Ivo Brosens1 and Giuseppe Benagiano2
Leuven Institute for Fertility and Embryology, Catholic University Leuven, Leuven, Belgium
Department of Gynecology, Obstetrics and Urology, Sapienza University, Rome, Italy
An association between endometriosis and infertility has been confirmed by a large number of studies, although mechanisms are still debated. The availability of in vitro fertilization represented a major step forward in achieving pregnancy in women with endometriosis, although in both peritoneal and ovarian disease, there is an adverse effect on ovulation rates, markers of ovarian reserve, and response to ovarian stimulation. Results have improved using intracytoplasmic sperm injection.
When achieved, pregnancy may be complicated by spontaneous hemoperitoneum, a rare but potentially fatal event. Data on incidence of preeclampsia, small for gestational age (SGA), and preterm birth are not univocal. A large cohort study found an increased risk of preterm birth; another observed no evidence for an association between endometriosis and risk of pregnancy hypertension, or preeclampsia; a third found increased rates of both preterm birth and SGA. In pregnancies complicated by the presence of ovarian endometrioma no differences have been observed in late pregnancy and neonatal outcomes.
Endometriosis patients seem to be at an increased risk of placenta previa and postpartum hemorrhage. An association has been found also when pregnancy is achieved through in vitro fertilization, suggesting that events around the time of implantation may be responsible.
With regard to pathophysiology, the hypothesis has been proposed that defective spiral artery remodeling may be the cause of major obstetrical syndromes in endometriosis and adenomyosis and that endometrial and myometrial junctional zone (MJZ) abnormalities represent a risk factor for the vascular development of the placental bed.
Available evidence supports the idea of a reversibility of MJZ changes by appropriate medication inducing a prolonged hypoestrogenic period.
AdenomyosisEndometriosisObstetrical complicationsSpontaneous hemoperitoneum
A clinical association between endometriosis and infertility has been suspected for more than 60 years [1, 2] and confirmed by a large number of studies, although mechanisms are still debated [3, 4]. Indeed, a study conducted some time ago reported that between 30 and 50 % of women with endometriosis are infertile and the prevalence of endometriosis in women with infertility may be between 25 and 50 % . Recently, an opinion by the American Society for Reproductive Medicine  confirmed such an association stating that “endometriosis typically present with pelvic pain, infertility, or an adnexal mass, and may require surgery.”
Although decreased fertility in women with endometriosis is today well established, causes seem to be multifactorial, involving mechanical, molecular, genetic, and environmental ones [4–6].
In the event of severe disease causes are usually evident, since pelvic anatomy becomes distorted and, when this happens, mechanical factors, such as pelvic adhesions, may directly impair fertility disrupting oocyte release or pickup, altering sperm motility, disorganizing myometrial contractions, and impairing fertilization and tubal embryo transport .
In 2010, de Ziegler et al.  summarized possible mechanisms through which endometriosis may impair fertility at all stages. These include:
· Changes in the composition and characteristics of peritoneal fluid capable of affecting fertilization and associated with pelvic inflammation. As a result, sperm motility may be impaired and sperm capacitation inhibited; in addition, oocyte–sperm interactions may also be hindered, sperm binding to the zona pellucida decreased, and the acrosome reaction and sperm–oocyte fusion impaired.
· A direct effect of endometriosis on oocyte and embryo quality has been proposed, although there is no agreement on this point.
· In the presence of an ovarian endometrioma, the age-dependent decline in the number of ovarian follicles can occur earlier in life.
· The eutopic endometrium is altered in women with endometriosis and may become less receptive because of a local production of estradiol and of progesterone resistance.
In conclusion, endocrine and paracrine pathways in human endometriotic cells that are modulated by estrogens and progestogens, including chemotaxis and apoptosis, are perturbed in women with endometriosis, contributing to inflammatory responses. These phenomena promote adhesion formation and infertility .
The availability of in vitro fertilization (IVF) followed by embryo transfer (ET) has been considered as a major step forward in achieving pregnancy in women suffering from endometriosis. Unfortunately, it was soon found that in both peritoneal and ovarian diseases, there is an adverse effect on ovulation rates, markers of ovarian reserve, and response to ovarian stimulation . In particular, the presence of an endometrioma can reduce ovarian reserve and decrease the number of oocytes retrieved [10, 11]; this effect has been attributed to endometriosis itself , although these findings are controversial [12–14].
In a recent Chinese cohort study, following surgery for endometrioma, the bFSH level was higher and the numbers of oocytes retrieved were lower . It seems therefore that, on the one hand, cystectomy carries away ovarian follicles and, on the other, endometriosis itself seems to have a detrimental effect on ovarian follicles.
The latter hypothesis is substantiated by studies involving patients with peritoneal endometriosis: back in 2001, Hock et al. found that women with stage III/IV (rAFS) have a reduced ovarian reserve compared to women with stage I/II . This observation is consistent with progressive loss of ovarian reserve in women with increasing stages of endometriosis, independent of age. As pointed out by Hauzman et al. , in patients with endometriosis, endometrial receptivity is also compromised; this is evidenced in oocyte donation cycles, where lower implantation rates can be observed in subjects without endometriosis if they receive an oocyte from a patient with endometriosis. Interestingly, oocytes donated by healthy subjects provide the patient with endometriosis similar chances to achieve pregnancy to women without the disease.
The solution proposed for women with endometriosis who wish to achieve pregnancy through IVF-ET is the use of intracytoplasmic sperm injection (ICSI). Indeed, a recent Norwegian study  found that, using ICSI and leaving aside patients with endometrioma, infertile women with various stages of endometriosis have the same success rates as patients with tubal factor. On the basis of their results these authors have urged the European Society of Human Reproduction and Embryology (ESHRE) to modify its recommendations.
Notwithstanding the abovementioned problems, a large number of women with endometriosis-associated infertility can today conceive following surgery and/or IVF-ET. This makes mandatory an evaluation of pregnancy and its outcome in women with endometriosis, given that recent epidemiological studies are drawing the attention to changes in the uterine environment in association with this condition. The cellular and molecular changes in the endometrium in association with endometriosis and adenomyosis have been reviewed by Benagiano et al. . Changes in the inner myometrium, the so-called myometrial junction zone (JZ), have been observed since it became possible to diagnose adenomyosis by magnetic resonance (MR) imaging. These structural modifications were first described by Bazot et al. [20, 21] and Kunz et al. [22, 23]. However, endometriosis and adenomyosis are at present diagnosed, respectively, by laparoscopy and imaging techniques (MR and ultrasonography) and the two are not both routinely performed as complementary examinations when endometriosis or adenomyosis is diagnosed . At any rate, in reviewing obstetrical complications in association with endometriosis, the presence of alteration in the myometrial JZ is of critical importance. Therefore, this review will also include studies on pregnancy complications in women with adenomyosis. After reviewing the obstetrical complications the underlying mechanisms in the endometrium and myometrial JZ will be discussed.
28.2 Spontaneous Hemoperitoneum in Pregnancy and Postpartum
28.2.1 Rare, but Dramatic
Pregnancy may have a beneficial effect on endometriotic implants, but carries an increased risk of spontaneous hemoperitoneum in pregnancy (SHiP), fortunately a rare event, but an important cause of maternal and fetal death . A review of case reports suggests a major role of pelvic endometriosis in the pathogenesis of SHiP . Even cases where no endometriosis is noted at the time of intervention may be caused by endometriosis, since peritoneal endometriotic implants undergo decidual changes in the first trimester of pregnancy, characterized by loss of pigmentation and fibrosis, which renders visual diagnosis more difficult . If the lesion is not biopsied at the time of an emergency laparotomy, the diagnosis of endometriosis as a cause for SHiP will often be missed.
Massive spontaneous hemoperitoneum associated with mild endometriosis has also been described in the postpartum period and at the time of menstruation [28–30]. In addition, rupture of the sigmoid or appendix during late pregnancy in nulliparous women has been related to decidualization of endometriotic implants [31–33].
Invasiveness of severe endometriosis has been suggested as a reason for SHiP, but there is no apparent correlation between SHiP and stage of endometriosis. An alternative explanation is that SHiP results from involution of decidualized ectopic endometrium during pregnancy. In the differentiation of mesenchymal cells, decidualization represents “the point of no return”; after which the cellular integrity becomes inextricably dependent upon sustained progesterone signaling . Falling progesterone levels not only reverse the decidual phenotype, but also induce the expression of a gene network that encodes for chemokines, proinflammatory cytokines, matrix metalloproteinases, and apoptotic factors, leading to influx of inflammatory cells, proteolytic breakdown of the extracellular matrix, cell death, and bleeding. Interestingly, emerging evidence suggests that endometriosis is associated with progesterone resistance, characterized by suboptimal expression of target genes . Therefore, it is tempting to speculate that “functional” progesterone withdrawal triggers involution of the decidual phenotype of the ectopic endometrium surrounding distended parametrial veins, leading to peritoneal bleeding of unpredictable severity.
28.3 Obstetrical Complications Associated with Endometriosis
28.3.1 Preeclampsia, Small for Gestational Age (SGA), and Preterm Birth
In 2003, a matched case-control study of 137 pregnant patients with endometriosis, including IVF patients, found no difference in pregnancy outcome . A few years later, a retrospective case-control study of infertile women with laparoscopy-confirmed endometriosis from the University of Ghent found a significantly lower incidence of preeclampsia and pregnancy-induced hypertension in women with endometriosis than in a control group of male-factor infertility (0.8 % versus 7.5 %, 95 % CI: 1.7–33.3) . These studies set the stage for several other investigations evaluating the risk of obstetrical complications in women with endometriosis (Table 28.1).
Obstetrical complications of pregnancy after ART in women with endometriosis
Nature of complication
In comparison with
ART without endometriosis
Increased (38, 40)a
No increase (38)
No increase (38)
aIncreased only if endometrioma
A nationwide Swedish study including 1,442,675 singleton births between 1992 and 2006 reported in 13.090 singleton births among 8,922 women diagnosed with endometriosis, an increased risk of preterm birth irrespective of assisted reproduction technology (ART), antepartal bleeding/placental complications, preeclampsia, and Caesarean section. There was no association between endometriosis and SGA or stillbirth . On the other hand, a population-based, longitudinal Australian study found in 3,239 women with endometriosis aged between 15 and 45 years no evidence for an association between endometriosis and subsequent risk of either pregnancy hypertension or preeclampsia, even after adjusting for age and gestational age . A retrospective cohort study by Fernando et al.  found in 95 singletons ART babies from patients with ovarian endometriomas increased rates of preterm birth and SGA in comparison with community birth records and with other forms of endometriosis.
The association between endometriosis and preeclampsia remains controversial. Unfortunately, the epidemiological studies were not controlled for changes in the myometrial JZ that plays a critical role in the pathogenesis of pregnancy complications such as preeclampsia or SGA and to a lesser extent in preterm birth and preterm premature rupture of the membranes [41–43]. It should be noted that a case-control study of preterm delivery in patients with adenomyosis by Juang et al.  found an increased risk of both spontaneous preterm delivery and preterm premature rupture of the membranes. This finding underlines the interest to evaluate potential changes in the myometrial JZ in studies on obstetrical complications in women with endometriosis.
28.3.2 Presence of Ovarian Endometrioma During Pregnancy
Pregnancy complicated by ovarian endometrioma is a rare event . Benaglia et al.  analyzed data from patients achieving singleton clinical pregnancies through IVF comparing the pregnancy outcome between 78 pregnant women with endometriomas at the time of IVF and 156 patients who achieved pregnancy through IVF without endometriomas. No differences were observed in late pregnancy and neonatal outcomes between the two groups. In particular, the rate of preterm birth and SGA was similar. However, the study included all hemorrhagic cysts from 1 cm persisting for 2 months. Garcia-Velasco and Somigliana  recommended proceeding directly to IVF to reduce time to pregnancy, to avoid potential surgical complications, and to limit patient costs. On the other hand, no attention is paid to the progressive vascular sclerosis in the endometrioma bed as demonstrated by the color Doppler sonographic studies of Qiu et al.  indicating that the delayed diagnosis and surgery are the main factors of follicular loss.
28.3.3 Placenta Previa and Postpartum Hemorrhage
ART has been suspected for some reason to increase the risk of obstetrical hemorrhages including placenta previa, a life-threatening complication of pregnancy. The retrospective cohort study by Healy et al.  compared the prevalence of antepartum hemorrhage, placenta previa, placental abruption, and primary postpartum hemorrhage in women with singleton births between 1991 and 2004. Endometriosis patients had more placenta previa (1.7; 1.2–2.4) and postpartum hemorrhage (1.3; 1.1–1.6) than those without endometriosis. The exploratory analysis of factors in the IVF/ICSI group, showing associations with fresh embryo transfers in stimulated cycles, endometriosis, and hormone treatments, suggested that events around the time of implantation may be responsible and that suboptimal endometrial function is the critical mechanism. Takemura et al.  confirmed by logistic regression analysis in a group of consecutive 318 pregnancies conceived by ART that the risk of placenta previa in relation of ten variables (maternal age, gravidity, parity, male or female fetus, previous abortion, previous Caesarean delivery, endometriosis, ovulatory disorder, tubal disease, and male infertility) is related to endometriosis (odds ratio = 15.1; 95 % CI = 7.6–500.0) and tubal disease (odds ratio = 4.4; 95 % CI = 1.1–26.3). According to the study of Sazonova et al.  blastocyst transfer increases the risk of placenta previa after IVF in singleton pregnancies.
In a recent retrospective study, Vercellini et al.  assessed pregnancy outcome in 419 women who achieved a first spontaneous singleton pregnancy after surgery for different types of endometriosis. The study found an incidence of placenta previa of 7.6 % in 150 women with rectovaginal lesions; 2.1 % in 69 with ovarian endometriomas plus peritoneal implants; and 2.4 % in 100 women with peritoneal implants only. No case of placenta previa was observed in 100 women with ovarian endometriomas only.
28.3.4 Pathophysiology of the Myometrial Junction Zone in Endometriosis
Endometriosis, a chronic inflammatory disorder, disrupts coordinated progesterone responses throughout the reproductive tract, including in the endometrium. This phenomenon is increasingly referred to as “progesterone resistance.” Emerging evidence suggests that progesterone resistance in endometriosis is not just a consequence of perturbed progesterone signal transduction caused by chronic inflammation, but is associated with epigenetic chromatin changes that determine the intrinsic responsiveness of endometrial cells to differentiation cues . Petraglia et al.  speculated that an exaggerated inflammatory reaction or the lack of a response can activate the inflammatory process in placental membranes and myometrium. An overlap of molecules and mechanisms may explain the evidence that preterm birth is a common outcome in pregnant patients with endometriosis. A correlation with preterm birth has been suggested for both endometriosis [38, 40] and adenomyosis .
In the human, the process of tissue remodeling in preparation of deep placentation starts in the secretory phase of the menstrual cycle. Successful pregnancy requires full transformation of the spiral arteries in the placental bed artery from their origin in the myometrial junction zone . Recently Brosens et al.  discussed the hypothesis of defective spiral artery remodeling as a cause of major obstetrical syndromes in endometriosis and adenomyosis. The process is first characterized by an influx of specialized uterine natural killer cells and decidualization of the endometrial stroma and its vasculature; then, after implantation, the interstitial and endovascular trophoblast invasion begins. The final process results in transformation of the spiral arteries into large uteroplacental arteries in the endometrium and myometrial JZ. Kim et al. [42, 43] suggested that in the absence of an adequate decidual effect endovascular trophoblast cell invasion is arrested at the level of the endometrial–myometrial junction and failed to progress into the myometrial spiral arteries. This could explain the vascular resistance in preterm premature rupture of the membranes and preterm birth. Defective endovascular trophoblast invasion can also be secondary to absence of natural killer cells in the thickened myometrial JZ. It is generally accepted that natural killer cells, which are present around spiral arteries in the basal decidua, but not deeper in the myometrium, play a role in determining the depth of interstitial and endovascular trophoblast [57, 58].
The question then arises whether the endometrial and myometrial JZ abnormalities associated with endometriosis at the time of implantation represent a risk factor for the vascular development of the placental bed. Unfortunately, no studies have yet been performed on biopsies of the placental bed in women with endometriosis to investigate the pattern and extent of deep placentation decidualization. Despite the lack of histopathological investigations, clinical studies have reported an association between endometriosis and disorders such as preterm delivery that are associated with defective deep placentation.
28.4 Pituitary Downregulation and Pregnancy Outcome in Endometriosis and Adenomyosis
The vital question is whether the uterine microenvironment in endometriosis and adenomyosis can be improved by medical therapy and pregnancy rates in infertile patients enhanced.
Recently, Maubon et al.  investigated in a retrospective study the impact of the JZ structure on the likelihood of pregnancy after IVF-ET treatment and found that a pelvic MR scan showing a thickened uterine JZ represents a negative predictive factor for embryo implantation after IVF-ET.
Nakagawa et al.  suggested that treatment with a superagonist gonadotropin-releasing hormone analog (GnRHa) prior to IVF-ET could improve the implantation rate following IVF in infertile patients with endometriosis. The results of this study were confirmed in a retrospective study of 74 infertile patients with surgically proven endometriosis and adenomyosis who were treated with IVF-ET . All patients were pretreated with long-term GnRHa prior to IVF-ET. The contemporary presence of adenomyosis had apparently no adverse effects on IVF-ET outcomes in women with endometriosis when pretreated with long-term pituitary downregulation. In a small case series Tremellen and Russell  described four women, who previously had undergone multiple unsuccessful IVF cycles because of failure of implantation of good quality embryos who had a coexisting uterine adenomyosis. The inactivation of adenomyosis by an ultra-long pituitary downregulation regime promptly resulted in successful pregnancy for all four women. Given that the majority of fertility clinics are now moving towards the more “patient-friendly” antagonist protocol, where patients are not placed in a hypoestrogen state before commencing ovarian stimulation, the question of whether adenomyosis has an impact on IVF success rates in GnRHa antagonist-stimulated IVF treatment needed to be examined. In a recent retrospective cohort study of 748 patients who underwent a screening transvaginal ultrasound to identify possible pelvic pathology before commencing their IVF treatment, Talluri and Tremellen  identified 213 patients who were eligible to be included in the adenomyosis study as they had no obvious underlying uterine or embryonic factors that could have interfered with successful implantation. The adenomyosis group had a viable clinical pregnancy rate of 23.6 compared with 44.6 in the non-adenomyosis group (P = 0. 017). This is the first study to clearly describe an implantation problem in a relatively large cohort exclusively undergoing GnRHa antagonist cycles in women with ultrasound-diagnosed adenomyosis. Thus, available evidence supports the idea of a reversibility of myometrial JZ changes by appropriate medication inducing a prolonged hypoestrogenic period. More studies will be required to evaluate the beneficial effect of pituitary downregulation during the cycle of conception on deep placentation in women with adenomyosis and the potential of this treatment for the prevention of major obstetrical complications associated with defective deep placentation.
Subtle lesions and symptoms of endometriosis often disappear during pregnancy and postpartum. The shedding of decidualized tissue may cause bleeding and the differential diagnosis of spontaneous hemoperitoneum should be taken into account in pregnancy and postpartum, since both maternal and fetal outcomes can be dramatic.
The available data on the association between endometriosis and obstetrical complications are still controversial for several reasons. In the first place, studies are frequently based on laparoscopy for the diagnosis of endometriosis and fail to take into account myometrial JZ thickening or adenomyosis as a potential risk of obstetrical complications. Secondly, the diagnosis of the endometrioma is still based on laparoscopy and ultrasound, but fails to take into account the degree of vascular sclerosis and follicular loss, as demonstrated by the color Doppler flow sonographic studies of Qiu et al. . Finally, the potential effect of prolonged hypoestrogenic treatment may modify risk factors at the time of conception. It is clear that, together with studies reporting an increased risk for preterm birth in women with endometriosis, physicians must be aware that close antenatal follow-up and early diagnosis of vascular complications are crucial.
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