Pregnancy complications in patients with endometriosis Zullo et al. have done an extensive and thorough meta-analysis of the literature concerning endometriosis and pregnancy complications, one of the largest and most comprehensive studies to date (1). Their study provides further insight into endometriosis and pregnancy by combining the many heterogeneous studies on this topic, and it raises awareness of the many implications of endometriosis (2). Endometriosis is a common disorder estimated to affect 10% of women. There has been an increase in the diagnosis of endometriosis in pregnancy and endometriosis-associated complications in pregnancy. This is likely due to a combination of greater awareness of the disease among physicians and patients, improvement in imaging techniques, and significant technological advancement in video-laparoscopy. The increasing role of assisted reproductive technologies (ART) may successfully circumvent the infertility caused by endometriosis but may also exacerbate preexisting endometriosis. Complete and thorough treatment of endometriosis before or as an alternative to ART has been suggested (2, 3). Surgical treatment of mild to moderate endometriosis is generally accepted as the first-line treatment for subfertility (4) and has been shown to improve in vitro fertilization (IVF) outcomes (2). Endometriosis has been associated with lower live birth and pregnancy rates as well as lower numbers of oocyte retrievals with IVF. Surgical treatment of endometriosis, whenever possible, may have a number of advantages compared with ART without treatment of endometriosis. Although it is important to consider the risks of surgery (decreased ovarian reserve, potential damage to ovarian tissue, risk of oophorectomy, pelvic adhesion formation, etc.), we think that in experienced hands, these risks are small and that the benefits of treatment outweigh the risks. This is especially important given that women with endometriomas have been shown to have lower baseline antim€ ullerian hormone levels compared with women without endometriomas.
Prevention of Disease Progression Endometriosis is a progressive disease that, if not treated at an early stage, may lead to severe adhesive disease, pain, and organ dysfunction. Deep infiltrating endometriosis may result in significant morbidity, such as ureteral and bowel obstruction, etc. Treatment of endometriosis and spontaneous conception also avoids the use of ART. The high hormonal milieu associated with ART may stimulate growth of endometriotic implants and endometriomas.
Reduction in Ovarian Cancer Risk Endometriosis has been shown to be associated with endometrioid and clear cell ovarian cancer. Although imaging is neither sensitive nor specific for the malignant transformation of endometriotic implants, the finding most suggestive of malignant change is the presence of one or more contrast-enhanced mural nodules within a cystic mass. Due 602
to their endometriosis-related symptomatology, these cancers are more frequently diagnosed at stage I, have fewer cases of residual tumor burden, and have better survival rates. For patients with disease confined to the site of origin, 5-year survival rates range from 82% to 100%, whereas patients with disseminated intraperitoneal disease face a poor prognosis of 0%–12% 5-year survival (5). Complete surgical resection followed by medical therapy for elimination of endometriosis has the potential to substantially decrease the risk of malignant transformation; therefore, we recommend early treatment to decrease the risks of epithelial ovarian cancer.
Improved Pregnancy Outcomes Treatment of endometriosis may prevent a number of associated complications of pregnancy, as discussed by Zullo et al. There are numerous theories regarding the pathophysiology of adverse pregnancy outcomes associated with endometriosis. They may be due to a proinflammatory environment with high levels of cytokine production as well as changes to the inner myometrium referred to as the ‘‘junctional zone.’’ Complications include preterm birth, placenta previa, small for gestational age, cesarean section, and miscarriage (1). Other rarer complications of endometriosis in pregnancy also have been described: spontaneous hemoperitoneum in pregnancy, obstetrical hemorrhage, bowel perforation, and appendiceal rupture. Although many endometriomas regress during pregnancy owing to progestational effects, there have been cases of endometrioma rupture and abscess formation. These complications are associated with significant maternal and fetal morbidity and potential mortality. It is not known if endometriosis is the cause of these complications or merely a marker of an independent risk factor, and no studies have evaluated if antepartum treatment of endometriosis or endometrioma improves pregnancy outcomes. One study showed that subfertile women who conceived spontaneously were also at increased risk of pregnancy complications, such as antepartum hemorrhage, cesarean section, pregnancyinduced hypertension, preeclampsia, and very preterm birth. Further studies are needed to elucidate the true relationship between endometriosis and pregnancy complications. One potential confounding variable in many of the studies is the use of ART, which is commonly used in patients with endometriosis. ART itself may be associated with pregnancy complications, such as miscarriage, preterm birth, and cesarean section. A large population-based study of 82,793 Danish women found that adverse pregnancy outcomes remained the same when stratified for those who received ART versus those who did not. This supports the notion that endometriosis is an independent risk factor for adverse pregnancy outcomes regardless of ART. The lack of well designed studies and the heterogeneity in results supports the need for more research in this area. We need to focus on a noninvasive test for early diagnosis, treatment, and prevention of this disease. CA-125 levels are VOL. 108 NO. 4 / OCTOBER 2017
Fertility and Sterility® nonspecific, but there has been some promise with serum interleukin-6 as a noninvasive marker for endometriosis in a number of studies. Serum soluble intercellular adhesion molecule 1 also may be useful in detecting cases of deep peritoneal endometriosis. However, larger studies are still needed before these tests can be put to widespread use. Congratulations to the authors for this welcome addition to the literature. Camran Nezhat, M.D.a,b,c Stacy Young, M.D.a,b Megan Kennedy Burns, M.D., M.A.a,b Elizabeth Johns, M.S.c Pengfei Wang, M.D., Ph.D.d a Center for Special Minimally Invasive and Robotic Surgery and Camran Nezhat Institute, Palo Alto, California; b Stanford University Medical Center, Stanford, California; c University of California, San Francisco, California; and d New York University–Winthrop Hospital, New York, New York
You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/19284-24823
REFERENCES 1.
2.
3.
4.
5.
http://dx.doi.org/10.1016/j.fertnstert.2017.08.014
VOL. 108 NO. 4 / OCTOBER 2017
Zullo F, Spagnolo E, Saccone G, Acunzo M, Xodo S, Ceccaroni M, Berghella V. Endometriosis and obstetrics complications: a systematic review and metaanalysis. Fertil Steril 2017;108:667–72. Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005;84:1574–8. Soriano D, Adler I, Bouaziz J, Zolti M, Eisenberg VH, Goldenberg M, Seidman DS, Elizur SE. Fertility outcome of laparoscopic treatment in patients with severe endometriosis and repeated in vitro fertilization failures. Fertil Steril 2016;106:1264–9. Duffy JM, Arambage K, Correa FJ, Olive D, Garry R, Barlow DH, Farquhar C, Jacobson TZ. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev 2014, Issue 3. Art. No.:CD011031. Nezhat F, Datta SM, Hanson V, Pejovic T, Nezhat C, Nezhat C. The relationship of endometriosis and ovarian malignancy: a review. Fertil Steril 2008;90:1559–70.
603
Prevention of Disease Progression Endometriosis is a progressive disease that, if not treated at an early stage, may lead to severe adhesive disease, pain, and organ dysfunction. Deep infiltrating endometriosis may result in significant morbidity, such as ureteral and bowel obstruction, etc. Treatment of endometriosis and spontaneous conception also avoids the use of ART. The high hormonal milieu associated with ART may stimulate growth of endometriotic implants and endometriomas.
Reduction in Ovarian Cancer Risk Endometriosis has been shown to be associated with endometrioid and clear cell ovarian cancer. Although imaging is neither sensitive nor specific for the malignant transformation of endometriotic implants, the finding most suggestive of malignant change is the presence of one or more contrast-enhanced mural nodules within a cystic mass. Due 602
to their endometriosis-related symptomatology, these cancers are more frequently diagnosed at stage I, have fewer cases of residual tumor burden, and have better survival rates. For patients with disease confined to the site of origin, 5-year survival rates range from 82% to 100%, whereas patients with disseminated intraperitoneal disease face a poor prognosis of 0%–12% 5-year survival (5). Complete surgical resection followed by medical therapy for elimination of endometriosis has the potential to substantially decrease the risk of malignant transformation; therefore, we recommend early treatment to decrease the risks of epithelial ovarian cancer.
Improved Pregnancy Outcomes Treatment of endometriosis may prevent a number of associated complications of pregnancy, as discussed by Zullo et al. There are numerous theories regarding the pathophysiology of adverse pregnancy outcomes associated with endometriosis. They may be due to a proinflammatory environment with high levels of cytokine production as well as changes to the inner myometrium referred to as the ‘‘junctional zone.’’ Complications include preterm birth, placenta previa, small for gestational age, cesarean section, and miscarriage (1). Other rarer complications of endometriosis in pregnancy also have been described: spontaneous hemoperitoneum in pregnancy, obstetrical hemorrhage, bowel perforation, and appendiceal rupture. Although many endometriomas regress during pregnancy owing to progestational effects, there have been cases of endometrioma rupture and abscess formation. These complications are associated with significant maternal and fetal morbidity and potential mortality. It is not known if endometriosis is the cause of these complications or merely a marker of an independent risk factor, and no studies have evaluated if antepartum treatment of endometriosis or endometrioma improves pregnancy outcomes. One study showed that subfertile women who conceived spontaneously were also at increased risk of pregnancy complications, such as antepartum hemorrhage, cesarean section, pregnancyinduced hypertension, preeclampsia, and very preterm birth. Further studies are needed to elucidate the true relationship between endometriosis and pregnancy complications. One potential confounding variable in many of the studies is the use of ART, which is commonly used in patients with endometriosis. ART itself may be associated with pregnancy complications, such as miscarriage, preterm birth, and cesarean section. A large population-based study of 82,793 Danish women found that adverse pregnancy outcomes remained the same when stratified for those who received ART versus those who did not. This supports the notion that endometriosis is an independent risk factor for adverse pregnancy outcomes regardless of ART. The lack of well designed studies and the heterogeneity in results supports the need for more research in this area. We need to focus on a noninvasive test for early diagnosis, treatment, and prevention of this disease. CA-125 levels are VOL. 108 NO. 4 / OCTOBER 2017
Fertility and Sterility® nonspecific, but there has been some promise with serum interleukin-6 as a noninvasive marker for endometriosis in a number of studies. Serum soluble intercellular adhesion molecule 1 also may be useful in detecting cases of deep peritoneal endometriosis. However, larger studies are still needed before these tests can be put to widespread use. Congratulations to the authors for this welcome addition to the literature. Camran Nezhat, M.D.a,b,c Stacy Young, M.D.a,b Megan Kennedy Burns, M.D., M.A.a,b Elizabeth Johns, M.S.c Pengfei Wang, M.D., Ph.D.d a Center for Special Minimally Invasive and Robotic Surgery and Camran Nezhat Institute, Palo Alto, California; b Stanford University Medical Center, Stanford, California; c University of California, San Francisco, California; and d New York University–Winthrop Hospital, New York, New York
You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/19284-24823
REFERENCES 1.
2.
3.
4.
5.
http://dx.doi.org/10.1016/j.fertnstert.2017.08.014
VOL. 108 NO. 4 / OCTOBER 2017
Zullo F, Spagnolo E, Saccone G, Acunzo M, Xodo S, Ceccaroni M, Berghella V. Endometriosis and obstetrics complications: a systematic review and metaanalysis. Fertil Steril 2017;108:667–72. Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005;84:1574–8. Soriano D, Adler I, Bouaziz J, Zolti M, Eisenberg VH, Goldenberg M, Seidman DS, Elizur SE. Fertility outcome of laparoscopic treatment in patients with severe endometriosis and repeated in vitro fertilization failures. Fertil Steril 2016;106:1264–9. Duffy JM, Arambage K, Correa FJ, Olive D, Garry R, Barlow DH, Farquhar C, Jacobson TZ. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev 2014, Issue 3. Art. No.:CD011031. Nezhat F, Datta SM, Hanson V, Pejovic T, Nezhat C, Nezhat C. The relationship of endometriosis and ovarian malignancy: a review. Fertil Steril 2008;90:1559–70.
603
