Master Class

Introduction: Imaging for Endometriosis — A Necessary Prerequisite

While the gold standard in the diagnosis of endometriosis remains laparoscopy, it is now recognized that thorough evaluation via ultrasound offers an acceptable, less expensive, and less invasive alternative. It is especially useful for the diagnosis of deep infiltrative disease, which penetrates more than 5 mm into the peritoneum, ovarian endometrioma, and when anatomic distortion occurs, such as to the path of the ureter.

Besides establishing the diagnosis, ultrasound imaging has become, along with MRI, the most important aid for proper preoperative planning. Not only does imaging provide the surgeon and patient with knowledge regarding the extent of the upcoming procedure, but it also allows the minimally invasive gynecologic (MIG) surgeon to involve colleagues, such as colorectal surgeons or urologists. For example, deep infiltrative endometriosis penetrating into the bowel mucosa will require a discoid or segmental bowel resection.

Miller_Charles_E 2014_web.jpg

While many endometriosis experts rely on MRI, many MIG surgeons are dependent on ultrasound. I would not consider taking a patient with signs and symptoms suggestive of endometriosis to surgery without 2D/3D transvaginal ultrasound. If the patient possesses a uterus, a saline-infused sonogram is performed to potentially diagnose adenomyosis.

It is a pleasure and honor to welcome Professor Caterina Exacoustos MD, PhD, associate professor of ob.gyn. at the University of Rome “Tor Vergata,” to this edition of the Master Class in Gynecologic Surgery to discuss “Ultrasound and Its Role in the Diagnosis of and Management of Endometriosis, Including DIE.”

Prof. Exacoustos’ main areas of interest are endometriosis and benign diseases including uterine pathology and infertility. Her extensive body of work comprises over 120 scientific publications and numerous book chapters both in English and in Italian.

Prof. Exacoustos continues to be one of the most well respected lecturers speaking about ultrasound throughout the world.
 

Dr. Miller is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. Dr. Miller has no conflicts of interest to report.

Ultrasound and Its Role In Diagnosing and Managing Endometriosis

Endometriosis affects approximately 10%-20% of premenopausal women worldwide. It is the leading cause of chronic pelvic pain, is often associated with infertility, and has a significant impact on quality of life. Although the natural history of endometriosis remains unknown, emerging evidence suggests that the pathophysiological steps of initiation and development of endometriosis must occur earlier in the lifespan. Most notably, the onset of endometriosis-associated pain symptoms is often reported during adolescence and young adulthood.¹

While many patients with endometriosis are referred with dysmenorrhea at a young age, at age ≤ 25 years,² symptoms are often highly underestimated and considered to be normal and transient.^3,4 Clinical and pelvic exams are often negative in young women, and delays in endometriosis diagnosis are well known.

The presentation of primary dysmenorrhea with no anatomical cause embodies the paradigm that dysmenorrhea in adolescents is most often an insignificant disorder. This perspective is probably a root cause of delayed endometriosis diagnosis in young patients. However, another issue behind delayed diagnosis is the reluctance of the physician to perform a diagnostic laparoscopy — historically the gold standard for diagnosing endometriosis — for seemingly common symptoms such as dysmenorrhea in young patients.

Today we know that there are typical aspects of ultrasound imaging that identify endometriosis in the pelvis, and notably, the 2022 European Society for Human Reproduction and Embryology (ESHRE) endometriosis guideline⁵ recognizes imaging (ultrasound or MRI) as the standard for endometriosis diagnosis without requiring laparoscopic or histological confirmation.

An early and noninvasive method of diagnosis aids in timely diagnosis and provides for the timely initiation of medical management to improve quality of life and prevent progression of disease (Figure 1).

167312_Figure 1_web.jpg

(A. Transvaginal ultrasound appearance of a small ovarian endometrioma in a 16-year-old girl. Note the unilocular cyst with ground glass echogenicity surrounded by multifollicular ovarian tissue. B. Ultrasound image of a retroverted uterus of an 18-year-old girl with focal adenomyosis of the posterior wall. Note the round cystic anechoic areas in the inner myometrium or junctional zone. The small intra-myometrial cyst is surrounded by a hyperechoic ring).

Indeed, the typical appearance of endometriotic pelvic lesions on transvaginal sonography, such as endometriomas and rectal deep infiltrating endometriosis (DIE) — as well as adenomyosis – can be medically treated without histologic confirmation .

When surgery is advisable, ultrasound findings also play a valuable role in presurgical staging, planning, and counseling for patients of all ages. Determining the extent and location of DIE preoperatively, for instance, facilitates the engagement of the appropriate surgical specialists so that multiple surgeries can be avoided. It also enables patients to be optimally informed before surgery of possible outcomes and complications.

Moreover, in the context of infertility, ultrasound can be a valuable tool for understanding uterine pathology and assessing for adenomyosis so that affected patients may be treated surgically or medically before turning to assisted reproductive technology.
 

Uniformity, Standardization in the Sonographic Assessment

In Europe, as in the United States, transvaginal sonography (TVS) is the first-line imaging tool for the diagnosis and management of endometriosis. In Europe, many ob.gyns. perform ultrasound themselves, as do treating surgeons. When diagnostic findings are negative but clinical suspicion is high, MRI is often utilized. Laparoscopy may then be considered in patients with negative imaging results.

Efforts to standardize terms, definitions, measurements, and sonographic features of different types of endometriosis have been made to make it easier for physicians to share data and communicate with each other. A lack of uniformity has contributed to variability in the reported diagnostic accuracy of TVS.

About 10 years ago, in one such effort, we assessed the accuracy of TVS for DIE by comparing TVS results with laparoscopic/histologic findings, and developed an ultrasound mapping system to accurately record the location, size and depth of lesions visualized by TVS. The accuracy of TVS ranged from 76% for the diagnosis of vaginal endometriosis to 97% for the diagnosis of bladder lesions and posterior cul-de-sac obliteration. Accuracy was 93% and 91% for detecting ureteral involvement (right and left); 87% for uterosacral ligament endometriotic lesions; and 87% for parametrial involvement.⁶

Shortly after, with a focus on DIE, expert sonographers and physician-sonographers from across Europe — as well as some experts from Australia, Japan, Brazil, Chile, and the United States (Y. Osuga from Brigham and Women’s Hospital and Harvard Medical School) — came together to agree on a uniform approach to the sonographic evaluation for suspected endometriosis and a standardization of terminology.

The consensus opinion from the International Deep Endometriosis Analysis (IDEA) group details four steps for examining women with suspected DIE: 1) Evaluation of the uterus and adnexa, 2) evaluation of transvaginal sonographic “soft markers” (ie. site-specific tenderness and ovarian mobility), 3) assessment of the status of the posterior cul-de-sac using real-time ultrasound-based “sliding sign,” and 4) assessment for DIE nodules in the anterior and posterior compartments.⁷

Our paper describing a mapping system and the IDEA paper describe how to detect deep endometriosis in the pelvis by utilizing an ultrasound view of normal anatomy and pelvic organ structure to provide landmarks for accurately defining the site of DIE lesions (Figure 2).

167312_figure 2_web.jpg

(A. Ultrasound appearance of a small DIE lesion of the retrocervical area [white arrows], which involved the torus uterinum and the right uterosacral ligament [USL]. The lesion appears as hypoechoic tissue with irregular margins caused by the fibrosis induced by the DIE. B. TVS appearance of small nodules of DIE of the left USL. Note the small retrocervical DIE lesion [white arrows], which appears hypoechoic due to the infiltration of the hyperechoic USL. C) Ultrasound appearance of a DIE nodule of the recto-sigmoid wall. Note the hypoechoic thickening of the muscular layers of the bowel wall attached to the corpus of the uterus and the adenomyosis of the posterior wall. The retrocervical area is free. D. TVS appearance of nodules of DIE of the lower rectal wall. Note the hypoechoic lesion [white arrows] of the rectum is attached to a retrocervical DIE fibrosis of the torus and USL [white dotted line]).

So-called rectovaginal endometriosis can be well assessed, for instance, since the involvement of the rectum, sigmoid colon, vaginal wall, rectovaginal septum, and posterior cul-de-sac uterosacral ligament can be seen by ultrasound as a single structure, making the location, size, and depth of any lesions discernible.

Again, this evaluation of the extent of disease is important for presurgical assessment so the surgeon can organize the right team and time of surgery and so the patient can be counseled on the advantages and possible complications of the treatment.

Notably, an accurate ultrasound description of pelvic endometriosis is helpful for accurate classification of disease. Endometriosis classification systems such as that of the American Association of Gynecologic Laparoscopists (AAGL)⁸ and the American Society of Reproductive Medicine (ASRM),⁹ as well as the #Enzian surgical description system,¹⁰ have been adapted to cover findings from ultrasound as well as MRI imaging.
 

A Systematic Evaluation

In keeping with the IDEA consensus opinion and based on our years of experience at the University of Rome, I advise that patients with typical pain symptoms of endometriosis or infertility undergo an accurate sonographic assessment of the pelvis with particular evaluation not only of the uterus and ovaries but of all pelvic retroperitoneal spaces.

The TVS examination should start with a slightly filled bladder, which permits a better evaluation of the bladder walls and the presence of endometriotic nodules. These nodules appear as hyperechoic linear or spherical lesions bulging toward the lumen and involving the serosa, muscularis, or (sub)mucosa of the bladder.

Then, an accurate evaluation of the uterus in 2D and 3D permits the diagnosis of adenomyosis. 3D sonographic evaluation of the myometrium and of the junctional zone are important; alteration and infiltration of the junctional zone and the presence of small adenomyotic cysts in the inner or outer myometrium are direct, specific signs of adenomyosis and should be ruled out in patients with dysmenorrhea, heavy menstrual bleeding, infertility, and pregnancy complications.

Endometriomas of the ovaries can be easily detected as having the typical appearance of a cyst with ground glass content. Adhesions of the ovaries and the uterus also should be evaluated with a dynamic ultrasound approach that utilizes the sliding sign and mobilization by palpation of the organs during the TVS scan.

Finally, the posterior and lateral retroperitoneal compartments should be carefully evaluated, with symptoms guiding the TVS examination whenever possible. Deep endometriotic nodules of the rectum appear as hypoechoic lesions or linear or nodular retroperitoneal thickening with irregular borders, penetrating into the intestinal wall and distorting its normal structure. In young patients, it seems very important to assess for small lesions below the peritoneum between the vagina and rectum, and in the parametria and around the ureter and nerves — lesions that, notably, would not be seen by diagnostic laparoscopy.
 

The Evaluation of Young Patients

In adolescent and young patients, endometriosis and adenomyosis are often present with small lesions and shallow tissue invasion, making a very careful and experienced approach to ultrasound essential for detection. Endometriomas are often of small diameter, and DIE is not always easily diagnosed because retroperitoneal lesions are similarly very small.

In a series of 270 adolescents (ages 12-20) who were referred to our outpatient gynecologic ultrasound unit over a 5-year period for various indications, at least one ultrasound feature of endometriosis was observed in 13.3%. In those with dysmenorrhea, the detection of endometriosis increased to 21%. Endometrioma was the most common type of endometriosis we found in the study, but DIE and adenomyosis were found in 4%-11%.

Although endometriotic lesions typically are small in young patients, they are often associated with severe pain symptoms, including chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia, all of which can have a serious effect on the quality of life of these young women. These symptoms keep them away from school during menstruation, away from sports, and cause painful intercourse and infertility. In young patients, an accurate TVS can provide a lot of information, and the ability to detect retroperitoneal endometriotic lesions and adenomyosis is probably better than with purely diagnostic laparoscopy, which would evaluate only superficial lesions.

TVS or, when needed, transrectal ultrasound, can enable adequate treatment and follow-up of the disease and its symptoms. There are no guidelines recommending adequate follow-up times to evaluate the effectiveness of medical therapy in patients with ultrasound signs of endometriosis. (Likewise, there are no indications for follow-up in patients with severe dysmenorrhea without ultrasound signs of endometriosis.) Certainly, our studies suggest careful evaluation over time of young patients with severe dysmenorrhea by serial ultrasound scans. With such follow-up, disease progress can be monitored and the medical or surgical treatment approach modified if needed.

The diagnosis of endometriosis at a young age has significant benefits not only in avoiding or reducing progression of the disease, but also in improving quality of life and aiding women in their desire for pregnancy.
 

Dr. Exacoustos is associate professor of ob.gyn. at the University of Rome “Tor Vergata.” She has no conflicts of interest to report.

References

1. Zondervan KT et al. N Engl J Med. 2020;382:1244-56.

2. Greene R et al. Fertil Steril. 2009;91:32-9.

3. Chapron C et al. J Pediatr Adolesc Gynecol. 2011;24:S7-12.

4. Randhawa AE et al. J Pediatr Adolesc Gynecol. 2021;34:643-8.

5. Becker CM et al. Hum Reprod Open. 2022(2):hoac009.

6. Exacoustos C et al. Fertil Steril. 2014;102:143-9. 7. Guerriero S et al. Ultrasound Obstet Gynecol. 2016;48(3):318-32.

8. Abrao MS et al. J Minim Invasive Gynecol. 2021;28:1941-50.9. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817-21. 10. Keckstein J et al. Acta Obstet Gynecol Scand. 2021;100:1165-75.

11. Martire FG et al. Fertil Steril. 2020;114(5):1049-57.

Introduction: Imaging for Endometriosis — A Necessary Prerequisite

While the gold standard in the diagnosis of endometriosis remains laparoscopy, it is now recognized that thorough evaluation via ultrasound offers an acceptable, less expensive, and less invasive alternative. It is especially useful for the diagnosis of deep infiltrative disease, which penetrates more than 5 mm into the peritoneum, ovarian endometrioma, and when anatomic distortion occurs, such as to the path of the ureter.

Besides establishing the diagnosis, ultrasound imaging has become, along with MRI, the most important aid for proper preoperative planning. Not only does imaging provide the surgeon and patient with knowledge regarding the extent of the upcoming procedure, but it also allows the minimally invasive gynecologic (MIG) surgeon to involve colleagues, such as colorectal surgeons or urologists. For example, deep infiltrative endometriosis penetrating into the bowel mucosa will require a discoid or segmental bowel resection.

Miller_Charles_E 2014_web.jpg

While many endometriosis experts rely on MRI, many MIG surgeons are dependent on ultrasound. I would not consider taking a patient with signs and symptoms suggestive of endometriosis to surgery without 2D/3D transvaginal ultrasound. If the patient possesses a uterus, a saline-infused sonogram is performed to potentially diagnose adenomyosis.

It is a pleasure and honor to welcome Professor Caterina Exacoustos MD, PhD, associate professor of ob.gyn. at the University of Rome “Tor Vergata,” to this edition of the Master Class in Gynecologic Surgery to discuss “Ultrasound and Its Role in the Diagnosis of and Management of Endometriosis, Including DIE.”

Prof. Exacoustos’ main areas of interest are endometriosis and benign diseases including uterine pathology and infertility. Her extensive body of work comprises over 120 scientific publications and numerous book chapters both in English and in Italian.

Prof. Exacoustos continues to be one of the most well respected lecturers speaking about ultrasound throughout the world.
 

Dr. Miller is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. Dr. Miller has no conflicts of interest to report.

Ultrasound and Its Role In Diagnosing and Managing Endometriosis

Endometriosis affects approximately 10%-20% of premenopausal women worldwide. It is the leading cause of chronic pelvic pain, is often associated with infertility, and has a significant impact on quality of life. Although the natural history of endometriosis remains unknown, emerging evidence suggests that the pathophysiological steps of initiation and development of endometriosis must occur earlier in the lifespan. Most notably, the onset of endometriosis-associated pain symptoms is often reported during adolescence and young adulthood.¹

While many patients with endometriosis are referred with dysmenorrhea at a young age, at age ≤ 25 years,² symptoms are often highly underestimated and considered to be normal and transient.^3,4 Clinical and pelvic exams are often negative in young women, and delays in endometriosis diagnosis are well known.

The presentation of primary dysmenorrhea with no anatomical cause embodies the paradigm that dysmenorrhea in adolescents is most often an insignificant disorder. This perspective is probably a root cause of delayed endometriosis diagnosis in young patients. However, another issue behind delayed diagnosis is the reluctance of the physician to perform a diagnostic laparoscopy — historically the gold standard for diagnosing endometriosis — for seemingly common symptoms such as dysmenorrhea in young patients.

Today we know that there are typical aspects of ultrasound imaging that identify endometriosis in the pelvis, and notably, the 2022 European Society for Human Reproduction and Embryology (ESHRE) endometriosis guideline⁵ recognizes imaging (ultrasound or MRI) as the standard for endometriosis diagnosis without requiring laparoscopic or histological confirmation.

An early and noninvasive method of diagnosis aids in timely diagnosis and provides for the timely initiation of medical management to improve quality of life and prevent progression of disease (Figure 1).

167312_Figure 1_web.jpg

(A. Transvaginal ultrasound appearance of a small ovarian endometrioma in a 16-year-old girl. Note the unilocular cyst with ground glass echogenicity surrounded by multifollicular ovarian tissue. B. Ultrasound image of a retroverted uterus of an 18-year-old girl with focal adenomyosis of the posterior wall. Note the round cystic anechoic areas in the inner myometrium or junctional zone. The small intra-myometrial cyst is surrounded by a hyperechoic ring).

Indeed, the typical appearance of endometriotic pelvic lesions on transvaginal sonography, such as endometriomas and rectal deep infiltrating endometriosis (DIE) — as well as adenomyosis – can be medically treated without histologic confirmation .

When surgery is advisable, ultrasound findings also play a valuable role in presurgical staging, planning, and counseling for patients of all ages. Determining the extent and location of DIE preoperatively, for instance, facilitates the engagement of the appropriate surgical specialists so that multiple surgeries can be avoided. It also enables patients to be optimally informed before surgery of possible outcomes and complications.

Moreover, in the context of infertility, ultrasound can be a valuable tool for understanding uterine pathology and assessing for adenomyosis so that affected patients may be treated surgically or medically before turning to assisted reproductive technology.
 

Uniformity, Standardization in the Sonographic Assessment

In Europe, as in the United States, transvaginal sonography (TVS) is the first-line imaging tool for the diagnosis and management of endometriosis. In Europe, many ob.gyns. perform ultrasound themselves, as do treating surgeons. When diagnostic findings are negative but clinical suspicion is high, MRI is often utilized. Laparoscopy may then be considered in patients with negative imaging results.

Efforts to standardize terms, definitions, measurements, and sonographic features of different types of endometriosis have been made to make it easier for physicians to share data and communicate with each other. A lack of uniformity has contributed to variability in the reported diagnostic accuracy of TVS.

About 10 years ago, in one such effort, we assessed the accuracy of TVS for DIE by comparing TVS results with laparoscopic/histologic findings, and developed an ultrasound mapping system to accurately record the location, size and depth of lesions visualized by TVS. The accuracy of TVS ranged from 76% for the diagnosis of vaginal endometriosis to 97% for the diagnosis of bladder lesions and posterior cul-de-sac obliteration. Accuracy was 93% and 91% for detecting ureteral involvement (right and left); 87% for uterosacral ligament endometriotic lesions; and 87% for parametrial involvement.⁶

Shortly after, with a focus on DIE, expert sonographers and physician-sonographers from across Europe — as well as some experts from Australia, Japan, Brazil, Chile, and the United States (Y. Osuga from Brigham and Women’s Hospital and Harvard Medical School) — came together to agree on a uniform approach to the sonographic evaluation for suspected endometriosis and a standardization of terminology.

The consensus opinion from the International Deep Endometriosis Analysis (IDEA) group details four steps for examining women with suspected DIE: 1) Evaluation of the uterus and adnexa, 2) evaluation of transvaginal sonographic “soft markers” (ie. site-specific tenderness and ovarian mobility), 3) assessment of the status of the posterior cul-de-sac using real-time ultrasound-based “sliding sign,” and 4) assessment for DIE nodules in the anterior and posterior compartments.⁷

Our paper describing a mapping system and the IDEA paper describe how to detect deep endometriosis in the pelvis by utilizing an ultrasound view of normal anatomy and pelvic organ structure to provide landmarks for accurately defining the site of DIE lesions (Figure 2).

167312_figure 2_web.jpg

(A. Ultrasound appearance of a small DIE lesion of the retrocervical area [white arrows], which involved the torus uterinum and the right uterosacral ligament [USL]. The lesion appears as hypoechoic tissue with irregular margins caused by the fibrosis induced by the DIE. B. TVS appearance of small nodules of DIE of the left USL. Note the small retrocervical DIE lesion [white arrows], which appears hypoechoic due to the infiltration of the hyperechoic USL. C) Ultrasound appearance of a DIE nodule of the recto-sigmoid wall. Note the hypoechoic thickening of the muscular layers of the bowel wall attached to the corpus of the uterus and the adenomyosis of the posterior wall. The retrocervical area is free. D. TVS appearance of nodules of DIE of the lower rectal wall. Note the hypoechoic lesion [white arrows] of the rectum is attached to a retrocervical DIE fibrosis of the torus and USL [white dotted line]).

So-called rectovaginal endometriosis can be well assessed, for instance, since the involvement of the rectum, sigmoid colon, vaginal wall, rectovaginal septum, and posterior cul-de-sac uterosacral ligament can be seen by ultrasound as a single structure, making the location, size, and depth of any lesions discernible.

Again, this evaluation of the extent of disease is important for presurgical assessment so the surgeon can organize the right team and time of surgery and so the patient can be counseled on the advantages and possible complications of the treatment.

Notably, an accurate ultrasound description of pelvic endometriosis is helpful for accurate classification of disease. Endometriosis classification systems such as that of the American Association of Gynecologic Laparoscopists (AAGL)⁸ and the American Society of Reproductive Medicine (ASRM),⁹ as well as the #Enzian surgical description system,¹⁰ have been adapted to cover findings from ultrasound as well as MRI imaging.
 

A Systematic Evaluation

In keeping with the IDEA consensus opinion and based on our years of experience at the University of Rome, I advise that patients with typical pain symptoms of endometriosis or infertility undergo an accurate sonographic assessment of the pelvis with particular evaluation not only of the uterus and ovaries but of all pelvic retroperitoneal spaces.

The TVS examination should start with a slightly filled bladder, which permits a better evaluation of the bladder walls and the presence of endometriotic nodules. These nodules appear as hyperechoic linear or spherical lesions bulging toward the lumen and involving the serosa, muscularis, or (sub)mucosa of the bladder.

Then, an accurate evaluation of the uterus in 2D and 3D permits the diagnosis of adenomyosis. 3D sonographic evaluation of the myometrium and of the junctional zone are important; alteration and infiltration of the junctional zone and the presence of small adenomyotic cysts in the inner or outer myometrium are direct, specific signs of adenomyosis and should be ruled out in patients with dysmenorrhea, heavy menstrual bleeding, infertility, and pregnancy complications.

Endometriomas of the ovaries can be easily detected as having the typical appearance of a cyst with ground glass content. Adhesions of the ovaries and the uterus also should be evaluated with a dynamic ultrasound approach that utilizes the sliding sign and mobilization by palpation of the organs during the TVS scan.

Finally, the posterior and lateral retroperitoneal compartments should be carefully evaluated, with symptoms guiding the TVS examination whenever possible. Deep endometriotic nodules of the rectum appear as hypoechoic lesions or linear or nodular retroperitoneal thickening with irregular borders, penetrating into the intestinal wall and distorting its normal structure. In young patients, it seems very important to assess for small lesions below the peritoneum between the vagina and rectum, and in the parametria and around the ureter and nerves — lesions that, notably, would not be seen by diagnostic laparoscopy.
 

The Evaluation of Young Patients

In adolescent and young patients, endometriosis and adenomyosis are often present with small lesions and shallow tissue invasion, making a very careful and experienced approach to ultrasound essential for detection. Endometriomas are often of small diameter, and DIE is not always easily diagnosed because retroperitoneal lesions are similarly very small.

In a series of 270 adolescents (ages 12-20) who were referred to our outpatient gynecologic ultrasound unit over a 5-year period for various indications, at least one ultrasound feature of endometriosis was observed in 13.3%. In those with dysmenorrhea, the detection of endometriosis increased to 21%. Endometrioma was the most common type of endometriosis we found in the study, but DIE and adenomyosis were found in 4%-11%.

Although endometriotic lesions typically are small in young patients, they are often associated with severe pain symptoms, including chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia, all of which can have a serious effect on the quality of life of these young women. These symptoms keep them away from school during menstruation, away from sports, and cause painful intercourse and infertility. In young patients, an accurate TVS can provide a lot of information, and the ability to detect retroperitoneal endometriotic lesions and adenomyosis is probably better than with purely diagnostic laparoscopy, which would evaluate only superficial lesions.

TVS or, when needed, transrectal ultrasound, can enable adequate treatment and follow-up of the disease and its symptoms. There are no guidelines recommending adequate follow-up times to evaluate the effectiveness of medical therapy in patients with ultrasound signs of endometriosis. (Likewise, there are no indications for follow-up in patients with severe dysmenorrhea without ultrasound signs of endometriosis.) Certainly, our studies suggest careful evaluation over time of young patients with severe dysmenorrhea by serial ultrasound scans. With such follow-up, disease progress can be monitored and the medical or surgical treatment approach modified if needed.

The diagnosis of endometriosis at a young age has significant benefits not only in avoiding or reducing progression of the disease, but also in improving quality of life and aiding women in their desire for pregnancy.
 

Dr. Exacoustos is associate professor of ob.gyn. at the University of Rome “Tor Vergata.” She has no conflicts of interest to report.

References

1. Zondervan KT et al. N Engl J Med. 2020;382:1244-56.

2. Greene R et al. Fertil Steril. 2009;91:32-9.

3. Chapron C et al. J Pediatr Adolesc Gynecol. 2011;24:S7-12.

4. Randhawa AE et al. J Pediatr Adolesc Gynecol. 2021;34:643-8.

5. Becker CM et al. Hum Reprod Open. 2022(2):hoac009.

6. Exacoustos C et al. Fertil Steril. 2014;102:143-9. 7. Guerriero S et al. Ultrasound Obstet Gynecol. 2016;48(3):318-32.

8. Abrao MS et al. J Minim Invasive Gynecol. 2021;28:1941-50.9. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817-21. 10. Keckstein J et al. Acta Obstet Gynecol Scand. 2021;100:1165-75.

11. Martire FG et al. Fertil Steril. 2020;114(5):1049-57.

Introduction: Imaging for Endometriosis — A Necessary Prerequisite

While the gold standard in the diagnosis of endometriosis remains laparoscopy, it is now recognized that thorough evaluation via ultrasound offers an acceptable, less expensive, and less invasive alternative. It is especially useful for the diagnosis of deep infiltrative disease, which penetrates more than 5 mm into the peritoneum, ovarian endometrioma, and when anatomic distortion occurs, such as to the path of the ureter.

Besides establishing the diagnosis, ultrasound imaging has become, along with MRI, the most important aid for proper preoperative planning. Not only does imaging provide the surgeon and patient with knowledge regarding the extent of the upcoming procedure, but it also allows the minimally invasive gynecologic (MIG) surgeon to involve colleagues, such as colorectal surgeons or urologists. For example, deep infiltrative endometriosis penetrating into the bowel mucosa will require a discoid or segmental bowel resection.

Miller_Charles_E 2014_web.jpg

While many endometriosis experts rely on MRI, many MIG surgeons are dependent on ultrasound. I would not consider taking a patient with signs and symptoms suggestive of endometriosis to surgery without 2D/3D transvaginal ultrasound. If the patient possesses a uterus, a saline-infused sonogram is performed to potentially diagnose adenomyosis.

It is a pleasure and honor to welcome Professor Caterina Exacoustos MD, PhD, associate professor of ob.gyn. at the University of Rome “Tor Vergata,” to this edition of the Master Class in Gynecologic Surgery to discuss “Ultrasound and Its Role in the Diagnosis of and Management of Endometriosis, Including DIE.”

Prof. Exacoustos’ main areas of interest are endometriosis and benign diseases including uterine pathology and infertility. Her extensive body of work comprises over 120 scientific publications and numerous book chapters both in English and in Italian.

Prof. Exacoustos continues to be one of the most well respected lecturers speaking about ultrasound throughout the world.
 

Dr. Miller is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. Dr. Miller has no conflicts of interest to report.

Ultrasound and Its Role In Diagnosing and Managing Endometriosis

Endometriosis affects approximately 10%-20% of premenopausal women worldwide. It is the leading cause of chronic pelvic pain, is often associated with infertility, and has a significant impact on quality of life. Although the natural history of endometriosis remains unknown, emerging evidence suggests that the pathophysiological steps of initiation and development of endometriosis must occur earlier in the lifespan. Most notably, the onset of endometriosis-associated pain symptoms is often reported during adolescence and young adulthood.¹

While many patients with endometriosis are referred with dysmenorrhea at a young age, at age ≤ 25 years,² symptoms are often highly underestimated and considered to be normal and transient.^3,4 Clinical and pelvic exams are often negative in young women, and delays in endometriosis diagnosis are well known.

The presentation of primary dysmenorrhea with no anatomical cause embodies the paradigm that dysmenorrhea in adolescents is most often an insignificant disorder. This perspective is probably a root cause of delayed endometriosis diagnosis in young patients. However, another issue behind delayed diagnosis is the reluctance of the physician to perform a diagnostic laparoscopy — historically the gold standard for diagnosing endometriosis — for seemingly common symptoms such as dysmenorrhea in young patients.

Today we know that there are typical aspects of ultrasound imaging that identify endometriosis in the pelvis, and notably, the 2022 European Society for Human Reproduction and Embryology (ESHRE) endometriosis guideline⁵ recognizes imaging (ultrasound or MRI) as the standard for endometriosis diagnosis without requiring laparoscopic or histological confirmation.

An early and noninvasive method of diagnosis aids in timely diagnosis and provides for the timely initiation of medical management to improve quality of life and prevent progression of disease (Figure 1).

167312_Figure 1_web.jpg

(A. Transvaginal ultrasound appearance of a small ovarian endometrioma in a 16-year-old girl. Note the unilocular cyst with ground glass echogenicity surrounded by multifollicular ovarian tissue. B. Ultrasound image of a retroverted uterus of an 18-year-old girl with focal adenomyosis of the posterior wall. Note the round cystic anechoic areas in the inner myometrium or junctional zone. The small intra-myometrial cyst is surrounded by a hyperechoic ring).

Indeed, the typical appearance of endometriotic pelvic lesions on transvaginal sonography, such as endometriomas and rectal deep infiltrating endometriosis (DIE) — as well as adenomyosis – can be medically treated without histologic confirmation .

When surgery is advisable, ultrasound findings also play a valuable role in presurgical staging, planning, and counseling for patients of all ages. Determining the extent and location of DIE preoperatively, for instance, facilitates the engagement of the appropriate surgical specialists so that multiple surgeries can be avoided. It also enables patients to be optimally informed before surgery of possible outcomes and complications.

Moreover, in the context of infertility, ultrasound can be a valuable tool for understanding uterine pathology and assessing for adenomyosis so that affected patients may be treated surgically or medically before turning to assisted reproductive technology.
 

Uniformity, Standardization in the Sonographic Assessment

In Europe, as in the United States, transvaginal sonography (TVS) is the first-line imaging tool for the diagnosis and management of endometriosis. In Europe, many ob.gyns. perform ultrasound themselves, as do treating surgeons. When diagnostic findings are negative but clinical suspicion is high, MRI is often utilized. Laparoscopy may then be considered in patients with negative imaging results.

Efforts to standardize terms, definitions, measurements, and sonographic features of different types of endometriosis have been made to make it easier for physicians to share data and communicate with each other. A lack of uniformity has contributed to variability in the reported diagnostic accuracy of TVS.

About 10 years ago, in one such effort, we assessed the accuracy of TVS for DIE by comparing TVS results with laparoscopic/histologic findings, and developed an ultrasound mapping system to accurately record the location, size and depth of lesions visualized by TVS. The accuracy of TVS ranged from 76% for the diagnosis of vaginal endometriosis to 97% for the diagnosis of bladder lesions and posterior cul-de-sac obliteration. Accuracy was 93% and 91% for detecting ureteral involvement (right and left); 87% for uterosacral ligament endometriotic lesions; and 87% for parametrial involvement.⁶

Shortly after, with a focus on DIE, expert sonographers and physician-sonographers from across Europe — as well as some experts from Australia, Japan, Brazil, Chile, and the United States (Y. Osuga from Brigham and Women’s Hospital and Harvard Medical School) — came together to agree on a uniform approach to the sonographic evaluation for suspected endometriosis and a standardization of terminology.

The consensus opinion from the International Deep Endometriosis Analysis (IDEA) group details four steps for examining women with suspected DIE: 1) Evaluation of the uterus and adnexa, 2) evaluation of transvaginal sonographic “soft markers” (ie. site-specific tenderness and ovarian mobility), 3) assessment of the status of the posterior cul-de-sac using real-time ultrasound-based “sliding sign,” and 4) assessment for DIE nodules in the anterior and posterior compartments.⁷

Our paper describing a mapping system and the IDEA paper describe how to detect deep endometriosis in the pelvis by utilizing an ultrasound view of normal anatomy and pelvic organ structure to provide landmarks for accurately defining the site of DIE lesions (Figure 2).

167312_figure 2_web.jpg

(A. Ultrasound appearance of a small DIE lesion of the retrocervical area [white arrows], which involved the torus uterinum and the right uterosacral ligament [USL]. The lesion appears as hypoechoic tissue with irregular margins caused by the fibrosis induced by the DIE. B. TVS appearance of small nodules of DIE of the left USL. Note the small retrocervical DIE lesion [white arrows], which appears hypoechoic due to the infiltration of the hyperechoic USL. C) Ultrasound appearance of a DIE nodule of the recto-sigmoid wall. Note the hypoechoic thickening of the muscular layers of the bowel wall attached to the corpus of the uterus and the adenomyosis of the posterior wall. The retrocervical area is free. D. TVS appearance of nodules of DIE of the lower rectal wall. Note the hypoechoic lesion [white arrows] of the rectum is attached to a retrocervical DIE fibrosis of the torus and USL [white dotted line]).

So-called rectovaginal endometriosis can be well assessed, for instance, since the involvement of the rectum, sigmoid colon, vaginal wall, rectovaginal septum, and posterior cul-de-sac uterosacral ligament can be seen by ultrasound as a single structure, making the location, size, and depth of any lesions discernible.

Again, this evaluation of the extent of disease is important for presurgical assessment so the surgeon can organize the right team and time of surgery and so the patient can be counseled on the advantages and possible complications of the treatment.

Notably, an accurate ultrasound description of pelvic endometriosis is helpful for accurate classification of disease. Endometriosis classification systems such as that of the American Association of Gynecologic Laparoscopists (AAGL)⁸ and the American Society of Reproductive Medicine (ASRM),⁹ as well as the #Enzian surgical description system,¹⁰ have been adapted to cover findings from ultrasound as well as MRI imaging.
 

A Systematic Evaluation

In keeping with the IDEA consensus opinion and based on our years of experience at the University of Rome, I advise that patients with typical pain symptoms of endometriosis or infertility undergo an accurate sonographic assessment of the pelvis with particular evaluation not only of the uterus and ovaries but of all pelvic retroperitoneal spaces.

The TVS examination should start with a slightly filled bladder, which permits a better evaluation of the bladder walls and the presence of endometriotic nodules. These nodules appear as hyperechoic linear or spherical lesions bulging toward the lumen and involving the serosa, muscularis, or (sub)mucosa of the bladder.

Then, an accurate evaluation of the uterus in 2D and 3D permits the diagnosis of adenomyosis. 3D sonographic evaluation of the myometrium and of the junctional zone are important; alteration and infiltration of the junctional zone and the presence of small adenomyotic cysts in the inner or outer myometrium are direct, specific signs of adenomyosis and should be ruled out in patients with dysmenorrhea, heavy menstrual bleeding, infertility, and pregnancy complications.

Endometriomas of the ovaries can be easily detected as having the typical appearance of a cyst with ground glass content. Adhesions of the ovaries and the uterus also should be evaluated with a dynamic ultrasound approach that utilizes the sliding sign and mobilization by palpation of the organs during the TVS scan.

Finally, the posterior and lateral retroperitoneal compartments should be carefully evaluated, with symptoms guiding the TVS examination whenever possible. Deep endometriotic nodules of the rectum appear as hypoechoic lesions or linear or nodular retroperitoneal thickening with irregular borders, penetrating into the intestinal wall and distorting its normal structure. In young patients, it seems very important to assess for small lesions below the peritoneum between the vagina and rectum, and in the parametria and around the ureter and nerves — lesions that, notably, would not be seen by diagnostic laparoscopy.
 

The Evaluation of Young Patients

In adolescent and young patients, endometriosis and adenomyosis are often present with small lesions and shallow tissue invasion, making a very careful and experienced approach to ultrasound essential for detection. Endometriomas are often of small diameter, and DIE is not always easily diagnosed because retroperitoneal lesions are similarly very small.

In a series of 270 adolescents (ages 12-20) who were referred to our outpatient gynecologic ultrasound unit over a 5-year period for various indications, at least one ultrasound feature of endometriosis was observed in 13.3%. In those with dysmenorrhea, the detection of endometriosis increased to 21%. Endometrioma was the most common type of endometriosis we found in the study, but DIE and adenomyosis were found in 4%-11%.

Although endometriotic lesions typically are small in young patients, they are often associated with severe pain symptoms, including chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia, all of which can have a serious effect on the quality of life of these young women. These symptoms keep them away from school during menstruation, away from sports, and cause painful intercourse and infertility. In young patients, an accurate TVS can provide a lot of information, and the ability to detect retroperitoneal endometriotic lesions and adenomyosis is probably better than with purely diagnostic laparoscopy, which would evaluate only superficial lesions.

TVS or, when needed, transrectal ultrasound, can enable adequate treatment and follow-up of the disease and its symptoms. There are no guidelines recommending adequate follow-up times to evaluate the effectiveness of medical therapy in patients with ultrasound signs of endometriosis. (Likewise, there are no indications for follow-up in patients with severe dysmenorrhea without ultrasound signs of endometriosis.) Certainly, our studies suggest careful evaluation over time of young patients with severe dysmenorrhea by serial ultrasound scans. With such follow-up, disease progress can be monitored and the medical or surgical treatment approach modified if needed.

The diagnosis of endometriosis at a young age has significant benefits not only in avoiding or reducing progression of the disease, but also in improving quality of life and aiding women in their desire for pregnancy.
 

Dr. Exacoustos is associate professor of ob.gyn. at the University of Rome “Tor Vergata.” She has no conflicts of interest to report.

References

1. Zondervan KT et al. N Engl J Med. 2020;382:1244-56.

2. Greene R et al. Fertil Steril. 2009;91:32-9.

3. Chapron C et al. J Pediatr Adolesc Gynecol. 2011;24:S7-12.

4. Randhawa AE et al. J Pediatr Adolesc Gynecol. 2021;34:643-8.

5. Becker CM et al. Hum Reprod Open. 2022(2):hoac009.

6. Exacoustos C et al. Fertil Steril. 2014;102:143-9. 7. Guerriero S et al. Ultrasound Obstet Gynecol. 2016;48(3):318-32.

8. Abrao MS et al. J Minim Invasive Gynecol. 2021;28:1941-50.9. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817-21. 10. Keckstein J et al. Acta Obstet Gynecol Scand. 2021;100:1165-75.

11. Martire FG et al. Fertil Steril. 2020;114(5):1049-57.

Introduction: The Many Lanes of Research on Magnesium Sulfate

The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.

Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.

Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.

This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.

Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.

Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.

Reece_E_Albert_web.jpg

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.
 

Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth

Without a doubt, magnesium sulfate (MgSO₄) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.

Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.

Burd_Irina_MD_web.jpg

Origins and Biologic Plausibility

The MgSO₄ story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.¹ MgSO₄ was first used for eclampsia in 1906,² and was first reported in the American literature for eclampsia in 1925.³ In 1959, its effect as a tocolytic agent was reported.⁴

More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).⁵ The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.

The precise molecular mechanisms of action of MgSO₄ for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.

Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO₄ may ameliorate both.^6,7

Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO₄ sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).

166473_graphic_web.jpg

The Long Route of Research

The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO₄ to prevent seizures in preeclampsia or as a tocolytic agent.⁵ In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO₄ was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.

This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO₄ had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”⁹

In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.

The six published randomized controlled trials looking at MgSO₄ and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO₄ administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).^10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO₄ for preventing preeclampsia.

166473_table_web.jpg

Moving Forward

The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.¹⁹ For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.¹⁹

In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”²⁰

Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO₄ administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).

The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.²¹

N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.²¹ Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.

Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.  
 

References

1. Clio Med. 1984;19(1-2):1-21.

2. Medicinsk Rev. (Bergen) 1906;32:264-272.

3. Am J Obstet Gynecol. 1996;174(4):1390-1391.

4. Am J Obstet Gynecol. 1959;78(1):27-32.

5. Pediatrics. 1995;95(2):263-269.

6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.

7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.

8. Pediatr Res. 2020;87(3):463-471.

9. J Child Neurol. 1992;7(1):70-76.

10. Lancet. 1997;350:1517-1518.

11. JAMA. 2003;290:2669-2676.

12. BJOG. 2007;114(3):310-318.

13. Lancet. 2002;359(9321):1877-1890.

14. N Engl J Med. 2008;359:895-905.

15. Obstet Gynecol. 2009;113(6):1327-1333.

16. Am J Obstet Gynecol. 2009;200(6):595-609.

17. Obstet Gynecol 2009;114:354-364.

18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.

19. www.thennt.com.

20. Obstet Gynecol. 2010;115:669-671.

21. Front Synaptic Neurosci. 2012;13:680899.

*This story was corrected on June 10, 2024.

Introduction: The Many Lanes of Research on Magnesium Sulfate

The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.

Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.

Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.

This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.

Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.

Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.

Reece_E_Albert_web.jpg

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.
 

Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth

Without a doubt, magnesium sulfate (MgSO₄) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.

Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.

Burd_Irina_MD_web.jpg

Origins and Biologic Plausibility

The MgSO₄ story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.¹ MgSO₄ was first used for eclampsia in 1906,² and was first reported in the American literature for eclampsia in 1925.³ In 1959, its effect as a tocolytic agent was reported.⁴

More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).⁵ The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.

The precise molecular mechanisms of action of MgSO₄ for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.

Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO₄ may ameliorate both.^6,7

Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO₄ sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).

166473_graphic_web.jpg

The Long Route of Research

The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO₄ to prevent seizures in preeclampsia or as a tocolytic agent.⁵ In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO₄ was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.

This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO₄ had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”⁹

In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.

The six published randomized controlled trials looking at MgSO₄ and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO₄ administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).^10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO₄ for preventing preeclampsia.

166473_table_web.jpg

Moving Forward

The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.¹⁹ For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.¹⁹

In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”²⁰

Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO₄ administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).

The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.²¹

N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.²¹ Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.

Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.  
 

References

1. Clio Med. 1984;19(1-2):1-21.

2. Medicinsk Rev. (Bergen) 1906;32:264-272.

3. Am J Obstet Gynecol. 1996;174(4):1390-1391.

4. Am J Obstet Gynecol. 1959;78(1):27-32.

5. Pediatrics. 1995;95(2):263-269.

6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.

7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.

8. Pediatr Res. 2020;87(3):463-471.

9. J Child Neurol. 1992;7(1):70-76.

10. Lancet. 1997;350:1517-1518.

11. JAMA. 2003;290:2669-2676.

12. BJOG. 2007;114(3):310-318.

13. Lancet. 2002;359(9321):1877-1890.

14. N Engl J Med. 2008;359:895-905.

15. Obstet Gynecol. 2009;113(6):1327-1333.

16. Am J Obstet Gynecol. 2009;200(6):595-609.

17. Obstet Gynecol 2009;114:354-364.

18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.

19. www.thennt.com.

20. Obstet Gynecol. 2010;115:669-671.

21. Front Synaptic Neurosci. 2012;13:680899.

*This story was corrected on June 10, 2024.

Introduction: The Many Lanes of Research on Magnesium Sulfate

The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.

Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.

Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.

This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.

Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.

Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.

Reece_E_Albert_web.jpg

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.
 

Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth

Without a doubt, magnesium sulfate (MgSO₄) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.

Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.

Burd_Irina_MD_web.jpg

Origins and Biologic Plausibility

The MgSO₄ story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.¹ MgSO₄ was first used for eclampsia in 1906,² and was first reported in the American literature for eclampsia in 1925.³ In 1959, its effect as a tocolytic agent was reported.⁴

More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).⁵ The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.

The precise molecular mechanisms of action of MgSO₄ for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.

Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO₄ may ameliorate both.^6,7

Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO₄ sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).

166473_graphic_web.jpg

The Long Route of Research

The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO₄ to prevent seizures in preeclampsia or as a tocolytic agent.⁵ In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO₄ was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.

This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO₄ had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”⁹

In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.

The six published randomized controlled trials looking at MgSO₄ and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO₄ administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).^10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO₄ for preventing preeclampsia.

166473_table_web.jpg

Moving Forward

The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.¹⁹ For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.¹⁹

In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”²⁰

Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO₄ administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).

The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.²¹

N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.²¹ Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.

Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.  
 

References

1. Clio Med. 1984;19(1-2):1-21.

2. Medicinsk Rev. (Bergen) 1906;32:264-272.

3. Am J Obstet Gynecol. 1996;174(4):1390-1391.

4. Am J Obstet Gynecol. 1959;78(1):27-32.

5. Pediatrics. 1995;95(2):263-269.

6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.

7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.

8. Pediatr Res. 2020;87(3):463-471.

9. J Child Neurol. 1992;7(1):70-76.

10. Lancet. 1997;350:1517-1518.

11. JAMA. 2003;290:2669-2676.

12. BJOG. 2007;114(3):310-318.

13. Lancet. 2002;359(9321):1877-1890.

14. N Engl J Med. 2008;359:895-905.

15. Obstet Gynecol. 2009;113(6):1327-1333.

16. Am J Obstet Gynecol. 2009;200(6):595-609.

17. Obstet Gynecol 2009;114:354-364.

18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.

19. www.thennt.com.

20. Obstet Gynecol. 2010;115:669-671.

21. Front Synaptic Neurosci. 2012;13:680899.

*This story was corrected on June 10, 2024.

Introduction: Reassurance through pregnancy loss and workups

Pregnancy loss is not an uncommon complication but it can be associated with significant stress among parents and loved ones when it occurs. Especially when recurrent, it also becomes a medical dilemma for physicians and nurses because the cause is not always obvious immediately, and even with exploration, the cause may not always be found.

First and foremost, it is important that physicians provide counseling and reassurance to families experiencing loss, and that they encourage a level of patience while the investigation for loss is done. Investigations tend not to be linear. One must look at a number of diagnostic areas including genetics, anatomy, immunology, and infections.

Reece_E_Albert_web.jpg

Even with an extensive workup, what often is found are potential associations rather than precise causes. For instance, one may find that certain antibodies or certain conditions are present, or that certain anatomic structures are abnormal. While such findings are not necessarily causative, there are therapeutic interventions that we can offer to address many of the conditions (e.g., surgical correction of the septate uterus, and low-dose aspirin and heparin for antiphospholipid syndrome).

Less than 1% of couples experience recurrent pregnancy loss (traditionally defined as three or more losses), so parents who experience one loss should be given reassurance that their loss was likely a sporadic miscarriage and that chances of recurrence will be low. Even as workups proceed, reassurance is important.

For this month’s Master Class in Obstetrics we’ve invited Wendy L. Kinzler, MD, and Anthony Vintzileos, MD, both of whom have expertise in the area of recurrent pregnancy loss, to review the potential causes and the management approach. They focus on the first trimester, when genetic causes predominate, and the early second trimester, when undetected uterine factors can be at play. They explain that the gestational age at which recurrent losses occur is an important factor in decoding etiology and management.

Dr. Kinzler is associate dean, graduate medical education, and professor of obstetrics and gynecology at NYU Long Island School of Medicine, Mineola, N.Y., and Dr. Vintzileos is chief patient safety officer for obstetrics, Northwell Health–Western Region, and professor in the department of obstetrics and gynecology in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. Dr. Kinzler and Dr. Vintzileos reported no relevant disclosures.
 

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.

Investigating the etiology of recurrent pregnancy loss

Pregnancy loss is defined as a loss occurring at < 20 weeks’ gestation. Any pregnancy loss is a devastating experience and couples deserve a thoughtful approach to identifying possible causes and/or predisposing factors.

Consideration of the timing of the pregnancy loss can provide a useful guide to this evaluation, as etiologies vary depending on when in gestation losses occur. In this Master Class, we will address the evaluation of pregnancy loss at < 20 weeks’ gestation, with particular attention to first trimester and early second trimester causes. Literature on the role of the cervix and intra-amniotic infection in midtrimester loss is extensive and will not be covered here.

163307_graphic_web.png

Although early first trimester miscarriage is common, occurring in approximately 15% of clinically recognized pregnancies, only 2%-3% of couples experience two or more miscarriages and 0.5%-1% experience three or more.

When to begin a diagnostic workup should be part of a shared decision-making process, taking into consideration future family planning, parity, number of previous losses, and notably, the gestational age at which loss(es) occurred. Recurrence rates for first trimester miscarriage are similar after two versus three consecutive losses and either situation usually prompts an evaluation, whereas any second-trimester loss should be evaluated.

Increasingly, we are appreciating the value of a more targeted, gestational age–driven approach to the evaluation of pregnancy loss in an attempt to provide grieving parents with useful information without subjecting them to a wide array of expensive and unnecessary tests.
 

Genetic causes

The earlier the pregnancy loss, the more likely it is the result of abnormal fetal genetics. Genetic factors should be considered as the most likely cause for first trimester pregnancy losses (especially those occurring at < 10 weeks’ gestation), the most frequent being autosomal trisomies or monosomy X. The vast majority of trisomy conceptuses are sporadic in nature and are related to the natural aging process of the ovary (increasing the rate of meiotic nondisjunction).

Kinzler_Wendy_L_NY_web.jpg

If fetal aneuploidy is identified in a pregnancy loss, couples can be counseled about the definitive cause of the loss and can be counseled about recurrence based on age-related risks and/or tests of ovarian reserve. Recurrent pregnancy loss (RPL) is only rarely associated with a parental translocation (< 5%). Testing parental karyotypes should be reserved for cases in which the fetal karyotypes are unknown or in which an unbalanced translocation was identified in the fetus.

When a first trimester pregnancy loss is diagnosed, chorionic villus sampling (CVS) with microarray testing is the most reliable and comprehensive method for evaluating potential genetic causes. It provides valuable information even when cells are not viable and reduces the risk of maternal cell contamination – two significant limitations to standard karyotype analysis performed on tissue passed spontaneously or at the time of D&C. Studies of products of conception (POC) testing with microarray have documented the detection of abnormalities in an additional 10%-15% of cases compared with traditional karyotype analysis.

Vintzileos_Anthony_NY_web.jpg

When CVS is not feasible, testing maternal serum for cell-free DNA is a reasonable alternative. In a prospective cohort study of 50 maternal blood samples taken after fetal demise, 76% of samples yielded cell-free DNA results, meaning fetal fractions were within the detectable range. The higher the gestational age at the time of loss, the higher the chance of obtaining a result: Findings in the study were possible in 88% of samples when the gestational age was 8 weeks or greater, and in 53% of cases involving a lower gestational age. The time from demise to blood draw did not affect the likelihood of obtaining a result (Obstet Gynecol. 2015 Jun;125[6]:1321-29).

When neither CVS nor cell-free DNA analysis is feasible, analysis of either spontaneously passed tissue or tissue obtained at the time of a D&C may still be worthwhile. Maternal cell contamination, of course, is the main downside.

A paper published in 2020 documented the value of refocusing the initial workup. Researchers reported that 57% of 1,400 cases of recurrent pregnancy loss went unexplained using the 2012 ASRM guidelines, which included parental karyotyping but not POC cytogenetic analysis. When parental karyotypes were omitted from the initial workup and POC analysis with 24-chromosome microarray was added, at least one potential explanation for loss could be identified in 92% of cases. Only 8% were left “unexplained” (Curr Opin Obstet Gynecol. 2020 Oct;32[5]:371-9).
 

When genetics are ruled out

Issues that are top of mind when we lack genetic information or when genetic causes are ruled out include maternal metabolic disorders (uncontrolled diabetes, obesity, uncontrolled thyroid disease), environmental exposures (smoking), uterine abnormalities, and antiphospholipid syndrome.

Thorough evaluation of the uterine cavity after recurrent first trimester miscarriage – or after any second trimester loss – is too often a missing element of investigation. It is a vital component of the evaluation, and information about uterine structure is easily obtained.

A saline infusion sonogram (SIS) allows us to look at the external contour of the uterus, assess the myometrium for muscular abnormalities, visualize the uterine lining, and assess uterine orientation. Performed in the nonpregnant state, and ideally coupled with 3D technology, this relatively simple test can identify congenital uterine anomalies, intracavitary abnormalities (such as fibroids, polyps, or synechiae) which can surgically be removed prior to another pregnancy, a retroverted uterus that may be predisposed to incarceration during pregnancy, and other potentially impactful conditions, such as adenomyosis.
 

Structural anomalies

Congenital uterine anomalies are associated with first trimester miscarriage, second trimester pregnancy loss, and preterm birth. A uterine septum is of particular concern for early miscarriage, as the early embryo can implant on the relatively avascular septum.

Other congenital uterine anomalies (bicornuate, didelphys, unicornuate) can be associated with concomitant cervical structural abnormalities leading to cervical insufficiency and/or result in pathologic uterine stretch of a space-limited cavity, leading to midtrimester loss or preterm birth. The diagnosis of these anomalies is an important part of the evaluation of pregnancy loss, as it can guide monitoring in future pregnancies, or can be surgically corrected, as in the case of a uterine septum, significantly improving pregnancy outcomes.

A short cervix can result either congenitally or from injury or trauma and may also be associated with cervical insufficiency and miscarriage. It can be evaluated and monitored by ultrasound and, in some cases, treated by surgical cerclage. Pregnancy losses due to cervical insufficiency usually occur after 16 weeks of gestation and frequently are associated with intra-amniotic infections.
 

Incarcerated uterus and adenomyosis

Other uterine factors that can contribute to pregnancy loss and that are largely underdiagnosed or undiagnosed are an incarcerated retroverted uterus and adenomyosis.

163307_Uterus_image 1_web.jpg

Most of the time, a retroverted uterus naturally assumes an anteverted position by the late first trimester or early second trimester, allowing for continued growth of the uterus and developing fetus. In approximately 10% of cases, however, the retroverted uterus becomes “stuck” or incarcerated in the posterior pelvis. This is more likely if there are large uterine fibroids or in the presence of pelvic adhesions due to endometriosis or previous pelvic surgery.

When this occurs, the fundus is wedged on the sacral promontory (may cause pelvic discomfort and constipation) and the cervix is markedly displaced anteriorly under the pubic symphysis (causing bladder outlet obstruction and urinary retention).

It is critical that ob.gyns. and emergency medicine providers are aware of this condition, which typically presents between 12 and 16 weeks’ gestation. The most frequent complaint is lower abdominal discomfort due to distended bladder and inability to void, which usually leads to bladder catheterization with drainage of large amounts of urine. An incarcerated uterus can predispose to pregnancy loss during this time (few other conditions cause loss during this time window), presumably due to impaired uterine artery blood flow.

Once the diagnosis is made, uterine incarceration may be corrected by elevating the gravid uterus out of the pelvis either manually, or by using a transvaginal ultrasound probe. (The latter minimally invasive approach was described in March at the American Institute of Ultrasound in Medicine’s annual conference by Martin Chavez, MD, and coinvestigators. More invasive approaches are rarely required but include CO₂ intraperitoneal insufflation, as used prior to laparoscopy, or laparotomy.

The later in gestation the condition is allowed to persist, the less likely correction will be possible due to the enlarging fundus. Correction between 14 and 16 weeks, or earlier if symptoms develop, is recommended.

163307_Uterus_image 2_web.jpg

A word about antiphospholipid syndrome

Antiphospholipid syndrome can cause a variety of adverse pregnancy outcomes, including first and second trimester pregnancy loss, fetal demise, fetal growth restriction, preeclampsia, preterm birth, and maternal thromboembolism. The classical presentation of miscarriage due to untreated antiphospholipid antibody syndrome is early severe fetal growth restriction, oligohydramnios, and IUFD in the second trimester.

The diagnosis requires at least one clinical criterion and one laboratory criterion. The mere presence of low level antibodies does not make the diagnosis of antiphospholipid antibody syndrome, and care should be taken to consider both the clinical and laboratory diagnostic criteria to make an accurate diagnosis.

When present, close maternal and fetal surveillance and a combination of low-dose aspirin and heparin are mainstays of treatment. The majority of studies suggest that low-molecular weight heparin (LMWH) and unfractionated heparin have comparable clinical efficacy. However, if a recurrent loss is experienced despite treatment with LMWH, the use of unfractionated heparin in a subsequent pregnancy should be considered.

Introduction: Reassurance through pregnancy loss and workups

Pregnancy loss is not an uncommon complication but it can be associated with significant stress among parents and loved ones when it occurs. Especially when recurrent, it also becomes a medical dilemma for physicians and nurses because the cause is not always obvious immediately, and even with exploration, the cause may not always be found.

First and foremost, it is important that physicians provide counseling and reassurance to families experiencing loss, and that they encourage a level of patience while the investigation for loss is done. Investigations tend not to be linear. One must look at a number of diagnostic areas including genetics, anatomy, immunology, and infections.

Reece_E_Albert_web.jpg

Even with an extensive workup, what often is found are potential associations rather than precise causes. For instance, one may find that certain antibodies or certain conditions are present, or that certain anatomic structures are abnormal. While such findings are not necessarily causative, there are therapeutic interventions that we can offer to address many of the conditions (e.g., surgical correction of the septate uterus, and low-dose aspirin and heparin for antiphospholipid syndrome).

Less than 1% of couples experience recurrent pregnancy loss (traditionally defined as three or more losses), so parents who experience one loss should be given reassurance that their loss was likely a sporadic miscarriage and that chances of recurrence will be low. Even as workups proceed, reassurance is important.

For this month’s Master Class in Obstetrics we’ve invited Wendy L. Kinzler, MD, and Anthony Vintzileos, MD, both of whom have expertise in the area of recurrent pregnancy loss, to review the potential causes and the management approach. They focus on the first trimester, when genetic causes predominate, and the early second trimester, when undetected uterine factors can be at play. They explain that the gestational age at which recurrent losses occur is an important factor in decoding etiology and management.

Dr. Kinzler is associate dean, graduate medical education, and professor of obstetrics and gynecology at NYU Long Island School of Medicine, Mineola, N.Y., and Dr. Vintzileos is chief patient safety officer for obstetrics, Northwell Health–Western Region, and professor in the department of obstetrics and gynecology in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. Dr. Kinzler and Dr. Vintzileos reported no relevant disclosures.
 

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.

Investigating the etiology of recurrent pregnancy loss

Pregnancy loss is defined as a loss occurring at < 20 weeks’ gestation. Any pregnancy loss is a devastating experience and couples deserve a thoughtful approach to identifying possible causes and/or predisposing factors.

Consideration of the timing of the pregnancy loss can provide a useful guide to this evaluation, as etiologies vary depending on when in gestation losses occur. In this Master Class, we will address the evaluation of pregnancy loss at < 20 weeks’ gestation, with particular attention to first trimester and early second trimester causes. Literature on the role of the cervix and intra-amniotic infection in midtrimester loss is extensive and will not be covered here.

163307_graphic_web.png

Although early first trimester miscarriage is common, occurring in approximately 15% of clinically recognized pregnancies, only 2%-3% of couples experience two or more miscarriages and 0.5%-1% experience three or more.

When to begin a diagnostic workup should be part of a shared decision-making process, taking into consideration future family planning, parity, number of previous losses, and notably, the gestational age at which loss(es) occurred. Recurrence rates for first trimester miscarriage are similar after two versus three consecutive losses and either situation usually prompts an evaluation, whereas any second-trimester loss should be evaluated.

Increasingly, we are appreciating the value of a more targeted, gestational age–driven approach to the evaluation of pregnancy loss in an attempt to provide grieving parents with useful information without subjecting them to a wide array of expensive and unnecessary tests.
 

Genetic causes

The earlier the pregnancy loss, the more likely it is the result of abnormal fetal genetics. Genetic factors should be considered as the most likely cause for first trimester pregnancy losses (especially those occurring at < 10 weeks’ gestation), the most frequent being autosomal trisomies or monosomy X. The vast majority of trisomy conceptuses are sporadic in nature and are related to the natural aging process of the ovary (increasing the rate of meiotic nondisjunction).

Kinzler_Wendy_L_NY_web.jpg

If fetal aneuploidy is identified in a pregnancy loss, couples can be counseled about the definitive cause of the loss and can be counseled about recurrence based on age-related risks and/or tests of ovarian reserve. Recurrent pregnancy loss (RPL) is only rarely associated with a parental translocation (< 5%). Testing parental karyotypes should be reserved for cases in which the fetal karyotypes are unknown or in which an unbalanced translocation was identified in the fetus.

When a first trimester pregnancy loss is diagnosed, chorionic villus sampling (CVS) with microarray testing is the most reliable and comprehensive method for evaluating potential genetic causes. It provides valuable information even when cells are not viable and reduces the risk of maternal cell contamination – two significant limitations to standard karyotype analysis performed on tissue passed spontaneously or at the time of D&C. Studies of products of conception (POC) testing with microarray have documented the detection of abnormalities in an additional 10%-15% of cases compared with traditional karyotype analysis.

Vintzileos_Anthony_NY_web.jpg

When CVS is not feasible, testing maternal serum for cell-free DNA is a reasonable alternative. In a prospective cohort study of 50 maternal blood samples taken after fetal demise, 76% of samples yielded cell-free DNA results, meaning fetal fractions were within the detectable range. The higher the gestational age at the time of loss, the higher the chance of obtaining a result: Findings in the study were possible in 88% of samples when the gestational age was 8 weeks or greater, and in 53% of cases involving a lower gestational age. The time from demise to blood draw did not affect the likelihood of obtaining a result (Obstet Gynecol. 2015 Jun;125[6]:1321-29).

When neither CVS nor cell-free DNA analysis is feasible, analysis of either spontaneously passed tissue or tissue obtained at the time of a D&C may still be worthwhile. Maternal cell contamination, of course, is the main downside.

A paper published in 2020 documented the value of refocusing the initial workup. Researchers reported that 57% of 1,400 cases of recurrent pregnancy loss went unexplained using the 2012 ASRM guidelines, which included parental karyotyping but not POC cytogenetic analysis. When parental karyotypes were omitted from the initial workup and POC analysis with 24-chromosome microarray was added, at least one potential explanation for loss could be identified in 92% of cases. Only 8% were left “unexplained” (Curr Opin Obstet Gynecol. 2020 Oct;32[5]:371-9).
 

When genetics are ruled out

Issues that are top of mind when we lack genetic information or when genetic causes are ruled out include maternal metabolic disorders (uncontrolled diabetes, obesity, uncontrolled thyroid disease), environmental exposures (smoking), uterine abnormalities, and antiphospholipid syndrome.

Thorough evaluation of the uterine cavity after recurrent first trimester miscarriage – or after any second trimester loss – is too often a missing element of investigation. It is a vital component of the evaluation, and information about uterine structure is easily obtained.

A saline infusion sonogram (SIS) allows us to look at the external contour of the uterus, assess the myometrium for muscular abnormalities, visualize the uterine lining, and assess uterine orientation. Performed in the nonpregnant state, and ideally coupled with 3D technology, this relatively simple test can identify congenital uterine anomalies, intracavitary abnormalities (such as fibroids, polyps, or synechiae) which can surgically be removed prior to another pregnancy, a retroverted uterus that may be predisposed to incarceration during pregnancy, and other potentially impactful conditions, such as adenomyosis.
 

Structural anomalies

Congenital uterine anomalies are associated with first trimester miscarriage, second trimester pregnancy loss, and preterm birth. A uterine septum is of particular concern for early miscarriage, as the early embryo can implant on the relatively avascular septum.

Other congenital uterine anomalies (bicornuate, didelphys, unicornuate) can be associated with concomitant cervical structural abnormalities leading to cervical insufficiency and/or result in pathologic uterine stretch of a space-limited cavity, leading to midtrimester loss or preterm birth. The diagnosis of these anomalies is an important part of the evaluation of pregnancy loss, as it can guide monitoring in future pregnancies, or can be surgically corrected, as in the case of a uterine septum, significantly improving pregnancy outcomes.

A short cervix can result either congenitally or from injury or trauma and may also be associated with cervical insufficiency and miscarriage. It can be evaluated and monitored by ultrasound and, in some cases, treated by surgical cerclage. Pregnancy losses due to cervical insufficiency usually occur after 16 weeks of gestation and frequently are associated with intra-amniotic infections.
 

Incarcerated uterus and adenomyosis

Other uterine factors that can contribute to pregnancy loss and that are largely underdiagnosed or undiagnosed are an incarcerated retroverted uterus and adenomyosis.

163307_Uterus_image 1_web.jpg

Most of the time, a retroverted uterus naturally assumes an anteverted position by the late first trimester or early second trimester, allowing for continued growth of the uterus and developing fetus. In approximately 10% of cases, however, the retroverted uterus becomes “stuck” or incarcerated in the posterior pelvis. This is more likely if there are large uterine fibroids or in the presence of pelvic adhesions due to endometriosis or previous pelvic surgery.

When this occurs, the fundus is wedged on the sacral promontory (may cause pelvic discomfort and constipation) and the cervix is markedly displaced anteriorly under the pubic symphysis (causing bladder outlet obstruction and urinary retention).

It is critical that ob.gyns. and emergency medicine providers are aware of this condition, which typically presents between 12 and 16 weeks’ gestation. The most frequent complaint is lower abdominal discomfort due to distended bladder and inability to void, which usually leads to bladder catheterization with drainage of large amounts of urine. An incarcerated uterus can predispose to pregnancy loss during this time (few other conditions cause loss during this time window), presumably due to impaired uterine artery blood flow.

Once the diagnosis is made, uterine incarceration may be corrected by elevating the gravid uterus out of the pelvis either manually, or by using a transvaginal ultrasound probe. (The latter minimally invasive approach was described in March at the American Institute of Ultrasound in Medicine’s annual conference by Martin Chavez, MD, and coinvestigators. More invasive approaches are rarely required but include CO₂ intraperitoneal insufflation, as used prior to laparoscopy, or laparotomy.

The later in gestation the condition is allowed to persist, the less likely correction will be possible due to the enlarging fundus. Correction between 14 and 16 weeks, or earlier if symptoms develop, is recommended.

163307_Uterus_image 2_web.jpg

A word about antiphospholipid syndrome

Antiphospholipid syndrome can cause a variety of adverse pregnancy outcomes, including first and second trimester pregnancy loss, fetal demise, fetal growth restriction, preeclampsia, preterm birth, and maternal thromboembolism. The classical presentation of miscarriage due to untreated antiphospholipid antibody syndrome is early severe fetal growth restriction, oligohydramnios, and IUFD in the second trimester.

The diagnosis requires at least one clinical criterion and one laboratory criterion. The mere presence of low level antibodies does not make the diagnosis of antiphospholipid antibody syndrome, and care should be taken to consider both the clinical and laboratory diagnostic criteria to make an accurate diagnosis.

When present, close maternal and fetal surveillance and a combination of low-dose aspirin and heparin are mainstays of treatment. The majority of studies suggest that low-molecular weight heparin (LMWH) and unfractionated heparin have comparable clinical efficacy. However, if a recurrent loss is experienced despite treatment with LMWH, the use of unfractionated heparin in a subsequent pregnancy should be considered.

Introduction: Reassurance through pregnancy loss and workups

Pregnancy loss is not an uncommon complication but it can be associated with significant stress among parents and loved ones when it occurs. Especially when recurrent, it also becomes a medical dilemma for physicians and nurses because the cause is not always obvious immediately, and even with exploration, the cause may not always be found.

First and foremost, it is important that physicians provide counseling and reassurance to families experiencing loss, and that they encourage a level of patience while the investigation for loss is done. Investigations tend not to be linear. One must look at a number of diagnostic areas including genetics, anatomy, immunology, and infections.

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Even with an extensive workup, what often is found are potential associations rather than precise causes. For instance, one may find that certain antibodies or certain conditions are present, or that certain anatomic structures are abnormal. While such findings are not necessarily causative, there are therapeutic interventions that we can offer to address many of the conditions (e.g., surgical correction of the septate uterus, and low-dose aspirin and heparin for antiphospholipid syndrome).

Less than 1% of couples experience recurrent pregnancy loss (traditionally defined as three or more losses), so parents who experience one loss should be given reassurance that their loss was likely a sporadic miscarriage and that chances of recurrence will be low. Even as workups proceed, reassurance is important.

For this month’s Master Class in Obstetrics we’ve invited Wendy L. Kinzler, MD, and Anthony Vintzileos, MD, both of whom have expertise in the area of recurrent pregnancy loss, to review the potential causes and the management approach. They focus on the first trimester, when genetic causes predominate, and the early second trimester, when undetected uterine factors can be at play. They explain that the gestational age at which recurrent losses occur is an important factor in decoding etiology and management.

Dr. Kinzler is associate dean, graduate medical education, and professor of obstetrics and gynecology at NYU Long Island School of Medicine, Mineola, N.Y., and Dr. Vintzileos is chief patient safety officer for obstetrics, Northwell Health–Western Region, and professor in the department of obstetrics and gynecology in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. Dr. Kinzler and Dr. Vintzileos reported no relevant disclosures.
 

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at obnews@mdedge.com.

Investigating the etiology of recurrent pregnancy loss

Pregnancy loss is defined as a loss occurring at < 20 weeks’ gestation. Any pregnancy loss is a devastating experience and couples deserve a thoughtful approach to identifying possible causes and/or predisposing factors.

Consideration of the timing of the pregnancy loss can provide a useful guide to this evaluation, as etiologies vary depending on when in gestation losses occur. In this Master Class, we will address the evaluation of pregnancy loss at < 20 weeks’ gestation, with particular attention to first trimester and early second trimester causes. Literature on the role of the cervix and intra-amniotic infection in midtrimester loss is extensive and will not be covered here.

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Although early first trimester miscarriage is common, occurring in approximately 15% of clinically recognized pregnancies, only 2%-3% of couples experience two or more miscarriages and 0.5%-1% experience three or more.

When to begin a diagnostic workup should be part of a shared decision-making process, taking into consideration future family planning, parity, number of previous losses, and notably, the gestational age at which loss(es) occurred. Recurrence rates for first trimester miscarriage are similar after two versus three consecutive losses and either situation usually prompts an evaluation, whereas any second-trimester loss should be evaluated.

Increasingly, we are appreciating the value of a more targeted, gestational age–driven approach to the evaluation of pregnancy loss in an attempt to provide grieving parents with useful information without subjecting them to a wide array of expensive and unnecessary tests.
 

Genetic causes

The earlier the pregnancy loss, the more likely it is the result of abnormal fetal genetics. Genetic factors should be considered as the most likely cause for first trimester pregnancy losses (especially those occurring at < 10 weeks’ gestation), the most frequent being autosomal trisomies or monosomy X. The vast majority of trisomy conceptuses are sporadic in nature and are related to the natural aging process of the ovary (increasing the rate of meiotic nondisjunction).

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If fetal aneuploidy is identified in a pregnancy loss, couples can be counseled about the definitive cause of the loss and can be counseled about recurrence based on age-related risks and/or tests of ovarian reserve. Recurrent pregnancy loss (RPL) is only rarely associated with a parental translocation (< 5%). Testing parental karyotypes should be reserved for cases in which the fetal karyotypes are unknown or in which an unbalanced translocation was identified in the fetus.

When a first trimester pregnancy loss is diagnosed, chorionic villus sampling (CVS) with microarray testing is the most reliable and comprehensive method for evaluating potential genetic causes. It provides valuable information even when cells are not viable and reduces the risk of maternal cell contamination – two significant limitations to standard karyotype analysis performed on tissue passed spontaneously or at the time of D&C. Studies of products of conception (POC) testing with microarray have documented the detection of abnormalities in an additional 10%-15% of cases compared with traditional karyotype analysis.

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When CVS is not feasible, testing maternal serum for cell-free DNA is a reasonable alternative. In a prospective cohort study of 50 maternal blood samples taken after fetal demise, 76% of samples yielded cell-free DNA results, meaning fetal fractions were within the detectable range. The higher the gestational age at the time of loss, the higher the chance of obtaining a result: Findings in the study were possible in 88% of samples when the gestational age was 8 weeks or greater, and in 53% of cases involving a lower gestational age. The time from demise to blood draw did not affect the likelihood of obtaining a result (Obstet Gynecol. 2015 Jun;125[6]:1321-29).

When neither CVS nor cell-free DNA analysis is feasible, analysis of either spontaneously passed tissue or tissue obtained at the time of a D&C may still be worthwhile. Maternal cell contamination, of course, is the main downside.

A paper published in 2020 documented the value of refocusing the initial workup. Researchers reported that 57% of 1,400 cases of recurrent pregnancy loss went unexplained using the 2012 ASRM guidelines, which included parental karyotyping but not POC cytogenetic analysis. When parental karyotypes were omitted from the initial workup and POC analysis with 24-chromosome microarray was added, at least one potential explanation for loss could be identified in 92% of cases. Only 8% were left “unexplained” (Curr Opin Obstet Gynecol. 2020 Oct;32[5]:371-9).
 

When genetics are ruled out

Issues that are top of mind when we lack genetic information or when genetic causes are ruled out include maternal metabolic disorders (uncontrolled diabetes, obesity, uncontrolled thyroid disease), environmental exposures (smoking), uterine abnormalities, and antiphospholipid syndrome.

Thorough evaluation of the uterine cavity after recurrent first trimester miscarriage – or after any second trimester loss – is too often a missing element of investigation. It is a vital component of the evaluation, and information about uterine structure is easily obtained.

A saline infusion sonogram (SIS) allows us to look at the external contour of the uterus, assess the myometrium for muscular abnormalities, visualize the uterine lining, and assess uterine orientation. Performed in the nonpregnant state, and ideally coupled with 3D technology, this relatively simple test can identify congenital uterine anomalies, intracavitary abnormalities (such as fibroids, polyps, or synechiae) which can surgically be removed prior to another pregnancy, a retroverted uterus that may be predisposed to incarceration during pregnancy, and other potentially impactful conditions, such as adenomyosis.
 

Structural anomalies

Congenital uterine anomalies are associated with first trimester miscarriage, second trimester pregnancy loss, and preterm birth. A uterine septum is of particular concern for early miscarriage, as the early embryo can implant on the relatively avascular septum.

Other congenital uterine anomalies (bicornuate, didelphys, unicornuate) can be associated with concomitant cervical structural abnormalities leading to cervical insufficiency and/or result in pathologic uterine stretch of a space-limited cavity, leading to midtrimester loss or preterm birth. The diagnosis of these anomalies is an important part of the evaluation of pregnancy loss, as it can guide monitoring in future pregnancies, or can be surgically corrected, as in the case of a uterine septum, significantly improving pregnancy outcomes.

A short cervix can result either congenitally or from injury or trauma and may also be associated with cervical insufficiency and miscarriage. It can be evaluated and monitored by ultrasound and, in some cases, treated by surgical cerclage. Pregnancy losses due to cervical insufficiency usually occur after 16 weeks of gestation and frequently are associated with intra-amniotic infections.
 

Incarcerated uterus and adenomyosis

Other uterine factors that can contribute to pregnancy loss and that are largely underdiagnosed or undiagnosed are an incarcerated retroverted uterus and adenomyosis.

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Most of the time, a retroverted uterus naturally assumes an anteverted position by the late first trimester or early second trimester, allowing for continued growth of the uterus and developing fetus. In approximately 10% of cases, however, the retroverted uterus becomes “stuck” or incarcerated in the posterior pelvis. This is more likely if there are large uterine fibroids or in the presence of pelvic adhesions due to endometriosis or previous pelvic surgery.

When this occurs, the fundus is wedged on the sacral promontory (may cause pelvic discomfort and constipation) and the cervix is markedly displaced anteriorly under the pubic symphysis (causing bladder outlet obstruction and urinary retention).

It is critical that ob.gyns. and emergency medicine providers are aware of this condition, which typically presents between 12 and 16 weeks’ gestation. The most frequent complaint is lower abdominal discomfort due to distended bladder and inability to void, which usually leads to bladder catheterization with drainage of large amounts of urine. An incarcerated uterus can predispose to pregnancy loss during this time (few other conditions cause loss during this time window), presumably due to impaired uterine artery blood flow.

Once the diagnosis is made, uterine incarceration may be corrected by elevating the gravid uterus out of the pelvis either manually, or by using a transvaginal ultrasound probe. (The latter minimally invasive approach was described in March at the American Institute of Ultrasound in Medicine’s annual conference by Martin Chavez, MD, and coinvestigators. More invasive approaches are rarely required but include CO₂ intraperitoneal insufflation, as used prior to laparoscopy, or laparotomy.

The later in gestation the condition is allowed to persist, the less likely correction will be possible due to the enlarging fundus. Correction between 14 and 16 weeks, or earlier if symptoms develop, is recommended.

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A word about antiphospholipid syndrome

Antiphospholipid syndrome can cause a variety of adverse pregnancy outcomes, including first and second trimester pregnancy loss, fetal demise, fetal growth restriction, preeclampsia, preterm birth, and maternal thromboembolism. The classical presentation of miscarriage due to untreated antiphospholipid antibody syndrome is early severe fetal growth restriction, oligohydramnios, and IUFD in the second trimester.

The diagnosis requires at least one clinical criterion and one laboratory criterion. The mere presence of low level antibodies does not make the diagnosis of antiphospholipid antibody syndrome, and care should be taken to consider both the clinical and laboratory diagnostic criteria to make an accurate diagnosis.

When present, close maternal and fetal surveillance and a combination of low-dose aspirin and heparin are mainstays of treatment. The majority of studies suggest that low-molecular weight heparin (LMWH) and unfractionated heparin have comparable clinical efficacy. However, if a recurrent loss is experienced despite treatment with LMWH, the use of unfractionated heparin in a subsequent pregnancy should be considered.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

[embed:render:related:node:259027]

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Reece_E_Albert_web.jpg

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

160552_visual1_web.jpg

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

Yang_Peixin_MD_web.jpg

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

mc.reece.visual.2_web.jpg

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

160552_visual3_web.jpg

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

[embed:render:related:node:259027]

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Reece_E_Albert_web.jpg

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

160552_visual1_web.jpg

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

Yang_Peixin_MD_web.jpg

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

mc.reece.visual.2_web.jpg

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

160552_visual3_web.jpg

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

[embed:render:related:node:259027]

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Reece_E_Albert_web.jpg

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

160552_visual1_web.jpg

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

Yang_Peixin_MD_web.jpg

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

mc.reece.visual.2_web.jpg

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

160552_visual3_web.jpg

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Moore_Thomas_R_CA_web.jpg

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Moore_Thomas_R_CA_web.jpg

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Moore_Thomas_R_CA_web.jpg

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Radical resection of deep infiltrating endometriosis (DIE) or pelvic malignancies can lead to inadvertent damage to the pelvic autonomic nerve bundles, causing urinary dysfunction in up to 41% of cases, as well as anorectal and sexual dysfunction.¹ Each of these sequelae can significantly affect the patient’s quality of life.

Nerve-sparing techniques have therefore been a trending topic in gynecologic surgery in the 21st century, starting with papers by Marc Possover, MD, of Switzerland, on the laparoscopic neuronavigation (LANN) technique. In an important 2005 publication, he described how the LANN technique can significantly reduce postoperative functional morbidity in laparoscopic radical pelvic surgery.²

Lemos_Nucelio_TORONTO_web.jpg

The LANN method utilizes intraoperative neurostimulation to identify and dissect the intrapelvic nerve bundles away from surrounding tissue prior to dissection of the DIE or pelvic malignancies. The nerves are exposed and preserved under direct visualization in a fashion similar to that used to expose and preserve the ureters. Pelvic dissection using the LANN technique is extensive and occurs down to the level of the sacral nerve roots.

Dr. Possover’s 2005 paper and others like it spurred increased awareness of the intrapelvic part of the autonomic nervous system – in particular, the hypogastric nerves, the pelvic splanchnic nerves, and the inferior hypogastric plexus. Across additional published studies, nerve-sparing techniques were shown to be effective in preserving neurologic pelvic functions, with significantly less urinary retention and rectal/sexual dysfunction than seen with traditional laparoscopy techniques.

For example, in a single-center prospective clinical trial reported in 2012, 56 of 65 (86.2%) patients treated with a classical laparoscopic technique for excision of DIE reported neurologic pelvic dysfunctions, compared with 1 of 61 (1.6%) patients treated with a nerve-sparing approach.³

While research has confirmed the importance of nerve-sparing techniques, it also shone light on the reality that the LANN technique is extremely technically challenging and requires a high level of surgical expertise and advanced training. In my teaching of the technique, I also saw that few gynecologic surgeons were able to incorporate the advanced nerve-sparing technique into their practices.

A group consisting of myself and collaborators at the University of Bologna, Italy, and the University of Cambridge, England, recently developed an alternative to the LANN approach that uses the hypogastric nerves as landmarks. The technique requires less dissection and should be technically achievable when the pelvic neuroanatomy and anatomy of the presacral fascia are well understood. The hypogastric nerve is identified and used as a landmark to preserve the deeper autonomic nerve bundles in the pelvis without exposure and without more extensive dissection to the level of the sacral nerve roots.^4,5

This hypogastric nerve-based technique will cover the vast majority of radical surgeries for DIE. When more advanced nerve sparing and more extensive dissection is needed for the very deepest levels of disease infiltration, patients can be referred to surgeons with advanced training, comfort, and experience with the LANN technique.
 

The pelvic neuroanatomy

As described in our video articles published in 2015 in Fertility and Sterility⁶ and 2019 in the Journal of Minimally Invasive Gynecology,⁵ the left and right hypogastric nerves are the main sympathetic nerves of the autonomic nervous system in the pelvis. They originate from the superior hypogastric plexus and, at the level of the middle rectal vessels, they join the pelvic sacral splanchnic nerves to form the inferior hypogastric plexus. They are easily identifiable at their origin and are the most superficial and readily identifiable component of the inferior hypogastric plexus.

159156_Fig 1_web.jpg

The sympathetic input from the hypogastric nerves causes the internal urethral and anal sphincters to contract, as well as detrusor relaxation and a reduction of peristalsis of the descending colon, sigmoid, and rectum; thus, hypogastric nerve input promotes continence.

The hypogastric nerves also carry afferent signals for pelvic visceral proprioception. Lesion to the hypogastric nerves will usually be subclinical and will put the patient at risk for unnoticeable bladder distension, which usually becomes symptomatic about 7 years after the procedure.⁷

159156_Fig 2_web.JPG

The thin pelvic splanchnic nerves – which merge with the hypogastric nerves into the pararectal fossae to form the inferior hypogastric plexus – arise from nerve roots S2 and S4 and carry all parasympathetic signals to the bladder, rectum, and the sigmoid and left colons. Lesions to these bundles are the main cause of neurogenic urinary retention.

The inferior hypogastric plexi split into the vesical, uterine, and rectal branches, which carry the sympathetic, parasympathetic, and sensory fibers from both the splanchnic and hypogastric nerves. Damage to the inferior hypogastric plexi and/or its branches may induce severe dysfunction to the target organs of the injured fibers.
 

A focus on the hypogastric nerve

Our approach was developed after we studied the anatomic reliability of the hypogastric nerves through a prospective observational study consisting of measurements during five cadaveric dissections and 10 in-vivo laparoscopic surgeries for rectosigmoid endometriosis.4 We took an interfascial approach to dissection.

Our goal was to clarify the distances between the hypogastric nerves and the ureters, the midsagittal plane, the midcervical plane, and the uterosacral ligaments in each hemipelvis, and in doing so, enable identification of the hypogastric nerves and establish recognizable limits for dissection.

We found quite a bit of variance in the anatomic position and appearance of the hypogastric nerves, but the variances were not very broad. Most notably, the right hypogastric nerve was significantly farther toward the ureter (mean, 14.5 mm; range, 10-25 mm) than the left one (mean, 8.6 mm; range, 7-12 mm).

The ureters were a good landmark for identification of the hypogastric nerves because the nerves were consistently found medially and posteriorly to the ureter at a mean distance of 11.6 mm. Overall, we demonstrated reproducibility in the identification and dissection of the hypogastric nerves using recognizable interfascial planes and anatomic landmarks.⁴

With good anatomic understanding, a stepwise approach can be taken to identify and preserve the hypogastric nerve and the deeper inferior hypogastric plexus without the need for more extensive dissection.

As shown in our 2019 video, the right hypogastric nerves can be identified transperitoneally in most cases.5 For confirmation, a gentle anterior pulling on the hypogastric nerve causes a caudal movement of the peritoneum overlying the superior hypogastric plexus. (Intermittent pulling on the nerve can also be helpful in localizing the left hypogastric nerve.)

To dissect a hypogastric nerve, the retroperitoneum is opened at the level of the pelvic brim, just inferomedially to the external iliac vessels, and the incision is extended anteriorly, with gentle dissection of the underlying tissue until the ureter is identified.

Once the ureter is identified and lateralized, dissection along the peritoneum is carried deeper and medially into the pelvis until the hypogastric nerve is identified. Lateral to this area are the internal iliac artery, the branching uterine artery, and the obliterated umbilical ligament. In the left hemipelvis, the hypogastric nerve can reliably be found at a mean distance of 8.6 mm from the ureter, while the right one will be found on average 14.5 mm away.

The hypogastric nerves form the posteromedial limit for a safe and simple nerve-sparing dissection. Any dissection posteriorly and laterally to these landmarks should start with the identification of sacral nerve roots and hypogastric nerves.

Dr. Lemos reported that he has no relevant disclosures.
 

Dr. Lemos is associate professor in the department of obstetrics and gynecology at the University of Toronto.

References

1. Imboden S et al. J Minim Invasive Gynecol. 2021 Aug;28(8):1544-51. doi: 10.1016/j.jmig.2021.01.009.

2. Possover M et al. J Am Coll Surg. 2005;201(6):913-7. doi: 10.1016/j.jamcollsurg.2005.07.006.

3. Ceccaroni M et al. Surg Endosc. 2012;26(7):2029-45. doi: 10.1007/s00464-012-2153-3.

4. Seracchioli R et al. J Minim Invasive Gynecol. 2019;26(7):1340-5. doi: 10.1016/j.jmig.2019.01.010.

5. Zakhari A et al. J Minim Invasive Gynecol. 2020;27(4):813-4. doi: 10.1016/j.jmig.2019.08.001

6. Lemos N et al. Fertil Steril. 2015 Nov;104(5):e11-2. doi: 10.1016/j.fertnstert.2015.07.1138. 

7. Possover M. Fertil Steril. 2014 Mar;101(3):754-8. doi: 10.1016/j.fertnstert.2013.12.019.

Radical resection of deep infiltrating endometriosis (DIE) or pelvic malignancies can lead to inadvertent damage to the pelvic autonomic nerve bundles, causing urinary dysfunction in up to 41% of cases, as well as anorectal and sexual dysfunction.¹ Each of these sequelae can significantly affect the patient’s quality of life.

Nerve-sparing techniques have therefore been a trending topic in gynecologic surgery in the 21st century, starting with papers by Marc Possover, MD, of Switzerland, on the laparoscopic neuronavigation (LANN) technique. In an important 2005 publication, he described how the LANN technique can significantly reduce postoperative functional morbidity in laparoscopic radical pelvic surgery.²

Lemos_Nucelio_TORONTO_web.jpg

The LANN method utilizes intraoperative neurostimulation to identify and dissect the intrapelvic nerve bundles away from surrounding tissue prior to dissection of the DIE or pelvic malignancies. The nerves are exposed and preserved under direct visualization in a fashion similar to that used to expose and preserve the ureters. Pelvic dissection using the LANN technique is extensive and occurs down to the level of the sacral nerve roots.

Dr. Possover’s 2005 paper and others like it spurred increased awareness of the intrapelvic part of the autonomic nervous system – in particular, the hypogastric nerves, the pelvic splanchnic nerves, and the inferior hypogastric plexus. Across additional published studies, nerve-sparing techniques were shown to be effective in preserving neurologic pelvic functions, with significantly less urinary retention and rectal/sexual dysfunction than seen with traditional laparoscopy techniques.

For example, in a single-center prospective clinical trial reported in 2012, 56 of 65 (86.2%) patients treated with a classical laparoscopic technique for excision of DIE reported neurologic pelvic dysfunctions, compared with 1 of 61 (1.6%) patients treated with a nerve-sparing approach.³

While research has confirmed the importance of nerve-sparing techniques, it also shone light on the reality that the LANN technique is extremely technically challenging and requires a high level of surgical expertise and advanced training. In my teaching of the technique, I also saw that few gynecologic surgeons were able to incorporate the advanced nerve-sparing technique into their practices.

A group consisting of myself and collaborators at the University of Bologna, Italy, and the University of Cambridge, England, recently developed an alternative to the LANN approach that uses the hypogastric nerves as landmarks. The technique requires less dissection and should be technically achievable when the pelvic neuroanatomy and anatomy of the presacral fascia are well understood. The hypogastric nerve is identified and used as a landmark to preserve the deeper autonomic nerve bundles in the pelvis without exposure and without more extensive dissection to the level of the sacral nerve roots.^4,5

This hypogastric nerve-based technique will cover the vast majority of radical surgeries for DIE. When more advanced nerve sparing and more extensive dissection is needed for the very deepest levels of disease infiltration, patients can be referred to surgeons with advanced training, comfort, and experience with the LANN technique.
 

The pelvic neuroanatomy

As described in our video articles published in 2015 in Fertility and Sterility⁶ and 2019 in the Journal of Minimally Invasive Gynecology,⁵ the left and right hypogastric nerves are the main sympathetic nerves of the autonomic nervous system in the pelvis. They originate from the superior hypogastric plexus and, at the level of the middle rectal vessels, they join the pelvic sacral splanchnic nerves to form the inferior hypogastric plexus. They are easily identifiable at their origin and are the most superficial and readily identifiable component of the inferior hypogastric plexus.

159156_Fig 1_web.jpg

The sympathetic input from the hypogastric nerves causes the internal urethral and anal sphincters to contract, as well as detrusor relaxation and a reduction of peristalsis of the descending colon, sigmoid, and rectum; thus, hypogastric nerve input promotes continence.

The hypogastric nerves also carry afferent signals for pelvic visceral proprioception. Lesion to the hypogastric nerves will usually be subclinical and will put the patient at risk for unnoticeable bladder distension, which usually becomes symptomatic about 7 years after the procedure.⁷

159156_Fig 2_web.JPG

The thin pelvic splanchnic nerves – which merge with the hypogastric nerves into the pararectal fossae to form the inferior hypogastric plexus – arise from nerve roots S2 and S4 and carry all parasympathetic signals to the bladder, rectum, and the sigmoid and left colons. Lesions to these bundles are the main cause of neurogenic urinary retention.

The inferior hypogastric plexi split into the vesical, uterine, and rectal branches, which carry the sympathetic, parasympathetic, and sensory fibers from both the splanchnic and hypogastric nerves. Damage to the inferior hypogastric plexi and/or its branches may induce severe dysfunction to the target organs of the injured fibers.
 

A focus on the hypogastric nerve

Our approach was developed after we studied the anatomic reliability of the hypogastric nerves through a prospective observational study consisting of measurements during five cadaveric dissections and 10 in-vivo laparoscopic surgeries for rectosigmoid endometriosis.4 We took an interfascial approach to dissection.

Our goal was to clarify the distances between the hypogastric nerves and the ureters, the midsagittal plane, the midcervical plane, and the uterosacral ligaments in each hemipelvis, and in doing so, enable identification of the hypogastric nerves and establish recognizable limits for dissection.

We found quite a bit of variance in the anatomic position and appearance of the hypogastric nerves, but the variances were not very broad. Most notably, the right hypogastric nerve was significantly farther toward the ureter (mean, 14.5 mm; range, 10-25 mm) than the left one (mean, 8.6 mm; range, 7-12 mm).

The ureters were a good landmark for identification of the hypogastric nerves because the nerves were consistently found medially and posteriorly to the ureter at a mean distance of 11.6 mm. Overall, we demonstrated reproducibility in the identification and dissection of the hypogastric nerves using recognizable interfascial planes and anatomic landmarks.⁴

With good anatomic understanding, a stepwise approach can be taken to identify and preserve the hypogastric nerve and the deeper inferior hypogastric plexus without the need for more extensive dissection.

As shown in our 2019 video, the right hypogastric nerves can be identified transperitoneally in most cases.5 For confirmation, a gentle anterior pulling on the hypogastric nerve causes a caudal movement of the peritoneum overlying the superior hypogastric plexus. (Intermittent pulling on the nerve can also be helpful in localizing the left hypogastric nerve.)

To dissect a hypogastric nerve, the retroperitoneum is opened at the level of the pelvic brim, just inferomedially to the external iliac vessels, and the incision is extended anteriorly, with gentle dissection of the underlying tissue until the ureter is identified.

Once the ureter is identified and lateralized, dissection along the peritoneum is carried deeper and medially into the pelvis until the hypogastric nerve is identified. Lateral to this area are the internal iliac artery, the branching uterine artery, and the obliterated umbilical ligament. In the left hemipelvis, the hypogastric nerve can reliably be found at a mean distance of 8.6 mm from the ureter, while the right one will be found on average 14.5 mm away.

The hypogastric nerves form the posteromedial limit for a safe and simple nerve-sparing dissection. Any dissection posteriorly and laterally to these landmarks should start with the identification of sacral nerve roots and hypogastric nerves.

Dr. Lemos reported that he has no relevant disclosures.
 

Dr. Lemos is associate professor in the department of obstetrics and gynecology at the University of Toronto.

References

1. Imboden S et al. J Minim Invasive Gynecol. 2021 Aug;28(8):1544-51. doi: 10.1016/j.jmig.2021.01.009.

2. Possover M et al. J Am Coll Surg. 2005;201(6):913-7. doi: 10.1016/j.jamcollsurg.2005.07.006.

3. Ceccaroni M et al. Surg Endosc. 2012;26(7):2029-45. doi: 10.1007/s00464-012-2153-3.

4. Seracchioli R et al. J Minim Invasive Gynecol. 2019;26(7):1340-5. doi: 10.1016/j.jmig.2019.01.010.

5. Zakhari A et al. J Minim Invasive Gynecol. 2020;27(4):813-4. doi: 10.1016/j.jmig.2019.08.001

6. Lemos N et al. Fertil Steril. 2015 Nov;104(5):e11-2. doi: 10.1016/j.fertnstert.2015.07.1138. 

7. Possover M. Fertil Steril. 2014 Mar;101(3):754-8. doi: 10.1016/j.fertnstert.2013.12.019.

Radical resection of deep infiltrating endometriosis (DIE) or pelvic malignancies can lead to inadvertent damage to the pelvic autonomic nerve bundles, causing urinary dysfunction in up to 41% of cases, as well as anorectal and sexual dysfunction.¹ Each of these sequelae can significantly affect the patient’s quality of life.

Nerve-sparing techniques have therefore been a trending topic in gynecologic surgery in the 21st century, starting with papers by Marc Possover, MD, of Switzerland, on the laparoscopic neuronavigation (LANN) technique. In an important 2005 publication, he described how the LANN technique can significantly reduce postoperative functional morbidity in laparoscopic radical pelvic surgery.²

Lemos_Nucelio_TORONTO_web.jpg

The LANN method utilizes intraoperative neurostimulation to identify and dissect the intrapelvic nerve bundles away from surrounding tissue prior to dissection of the DIE or pelvic malignancies. The nerves are exposed and preserved under direct visualization in a fashion similar to that used to expose and preserve the ureters. Pelvic dissection using the LANN technique is extensive and occurs down to the level of the sacral nerve roots.

Dr. Possover’s 2005 paper and others like it spurred increased awareness of the intrapelvic part of the autonomic nervous system – in particular, the hypogastric nerves, the pelvic splanchnic nerves, and the inferior hypogastric plexus. Across additional published studies, nerve-sparing techniques were shown to be effective in preserving neurologic pelvic functions, with significantly less urinary retention and rectal/sexual dysfunction than seen with traditional laparoscopy techniques.

For example, in a single-center prospective clinical trial reported in 2012, 56 of 65 (86.2%) patients treated with a classical laparoscopic technique for excision of DIE reported neurologic pelvic dysfunctions, compared with 1 of 61 (1.6%) patients treated with a nerve-sparing approach.³

While research has confirmed the importance of nerve-sparing techniques, it also shone light on the reality that the LANN technique is extremely technically challenging and requires a high level of surgical expertise and advanced training. In my teaching of the technique, I also saw that few gynecologic surgeons were able to incorporate the advanced nerve-sparing technique into their practices.

A group consisting of myself and collaborators at the University of Bologna, Italy, and the University of Cambridge, England, recently developed an alternative to the LANN approach that uses the hypogastric nerves as landmarks. The technique requires less dissection and should be technically achievable when the pelvic neuroanatomy and anatomy of the presacral fascia are well understood. The hypogastric nerve is identified and used as a landmark to preserve the deeper autonomic nerve bundles in the pelvis without exposure and without more extensive dissection to the level of the sacral nerve roots.^4,5

This hypogastric nerve-based technique will cover the vast majority of radical surgeries for DIE. When more advanced nerve sparing and more extensive dissection is needed for the very deepest levels of disease infiltration, patients can be referred to surgeons with advanced training, comfort, and experience with the LANN technique.
 

The pelvic neuroanatomy

As described in our video articles published in 2015 in Fertility and Sterility⁶ and 2019 in the Journal of Minimally Invasive Gynecology,⁵ the left and right hypogastric nerves are the main sympathetic nerves of the autonomic nervous system in the pelvis. They originate from the superior hypogastric plexus and, at the level of the middle rectal vessels, they join the pelvic sacral splanchnic nerves to form the inferior hypogastric plexus. They are easily identifiable at their origin and are the most superficial and readily identifiable component of the inferior hypogastric plexus.

159156_Fig 1_web.jpg

The sympathetic input from the hypogastric nerves causes the internal urethral and anal sphincters to contract, as well as detrusor relaxation and a reduction of peristalsis of the descending colon, sigmoid, and rectum; thus, hypogastric nerve input promotes continence.

The hypogastric nerves also carry afferent signals for pelvic visceral proprioception. Lesion to the hypogastric nerves will usually be subclinical and will put the patient at risk for unnoticeable bladder distension, which usually becomes symptomatic about 7 years after the procedure.⁷

159156_Fig 2_web.JPG

The thin pelvic splanchnic nerves – which merge with the hypogastric nerves into the pararectal fossae to form the inferior hypogastric plexus – arise from nerve roots S2 and S4 and carry all parasympathetic signals to the bladder, rectum, and the sigmoid and left colons. Lesions to these bundles are the main cause of neurogenic urinary retention.

The inferior hypogastric plexi split into the vesical, uterine, and rectal branches, which carry the sympathetic, parasympathetic, and sensory fibers from both the splanchnic and hypogastric nerves. Damage to the inferior hypogastric plexi and/or its branches may induce severe dysfunction to the target organs of the injured fibers.
 

A focus on the hypogastric nerve

Our approach was developed after we studied the anatomic reliability of the hypogastric nerves through a prospective observational study consisting of measurements during five cadaveric dissections and 10 in-vivo laparoscopic surgeries for rectosigmoid endometriosis.4 We took an interfascial approach to dissection.

Our goal was to clarify the distances between the hypogastric nerves and the ureters, the midsagittal plane, the midcervical plane, and the uterosacral ligaments in each hemipelvis, and in doing so, enable identification of the hypogastric nerves and establish recognizable limits for dissection.

We found quite a bit of variance in the anatomic position and appearance of the hypogastric nerves, but the variances were not very broad. Most notably, the right hypogastric nerve was significantly farther toward the ureter (mean, 14.5 mm; range, 10-25 mm) than the left one (mean, 8.6 mm; range, 7-12 mm).

The ureters were a good landmark for identification of the hypogastric nerves because the nerves were consistently found medially and posteriorly to the ureter at a mean distance of 11.6 mm. Overall, we demonstrated reproducibility in the identification and dissection of the hypogastric nerves using recognizable interfascial planes and anatomic landmarks.⁴

With good anatomic understanding, a stepwise approach can be taken to identify and preserve the hypogastric nerve and the deeper inferior hypogastric plexus without the need for more extensive dissection.

As shown in our 2019 video, the right hypogastric nerves can be identified transperitoneally in most cases.5 For confirmation, a gentle anterior pulling on the hypogastric nerve causes a caudal movement of the peritoneum overlying the superior hypogastric plexus. (Intermittent pulling on the nerve can also be helpful in localizing the left hypogastric nerve.)

To dissect a hypogastric nerve, the retroperitoneum is opened at the level of the pelvic brim, just inferomedially to the external iliac vessels, and the incision is extended anteriorly, with gentle dissection of the underlying tissue until the ureter is identified.

Once the ureter is identified and lateralized, dissection along the peritoneum is carried deeper and medially into the pelvis until the hypogastric nerve is identified. Lateral to this area are the internal iliac artery, the branching uterine artery, and the obliterated umbilical ligament. In the left hemipelvis, the hypogastric nerve can reliably be found at a mean distance of 8.6 mm from the ureter, while the right one will be found on average 14.5 mm away.

The hypogastric nerves form the posteromedial limit for a safe and simple nerve-sparing dissection. Any dissection posteriorly and laterally to these landmarks should start with the identification of sacral nerve roots and hypogastric nerves.

Dr. Lemos reported that he has no relevant disclosures.
 

Dr. Lemos is associate professor in the department of obstetrics and gynecology at the University of Toronto.

References

1. Imboden S et al. J Minim Invasive Gynecol. 2021 Aug;28(8):1544-51. doi: 10.1016/j.jmig.2021.01.009.

2. Possover M et al. J Am Coll Surg. 2005;201(6):913-7. doi: 10.1016/j.jamcollsurg.2005.07.006.

3. Ceccaroni M et al. Surg Endosc. 2012;26(7):2029-45. doi: 10.1007/s00464-012-2153-3.

4. Seracchioli R et al. J Minim Invasive Gynecol. 2019;26(7):1340-5. doi: 10.1016/j.jmig.2019.01.010.

5. Zakhari A et al. J Minim Invasive Gynecol. 2020;27(4):813-4. doi: 10.1016/j.jmig.2019.08.001

6. Lemos N et al. Fertil Steril. 2015 Nov;104(5):e11-2. doi: 10.1016/j.fertnstert.2015.07.1138. 

7. Possover M. Fertil Steril. 2014 Mar;101(3):754-8. doi: 10.1016/j.fertnstert.2013.12.019.

The pelvic autonomic nerves are responsible for the neurogenic control of the rectum and bladder and for sexual arousal. Over the past 30 years, different nerve-sparing techniques have been recommended and adopted to minimize risk of urinary or rectal dysfunction and incontinence, as well as sexual dysfunction, in radical surgery for rectal and early cervical cancer without compromising surgical outcome.

As the treatment of deep infiltrative endometriosis has become more aggressive and radical, it is certainly feasible to consider nerve-sparing techniques at the time of dissection and endometriosis excision to minimize the known risk of urinary, rectal, and sexual dysfunction. Interestingly, because endometriosis generally follows an asymmetric distribution, effect on bladder function is not as problematic as it is in the case of cancer surgery.

Miller_Charles_E 2014_web.jpg

Early innovators include Dr. Marc Possover from Switzerland and Dr. Marcello Ceccaroni from Italy. Both physicians are superior pelvic neuroanatomists. Both describe meticulous and extensive dissection of the nerves of the pelvis at the time of excision of deep infiltrative endometriosis. Unfortunately, their techniques would appear to be beyond the scope of even the most experienced excisional surgeons.

A simplified approach to nerve sparing at the time of excision of deep infiltrative endometriosis has been developed by our guest author, Dr. Nucelio Lemos, in collaboration with physicians at the University of Bologna and the University of Cambridge. By using the hypogastric nerves as the landmark, they have developed a more surgeon friendly and less radical approach to nerve sparing at the time of deep infiltrative endometriosis surgery.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of both Dr. Lemos and his fellow in advanced gynecologic surgery, Dr. Meghan McGrattan, from Mount Sinai and Women’s College Hospital in Toronto. Dr. McGrattan drew the anatomic illustrations that accompany Dr. Lemos’ description of the new technique.

Dr. Lemos is associate professor in the department of obstetrics and gynecology at the University of Toronto. He specializes in pelvic pain, pelvic floor dysfunction, pelvic organ prolapse, endometriosis, and neuropelveology. Dr. Lemos is a founding member and second vice president of the International Society of Neuropelveology. In addition, Dr. Lemos started the Pelvic Functional Surgery and Neuropelveology Clinic in the department of obstetrics and gynecology of Mount Sinai and Women’s College Hospitals, Toronto.

It is a pleasure and honor to welcome Dr. Lemos and Dr. McGrattan to this addition of the Master Class in Gynecologic Surgery.
 

Dr. Miller is a professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago, Ill. He has no conflicts of interest to report.

The pelvic autonomic nerves are responsible for the neurogenic control of the rectum and bladder and for sexual arousal. Over the past 30 years, different nerve-sparing techniques have been recommended and adopted to minimize risk of urinary or rectal dysfunction and incontinence, as well as sexual dysfunction, in radical surgery for rectal and early cervical cancer without compromising surgical outcome.

As the treatment of deep infiltrative endometriosis has become more aggressive and radical, it is certainly feasible to consider nerve-sparing techniques at the time of dissection and endometriosis excision to minimize the known risk of urinary, rectal, and sexual dysfunction. Interestingly, because endometriosis generally follows an asymmetric distribution, effect on bladder function is not as problematic as it is in the case of cancer surgery.

Miller_Charles_E 2014_web.jpg

Early innovators include Dr. Marc Possover from Switzerland and Dr. Marcello Ceccaroni from Italy. Both physicians are superior pelvic neuroanatomists. Both describe meticulous and extensive dissection of the nerves of the pelvis at the time of excision of deep infiltrative endometriosis. Unfortunately, their techniques would appear to be beyond the scope of even the most experienced excisional surgeons.

A simplified approach to nerve sparing at the time of excision of deep infiltrative endometriosis has been developed by our guest author, Dr. Nucelio Lemos, in collaboration with physicians at the University of Bologna and the University of Cambridge. By using the hypogastric nerves as the landmark, they have developed a more surgeon friendly and less radical approach to nerve sparing at the time of deep infiltrative endometriosis surgery.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of both Dr. Lemos and his fellow in advanced gynecologic surgery, Dr. Meghan McGrattan, from Mount Sinai and Women’s College Hospital in Toronto. Dr. McGrattan drew the anatomic illustrations that accompany Dr. Lemos’ description of the new technique.

Dr. Lemos is associate professor in the department of obstetrics and gynecology at the University of Toronto. He specializes in pelvic pain, pelvic floor dysfunction, pelvic organ prolapse, endometriosis, and neuropelveology. Dr. Lemos is a founding member and second vice president of the International Society of Neuropelveology. In addition, Dr. Lemos started the Pelvic Functional Surgery and Neuropelveology Clinic in the department of obstetrics and gynecology of Mount Sinai and Women’s College Hospitals, Toronto.

It is a pleasure and honor to welcome Dr. Lemos and Dr. McGrattan to this addition of the Master Class in Gynecologic Surgery.
 

Dr. Miller is a professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago, Ill. He has no conflicts of interest to report.

The pelvic autonomic nerves are responsible for the neurogenic control of the rectum and bladder and for sexual arousal. Over the past 30 years, different nerve-sparing techniques have been recommended and adopted to minimize risk of urinary or rectal dysfunction and incontinence, as well as sexual dysfunction, in radical surgery for rectal and early cervical cancer without compromising surgical outcome.

As the treatment of deep infiltrative endometriosis has become more aggressive and radical, it is certainly feasible to consider nerve-sparing techniques at the time of dissection and endometriosis excision to minimize the known risk of urinary, rectal, and sexual dysfunction. Interestingly, because endometriosis generally follows an asymmetric distribution, effect on bladder function is not as problematic as it is in the case of cancer surgery.

Miller_Charles_E 2014_web.jpg

Early innovators include Dr. Marc Possover from Switzerland and Dr. Marcello Ceccaroni from Italy. Both physicians are superior pelvic neuroanatomists. Both describe meticulous and extensive dissection of the nerves of the pelvis at the time of excision of deep infiltrative endometriosis. Unfortunately, their techniques would appear to be beyond the scope of even the most experienced excisional surgeons.

A simplified approach to nerve sparing at the time of excision of deep infiltrative endometriosis has been developed by our guest author, Dr. Nucelio Lemos, in collaboration with physicians at the University of Bologna and the University of Cambridge. By using the hypogastric nerves as the landmark, they have developed a more surgeon friendly and less radical approach to nerve sparing at the time of deep infiltrative endometriosis surgery.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of both Dr. Lemos and his fellow in advanced gynecologic surgery, Dr. Meghan McGrattan, from Mount Sinai and Women’s College Hospital in Toronto. Dr. McGrattan drew the anatomic illustrations that accompany Dr. Lemos’ description of the new technique.

Dr. Lemos is associate professor in the department of obstetrics and gynecology at the University of Toronto. He specializes in pelvic pain, pelvic floor dysfunction, pelvic organ prolapse, endometriosis, and neuropelveology. Dr. Lemos is a founding member and second vice president of the International Society of Neuropelveology. In addition, Dr. Lemos started the Pelvic Functional Surgery and Neuropelveology Clinic in the department of obstetrics and gynecology of Mount Sinai and Women’s College Hospitals, Toronto.

It is a pleasure and honor to welcome Dr. Lemos and Dr. McGrattan to this addition of the Master Class in Gynecologic Surgery.
 

Dr. Miller is a professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago, Ill. He has no conflicts of interest to report.

Multifetal pregnancy reduction (MPR) was developed in the 1980s in the wake of significant increases in the incidence of triplets and other higher-order multiples emanating from assisted reproductive technologies (ART). It was offered to reduce fetal number and improve outcomes for remaining fetuses by reducing rates of preterm delivery, fetal growth restriction, and other adverse perinatal outcomes, as well as maternal complications such as preeclampsia and postpartum hemorrhage.

In recent years, improvements in ART – mainly changes in ovulation induction practices and limitations in the number of embryos implanted to two at most – have reversed the increase in higher-order multiples. However, with intrauterine insemination, higher-order multiples still occur, and even without any reproductive assistance, the reality is that multiple pregnancies – particularly twins – continue to exist. In 2018, twins comprised about 3% of births in the United States.¹

Twin pregnancies have a significantly higher risk than singleton gestations of preterm birth, maternal complications, and neonatal morbidity and mortality. The pregnancies are complicated more often by preterm premature rupture of membranes, fetal growth restriction, and hypertensive disorders of pregnancy.

Monochorionic diamniotic twin pregnancies face additional, unique risks of twin-to-twin transfusion syndrome, twin reversed arterial perfusion sequence, and twin-anemia polycythemia sequence. These pregnancies account for about 20% of all twin gestations, and decades of experience with ART have shown us that monochorionic diamniotic gestations occur at a higher rate after in-vitro fertilization.

157501a_graphic_web.png

Although advances have improved the outcomes of multiple births, risks remain and elective MPR is still very relevant for twin gestations. Patients routinely receive counseling about the risks of twin gestations, but they often are not made aware of the option of elective fetal reduction.

157501b_graphic_web.png

We have offered elective reduction (of nonanomalous fetuses) to a singleton for almost 30 years and have published several reports documenting that MPR in dichorionic diamniotic pregnancies reduces the risk of preterm delivery and other complications without increasing the risk of pregnancy loss.

157501c_graphic_web.png

Most recently, we also published data comparing the outcomes of patients with monochorionic diamniotic gestations who underwent elective MPR by radiofrequency ablation (RFA) vs. those with ongoing monochorionic diamniotic gestations.² While the numbers were small, the data show significantly lower rates of preterm birth without an increased risk of pregnancy loss.
 

Experience with dichorionic diamniotic twins, genetic testing

Our most recent review³ of outcomes in dichorionic diamniotic gestations covered 855 patients, 29% of whom underwent planned elective MPR at less than 15 weeks, and 71% of whom had ongoing twin gestations. Those with ongoing twin gestations had adjusted odds ratios of preterm delivery at less than 37 weeks and less than 34 weeks of 5.62 and 2.22, respectively (adjustments controlled for maternal characteristics such as maternal age, BMI, use of chorionic villus sampling [CVS], and history of preterm birth).

Ongoing twin pregnancies were also more likely to have preeclampsia (AOR, 3.33), preterm premature rupture of membranes (3.86), and low birthweight (under the 5th and 10th percentiles). There were no significant differences in the rate of unintended pregnancy loss (2.4% vs. 2.3%), and rates for total pregnancy loss at less than 24 weeks and less than 20 weeks were similar.

An important issue in the consideration of MPR is that prenatal diagnosis of chromosomal abnormalities is very safe in twins. Multiple gestations are at greater risk of chromosomal abnormalities, so performing MPR selectively – if a chromosomally abnormal fetus is present – is desirable for many parents.

A recent meta-analysis and systematic review of studies reporting fetal loss following amniocentesis or CVS in twin pregnancies found an exceedingly low risk of loss. Procedure-related fetal loss (the primary outcome) was lower than previously reported, and the rate of fetal loss before 24 weeks gestation or within 4 weeks after the procedure (secondary outcomes), did not differ from the background risk in twin pregnancies not undergoing invasive prenatal testing.⁴

Our data have shown no significant differences in pregnancy loss between patients who underwent CVS prior to MPR and those who did not. Looking specifically at reduction to a singleton gestation, patients who underwent CVS prior to MPR had a fourfold reduction in loss.⁵ Therefore, we counsel patients that CVS provides useful information – especially now with the common use of chromosomal microarray – at almost negligible risk.
 

MPR for monochorionic diamniotic twins

Most of the literature on MPR from twin to singleton gestations reports on intrathoracic potassium chloride injection used in dichorionic diamniotic twins.

MPR in monochorionic diamniotic twins is reserved in the United States for monochorionic pregnancies in which there are severe fetal anomalies, severe growth restriction, or other significant complications. It is performed in such cases around 20 weeks gestation. However, given the significant risks of monochorionic twin pregnancies, we also have been offering MPR electively and earlier in pregnancy. While many modalities of intrafetal cord occlusion exist, RFA at the cord insertion site into the fetal abdomen is our preferred technique.

In our retrospective review of 315 monochorionic diamniotic twin gestations, the 14 patients who had RFA electively had no pregnancy losses and a significantly lower rate of preterm birth at less than 37-weeks gestation, compared with 301 ongoing monochorionic diamniotic twin pregnancies (29% vs. 76%).⁵ Reduction with RFA, performed at a mean gestational age of 15 weeks, also eliminated the risks unique to monochorionic twins, such as twin-to-twin transfusion syndrome and twin-anemia polycythemia sequence. (Of the ongoing twin gestations, 12% required medically indicated RFA, fetoscopic laser ablation, and/or amnioreduction; 4% had unintended loss of one fetus; and 4% had unintended loss of both fetuses before 24 weeks’ gestation. Fewer than 70% of the ongoing twin gestations had none of the significant adverse outcomes unique to monochorionic twins.)

Interestingly, there were still a couple of cases of fetal growth restriction in patients who underwent elective MPR – a rate higher than that seen in singleton gestations – most likely because of the early timing of the procedure.

Our numbers of MPRs in this review were small, but the data offer at least preliminary evidence that planned elective RFA before 17 weeks gestation may be offered to patients who do not want to assume the risks of monochorionic diamniotic twin pregnancies.

[embed:render:related:node:254032]

Counseling in twin pregnancies

We perform thorough, early assessments of fetal anatomy in our twin pregnancies, and we undertake thorough medical and obstetrical histories to uncover birth complications or medical conditions that would increase risks of preeclampsia, preterm birth, fetal growth restriction, and other complications.

Because monochorionic gestations are at particularly high risk for heart defects, we also routinely perform fetal echocardiography in these pregnancies.

Genetic testing is offered to all twin pregnancies, and as mentioned above, we especially counsel those considering MPR that such testing provides useful information.

Patients are made aware of the option of MPR and receive nondirective counseling. It is the patient’s choice. We recognize that elective termination is a controversial procedure, but we believe that the option of MPR should be available to patients who want to improve outcomes for their pregnancy.

When anomalies are discovered and selective termination is chosen, we usually try to perform MPR as early as possible. After 16 weeks, we’ve found, the rate of pregnancy loss increases slightly.
 

Dr. Stone is the Ellen and Howard C. Katz Chairman’s Chair, and Dr. DeBolt is a clinical fellow in maternal-fetal medicine, in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai, New York.

References

1. Martin JA and Osterman MJK. National Center of Health Statistics. NCHS Data Brief, 2019;no 351.

2. Manasa GR et al. Am J Obstet Gynecol MFM 2021;3:100447.

3. Vieira LA et al. Am J. Obstet Gynecol. 2019;221:253.e1-8.  

4. Di Mascio et al. Ultrasound Obstet Gynecol 2020 Nov;56(5):647-55.

5. Ferrara L et al. Am J Obstet Gynecol. 2008 Oct;199(4):408.e1-4.

Multifetal pregnancy reduction (MPR) was developed in the 1980s in the wake of significant increases in the incidence of triplets and other higher-order multiples emanating from assisted reproductive technologies (ART). It was offered to reduce fetal number and improve outcomes for remaining fetuses by reducing rates of preterm delivery, fetal growth restriction, and other adverse perinatal outcomes, as well as maternal complications such as preeclampsia and postpartum hemorrhage.

In recent years, improvements in ART – mainly changes in ovulation induction practices and limitations in the number of embryos implanted to two at most – have reversed the increase in higher-order multiples. However, with intrauterine insemination, higher-order multiples still occur, and even without any reproductive assistance, the reality is that multiple pregnancies – particularly twins – continue to exist. In 2018, twins comprised about 3% of births in the United States.¹

Twin pregnancies have a significantly higher risk than singleton gestations of preterm birth, maternal complications, and neonatal morbidity and mortality. The pregnancies are complicated more often by preterm premature rupture of membranes, fetal growth restriction, and hypertensive disorders of pregnancy.

Monochorionic diamniotic twin pregnancies face additional, unique risks of twin-to-twin transfusion syndrome, twin reversed arterial perfusion sequence, and twin-anemia polycythemia sequence. These pregnancies account for about 20% of all twin gestations, and decades of experience with ART have shown us that monochorionic diamniotic gestations occur at a higher rate after in-vitro fertilization.

157501a_graphic_web.png

Although advances have improved the outcomes of multiple births, risks remain and elective MPR is still very relevant for twin gestations. Patients routinely receive counseling about the risks of twin gestations, but they often are not made aware of the option of elective fetal reduction.

157501b_graphic_web.png

We have offered elective reduction (of nonanomalous fetuses) to a singleton for almost 30 years and have published several reports documenting that MPR in dichorionic diamniotic pregnancies reduces the risk of preterm delivery and other complications without increasing the risk of pregnancy loss.

157501c_graphic_web.png

Most recently, we also published data comparing the outcomes of patients with monochorionic diamniotic gestations who underwent elective MPR by radiofrequency ablation (RFA) vs. those with ongoing monochorionic diamniotic gestations.² While the numbers were small, the data show significantly lower rates of preterm birth without an increased risk of pregnancy loss.
 

Experience with dichorionic diamniotic twins, genetic testing

Our most recent review³ of outcomes in dichorionic diamniotic gestations covered 855 patients, 29% of whom underwent planned elective MPR at less than 15 weeks, and 71% of whom had ongoing twin gestations. Those with ongoing twin gestations had adjusted odds ratios of preterm delivery at less than 37 weeks and less than 34 weeks of 5.62 and 2.22, respectively (adjustments controlled for maternal characteristics such as maternal age, BMI, use of chorionic villus sampling [CVS], and history of preterm birth).

Ongoing twin pregnancies were also more likely to have preeclampsia (AOR, 3.33), preterm premature rupture of membranes (3.86), and low birthweight (under the 5th and 10th percentiles). There were no significant differences in the rate of unintended pregnancy loss (2.4% vs. 2.3%), and rates for total pregnancy loss at less than 24 weeks and less than 20 weeks were similar.

An important issue in the consideration of MPR is that prenatal diagnosis of chromosomal abnormalities is very safe in twins. Multiple gestations are at greater risk of chromosomal abnormalities, so performing MPR selectively – if a chromosomally abnormal fetus is present – is desirable for many parents.

A recent meta-analysis and systematic review of studies reporting fetal loss following amniocentesis or CVS in twin pregnancies found an exceedingly low risk of loss. Procedure-related fetal loss (the primary outcome) was lower than previously reported, and the rate of fetal loss before 24 weeks gestation or within 4 weeks after the procedure (secondary outcomes), did not differ from the background risk in twin pregnancies not undergoing invasive prenatal testing.⁴

Our data have shown no significant differences in pregnancy loss between patients who underwent CVS prior to MPR and those who did not. Looking specifically at reduction to a singleton gestation, patients who underwent CVS prior to MPR had a fourfold reduction in loss.⁵ Therefore, we counsel patients that CVS provides useful information – especially now with the common use of chromosomal microarray – at almost negligible risk.
 

MPR for monochorionic diamniotic twins

Most of the literature on MPR from twin to singleton gestations reports on intrathoracic potassium chloride injection used in dichorionic diamniotic twins.

MPR in monochorionic diamniotic twins is reserved in the United States for monochorionic pregnancies in which there are severe fetal anomalies, severe growth restriction, or other significant complications. It is performed in such cases around 20 weeks gestation. However, given the significant risks of monochorionic twin pregnancies, we also have been offering MPR electively and earlier in pregnancy. While many modalities of intrafetal cord occlusion exist, RFA at the cord insertion site into the fetal abdomen is our preferred technique.

In our retrospective review of 315 monochorionic diamniotic twin gestations, the 14 patients who had RFA electively had no pregnancy losses and a significantly lower rate of preterm birth at less than 37-weeks gestation, compared with 301 ongoing monochorionic diamniotic twin pregnancies (29% vs. 76%).⁵ Reduction with RFA, performed at a mean gestational age of 15 weeks, also eliminated the risks unique to monochorionic twins, such as twin-to-twin transfusion syndrome and twin-anemia polycythemia sequence. (Of the ongoing twin gestations, 12% required medically indicated RFA, fetoscopic laser ablation, and/or amnioreduction; 4% had unintended loss of one fetus; and 4% had unintended loss of both fetuses before 24 weeks’ gestation. Fewer than 70% of the ongoing twin gestations had none of the significant adverse outcomes unique to monochorionic twins.)

Interestingly, there were still a couple of cases of fetal growth restriction in patients who underwent elective MPR – a rate higher than that seen in singleton gestations – most likely because of the early timing of the procedure.

Our numbers of MPRs in this review were small, but the data offer at least preliminary evidence that planned elective RFA before 17 weeks gestation may be offered to patients who do not want to assume the risks of monochorionic diamniotic twin pregnancies.

[embed:render:related:node:254032]

Counseling in twin pregnancies

We perform thorough, early assessments of fetal anatomy in our twin pregnancies, and we undertake thorough medical and obstetrical histories to uncover birth complications or medical conditions that would increase risks of preeclampsia, preterm birth, fetal growth restriction, and other complications.

Because monochorionic gestations are at particularly high risk for heart defects, we also routinely perform fetal echocardiography in these pregnancies.

Genetic testing is offered to all twin pregnancies, and as mentioned above, we especially counsel those considering MPR that such testing provides useful information.

Patients are made aware of the option of MPR and receive nondirective counseling. It is the patient’s choice. We recognize that elective termination is a controversial procedure, but we believe that the option of MPR should be available to patients who want to improve outcomes for their pregnancy.

When anomalies are discovered and selective termination is chosen, we usually try to perform MPR as early as possible. After 16 weeks, we’ve found, the rate of pregnancy loss increases slightly.
 

Dr. Stone is the Ellen and Howard C. Katz Chairman’s Chair, and Dr. DeBolt is a clinical fellow in maternal-fetal medicine, in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai, New York.

References

1. Martin JA and Osterman MJK. National Center of Health Statistics. NCHS Data Brief, 2019;no 351.

2. Manasa GR et al. Am J Obstet Gynecol MFM 2021;3:100447.

3. Vieira LA et al. Am J. Obstet Gynecol. 2019;221:253.e1-8.  

4. Di Mascio et al. Ultrasound Obstet Gynecol 2020 Nov;56(5):647-55.

5. Ferrara L et al. Am J Obstet Gynecol. 2008 Oct;199(4):408.e1-4.

Multifetal pregnancy reduction (MPR) was developed in the 1980s in the wake of significant increases in the incidence of triplets and other higher-order multiples emanating from assisted reproductive technologies (ART). It was offered to reduce fetal number and improve outcomes for remaining fetuses by reducing rates of preterm delivery, fetal growth restriction, and other adverse perinatal outcomes, as well as maternal complications such as preeclampsia and postpartum hemorrhage.

In recent years, improvements in ART – mainly changes in ovulation induction practices and limitations in the number of embryos implanted to two at most – have reversed the increase in higher-order multiples. However, with intrauterine insemination, higher-order multiples still occur, and even without any reproductive assistance, the reality is that multiple pregnancies – particularly twins – continue to exist. In 2018, twins comprised about 3% of births in the United States.¹

Twin pregnancies have a significantly higher risk than singleton gestations of preterm birth, maternal complications, and neonatal morbidity and mortality. The pregnancies are complicated more often by preterm premature rupture of membranes, fetal growth restriction, and hypertensive disorders of pregnancy.

Monochorionic diamniotic twin pregnancies face additional, unique risks of twin-to-twin transfusion syndrome, twin reversed arterial perfusion sequence, and twin-anemia polycythemia sequence. These pregnancies account for about 20% of all twin gestations, and decades of experience with ART have shown us that monochorionic diamniotic gestations occur at a higher rate after in-vitro fertilization.

157501a_graphic_web.png

Although advances have improved the outcomes of multiple births, risks remain and elective MPR is still very relevant for twin gestations. Patients routinely receive counseling about the risks of twin gestations, but they often are not made aware of the option of elective fetal reduction.

157501b_graphic_web.png

We have offered elective reduction (of nonanomalous fetuses) to a singleton for almost 30 years and have published several reports documenting that MPR in dichorionic diamniotic pregnancies reduces the risk of preterm delivery and other complications without increasing the risk of pregnancy loss.

157501c_graphic_web.png

Most recently, we also published data comparing the outcomes of patients with monochorionic diamniotic gestations who underwent elective MPR by radiofrequency ablation (RFA) vs. those with ongoing monochorionic diamniotic gestations.² While the numbers were small, the data show significantly lower rates of preterm birth without an increased risk of pregnancy loss.
 

Experience with dichorionic diamniotic twins, genetic testing

Our most recent review³ of outcomes in dichorionic diamniotic gestations covered 855 patients, 29% of whom underwent planned elective MPR at less than 15 weeks, and 71% of whom had ongoing twin gestations. Those with ongoing twin gestations had adjusted odds ratios of preterm delivery at less than 37 weeks and less than 34 weeks of 5.62 and 2.22, respectively (adjustments controlled for maternal characteristics such as maternal age, BMI, use of chorionic villus sampling [CVS], and history of preterm birth).

Ongoing twin pregnancies were also more likely to have preeclampsia (AOR, 3.33), preterm premature rupture of membranes (3.86), and low birthweight (under the 5th and 10th percentiles). There were no significant differences in the rate of unintended pregnancy loss (2.4% vs. 2.3%), and rates for total pregnancy loss at less than 24 weeks and less than 20 weeks were similar.

An important issue in the consideration of MPR is that prenatal diagnosis of chromosomal abnormalities is very safe in twins. Multiple gestations are at greater risk of chromosomal abnormalities, so performing MPR selectively – if a chromosomally abnormal fetus is present – is desirable for many parents.

A recent meta-analysis and systematic review of studies reporting fetal loss following amniocentesis or CVS in twin pregnancies found an exceedingly low risk of loss. Procedure-related fetal loss (the primary outcome) was lower than previously reported, and the rate of fetal loss before 24 weeks gestation or within 4 weeks after the procedure (secondary outcomes), did not differ from the background risk in twin pregnancies not undergoing invasive prenatal testing.⁴

Our data have shown no significant differences in pregnancy loss between patients who underwent CVS prior to MPR and those who did not. Looking specifically at reduction to a singleton gestation, patients who underwent CVS prior to MPR had a fourfold reduction in loss.⁵ Therefore, we counsel patients that CVS provides useful information – especially now with the common use of chromosomal microarray – at almost negligible risk.
 

MPR for monochorionic diamniotic twins

Most of the literature on MPR from twin to singleton gestations reports on intrathoracic potassium chloride injection used in dichorionic diamniotic twins.

MPR in monochorionic diamniotic twins is reserved in the United States for monochorionic pregnancies in which there are severe fetal anomalies, severe growth restriction, or other significant complications. It is performed in such cases around 20 weeks gestation. However, given the significant risks of monochorionic twin pregnancies, we also have been offering MPR electively and earlier in pregnancy. While many modalities of intrafetal cord occlusion exist, RFA at the cord insertion site into the fetal abdomen is our preferred technique.

In our retrospective review of 315 monochorionic diamniotic twin gestations, the 14 patients who had RFA electively had no pregnancy losses and a significantly lower rate of preterm birth at less than 37-weeks gestation, compared with 301 ongoing monochorionic diamniotic twin pregnancies (29% vs. 76%).⁵ Reduction with RFA, performed at a mean gestational age of 15 weeks, also eliminated the risks unique to monochorionic twins, such as twin-to-twin transfusion syndrome and twin-anemia polycythemia sequence. (Of the ongoing twin gestations, 12% required medically indicated RFA, fetoscopic laser ablation, and/or amnioreduction; 4% had unintended loss of one fetus; and 4% had unintended loss of both fetuses before 24 weeks’ gestation. Fewer than 70% of the ongoing twin gestations had none of the significant adverse outcomes unique to monochorionic twins.)

Interestingly, there were still a couple of cases of fetal growth restriction in patients who underwent elective MPR – a rate higher than that seen in singleton gestations – most likely because of the early timing of the procedure.

Our numbers of MPRs in this review were small, but the data offer at least preliminary evidence that planned elective RFA before 17 weeks gestation may be offered to patients who do not want to assume the risks of monochorionic diamniotic twin pregnancies.

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Counseling in twin pregnancies

We perform thorough, early assessments of fetal anatomy in our twin pregnancies, and we undertake thorough medical and obstetrical histories to uncover birth complications or medical conditions that would increase risks of preeclampsia, preterm birth, fetal growth restriction, and other complications.

Because monochorionic gestations are at particularly high risk for heart defects, we also routinely perform fetal echocardiography in these pregnancies.

Genetic testing is offered to all twin pregnancies, and as mentioned above, we especially counsel those considering MPR that such testing provides useful information.

Patients are made aware of the option of MPR and receive nondirective counseling. It is the patient’s choice. We recognize that elective termination is a controversial procedure, but we believe that the option of MPR should be available to patients who want to improve outcomes for their pregnancy.

When anomalies are discovered and selective termination is chosen, we usually try to perform MPR as early as possible. After 16 weeks, we’ve found, the rate of pregnancy loss increases slightly.
 

Dr. Stone is the Ellen and Howard C. Katz Chairman’s Chair, and Dr. DeBolt is a clinical fellow in maternal-fetal medicine, in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai, New York.

References

1. Martin JA and Osterman MJK. National Center of Health Statistics. NCHS Data Brief, 2019;no 351.

2. Manasa GR et al. Am J Obstet Gynecol MFM 2021;3:100447.

3. Vieira LA et al. Am J. Obstet Gynecol. 2019;221:253.e1-8.  

4. Di Mascio et al. Ultrasound Obstet Gynecol 2020 Nov;56(5):647-55.

5. Ferrara L et al. Am J Obstet Gynecol. 2008 Oct;199(4):408.e1-4.

For over 2 years, the world has reeled from the COVID-19 pandemic. Life has changed dramatically, priorities have been re-examined, and the collective approach to health care has shifted tremendously. While concerns regarding coronavirus and its variants are warranted, another “pandemic” is ravaging the world and has yet to be fully addressed: pregnancy-related maternal mortality.

The rate of pregnancy-related deaths in the United States is unconscionable. Compared with other developed nations – such as Germany, the United Kingdom, and Canada – we lag far behind. Data published in 2020 showed that the rate of maternal deaths per 100,000 live births in the United States was 17.4, more than double that of France (8.7 deaths per 100,000 live births),¹ the country with the next-highest rate. Americans like being first – first to invent the light bulb, first to perform a successful solid organ xenotransplantation, first to go to the moon – but holding “first place” in maternal mortality is not something we should wish to maintain.

[embed:render:related:node:254033]

Ob.gyns. have long raised the alarm regarding the exceedingly high rates of pregnancy-related deaths in the United States. While there have been many advances in antenatal care to reduce these severe adverse events – improvements in surveillance and data reporting, maternal-focused telemedicine services, multidisciplinary care team models, and numerous research initiatives by federal and nonprofit organizations² – the recent wave of legislation restricting reproductive choice may also have the unintended consequence of further increasing the rate of pregnancy-related maternal morbidity and mortality.³

While we have an obligation to provide our maternal and fetal patients with the best possible care, under some circumstances, that care may require prioritizing the mother’s health above all else.

To discuss the judicious use of multifetal pregnancy reduction, we have invited Dr. Joanne Stone, The Ellen and Howard C. Katz Chairman’s Chair, and Dr. Chelsea DeBolt, clinical fellow in maternal-fetal medicine, both in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai.

Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.

References

1. Tikkanen R et al. The Commonwealth Fund. Nov 2020. doi: 10.26099/411v-9255

2. Ahn R et al. Ann Intern Med. 2020;173(11 Suppl):S3-10. doi: 10.7326/M19-3258.

3. Pabayo R et al. Int J Environ Res Public Health. 2020;17(11):3773. doi: 10.3390/ijerph17113773.

For over 2 years, the world has reeled from the COVID-19 pandemic. Life has changed dramatically, priorities have been re-examined, and the collective approach to health care has shifted tremendously. While concerns regarding coronavirus and its variants are warranted, another “pandemic” is ravaging the world and has yet to be fully addressed: pregnancy-related maternal mortality.

The rate of pregnancy-related deaths in the United States is unconscionable. Compared with other developed nations – such as Germany, the United Kingdom, and Canada – we lag far behind. Data published in 2020 showed that the rate of maternal deaths per 100,000 live births in the United States was 17.4, more than double that of France (8.7 deaths per 100,000 live births),¹ the country with the next-highest rate. Americans like being first – first to invent the light bulb, first to perform a successful solid organ xenotransplantation, first to go to the moon – but holding “first place” in maternal mortality is not something we should wish to maintain.

[embed:render:related:node:254033]

Ob.gyns. have long raised the alarm regarding the exceedingly high rates of pregnancy-related deaths in the United States. While there have been many advances in antenatal care to reduce these severe adverse events – improvements in surveillance and data reporting, maternal-focused telemedicine services, multidisciplinary care team models, and numerous research initiatives by federal and nonprofit organizations² – the recent wave of legislation restricting reproductive choice may also have the unintended consequence of further increasing the rate of pregnancy-related maternal morbidity and mortality.³

While we have an obligation to provide our maternal and fetal patients with the best possible care, under some circumstances, that care may require prioritizing the mother’s health above all else.

To discuss the judicious use of multifetal pregnancy reduction, we have invited Dr. Joanne Stone, The Ellen and Howard C. Katz Chairman’s Chair, and Dr. Chelsea DeBolt, clinical fellow in maternal-fetal medicine, both in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai.

Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.

References

1. Tikkanen R et al. The Commonwealth Fund. Nov 2020. doi: 10.26099/411v-9255

2. Ahn R et al. Ann Intern Med. 2020;173(11 Suppl):S3-10. doi: 10.7326/M19-3258.

3. Pabayo R et al. Int J Environ Res Public Health. 2020;17(11):3773. doi: 10.3390/ijerph17113773.

For over 2 years, the world has reeled from the COVID-19 pandemic. Life has changed dramatically, priorities have been re-examined, and the collective approach to health care has shifted tremendously. While concerns regarding coronavirus and its variants are warranted, another “pandemic” is ravaging the world and has yet to be fully addressed: pregnancy-related maternal mortality.

The rate of pregnancy-related deaths in the United States is unconscionable. Compared with other developed nations – such as Germany, the United Kingdom, and Canada – we lag far behind. Data published in 2020 showed that the rate of maternal deaths per 100,000 live births in the United States was 17.4, more than double that of France (8.7 deaths per 100,000 live births),¹ the country with the next-highest rate. Americans like being first – first to invent the light bulb, first to perform a successful solid organ xenotransplantation, first to go to the moon – but holding “first place” in maternal mortality is not something we should wish to maintain.

[embed:render:related:node:254033]

Ob.gyns. have long raised the alarm regarding the exceedingly high rates of pregnancy-related deaths in the United States. While there have been many advances in antenatal care to reduce these severe adverse events – improvements in surveillance and data reporting, maternal-focused telemedicine services, multidisciplinary care team models, and numerous research initiatives by federal and nonprofit organizations² – the recent wave of legislation restricting reproductive choice may also have the unintended consequence of further increasing the rate of pregnancy-related maternal morbidity and mortality.³

While we have an obligation to provide our maternal and fetal patients with the best possible care, under some circumstances, that care may require prioritizing the mother’s health above all else.

To discuss the judicious use of multifetal pregnancy reduction, we have invited Dr. Joanne Stone, The Ellen and Howard C. Katz Chairman’s Chair, and Dr. Chelsea DeBolt, clinical fellow in maternal-fetal medicine, both in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai.

Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.

References

1. Tikkanen R et al. The Commonwealth Fund. Nov 2020. doi: 10.26099/411v-9255

2. Ahn R et al. Ann Intern Med. 2020;173(11 Suppl):S3-10. doi: 10.7326/M19-3258.

3. Pabayo R et al. Int J Environ Res Public Health. 2020;17(11):3773. doi: 10.3390/ijerph17113773.