproduction only 1 1265 5465 – 1.21 [0.96, 1.52] Subchorionic hematoma Combined spontaneous and assisted 1 40 48 – 2.47 [0.22, 28.33] Placental abruption Combined spontaneous and assisted 12 25 248 1 167 908 53% 1.46 [0.98, 2.19] Spontaneous only 2 270 549 71% 2.53 [0.08, 79.34] Assisted reproduction only 3 349 412 0% 0.35 [0.09, 1.32] Antepartum hospital admissions Combined spontaneous and assisted 1 996 297 987 – 3.18 [2.60, 3.87] Induction of labor Combined spontaneous and assisted 2 578 2447 94% 1.23 [0.44, 3.44] Malpresentation Combined spontaneous and assisted 1 996 297 987 – 1.71 [1.34, 2.18] Labor dystocia Combined spontaneous and assisted 1 996 297 987 – 1.45 [1.04, 2.01] Operative vaginal delivery Combined spontaneous and assisted 5 5722 307 054 69% 1.05 [0.70, 1.57] Cesarean section Combined spontaneous and assisted 20 41 974 2 952 659 98% 1.86 [1.51, 2.29] Spontaneous only 6 2326 364 017 39% 1.76 [1.51, 2.06] Assisted reproduction only 7 1295 4419 78% 1.24 [0.89, 1.71] Postpartum hemorrhage Combined spontaneous and assisted 10 27 817 1 220 226 95% 1.19 [0.89, 1.59] Spontaneous only 2 1426 65 433 0% 0.85 [0.70, 1.04] Assisted reproduction only 3 380 1875 0% 1.21 [0.86, 1.71] –Pooled analysis was not performed for single studies. Association between endometriosis and adverse maternal outcomes. –Pooled analysis was not performed for single studies. Forest plot for association between endometriosis and placenta praevia by mode of conception. Forest plot for association between endometriosis and cesarean section by mode of conception. Fetuses and neonates of women with endometriosis were also more likely to have preterm premature rupture of membranes (PPROM) (7 studies; OR = 2.33 [1.39–3.90]), preterm birth (23 studies; OR = 1.70 [1.40–2.06]) (Fig. 4 ), small for gestational age < 10th percentile (19 studies; OR = 1.28 [1.11–1.49]), NICU admission (7 studies; OR = 1.39 [1.08–1.78]), stillbirth (7 studies; OR = 1.29 [1.10, 1.52]) (Fig. 5 ) and neonatal death (3 studies; OR = 1.78 [1.46–2.16]). Maternal endometriosis had borderline asociation with infant low birth weight <2500 g (12 studies; OR = 1.13 [1.00–1.27]) (Table III ). Table III Association between endometriosis and adverse fetal and neonatal outcomes. Outcome indicator Study population No. of studies Patients with endometriosis Patients without endometriosis I 2 OR [95% CI] Preterm birth Combined spontaneous and assisted 23 43 267 3 019 058 92% 1.70 [1.40, 2.06] Spontaneous only 7 11 264 1 435 624 57% 1.70 [1.38, 2.10] Assisted reproduction only 10 3072 20 600 41% 1.27 [1.04, 1.55] Premature preterm rupture of membranes (PPROM) Combined spontaneous and assisted 7 1751 63 580 64% 2.33 [1.39, 3.90] Small for gestational age <10th percentile Combined spontaneous and assisted 19 38 514 2 952 409 64% 1.28 [1.11, 1.49] Spontaneous only 6 2326 3 64 017 0% 1.13 [0.92, 1.40] Assisted reproduction only 9 1857 5901 12% 1.04 [0.83, 1.30] Low birth weight <2500 g Combined spontaneous and assisted 12 7597 414 803 7% 1.13 [1.00, 1.27] Spontaneous only 3 879 298 284 0% 1.52 [1.13, 2.05] Assisted reproduction only 6 1096 2732 41% 0.87 [0.59, 1.27] APGAR <7 at 1 min Combined spontaneous and assisted 2 172 604 0% 0.75 [0.34, 1.68] APGAR <7 at 5 min Combined spontaneous and assisted 4 287 952 0% 0.65 [0.20, 2.11] Low venous pH (<7.15) Combined spontaneous and assisted 1 137 137 – 2.01 [0.18, 22.48] NICU admission Combined spontaneous and assisted 7 1371 81 074 23% 1.39 [1.08, 1.78] Spontaneous only 1 40 48 – 0.81 [0.28, 2.36] Assisted reproduction only 3 409 406 24% 1.58 [0.91, 2.75] Stillbirth Combined spontaneous and assisted 7 38 009 2 547 756 5% 1.29 [1.10, 1.52] Assisted reproduction only 2 242 404 0% 7.16 [0.74, 69.57] Neonatal death Combined spontaneous and assisted 3 23 700 1 078 764 0% 1.78 [1.46, 2.16] –Pooled analysis was not performed for single studies. Association between endometriosis and adverse fetal and neonatal outcomes. –Pooled analysis was not performed for single studies. Forest plot for association between endometriosis and preterm birth by mode of conception. Forest plot for association between endometriosis and stillbirth by mode of conception. Endometriosis was not found to be associated with subchorionic hematoma (1 study; OR = 2.47 [0.22–28.33]), placental abruption (12 studies; OR = 1.46 [0.98–2.19]), induction of labor (2 studies; OR = 1.23 [0.44–3.44]), operative vaginal delivery (5 studies; OR = 1.05 [0.70–1.57]), postpartum hemorrhage (10 studies; OR = 1.19 [0.89–1.59]), APGAR <7 at 5 min (4 studies; OR = 0.65 [0.20–2.11]), APGAR <7 at 1 min (2 studies; OR = 0.75 [0.34–1.68]) and low venous pH <7.15 (1 study; OR = 2.01 [0.18–22.48]) (Tables II and III ). Among the subgroup of women who conceived spontaneously, the presence of endometriosis was found to be associated with placenta praevia (3 studies; OR = 6.83 [2.10–22.24]) (Fig. 2 ), cesarean section (6 studies; OR = 1.76 [1.51–2.06]) (Fig. 3 ), preterm birth (7 studies; OR = 1.70 [1.38–2.10]) (Fig. 4 ) and low birth weight <2500 g (3 studies; OR = 1.52 [1.13, 2.05]) (Tables II and III ). For women who conceived spontaneously, endometriosis was not found to be associated with pre-eclampsia (2 studies; OR = 1.21 [0.94, 1.56]), gestational hypertension and/or pre-eclampsia (5 studies; OR = 1.12 [0.90, 1.39]), gestational diabetes (2 studies; OR = 1.30 [0.85, 1.98]), placental abruption (2 studies; OR = 2.53 [0.08, 79.34]), postpartum hemorrhage (2 studies; OR = 0.85 [0.70, 1.04]), small for gestational age <10th percentile (6 studies; OR = 1.13 [0.92, 1.40]) and NICU admission (1 studies; OR = 0.81 [0.28, 2.36]) (Tables II and III ). Among the subgroup of women who conceived with the use of assisted reproductive technology, the presence of endometriosis was found to be associated with placenta praevia (8 studies; OR = 3.33 [1.52–7.30]) (Fig. 2 ) and preterm birth (10 studies; OR = 1.27 [1.04–1.55]) (Fig. 4 ) (Tables II and III ). For women with assisted reproduction, endometriosis was not found to be associated with pre-eclampsia (7 studies; OR = 0.89 [0.48–1.67]), gestational hypertension and/or pre-eclampsia (5 studies; OR = 0.79 [0.56, 1.11]), gestational diabetes (5 studies; OR = 1.08 [0.73–1.60]), gestational cholestasis (2 studies; OR = 1.01 [0.05–21.97]), antepartum hemorrhage (1 studies; OR = 1.21 [0.96–1.52]), placental abruption (3 studies; OR = 0.35 [0.09–1.32]), cesarean section (7 studies; OR = 1.24 [0.89–1.71]) (Fig. 3 ), postpartum hemorrhage (3 studies; OR = 1.21 [0.86–1.71]), small for gestational age <10th percentile (9 studies; OR = 1.04 [0.83–1.30]), low birthweight <2500 g (6 studies; OR = 0.87 [0.59–1.27]), NICU admission (3 studies; OR = 1.58 [0.91–2.75]) and stillbirth (2 studies; OR = 7.16 [0.74–69.57]) (Fig. 5 ) (Tables II and III ). There was insufficient information specific to either of these subgroups of women to assess the association with antepartum admission, PPROM, malpresentation, labor dystocia, induction of labor, operative vaginal delivery, low APGAR, low venous pH, subchorionic hematoma and neonatal death. Following assessment using the NOS, three studies had a medium risk of bias, with stars/scores of NOS 4 ( Takemura et al. , 2013 ; Baggio et al. , 2015 ) and NOS 6 ( Kuivasaari-Pirinen et al. , 2012 ). The remaining 30 studies had an NOS stars/scores of 7 or greater, indicating low risk of bias ( Supplementary Table SI ).

In our systematic search of the literature, we found that the number of studies investigating the effect of endometriosis on pregnancy outcomes has risen substantially in recent years, verifying the growing relevance of this topic in an era of increasing use of assisted conception. The relationship between endometriosis and pre-eclampsia has been reported in the literature with conflicting findings, with some studies reporting increased risk ( Berlac et al. , 2017 ), no risk ( Hadfield et al. , 2009 ; Harada et al. , 2016 ) and even decreased risk ( Brosens et al. , 2007 ). Our pooled results suggest that there is an association between endometriosis and pre-eclampsia. Similarly, endometriosis was also found to be associated with gestational diabetes. This stands in contrast to another review specific to this outcome, which did not find an association, possibly due to a smaller number of included studies and smaller sample size ( Pérez-López et al. , 2017 ). When subgroup analysis was performed for both of these outcomes, no association was seen in either subgroup. Given the lack of association on subgroup analysis and the modest effect sizes observed, the findings are difficult to interpret in light of the observational nature of the included studies. Only one study reported outcomes for gestational cholestasis ( Mannini et al. , 2017 ), an interesting finding that warrants further exploration. The finding of the association between endometriosis and placenta praevia is well-documented ( Maggiore et al. , 2016 ) and may explain other less reported findings, such as the increased odds of antepartum hemorrhage and antepartum admission. While it has been suggested that the relationship may be confounded by the increased use of assisted reproduction in women with endometriosis, we found that the association was observed in both women who had spontaneous conception and assisted reproduction. The findings of malpresentation and cesarean section may be explained in part by the association with placenta praevia, though one study reported increased risk of labor dystocia as well. However, this latter finding may require further corroboration, as pooled results from five studies did not detect increased odds of operative vaginal delivery. The association between endometriosis and preterm birth observed in our review is consistent with the literature ( Kuivasaari-Pirinen et al. , 2012 ; Conti et al. , 2014 ; Exacoustos et al. , 2016 ; Berlac et al. , 2017 ). While one potential explanation could be confounding with assisted reproduction, we found that this relationship was observed in both women with spontaneous conception and assisted reproduction ( Stephansson et al. , 2009 ; Exacoustos et al. , 2016 ; Glavind et al. , 2017 ; Mannini et al. , 2017 ). Our findings are also consistent with the observation that endometriosis was associated with other adverse neonatal outcomes that have not been as extensively reported in the literature, including preterm premature rupture of membranes, small for gestational age, low birth weight and admission to neonatal intensive care. Stillbirth and neonatal death are uncommon but morbid adverse pregnancy outcome affecting <1% of all pregnancies ( Say et al. , 2006 ). Due to the low frequency of this event, the detection of statistically significant differences for this outcome requires large sample sizes that are difficult to achieve through individual studies. One consistent finding between studies was that all studies reporting these outcomes had odds ratios greater than one, despite variable confidence intervals. When pooled, we found that women with endometriosis had 1.29-fold (95% CI: 1.10–1.52) increased odds of stillbirth and 1.78-fold (95% CI: 1.46–2.16) increased odds of neonatal death compared with women without endometriosis. Several postulated mechanisms for these observations have been presented in the literature. Mechanisms involving altered vascular endothelial growth factor and angiogenesis ( Palei et al. , 2013 ; Laschke and Menger, 2018 ), deferred implantation due to altered contractility and increased progesterone resistance ( Maggiore et al. , 2016 ), altered eutopic endometrium due to increased secretion of interleukins and chronic inflammation ( Brosens et al. , 2007 ), and increased history of uterine trauma from increased pregnancy loss among women with endometriosis ( Chen et al. , 2018 ) help explain the findings of altered placentation and pre-eclampsia. In addition to suboptimal placentation, the increased expression of Cox-2, secretion of prostaglandins and chronic inflammation at the eutopic endometrium ( Harada et al. , 2016 ; Maggiore et al. , 2016 ), early cervical ripening and increased uterine tone and contractilility ( Brosens et al. , 2007 ) in women with endometriosis can lead to a variety of adverse fetal and neonatal effects. For the pregnancy outcomes of cesarean section and low birth weight, we found an association with endometriosis among women with spontaneous conception but not women with assisted reproduction. While this may seem counter-intuitive, one potential explanation may be that assisted reproduction may be an independent risk factor for such adverse pregnancy outcomes for both women with and without endometriosis, so fewer adverse pregnancy complications can be attributed to endometriosis alone. However, it is also possible that the lack of statistically significant associations in the subgroup of women with assisted reproduction may be due in part to beta-error. There are several methodologic strengths to our review. First, it was registered a priori in the International Prospective Register of Systematic Reviews (PROSPERO), thereby reducing risk of reporting bias. Second, the search strategy includes the results of an extensive and updated search of the literature with over 3000 records, and resulted in the identification of several additional papers compared with a previous review whose electronic search included 250 records ( Zullo et al. , 2017 ). Third, it included several important pregnancy outcomes that have not yet been reported as pooled outcomes in prior reviews ( Maggiore et al. , 2016 ; Zullo et al. , 2017 ), especially for serious fetal and neonatal outcomes, such as stillbirth and neonatal death, and also. In addition to describing the pregnancy outcomes associated with endometriosis, we have also included outcomes that were found not to be associated, as well as outcomes for which there was insufficient evidence. Fourth, in addition to providing a descriptive review on the topic ( Maggiore et al. , 2016 ), we have also performed meta-analysis to provide a more precise estimate of the effect of endometriosis on various pregnancy outcomes. Fifth, where possible, subgroup analyses for spontaneous and assisted conception were performed to remove the effect of confounding by assisted reproduction and to enable comparison of the effect sizes between the two groups. While this type of subgroup analysis for women with assisted reproduction has been performed for preterm birth ( Zullo et al. , 2017 ), we were able to perform this type of stratified analyses for many other outcomes other than preterm birth. Finally, when necessary, authors of original studies were contacted to provide additional information to assist with the interpretation, synthesis and analysis of their study results. As with any systematic review on observational studies, the review is limited by the quality and heterogeneity of the studies included. One finding was that the diagnosis for endometriosis was not uniform between the studies. While smaller studies using surgical data were able to confirm a surgical diagnosis of endometriosis, large population-based studies used International Classification of Diseases (ICD) codes to identify endometriotic patients. Despite the potential lack of specificity with the use of ICD codes compared with surgical records, the effect of potential misclassification would be bias towards the null hypothesis. Also, selection of control groups was not uniform across studies, with some studies using fertile patients, subfertile patients or patients affected by male factor infertility as non-endometriotic controls. Despite these limitations, most studies adjusted for or restricted according to age, parity or number of gestations in pregnancy. These factors contributed towards the heterogeneity between the studies, which is generally expected for a systematic review on observational studies. Finally, although this review fulfills its purpose of providing a synthesis of the current literature on this important topic, the exact mechanism of how the presence of endometriosis leads to adverse pregnancy outcomes has yet to be elucidated.

Women with endometriosis are at elevated risk for serious and important adverse maternal, fetal and neonatal outcomes. Though effect sizes for specific outcomes may differ between the two subgroups, both women with spontaneous conception and assisted reproduction are at elevated risk for adverse pregnancy outcomes. The association of endometriosis with morbid fetal and neonatal outcomes, such as stillbirth and neonatal death, is concerning and warrants further study.

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