Current Women’s Health Reviews, 2012, 8, 121-130 121 Endometriosis and Perinatal Outcome – A Systematic Review of the Literature

Sevasti Masouridou*, Apostolos Mamopoulos, Georgios Mavromatidis and Vassilios Karagiannis

3rd University Department Obstetrics & Gynaecology, Aristotle University of Thessaloniki, Medical School, 546 22 Thessaloniki, Greece

Abstract: Objective: To assess any possible adverse effects of endometriosis on pregnancy outcome and complications, as well as in the postpartum period. Study Design: A systematic review of the literature. Data Sources: We searched all publications in Pubmed, Scopus and the Cochrane Library with the key words endometriosis, pregnancy outcome, preeclampsia, preterm birth, small-for gestational age babies (SGA) and postpartum. Eligibility Criteria for Selecting Studies: All studies reporting on endometriosis and perinatal outcome until December 2009. Results: According to the available bibliographic data, we found 38 reported cases of pregnancies, four being twin pregnancies, complicated by endometriosis (Table 1). Studies referring to specific pregnancy complications (preterm birth, small-for-gestational age babies, preeclampsia and postpartum complications) were limited to a total of 12 publications [61-63, 69, 75, 80, 82-86]. The few reported complications during pregnancy included hemoperitoneum and spontaneous [1, 9-21], perforations of the , and sigmoid colon [22-24], urohemoperitoneum [25], deciduosis of the appendix [26], deciduosis of the omentum [27], infected endometrioma [28], hemoperitoneum and [29], catamenial pneumothorax [30], endometriosis imitating a bladder tumor [31], decidualization mimicking ovarian malignancy [32], rupture of ovarian endometriotic cyst [23, 33], and rupture of the uterus affected by endometriosis [34] (Table 1). Data regarding the effect of endometriosis on preterm birth, small-for gestational age babies and preeclampsia, both in spontaneous pregnancies as well as in those conceived by Assisted Reproductive Techniques (ART) were conflicting. Conclusions: Symptoms of endometriosis often disappear during pregnancy. Yet, endometriosis must be included in the differential diagnosis of hemoperitoneum presenting during pregnancy or of heavy vaginal bleeding postpartum. Both maternal and fetal morbidity and mortality can be quite high and the woman’s childbearing ability might be irreversibly affected. The few available data on the association between endometriosis and preeclampsia are at present controversial. Together with the studies reporting an increased risk for preterm birth in women with endometriosis, physicians must be aware that close antenatal follow-up and early diagnosis is crucial. Postpartum manifestations of endometriosis, although extremely rare, can give rise to severe complications with a high possibility of irreversibly affecting the woman’s childbearing ability. Keywords: Endometriosis, postpartum, preeclampsia, pregnancy outcome, preterm birth, SGA (small for gestational age).

INTRODUCTION sterilization (5%) [4]. Other reports have confirmed that infertile women are 6 to 8 times more likely to have Endometriosis is one of the most common gynaecologic endometriosis than fertile women [5]. The hypothesis that disorders and is found in approximately 70% of patients with endometriosis causes infertility or a decrease in fecundity chronic pelvic pain [1, 2]. Early studies suggested that 25% remains controversial. While there is a reasonable body of to 50% of infertile women have endometriosis and that 30% evidence to demonstrate an association between endo- to 50% of women with endometriosis are infertile [3]. There metriosis and infertility, a cause and effect relationship has is a higher prevalence of endometriosis in infertile women not been established [6]. (48%) compared with fertile women undergoing tubal The most common symptoms of endometriosis are pelvic pain, late onset dysmenorrhea and dyspareunia, and rd *Address correspondence to this author at 3 University Department infertility. Clinical symptoms result from implantation of Obstetrics & Gynaecology, Aristotle University of Thessaloniki, Medical endometrial tissue on the pelvic organs. Thus, endometriosis School, 130 Egnatia str., 546 22 Thessaloniki, Greece; Tel: +306972427408; Fax: +302310230878; may result in bowel-related symptoms (e.g., tenesmus) and E-mail: [email protected] urinary tract symptoms. Physical findings associated with

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Table 1. Clinical Manifestations of Endometriosis During the Third Trimester of Pregnancy: Demographic Data and Pregnancy Outcome

References Mean Mean Gestational ART Symptoms-Signs Fetal Transfusion History of Maternal Age Age at Delivery Outcome Endometriosis

Grunewald [13] 33 28 No ALAP, HVS, HMP, NL (VB at Yes No (Exploratory ) term)

Wu [14] 31 33 (twins) Nl/NL

Chiodo [25] 22 31 No ALAP, HMU, UHMP SB PRD, FFP Yes

Dubuisson [15] 36 32 SB

Passos [35] 30 32 (twins) Yes SRM, VB and EMCS: FD, HMP Nl/NL No Yes

32 31 Yes ALAP, FD, HMP NL No Yes

Roche [17] ? 33 (twins) ? ALAP, HVS, HMP SB/SB ? ?

Bouet [29] 33 24 No ALAP, IRR, AFH, HMP, HMTHx SB ? No

Katorza [1] 29 28 (twins) Yes ALAP, HVS, HMP RDS/RDS 4 IU PRC, 4 No IU FFP

31 26 Yes ALAP, HMP TOP 6 IUPRC, 8 Yes IU FFP, 10 IU CRYOPP

32 29 Yes ALAP, HMP CP ? Yes

Schweitzer [81] 32 40 Yes ALAP, D, PNP, PSC NL No No

Roger [16] 34 27 NL

Aziz [5] 30 20 SB

Ismail [12] ? 33 ? ALAP, HMP NL ? ?

Leung [11] 35 33 SB

Mizumoto [10] 28 28 NND

Inoue [9] 37 29 ? ALAP, HMP NL ? ?

Kawabara [18] No Rupture of pregnant uterus

Nakatani [24] 25 26 No PA

Gini [22] 23 35 No SVB, PRIF, PA NL ? No

Clement [23] 28 37 No ALAP, PNP-PSC NL ? No

Haufler [23] 30 6 months No , PJ

Steinberg,Scott 8 cases No Rupture OEC [23], Noel, Brill [33], Vercellini, Anderson

Poder [32] 34 30 No Decidualization mimicking NL Yes Ovarian malignancy

Phupong [28] 35 35 No Infected endometrioma NL No Suspected mimicking acute

Feyereisl [31] 25 2nd trimester Imitating bladder tumor NL (term delivery)

Endometriosis and Perinatal Outcome Current Women’s Health Reviews, 2012, Vol. 8, No. 2 123

Table 1. contd….

References Mean Mean Gestational ART Symptoms-Signs Fetal Transfusion History of Maternal Age Age at Delivery Outcome Endometriosis

Sabatelle [19] 23 34 No ALAP, HMP SB, TAH

Doyle [20] 37 34 No ALAP, HMP MD, FDeath

Melody [27] 30 37 No ALAP Omentectomy

Konwer [21] 39 40 No ALAP, HMP MD, SB

ALAP: Acute Low Abdominal Pain, SRM: Spontaneous Rupture of Membranes HVS: Hypovolemic Shock HMP: Haemoperitoneum HMU: Haematuria, IRR: Increased Respiratory Rate, AFH: Absent Fetal Heart activity UHMP: Urohaemoperitoneum, HMTHx: Haemothorax, PNP: , D: Dyspnea, PSC: Perforation of Sigmoid Colon, PJ: Perforation of Jejunum, OEC: Ovarian Endometriotic Cyst EMCS: Emergency Cesarean Section, VB: Vaginal Birth FD: Fetal Distress, NL: Normal, RDS: Respiratory Distress Syndrome, NND: Neonatal Death, MD: Maternal Death, SB: Stillborn, CP: Cerebral Palsy, TOP: Termination of Pregnancy, TAH: Total Abdominal Hysterectomy, RPC: Red Packed Cells, FFP: Fresh Frozen Plasma SVB: Slight Vaginal Bleeding, PRIF: Pain in Right Iliac Fossa, PA: Perforation of Appendix ?: not mentioned endometriosis are variable and dependent on the severity 2 maternal deaths occurred in earlier years, one possible and location of the disease. Common findings include reason being the ongoing evolution of intensive care characteristic tender nodularity and tenderness of the units and rescuscitation techniques. One pregnancy was obliterated cul-de-sac, parametrial thickening, and adnexal terminated according to the parents’ request, at 26 weeks of masses. gestation after developing severe intrauterine asphyxia postoperatively. Four cases report massive transfusion. The etiology and pathophysiology of endometriosis are not well understood because of the lack of a suitable animal Studies referring to specific pregnancy complications model to study the anatomic correlates and natural history of (preterm birth, small-for-gestational age babies, preeclampsia disease. No cure exists for the disease, and treatment is and postpartum complications) were limited to a total of directed toward medical suppression, surgical excision, and twelve publications. At present , in lack of large population symptom alleviation. studies, the few available data on endometriosis and its possible adverse effects on pregnancy are conflicting. MATERIAL AND METHODS Endometriosis During Pregnancy Infertility appears to be one of the major problems in women suffering from endometriosis. Pregnancy can be The number of women with endometriosis is increasing achieved either spontaneously or, more commonly with the [2, 7]. Although severe endometriosis is commonly associated help of Assisted Reproductive Techniques (ART). There with infertility, treatment with assisted reproductive are only a few reports examining the possible association techniques, such as IVF (in vitro fertilisation), enables more between endometriosis and perinatal outcome. With the aim women with severe endometriosis to conceive [1]. It is of assessing any possible effects of endometriosis on generally believed that pregnancy “cures” endometriosis, and pregnancy outcome, we conducted a systematic review of all symptoms usually disappear during the gestational period. In relevant publications in Pubmed, Scopus and Cochrane contrast, several animal studies point in the opposite Library using the following key words: endometriosis, direction [8]. McArthur and Ulfelder [4] showed that the pregnancy outcome, preeclampsia, preterm labor, preterm endometriotic lesions become decidualized and this may birth, intrauterine growth retardation (IUGR), small for explain why these lesions enlarge during the first trimester. gestational age (SGA) and postpartum. Later in pregnancy the lesions usually shrink, probably because of decidual necrosis and involution [4]. Endo- According to the available bibliographic data, we metriosis is known to be associated with an increased risk for found 38 reported cases of pregnancies, four being twin early pregnancy complications, including pregnancies, complicated by endometriosis (Table 1). and miscarriage. However, little has so far been reported on Maternal age was between 22-37 years of age and gestational age ranged from 20 to 40 weeks. A history of endometriosis, complications linked to severe endometriosis occurring during the third trimester of pregnancy [1]. suspected or known, was seen in seven cases. Six women went through assisted reproductive techniques. It has to be The few reported complications during pregnancy mentioned that some case reports date from years that these include hemoperitoneum and spontaneous bleeding from techniques were not yet available. Of the 38 fetuses, 10 cases vessels secondary to endometriosis [1,9-21], per- of stillbirths (26.31%) were reported (1 twin pregnancy), one forations of the jejunum, appendix and sigmoid colon [22- case with neonatal birth, one case with cerebral palsy and 24], urohemoperitoneum [25], deciduosis of the appendix two cases of RDS (respiratory distress syndrome) in twin masked as acute appendicitis [26], deciduosis of the pregnancy and two maternal deaths. It should be mentioned omentum [27], infected endometrioma masquerading as that although stillbirths are reported even in recent years, the acute appendicitis [28], hemoperitoneum and hemothorax 124 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Masouridou et al.

[29], catamenial pneumothorax [30], endometriosis imitating cases and 1 (4%) case, respectively. In the majority of cases a bladder tumor [31], decidualization mimicking ovarian (90%) the bleeding site was on either the posterior side of malignancy [32], rupture of ovarian endometriotic cyst [23, the uterus or the parametrium [40]. Of these cases 13 (52%) 33], and rupture of the uterus affected by endometriosis [34] had a history of endometriosis. Six of these women were (Table 1). known to have endometriosis diagnosed by prior to pregnancy, six were diagnosed at the time of Endometriosis and Hemoperitoneum laparotomy, and in one case the diagnosis was made 3 months after delivery at the time of laparoscopy for Hemoperitoneum in pregnant women with a history of persistent pelvic pain. The stage of endometriosis varied endometriosis can be caused either by spontaneous rupture from minimal and mild (n=6) to severe (n=7) [40]. of utero-ovarian vessels or from bleeding of endometriotic implants [1]. Decidualized endometriosis (necrosis and Although the precise cause of this situation is still shedding) during pregnancy may cause utero-ovarian vessels unknown, several theories have been proposed. Hodgkinson perforation, perforation of the appendix and the sigmoid and Christensen [38] have suggested that the rupture can be colon. attributed to sudden increases in venous pressure of the utero-ovarian circulation, resulting from the physiologic Spontaneous utero-ovarian blood vessel rupture occurring during pregnancy is a rare yet dramatic cause of demands of pregnancy in combination with physical activity, defecation, coughing, lifting, coitus, or during the pushing hemoperitoneum, associated with high rates of maternal and phase of the second stage of labor. The tortuous nature, lack fetal morbidity and mortality. Since its original report by of valves, and repeated distension of these vessels during Williams in 1904, several reviews documenting this rare pregnancy was thought to predispose to rupture. A vascular pregnancy complication have appeared in the literature [1]. defect contributing to the weakness of the physiologically The cause of the spontaneous rupture remains unclear but, the extensive physiologic hypertrophy of the uterine vessels hypertrophied uterine vessels has also been suggested [36]. in combination with some additional vascular defect may be Inoue et al., [9] have suggested at least two possible implicated [1, 7]. explanations for the involvement of endometriosis: a) chronic inflammation due to endometriosis may make utero- The typical presentation of spontaneous utero-ovarian ovarian vessels more friable and, b) the resultant adhesions vessel rupture consists of a sudden onset of abdominal pain, without vaginal bleeding but, with signs of , may create further tension in these vessels when the uterus is enlarged during pregnancy. The presence of surgical scar hypovolemia and fetal distress. The correct diagnosis is tissue relating to the previous laparoscopic surgery may rarely made preoperatively due to the possible confounding further weaken vessel walls or provide points of fixation that obstetric and surgical conditions and the necessity of could be torn by the normal uterine contractions. immediate surgical intervention [35]. A marked reduction in haemoglobin level is a frequent finding [36, 37]. Moreover, although the symptoms of endometriosis are generally reduced during pregnancy, visible endometriotic Placental abruption is the most common pre-laparotomy lesions frequently undergo initial enlargement, with diagnosis in reported cases. Differential diagnosis includes occasional ulceration and bleeding during pregnancy, as , abdominal pregnancy, ruptured appendix, described in histopathological findings. This may weaken the HELLP syndrome, and rupture of the or or affected tissues and lead to rupture during the course of its vasculature. These causes of hemoperitoneum during pregnancy are extremely rare and abdominal ultrasound is pregnancy [10]. Another explanation might be that intrusion of decidualized stroma into the vessel wall may result in useful in revealing free peritoneal fluid. The condition narrowing of the lumen, thus, increasing backpressure appears to be more lethal if it occurs during labor, and finally resulting in rupture [41]. Brosens et al., found presumably because of the confounding influence of painful no apparent correlation between SHiP and stage of uterine contractions [38, 39]. Spontaneous utero-ovarian endometriosis. vessel rupture is most common during the third trimester of pregnancy, but cases in all trimesters and during the As mentioned above, an increasing number of IVF puerperium have been reported [39]. Ginsburg et al., [36] patients with a history of endometriosis become pregnant. reported that 29% of the cases occurred before the 33rd week Passos et al., cannot disregard the hypothesis that oocyte of gestation, 39% between 33 and 37 weeks, and only 32% retrieval may trigger tissue weakness in these patients, given were noted to occur at term. 61% of ruptures were diagnosed the large number of IVF cycles performed and the lack before the onset of labor, 18% during labor, and 21% in the of any case reports in patients without endometriosis. postpartum period. A high maternal mortality (49.3%) [38] Nevertheless, they consider highly unlikely that the was described before the improvement of intensive care but procedure of oocyte pick-up in itself could be a major factor it decreased to 3.6% between 1950 and 1985 [36]. On the for this complication [35]. other hand, perinatal mortality remained at a high level Another explanation for SHiP could be the involution of (31%), with 44% of the deaths attributable to maternal shock decidualizing ectopic endometrium during pregnancy. [36]. Decidualization represents “the point of no return” in the Brosens et al., (2009), in a review of 20 publications differentiation of mesenchymal cells. After that point the retrieving a total of 25 cases with spontaneous hemo- cellular integrity becomes inextricably dependent upon in pregnancy (SHiP), described the bleeding as sustained progesterone signaling [42]. Falling progesterone venous, arterial or unknown in 20 (80%) cases, 4 (16%) levels not only reverse the decidual phenotype, but also Endometriosis and Perinatal Outcome Current Women’s Health Reviews, 2012, Vol. 8, No. 2 125 induce the expression of a gene network, leading to influx of Endometriosis Mimicking Ovarian Malignancy in inflammatory cells, proteolytic breakdown of the extra- Pregnancy cellular matrix, cell death, and bleeding. Interestingly, The histopathologic diagnosis of endometriosis can be emerging evidence suggests that endometriosis is associated rendered difficult by decidualization, which is characterized with progesterone resistance, characterized by suboptimal expression of target genes [43]. Therefore, it is tempting to by deeply infiltrating glands and polymorphic nuclei within the decidual stroma and can resemble a malignant process speculate that “functional” progesterone withdrawal triggers [47]. involution of the decidual phenotype of the ectopic endo- metrium surrounding distended parametrial veins, leading Adnexal masses (excluding physiological corpus luteal to peritoneal bleeding of unpredictable severity. Massive cysts of early pregnancy) are seen in 0.5% to 1.2% of spontaneous hemoperitoneum associated with mild endo- pregnancies, and 11% of these are endometriomas [48]. metriosis has also been described in the postpartum period Despite the relative frequency of endometriomas in and at the time of menstruation [41, 44, 45]. pregnancy, decidualization resulting in an appearance that mimics malignancy seems very rare, with only a handful of Endometriosis and Hemothorax reported cases. The appearance of solid nodules within a cystic ovarian mass is suggestive of ovarian cancer, and all 8 Hemothorax is very likely secondary to a trans- diaphragmatic passage of blood cells that subsequently pass reported cases of decidualized endometrioma in the literature have resulted in surgery during pregnancy because of the through defects in the diaphragm and implant on the pleural suspicious imaging findings [49-53]. Ovarian cancer during surface. The high proportion of cribriform fenestrations in pregnancy occurs at a rate of 0.18 per thousand deliveries the right diaphragmatic leaf can explain the right sided [54] and less than 1% of adnexal masses found during predominance of pleural endometriosis [46]. Therefore, pregnancy are malignant [48, 54]. The management of a when acute abdominal pain with massive hemoperitoneum occurs in pregnant nulliparous women with concomitant suspicious ovarian mass during pregnancy requires a multidisciplinary approach. It should be noted that the respiratory symptoms, uterine vessel rupture should development of solid nodules in an endometrioma could also immediately be considered as a possible cause, particularly if indicate superimposed malignancy [55, 56] and the risk of the patient has a previous medical history of endometriosis. cancer arising in pre-existing endometriomas is estimated to An imaging exam (CT scan or a plain chest X-ray) should be be 0.7% to 1% [54]. Decidualized endometrioma should be performed in these cases in order to rule out a possible hemothorax [29]. the initial diagnosis when: a) the solid nodules appearing within it remain unchanged throughout the course of Endometriosis and Ureteral Rupture pregnancy, b) the solid nodules appear smoothly lobulated with a rich vasculature and, c) the nodules, as they appear at The finding of a concomitant ureteral rupture during the MRI (magnetic resonance imaging), are strikingly similar is intriguing. The possibility of to the decidualized endometrium [32]. simultaneous and independent rupture of the uterine artery Ueda et al., examined 7157 pregnancies with an adnexal and ureter appears unlikely. Chiodo et al., hypothesized that mass, from 1996 to 2007. They concluded that an ovarian the uterine artery may rupture first, leading to local endometriotic cyst is the most common adnexal mass extraperitoneal haemorrhage, pressure increase locally and complicating pregnancy and that its frequency has almost subsequent rupture of decidualized and weakened contiguous quadrupled during that 12-year period, rising from 0.14% to ureter [25]. Localized haematoma may then progress until peritoneal rupture occurs. As a consequence, a local tampon 0.52% (p=0.007) [57]. Thirteen out of twenty-five (52%) of these lesions regressed during pregnancy and they remained effect limiting haemorrhage breaks down and blood loss unchanged in 7 cases (28%). In 5 cases (20%) the rapidly increases leading to hemorrhagic shock. It has to be cyst increased in size and subsequently demonstrated emphasized that it cannot be discerned whether the reported decidualization, abscess and rupture. These findings suggest complication is actually consequent to progress of the that an enlarging ovarian endometrioma during pregnancy disease or, alternatively, to pregnancy-mediated modifications of a pre-existing lesion [25]. should be more carefully monitored bearing in mind that the size of the cyst at initial presentation is not correlated to the Endometriosis and Gastrointestinal Perforation outcome. A preterm delivery was documented in only two cases for reasons unrelated to ovarian endometriosis It is known that gastrointestinal endometriosis is mostly (placenta previa and twins). serosal (Williams and Pratt, 1977) and only in 2 out of 12 cases reported by Uohara and Kobara (1975) involved all the Awareness of the severity of complications implicated in pregnant women with a history of endometriosis, especially layers of the appendix. This coincidence probably facilitated in IVF patients, may facilitate the diagnosis and expedite perforation [22]. intervention [1, 9, 10, 58]. The sudden onset and the progressing Endometriosis of the colon usually results in narrowing severity of the patient’s clinical course, encountered by the of the gut lumen and, in some cases, obstruction. On obstetrician, make surgical treatment of severe endometriosis histological examination scattered islands of endometriotic before conception a crucial step that would improve tissue surrounded by hypertrophied smooth muscle and a infertility, preventing at the same time the significant greatly thickened muscularis propria can be found. Such possible complications that affect the mother and the foetus. patients are probably at little risk of developing a perforation Closer antenatal visits should probably be tailored for during pregnancy [23]. patients with a history of severe endometriosis. Clinically 126 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Masouridou et al. stable pregnant women with a history of severe endo- In agreement with the previous findings for women with metriosis with acute abdominal pain should be carefully any form of endometriosis, Omland et al., the only other investigated with U/S (ultrasound), CT (computerized tomo- study that has looked into birth outcomes in patients with graphy) scan, and MRI in order to rule out a hemo- endometriosis after ART, found no statistically significant peritoneum. Prompt decision should be made when differences in preterm delivery when ART patients with performing an urgent laparotomy for hemoperitoneum when minimal endometriosis were compared to women with there is a need for an elective caesarean section in order to unexplained infertility (OR: 1.03, P=0.36, CI 0.9-1.28) [63]. prevent possible irreversible fetal damage that cannot always The possible association between endometriosis and be monitored during surgery [1]. preterm labor could be explained by the biochemical events that seem to be involved both in term and preterm Endometriosis, Preterm Birth and Small-for Gestational parturition, including the activation of pro-inflammatory Age Babies mediators such as prostaglandin E2 (PGE2), Endometriosis is a common disease with an estimated cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) [64]. prevalence of around 10-15% in all women of reproductive The resulting local and systemic inflammation stimulates age but it can be found in up to 50% of subfertile women myometrial contractility thus facilitating cervical ripening. [59, 60]. Despite its common occurrence there are only a few Increased levels of prostaglandins and cytokines have been data regarding its effect on pregnancy outcome, both in found in the peritoneal fluid of women with endometriosis spontaneous pregnancies as well as in those conceived by [65]. Chronic inflammation may comprise of the assisted reproductive techniques (ART). biochemical background for preterm birth in women with endometriosis. Other diseases characterized by chronic Stephansson et al., in a nationwide Swedish study based inflammation, such as Crohn’s disease and rheumatoid on 1,442,675 singleton births, examined the association between adverse pregnancy outcome, ART and a history of arthritis, are also associated with preterm birth [61]. endometriosis [61]. There were 13.090 singleton births There is evidence that ovarian endometriosis may be a among 8922 women diagnosed with endometriosis that different form of the disease compared to peritoneal presented a higher risk for preterm birth (adjusted odds endometriosis [66] and Fernando et al., in their study ratio 1.33, 95% confidence interval (CI), 1.23-1.44) when reported that ART patients with ovarian endometriomas have compared to women without endometriosis. Among women a different birth outcome from other ART women with with endometriosis, 11.9% conceived after ART compared peritoneal and other types of endometriosis [62]. with 1.4% of women without endometriosis. The risk of Molecular abnormalities on the other hand, in preterm birth associated with endometriosis among women decidualization and angiogenesis leading to abnormal with ART was 1.24 (95% CI, 0.99-1.57), and among women placentation and preterm birth are found in women with without ART 1.37 (95% CI, 1.25-1.50), suggesting an effect ovarian endometriosis, speculating that ectopic endometrium modification. Women with endometriosis had a higher risk in these women would bear the same alterations [67, 68]. of antepartum bleeding, placental complications, pre- eclampsia and Caesarean section. Yet, there was no Endometriosis and Preeclampsia association between endometriosis and small for gestational age (SGA) babies or stillbirth, suggestive of a different Endometrial milieu at the time of conception is a well pathogenetic background. A limitation of the study was the known factor in determining embryo implantation and fact that the histological extent of endometriosis was not subsequent pregnancy outcome. Leukocyte infiltration and known and that data were limited to women being cytokines play a very important role in human reproduction. hospitalized, therefore more likely to present with more An increase in cytokine levels is associated with the severe stages of the disease. menstrual cycle, ovulation, implantation and cervical ripening. Angiogenic factors are also necessary in the Fernando et al., reported on a total of 4387 singleton proliferative phase of the menstrual cycle, in early pregnancies conceived with the help of ART [62]. The luteinization and implantation. Overall, processes that are retrospective cohort included 535 ART patients with plausible in the development of endometriosis are also endometriosis but without ovarian endometriotic cysts, 95 essential in normal placental development and maturation ART patients with ovarian endometriotic cysts, 1201 ART [69]. It is thus intriguing to find out whether pregnancy patients with other etiologies of infertility, 156 subfertile outcome is altered in patients with endometriosis. women, 1260 fertile controls for all forms of endometriosis, and 1140 fertile controls. This study demonstrated that Entire gene networks are thought to be important not infertile patients with ovarian endometriotic cysts requiring only for embryo implantation but also for controlled ART were present with twice the risk for delivering interstitial and endovascular trophoblast invasion and the prematurely (adjusted OR: 1.98, 95% CI 1.09-3.62) or for establishment of a functional placenta [70]. Their expression having an SGA baby (adjusted OR: 1.95, 95% CI 1.06-3.60) was found to be altered in women with endometriosis during [62]. They concluded that the type of endometriosis that the putative window of endometrial receptivity when includes endometriotic ovarian cysts might constitute compared with fertile controls [71]. Trophoblast invasion, a previously unrecognized cause of preterm birth and on the other hand, encompasses the inner myometrium SGA babies raising the issue of a possible benefit when (junctional zone), a site found to be thickened and with surgical management in those patients is performed prior to dysperistalsis in women with endometriosis. One could ART. therefore speculate that endometriosis may predispose to Endometriosis and Perinatal Outcome Current Women’s Health Reviews, 2012, Vol. 8, No. 2 127 pre-eclampsia, since this condition is also characterized by studied 378,283 pregnant women that delivered one or more the defective remodeling of junctional zone myometrial babies during the period 2000-2005. They identified 3239 spiral arteries in the placental bed [72]. (1.6%) women with a history of endometriosis and at least one subsequent singleton pregnancy during the study period Although many studies have examined the effect of endometriosis on fertilization and implantation rates after [80]. Of these women, 846 (26%) had ovarian disease and 2386 (74%) had pelvic endometriosis. The average age IVF treatment, little is known about the incidence of late at first birth in women diagnosed with endometriosis was pregnancy complications such as pre-eclampsia. A recent 31.4 years, significantly higher than for those with no history meta-analysis of 22 published studies reported significantly of endometriosis. They found no relationship between decreased fertilization, implantation and pregnancy rates endometriosis and subsequent risk of pregnancy induced after assisted conception in women with endometriosis- associated infertility when compared with those with other hypertension or pre-eclampsia (OR 0.96; 95% CI 0.9-1.3). The frequency of pre-eclampsia was not significantly causes of infertility [73]. Whether this is attributable to different amongst women with more severe endometriosis or impaired oocyte/embryo quality or to decreased endometrial endometriosis in conjunction with infertility when compared receptivity remains to be elucidated [74]. with those with no endometriosis. The difference remained Kortelahti et al., [69] examined the pregnancy outcome non-significant even after adjusting for maternal age or in a matched case–control study that included 137 women gestational age at birth. On the other hand, Stephansson with biopsy-proven endometriosis and 137 controls and et al., in a nationwide Swedish study including a total of failed to detect a significant effect of endometriosis on the 1,442,675 singleton births reported a higher risk for obstetric outcome. Yet it is noteworthy that the incidence of preeclampsia among 8,922 women with a history of preeclampsia in patients with endometriosis was 6.6% endometriosis compared to normal controls (adjusted OR: compared with 11% in the control group [69]. 1.13, 95% CI 1.02-1.26) [61]. In a retrospective case–control study, Brosens et al., An association between pre-eclampsia and endometriosis found that women with endometriosis had a significantly would allow for a more effective antenatal management of lower risk of pre-eclampsia than women without endo- these cases but, so far, the evidence is lacking. Multiple large metriosis [75]. The study included 245 women with a population studies are needed in order to confirm or reject previous history of endometriosis and a control group of 274 the hypothesis that those two conditions may be sharing the women without endometriosis. The incidence of pre- same pathophysiological pathway. eclampsia was significantly lower in the case group (0.8%) when compared with the control group (5.8%), giving an Endometriosis in the Postpartum Period odds ratio (OR) of 7.5 (95% CI 1.7–33.3) [75]. This Spontaneous intraperitoneal hemorrhage due to unexpected finding may reflect increased local expression of endometriosis is a very rare situation that can complicate angiogenic factors and enhanced endometrial vascular perfusion at the time of implantation in women with pregnancy and the puerperium as well. endometriosis. In early pregnancy, the level of angiogenesis According to the literature review, there are only five at the feto-maternal interface may be an important reported cases of post partum complications due to determinant of obstetric outcome and placental bed perfusion endometriosis. These mainly refer to hemoperitoneum may differ between women with and without endometriosis. caused from bleeding ectopic decidual tissue in the appendix Polymorphisms in angiogenesis-regulating genes, and omentum [82], in the left broad ligament [83], from a focus of ectopic decidualization with vascular intrusion (left vascular endothelial growth factor (VEGF) in particular, are hypogastric artery) [84], a fistula formation between associated with pregnancy complications, including endometriotic lesions in the ovary and the adjacent colon spontaneous abortion, spontaneous preterm delivery and with secondary formation of an ovarian abscess and rupture preeclampsia [75]. Endometriosis is one of the best-known into the peritoneal cavity [85], and from a caesarean section conditions in which angiogenesis is altered. In addition to VEGF, the expression of several other angiogenic growth scar [86] (Table 2). factors and cytokines (IL-1, IL-6 and IL-8, FGF, IGF and The pathophysiology of hemoperitoneum formation due PGF) is enhanced in both eutopic and ectopic endometrium to endometriosis has already been meticulously analyzed. in women with endometriosis [76]. A recent study provided Ectopic decidualization, referring to extrauterine decidual in vivo evidence of excessive angiogenesis in endometriosis, changes of endometriotic lesions during pregnancy, is a finding significantly higher endometrial perfusion rates common finding at the time of caesarean delivery. Still during the late secretory phase of the cycle [77]. On the pregnant women are rarely symptomatic and this other hand, pre-eclampsia is characterized by insufficient phenomenon usually constitutes nothing more than a angiogenesis, resulting in endothelial cell dysfunction, vessel pathologic finding [84]. When symptomatic, the patient may malformation or regression and impaired re-vascularization present with heavy vaginal bleeding with a primary [78]. Increased impedance of intra-placental blood velocity diagnosis of choriocarcinoma or placental site trophoblastic waveforms has been detected as early as the 8th week of tumor [86]. The presence of endometriotic deposits in gestation in women who subsequently developed pre- old caesarean section scars in hysterectomy specimens is eclampsia or preterm labor [79]. likely to have been under-reported by pathologists [86]. Still, one retrospective review of hysterectomy specimens The results of a large population based study were not in revealed “iatrogenic adenomyosis” confined to the caesarean agreement with the aforementioned findings. Hadfield et al., scar in 28% of specimens [87]. 128 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Masouridou et al.

Table 2. Clinical Manifestations of Endometriosis in the Postpartum Period: Demographic Data and Pregnancy Outcome

Age Postpartum Signs and Symptoms Transfusion Outcome

O’Leary [84] 41 9 days ALAP, F >10 U RPC, FFP TAH/BSO, DVT

Sholapurkar [86] 37 6 weeks HVB, HVS 12 U RPC TAH

Floberg [85] 34 4 hours ALAP, PNP No Resection of abscess, SA

Hulme-Moir [82] 35 9 days ALAP, HMP Recovery

Richter [83] 36 1 day ALAP, HMP TAH/BSO

ALAP: Acute Low Abdominal Pain, F: Fever TAH/BSO: Total Abdominal Hysterectomy with Bilateral Salpingoophorectomy HMP: Hemoperitoneum, PNP: Pneumoperitoneum, HVB: Heavy Vaginal Bleeding, HVS: Hypovolemic Shock DVT: Deep Venous , SA: end-to-end sigmoid anastomosis RPC: Red Packed Cells, FFP: Fresh Frozen Plasma

The exact mechanism of endometriosis in abdominal controversial. Together with the studies reporting an or uterine scars remains unknown. Possible explanations increased risk for preterm birth in women with endo- include a) endometriotic metaplasia, b) endometriotic metriosis, physicians must be aware that close antenatal metastasis, c) endometriosis implantation, where wiping of follow-up and early diagnosis is crucial. Because of the the endometrium with sponges may cause spillage of complex situation of the mother and the fetus, prompt decidual tissue into the incision site, and d) entrapment of intervention may be required together with an adequate decidual tissue when suturing the uterine incision [86]. preparation of blood products. Of the overall five reported cases of postpartum CONFLICT OF INTEREST endometriotic manifestations, 3 had undergone total abdominal hysterectomy with massive transfusion, with one Declared none. of these women being primiparous. One patient developed deep venous thrombosis of the right upper extremity (Table ACKNOWLEDGEMENT 2). It seems that postpartum manifestations of endometriosis, Declared none. although extremely rare, can give rise to severe com- plications with a high possibility of irreversibly affecting the REFERENCES woman’s childbearing ability. Bearing these outcomes in mind, one should always thoroughly investigate a woman [1] Katorza E, Soriano D, Stockheim D, et al. Severe intraabdominal presenting with acute low abdominal pain in the postpartum bleeding caused by endometriotic lesions during the third trimester of pregnancy. Am J Obstet Gynecol 2007; 197: 501. period, especially if she has a history of endometriosis. [2] Gruppo Italiano per lo Studio dell’ Endometriosi. Prevalence and Prompt intervention may be a life and fertility saving anatomical distribution of endometriosis in women with selected procedure. gynaecological conditions: results from a multicentric Italian study. Hum Reprod 1994; 9: 1158-62. CONCLUSION [3] McArthur J, Ulfelder H. The effect of pregnancy upon endometriosis. Obstet Gynecol Surv 1965; 20: 709-33. Patients with endometriosis are increasing in number, [4] Hammond C, Haney A. Conservative treatment of endometriosis. and although endometriosis is a well-known cause of Fertil Steril 1978; 30: 497-509. [5] Aziz U, Kulkarni A, Lazik D, Cullimore JE. Spontaneous rupture infertility, ART techniques enable more women with the of the uterine vessels in pregnancy. Obstet Gynecol 2004; 103: disease to become pregnant. 1089-91. [6] Endometriosis and infertility. The Practice Committee of the Ectopic deciduosis is usually no more than a pathology American Society for Reproductive Medicine. Fertil Steril 2006; finding, and symptoms of endometriosis often disappear 86(4): 156-60. during pregnancy. Yet, endometriosis must be included in [7] Mahmood TA, Templeton A. Prevalence and genesis of the differential diagnosis of hemoperitoneum presenting endometriosis. Hum Reprod 1991; 6: 544-9. [8] D’Hooghe TM, Bambra CS, De Jonge I, Lauweryns JM, during pregnancy or of heavy vaginal bleeding postpartum. Raeymaekers BM, Koninckx PR. The effect of pregnancy on Both maternal and fetal morbidity and mortality can be quite endometriosis in baboons (Papio anubis, Papio cynocephalus). high and the woman’s childbearing ability might be Arch Gynecol Obstet 1997; 261: 15-19. irreversibly affected. [9] Inoue T, Moriwaki T, Niki I. Endometriosis and spontaneous rupture of utero-ovarian vessels during pregnancy. Lancet 1992; The bleeding can occur from spontaneous rupture of 340: 240-1. utero-ovarian vessels, or from endometrial lesions. Enlarging [10] Mizumoto Y, Furuya K, Kikuchi Y, et al. Spontaneous rupture of the uterine vessels in a pregnancy complicated by endometriosis. ovarian endometriomas during pregnancy should be more Acta Obstet Gynecol Scand 1996; 75: 860-2. carefully observed as there might be a higher risk for abscess [11] Leung WC, Leung TW, Lam YH. Haemoperitoneum due to formation or rupture. Available data on the association cornual endometriosis during pregnancy resulting in intrauterine between endometriosis and preeclampsia are at present death. Aust N Z J Obstet Gynaecol 1998; 38: 156-7. Endometriosis and Perinatal Outcome Current Women’s Health Reviews, 2012, Vol. 8, No. 2 129

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Received: June 5, 2011 Revised: October 31, 2011 Accepted: December 30, 2011