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Tip for when using phenazophyridine
Tip for when using phenazophyridine
I enjoyed the review by Dr. Iglesia on agents that are used to demonstrate ureteral patency. I like phenazopyridine because it is cheap and readily available. It works great if you remember one thing: drain the bladder first so the orange color stands out in the colorless saline irrigant. Otherwise, the orange-dyed urine obscures the orange ureteral jets.
John H. Sand, MD
Ellensburg, Washington
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Tip for when using phenazophyridine
I enjoyed the review by Dr. Iglesia on agents that are used to demonstrate ureteral patency. I like phenazopyridine because it is cheap and readily available. It works great if you remember one thing: drain the bladder first so the orange color stands out in the colorless saline irrigant. Otherwise, the orange-dyed urine obscures the orange ureteral jets.
John H. Sand, MD
Ellensburg, Washington
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Tip for when using phenazophyridine
I enjoyed the review by Dr. Iglesia on agents that are used to demonstrate ureteral patency. I like phenazopyridine because it is cheap and readily available. It works great if you remember one thing: drain the bladder first so the orange color stands out in the colorless saline irrigant. Otherwise, the orange-dyed urine obscures the orange ureteral jets.
John H. Sand, MD
Ellensburg, Washington
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Rash goes undetected
Rash goes undetected
As a urogynecologist, in the past 5 years I have had 2 urgent emergency department referrals from 2 towns. The patients had excruciating flank pain and had a negative computed tomography scan and normal pelvic and renal examinations, but no physical exam. They were subsequently found to have shingles!
Bunan Alnaif, MD
Chesapeake, Virginia
Physical exam revealed suspicious mass
Two years ago a regular gynecologic patient of mine came in 2 months early for her Pap test because she was concerned about a pressure in her genital area. I had delivered her 3 children. She was now in her mid-40s. She had visited her usual physician about the problem; she was not physically examined but was advised to see a gastrointestinal specialist, since the pressure caused constipation with discomfort. She then consulted a gastroenterologist, who performed a colonoscopy that was reported as normal. The patient related that she had no pelvic or rectal examination at that time, although it is possible that one could have been done while she was under anesthesia.
She arrived at my office 3 weeks later, and while doing the pelvic and rectal exam, I noted she had a 3- to 4-cm perirectal mass, which I thought was a Bartholin’s tumor. I referred her to a gynecologic oncologist who happened to write a paper on this subject. My diagnosis was wrong—she had a rectal carcinoma, which fortunately was Stage 1.
The patient subsequently has done well. The delay in diagnosis could have been averted if a simple rectal examination had been performed by the first doctor.
James Moran, MD
Santa Monica, California
Case of an almost missed diagnosis
I have many examples of how not performing a physical examination can cause problems, but here is a recent one. This involved a 70-year-old woman who had been seeing only her primary care physician for the past 30 years, with no pelvic examinations done. She had symptoms of vaginal discharge and itch for which she was given multiple courses of antifungals and topical steroids. Finally, she was referred to me. Examination revealed findings of extensive raised, erythematous, hyperkeratotic, macerated lesions throughout the vulva. A punch biopsy revealed severe vulvar dysplasia with areas suspicious for squamous cell carcinoma. I referred the patient to a gynecologic oncologist, who performed a simple vulvectomy. There were extensive foci of vulvar intraepithelial neoplasia 3.
Susan Richman, MD
New Haven, Connecticut
Lack of physical exam leads to tortuous dx course
Here is a story of a patient who must have gone without having a pelvic examination or any evaluation for years. This 83-year-old woman had a previous transvaginal hysterectomy at age 49 for fibroids and bleeding. She is quite healthy and active for her age. She had problems with recurrent urinary tract infection for several years before being referred to a gynecologist. She had emergency room visits and multiple urgent care visits. She saw her primary care physician 3 times in 4 weeks for bladder pain and a sensation of incomplete bladder emptying. She reported that when she got up in the morning, it felt like her urine slowly leaked out for several hours. She was referred to a urologist, who saw her twice and did pelvic ultrasonography and postvoid residual urine testing—without a pelvic exam.
After 2 months of regular visits, an examination by her primary care physician revealed a complete fusion of the labia. Six months after her initial urology visit, the patient had an examination with a plan for cystoscopy, and the urologist ended up doing a “dilation of labial fusion” in the office. The patient’s urinary symptoms were improved slightly, and she had visits to the emergency room or urgent care once monthly for dysuria after dilation of the labia.
At that point she was referred to me. We tried topical estrogen for several months with minimal improvement in symptoms, and I performed a surgical separation of labial fusion in the operating room under monitored anesthesia care. After surgery the patient said that she felt like “I got my life back,” and she never knew how happy she could be to pee in the morning.
Theresa Gipps, MD
Walnut Creek, California
Agrees with importance of clinical exam
I fully agree that clinical examination skill is a dying art. But the American College of Obstetricians and Gynecologists has issued guidelines stating that pelvic examination is not required, especially in asymptomatic women. Another area of concern is hair removal procedures like waxing and laser treatments in the pubic area, and whether these do harm in any way or increase the likelihood of skin problems.
Manju Hotchandani, MD
New Delhi, India
Dr. Barbieri responds
I thank Drs. Alnaif, Moran, Richman, Gipps, and Hotchandani for sharing their comments and important clinical vignettes concerning the primacy of the physical examination with our readers. In clinical practice there are many competing demands on the time of clinicians, but we should strive to preserve time for a good physical examination. If not us, who is going to perform a competent physical examination?
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Rash goes undetected
As a urogynecologist, in the past 5 years I have had 2 urgent emergency department referrals from 2 towns. The patients had excruciating flank pain and had a negative computed tomography scan and normal pelvic and renal examinations, but no physical exam. They were subsequently found to have shingles!
Bunan Alnaif, MD
Chesapeake, Virginia
Physical exam revealed suspicious mass
Two years ago a regular gynecologic patient of mine came in 2 months early for her Pap test because she was concerned about a pressure in her genital area. I had delivered her 3 children. She was now in her mid-40s. She had visited her usual physician about the problem; she was not physically examined but was advised to see a gastrointestinal specialist, since the pressure caused constipation with discomfort. She then consulted a gastroenterologist, who performed a colonoscopy that was reported as normal. The patient related that she had no pelvic or rectal examination at that time, although it is possible that one could have been done while she was under anesthesia.
She arrived at my office 3 weeks later, and while doing the pelvic and rectal exam, I noted she had a 3- to 4-cm perirectal mass, which I thought was a Bartholin’s tumor. I referred her to a gynecologic oncologist who happened to write a paper on this subject. My diagnosis was wrong—she had a rectal carcinoma, which fortunately was Stage 1.
The patient subsequently has done well. The delay in diagnosis could have been averted if a simple rectal examination had been performed by the first doctor.
James Moran, MD
Santa Monica, California
Case of an almost missed diagnosis
I have many examples of how not performing a physical examination can cause problems, but here is a recent one. This involved a 70-year-old woman who had been seeing only her primary care physician for the past 30 years, with no pelvic examinations done. She had symptoms of vaginal discharge and itch for which she was given multiple courses of antifungals and topical steroids. Finally, she was referred to me. Examination revealed findings of extensive raised, erythematous, hyperkeratotic, macerated lesions throughout the vulva. A punch biopsy revealed severe vulvar dysplasia with areas suspicious for squamous cell carcinoma. I referred the patient to a gynecologic oncologist, who performed a simple vulvectomy. There were extensive foci of vulvar intraepithelial neoplasia 3.
Susan Richman, MD
New Haven, Connecticut
Lack of physical exam leads to tortuous dx course
Here is a story of a patient who must have gone without having a pelvic examination or any evaluation for years. This 83-year-old woman had a previous transvaginal hysterectomy at age 49 for fibroids and bleeding. She is quite healthy and active for her age. She had problems with recurrent urinary tract infection for several years before being referred to a gynecologist. She had emergency room visits and multiple urgent care visits. She saw her primary care physician 3 times in 4 weeks for bladder pain and a sensation of incomplete bladder emptying. She reported that when she got up in the morning, it felt like her urine slowly leaked out for several hours. She was referred to a urologist, who saw her twice and did pelvic ultrasonography and postvoid residual urine testing—without a pelvic exam.
After 2 months of regular visits, an examination by her primary care physician revealed a complete fusion of the labia. Six months after her initial urology visit, the patient had an examination with a plan for cystoscopy, and the urologist ended up doing a “dilation of labial fusion” in the office. The patient’s urinary symptoms were improved slightly, and she had visits to the emergency room or urgent care once monthly for dysuria after dilation of the labia.
At that point she was referred to me. We tried topical estrogen for several months with minimal improvement in symptoms, and I performed a surgical separation of labial fusion in the operating room under monitored anesthesia care. After surgery the patient said that she felt like “I got my life back,” and she never knew how happy she could be to pee in the morning.
Theresa Gipps, MD
Walnut Creek, California
Agrees with importance of clinical exam
I fully agree that clinical examination skill is a dying art. But the American College of Obstetricians and Gynecologists has issued guidelines stating that pelvic examination is not required, especially in asymptomatic women. Another area of concern is hair removal procedures like waxing and laser treatments in the pubic area, and whether these do harm in any way or increase the likelihood of skin problems.
Manju Hotchandani, MD
New Delhi, India
Dr. Barbieri responds
I thank Drs. Alnaif, Moran, Richman, Gipps, and Hotchandani for sharing their comments and important clinical vignettes concerning the primacy of the physical examination with our readers. In clinical practice there are many competing demands on the time of clinicians, but we should strive to preserve time for a good physical examination. If not us, who is going to perform a competent physical examination?
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Rash goes undetected
As a urogynecologist, in the past 5 years I have had 2 urgent emergency department referrals from 2 towns. The patients had excruciating flank pain and had a negative computed tomography scan and normal pelvic and renal examinations, but no physical exam. They were subsequently found to have shingles!
Bunan Alnaif, MD
Chesapeake, Virginia
Physical exam revealed suspicious mass
Two years ago a regular gynecologic patient of mine came in 2 months early for her Pap test because she was concerned about a pressure in her genital area. I had delivered her 3 children. She was now in her mid-40s. She had visited her usual physician about the problem; she was not physically examined but was advised to see a gastrointestinal specialist, since the pressure caused constipation with discomfort. She then consulted a gastroenterologist, who performed a colonoscopy that was reported as normal. The patient related that she had no pelvic or rectal examination at that time, although it is possible that one could have been done while she was under anesthesia.
She arrived at my office 3 weeks later, and while doing the pelvic and rectal exam, I noted she had a 3- to 4-cm perirectal mass, which I thought was a Bartholin’s tumor. I referred her to a gynecologic oncologist who happened to write a paper on this subject. My diagnosis was wrong—she had a rectal carcinoma, which fortunately was Stage 1.
The patient subsequently has done well. The delay in diagnosis could have been averted if a simple rectal examination had been performed by the first doctor.
James Moran, MD
Santa Monica, California
Case of an almost missed diagnosis
I have many examples of how not performing a physical examination can cause problems, but here is a recent one. This involved a 70-year-old woman who had been seeing only her primary care physician for the past 30 years, with no pelvic examinations done. She had symptoms of vaginal discharge and itch for which she was given multiple courses of antifungals and topical steroids. Finally, she was referred to me. Examination revealed findings of extensive raised, erythematous, hyperkeratotic, macerated lesions throughout the vulva. A punch biopsy revealed severe vulvar dysplasia with areas suspicious for squamous cell carcinoma. I referred the patient to a gynecologic oncologist, who performed a simple vulvectomy. There were extensive foci of vulvar intraepithelial neoplasia 3.
Susan Richman, MD
New Haven, Connecticut
Lack of physical exam leads to tortuous dx course
Here is a story of a patient who must have gone without having a pelvic examination or any evaluation for years. This 83-year-old woman had a previous transvaginal hysterectomy at age 49 for fibroids and bleeding. She is quite healthy and active for her age. She had problems with recurrent urinary tract infection for several years before being referred to a gynecologist. She had emergency room visits and multiple urgent care visits. She saw her primary care physician 3 times in 4 weeks for bladder pain and a sensation of incomplete bladder emptying. She reported that when she got up in the morning, it felt like her urine slowly leaked out for several hours. She was referred to a urologist, who saw her twice and did pelvic ultrasonography and postvoid residual urine testing—without a pelvic exam.
After 2 months of regular visits, an examination by her primary care physician revealed a complete fusion of the labia. Six months after her initial urology visit, the patient had an examination with a plan for cystoscopy, and the urologist ended up doing a “dilation of labial fusion” in the office. The patient’s urinary symptoms were improved slightly, and she had visits to the emergency room or urgent care once monthly for dysuria after dilation of the labia.
At that point she was referred to me. We tried topical estrogen for several months with minimal improvement in symptoms, and I performed a surgical separation of labial fusion in the operating room under monitored anesthesia care. After surgery the patient said that she felt like “I got my life back,” and she never knew how happy she could be to pee in the morning.
Theresa Gipps, MD
Walnut Creek, California
Agrees with importance of clinical exam
I fully agree that clinical examination skill is a dying art. But the American College of Obstetricians and Gynecologists has issued guidelines stating that pelvic examination is not required, especially in asymptomatic women. Another area of concern is hair removal procedures like waxing and laser treatments in the pubic area, and whether these do harm in any way or increase the likelihood of skin problems.
Manju Hotchandani, MD
New Delhi, India
Dr. Barbieri responds
I thank Drs. Alnaif, Moran, Richman, Gipps, and Hotchandani for sharing their comments and important clinical vignettes concerning the primacy of the physical examination with our readers. In clinical practice there are many competing demands on the time of clinicians, but we should strive to preserve time for a good physical examination. If not us, who is going to perform a competent physical examination?
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Treatment includes surgery
Treatment includes surgery
Thank you for the great article about hidradenitis suppurativa. It was very informative as usual, but a little shortsighted. As ObGyns we tend not to focus so much on these dermatologic conditions. However, I think something very important is missing in the article. I do not see it mentioned that hidradenitis suppurativa is a type of acne, also called acne inversa. As such, it should be treated like acne, with special attention to diet with zero dairy products as a prevention measure. Also, metformin is very important, as noted in the article. Retinoids are also needed, maybe for years.
According to experts, the primary approach to this condition is surgical, with punch biopsies and unroofing of the lesions, with medical therapies as prevention strategies. Fortunately, special task forces are now tackling this condition, especially in Europe. I strongly recommend the book, Acne: Causes and Practical Management, by F. William Danby.
Ivan Valencia, MD
Quito, Ecuador
Dr. Barbieri responds
Dr. Valencia provides an important perspective on the surgical treatment of hidradenitis suppurativa (HS). I agree that surgery is an important treatment for Stage III HS, but nonsurgical approaches are preferred and often effective for Stage I HS, a stage most likely to be treated by a gynecologist.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Treatment includes surgery
Thank you for the great article about hidradenitis suppurativa. It was very informative as usual, but a little shortsighted. As ObGyns we tend not to focus so much on these dermatologic conditions. However, I think something very important is missing in the article. I do not see it mentioned that hidradenitis suppurativa is a type of acne, also called acne inversa. As such, it should be treated like acne, with special attention to diet with zero dairy products as a prevention measure. Also, metformin is very important, as noted in the article. Retinoids are also needed, maybe for years.
According to experts, the primary approach to this condition is surgical, with punch biopsies and unroofing of the lesions, with medical therapies as prevention strategies. Fortunately, special task forces are now tackling this condition, especially in Europe. I strongly recommend the book, Acne: Causes and Practical Management, by F. William Danby.
Ivan Valencia, MD
Quito, Ecuador
Dr. Barbieri responds
Dr. Valencia provides an important perspective on the surgical treatment of hidradenitis suppurativa (HS). I agree that surgery is an important treatment for Stage III HS, but nonsurgical approaches are preferred and often effective for Stage I HS, a stage most likely to be treated by a gynecologist.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Treatment includes surgery
Thank you for the great article about hidradenitis suppurativa. It was very informative as usual, but a little shortsighted. As ObGyns we tend not to focus so much on these dermatologic conditions. However, I think something very important is missing in the article. I do not see it mentioned that hidradenitis suppurativa is a type of acne, also called acne inversa. As such, it should be treated like acne, with special attention to diet with zero dairy products as a prevention measure. Also, metformin is very important, as noted in the article. Retinoids are also needed, maybe for years.
According to experts, the primary approach to this condition is surgical, with punch biopsies and unroofing of the lesions, with medical therapies as prevention strategies. Fortunately, special task forces are now tackling this condition, especially in Europe. I strongly recommend the book, Acne: Causes and Practical Management, by F. William Danby.
Ivan Valencia, MD
Quito, Ecuador
Dr. Barbieri responds
Dr. Valencia provides an important perspective on the surgical treatment of hidradenitis suppurativa (HS). I agree that surgery is an important treatment for Stage III HS, but nonsurgical approaches are preferred and often effective for Stage I HS, a stage most likely to be treated by a gynecologist.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Incision site for cesarean delivery is important in infection prevention
Incision site for cesarean delivery is important in infection prevention
Dr. Barbieri’s editorial very nicely explained strategies to reduce the risk of post–cesarean delivery surgical site infection (SSI). However, what was not mentioned, in my opinion, is the most important preventive strategy. Selecting the site for the initial skin incision plays a great role in whether or not the patient will develop an infection postoperatively.
Pfannenstiel incisions are popular because of their obvious cosmetic benefit. In nonemergent cesarean deliveries, most ObGyns try to use this incision. However, exactly where the incision is placed plays a large role in the genesis of a postoperative wound infection. The worst place for such incisions is in the crease above the pubis and below the panniculus. Invariably, this area remains moist and macerated, especially in obese patients, thus providing a fertile breeding ground for bacteria. This problem can be avoided by incising the skin approximately 2 cm cranial to and parallel to the aforementioned crease, provided that the panniculus is not too large. The point is that the incision should be placed in an area where it has a chance to stay dry.
Sometimes patients who are hugely obese require great creativity in the placement of their transverse skin incision. I recall one patient, pregnant with triplets, whose abdomen was so large that her umbilicus was over the region of the lower uterine segment when she was supine on the operating room table. Some would have lifted up her immense panniculus and placed the incision in the usual crease site. This would be problematic for obtaining adequate exposure to deliver the babies, and the risk of developing an incisional infection would be very high. Therefore, a transverse incision was made just below her umbilicus. The panniculus was a nonissue regarding gaining adequate exposure and, when closed, the incision remained completely dry and uninfected. The patient did extremely well postoperatively and had no infectious sequelae.
David L. Zisow, MD
Baltimore, Maryland
Extraperitoneal approach should be considered
I enjoyed the editorial on reducing surgical site infection, especially the references to the historical Halsted principles of surgery. “He was the first in this country to promulgate the philosophy of ‘safe’ surgery.”1 Regarding surgical principles of cesarean delivery, the pioneering German obstetricians in the 1930s were keenly aware that avoiding the peritoneal cavity was instrumental in reducing morbidity and mortality. They championed the safety of the extraperitoneal approach as the fundamental principle of cesarean delivery for maternal safety.2
I learned to embrace the principles of Kaboth while learning the technique in 1968–1972. Thus, for more than 30 years, I used the extraperitoneal approach to access the lower uterine segment, avoiding entrance into the abdominal cavity. My patients seemed to benefit. As the surgeon, I also benefited: with short operative delivery times, less postoperative pain and minor morbidities, fewer phone calls from nursing staff, and less difficulty for my patients. I had not contaminated the peritoneal cavity and avoided all those inherent problems. The decision to open the peritoneal cavity has not been subjected to the rigors of critical analysis.3 I think that Kaboth’s principles remain worthy of consideration even today.
Contemporary experiences in large populations such as in India and China that use the extraperitoneal cesarean approach seem to implicitly support Kaboth’s principles. However, in the milieu of evidence-based medicine, extraperitoneal cesarean delivery has not been adequately studied.4 Just maybe the extraperitoneal approach should be considered and understood as a primary surgical technique for cesarean deliveries; just maybe it deserves a historical asterisk alongside the Halsted dicta.
Hedric Hanson, MD
Anchorage, Alaska
Dr. Barbieri responds
I thank Drs. Zisow and Hanson for their great recommendations and clinical pearls. I agree with Dr. Zisow that I should have mentioned the importance of optimal placement of the transverse skin incision. Incision in a skin crease that is perpetually moist increases the risk for a postoperative complication. When the abdomen is prepped for surgery, the skin crease above the pubis appears to be very inviting for placement of the skin incision. Dr. Hanson highlights the important option of an extraperitoneal approach to cesarean delivery. I have not thought about using this approach since the mid-1980s. Dr. Hanson’s recommendation that a randomized trial be performed comparing the SSI rate and other outcomes for extraperitoneal and intraperitoneal cesarean delivery is a great idea.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Cameron JL. William Steward Halsted: our surgical heritage. Ann Surg. 1997;225(5):445–458.
- Kaboth G. Die Technik des extraperitonealen Entibindungschnittes. Zentralblatt fur Gynakologie.1934;58(6):310–311.
- Berghella V, Baxter JK Chauhan SP. Evidence-based surgery for cesarean section. Am J Obstet Gynecol. 2005;193(5):1607–1617.
- Hofmeyr GJ, Mathai M, Shah AN, Novikova N. Techniques for caesarean section. Cochrane Database Syst Rev. 2008; CD004662.
Incision site for cesarean delivery is important in infection prevention
Dr. Barbieri’s editorial very nicely explained strategies to reduce the risk of post–cesarean delivery surgical site infection (SSI). However, what was not mentioned, in my opinion, is the most important preventive strategy. Selecting the site for the initial skin incision plays a great role in whether or not the patient will develop an infection postoperatively.
Pfannenstiel incisions are popular because of their obvious cosmetic benefit. In nonemergent cesarean deliveries, most ObGyns try to use this incision. However, exactly where the incision is placed plays a large role in the genesis of a postoperative wound infection. The worst place for such incisions is in the crease above the pubis and below the panniculus. Invariably, this area remains moist and macerated, especially in obese patients, thus providing a fertile breeding ground for bacteria. This problem can be avoided by incising the skin approximately 2 cm cranial to and parallel to the aforementioned crease, provided that the panniculus is not too large. The point is that the incision should be placed in an area where it has a chance to stay dry.
Sometimes patients who are hugely obese require great creativity in the placement of their transverse skin incision. I recall one patient, pregnant with triplets, whose abdomen was so large that her umbilicus was over the region of the lower uterine segment when she was supine on the operating room table. Some would have lifted up her immense panniculus and placed the incision in the usual crease site. This would be problematic for obtaining adequate exposure to deliver the babies, and the risk of developing an incisional infection would be very high. Therefore, a transverse incision was made just below her umbilicus. The panniculus was a nonissue regarding gaining adequate exposure and, when closed, the incision remained completely dry and uninfected. The patient did extremely well postoperatively and had no infectious sequelae.
David L. Zisow, MD
Baltimore, Maryland
Extraperitoneal approach should be considered
I enjoyed the editorial on reducing surgical site infection, especially the references to the historical Halsted principles of surgery. “He was the first in this country to promulgate the philosophy of ‘safe’ surgery.”1 Regarding surgical principles of cesarean delivery, the pioneering German obstetricians in the 1930s were keenly aware that avoiding the peritoneal cavity was instrumental in reducing morbidity and mortality. They championed the safety of the extraperitoneal approach as the fundamental principle of cesarean delivery for maternal safety.2
I learned to embrace the principles of Kaboth while learning the technique in 1968–1972. Thus, for more than 30 years, I used the extraperitoneal approach to access the lower uterine segment, avoiding entrance into the abdominal cavity. My patients seemed to benefit. As the surgeon, I also benefited: with short operative delivery times, less postoperative pain and minor morbidities, fewer phone calls from nursing staff, and less difficulty for my patients. I had not contaminated the peritoneal cavity and avoided all those inherent problems. The decision to open the peritoneal cavity has not been subjected to the rigors of critical analysis.3 I think that Kaboth’s principles remain worthy of consideration even today.
Contemporary experiences in large populations such as in India and China that use the extraperitoneal cesarean approach seem to implicitly support Kaboth’s principles. However, in the milieu of evidence-based medicine, extraperitoneal cesarean delivery has not been adequately studied.4 Just maybe the extraperitoneal approach should be considered and understood as a primary surgical technique for cesarean deliveries; just maybe it deserves a historical asterisk alongside the Halsted dicta.
Hedric Hanson, MD
Anchorage, Alaska
Dr. Barbieri responds
I thank Drs. Zisow and Hanson for their great recommendations and clinical pearls. I agree with Dr. Zisow that I should have mentioned the importance of optimal placement of the transverse skin incision. Incision in a skin crease that is perpetually moist increases the risk for a postoperative complication. When the abdomen is prepped for surgery, the skin crease above the pubis appears to be very inviting for placement of the skin incision. Dr. Hanson highlights the important option of an extraperitoneal approach to cesarean delivery. I have not thought about using this approach since the mid-1980s. Dr. Hanson’s recommendation that a randomized trial be performed comparing the SSI rate and other outcomes for extraperitoneal and intraperitoneal cesarean delivery is a great idea.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Incision site for cesarean delivery is important in infection prevention
Dr. Barbieri’s editorial very nicely explained strategies to reduce the risk of post–cesarean delivery surgical site infection (SSI). However, what was not mentioned, in my opinion, is the most important preventive strategy. Selecting the site for the initial skin incision plays a great role in whether or not the patient will develop an infection postoperatively.
Pfannenstiel incisions are popular because of their obvious cosmetic benefit. In nonemergent cesarean deliveries, most ObGyns try to use this incision. However, exactly where the incision is placed plays a large role in the genesis of a postoperative wound infection. The worst place for such incisions is in the crease above the pubis and below the panniculus. Invariably, this area remains moist and macerated, especially in obese patients, thus providing a fertile breeding ground for bacteria. This problem can be avoided by incising the skin approximately 2 cm cranial to and parallel to the aforementioned crease, provided that the panniculus is not too large. The point is that the incision should be placed in an area where it has a chance to stay dry.
Sometimes patients who are hugely obese require great creativity in the placement of their transverse skin incision. I recall one patient, pregnant with triplets, whose abdomen was so large that her umbilicus was over the region of the lower uterine segment when she was supine on the operating room table. Some would have lifted up her immense panniculus and placed the incision in the usual crease site. This would be problematic for obtaining adequate exposure to deliver the babies, and the risk of developing an incisional infection would be very high. Therefore, a transverse incision was made just below her umbilicus. The panniculus was a nonissue regarding gaining adequate exposure and, when closed, the incision remained completely dry and uninfected. The patient did extremely well postoperatively and had no infectious sequelae.
David L. Zisow, MD
Baltimore, Maryland
Extraperitoneal approach should be considered
I enjoyed the editorial on reducing surgical site infection, especially the references to the historical Halsted principles of surgery. “He was the first in this country to promulgate the philosophy of ‘safe’ surgery.”1 Regarding surgical principles of cesarean delivery, the pioneering German obstetricians in the 1930s were keenly aware that avoiding the peritoneal cavity was instrumental in reducing morbidity and mortality. They championed the safety of the extraperitoneal approach as the fundamental principle of cesarean delivery for maternal safety.2
I learned to embrace the principles of Kaboth while learning the technique in 1968–1972. Thus, for more than 30 years, I used the extraperitoneal approach to access the lower uterine segment, avoiding entrance into the abdominal cavity. My patients seemed to benefit. As the surgeon, I also benefited: with short operative delivery times, less postoperative pain and minor morbidities, fewer phone calls from nursing staff, and less difficulty for my patients. I had not contaminated the peritoneal cavity and avoided all those inherent problems. The decision to open the peritoneal cavity has not been subjected to the rigors of critical analysis.3 I think that Kaboth’s principles remain worthy of consideration even today.
Contemporary experiences in large populations such as in India and China that use the extraperitoneal cesarean approach seem to implicitly support Kaboth’s principles. However, in the milieu of evidence-based medicine, extraperitoneal cesarean delivery has not been adequately studied.4 Just maybe the extraperitoneal approach should be considered and understood as a primary surgical technique for cesarean deliveries; just maybe it deserves a historical asterisk alongside the Halsted dicta.
Hedric Hanson, MD
Anchorage, Alaska
Dr. Barbieri responds
I thank Drs. Zisow and Hanson for their great recommendations and clinical pearls. I agree with Dr. Zisow that I should have mentioned the importance of optimal placement of the transverse skin incision. Incision in a skin crease that is perpetually moist increases the risk for a postoperative complication. When the abdomen is prepped for surgery, the skin crease above the pubis appears to be very inviting for placement of the skin incision. Dr. Hanson highlights the important option of an extraperitoneal approach to cesarean delivery. I have not thought about using this approach since the mid-1980s. Dr. Hanson’s recommendation that a randomized trial be performed comparing the SSI rate and other outcomes for extraperitoneal and intraperitoneal cesarean delivery is a great idea.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Cameron JL. William Steward Halsted: our surgical heritage. Ann Surg. 1997;225(5):445–458.
- Kaboth G. Die Technik des extraperitonealen Entibindungschnittes. Zentralblatt fur Gynakologie.1934;58(6):310–311.
- Berghella V, Baxter JK Chauhan SP. Evidence-based surgery for cesarean section. Am J Obstet Gynecol. 2005;193(5):1607–1617.
- Hofmeyr GJ, Mathai M, Shah AN, Novikova N. Techniques for caesarean section. Cochrane Database Syst Rev. 2008; CD004662.
- Cameron JL. William Steward Halsted: our surgical heritage. Ann Surg. 1997;225(5):445–458.
- Kaboth G. Die Technik des extraperitonealen Entibindungschnittes. Zentralblatt fur Gynakologie.1934;58(6):310–311.
- Berghella V, Baxter JK Chauhan SP. Evidence-based surgery for cesarean section. Am J Obstet Gynecol. 2005;193(5):1607–1617.
- Hofmeyr GJ, Mathai M, Shah AN, Novikova N. Techniques for caesarean section. Cochrane Database Syst Rev. 2008; CD004662.
Epilepsy: Past, Present, and Future
Vijay M. Thadani,
Dr. Thadani is Professor of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He reports no conflict of interest.
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of epilepsy care and research. Epilepsy is a disease whose earliest descriptions date back to Egypt and Mesopotamia 3,000 years ago. A modern understanding of epilepsy as an electrical disorder of the brain dates back perhaps 150 years. The last 25 years have seen considerable progress in diagnosis and treatment, but in the Western world, the prevalence of epilepsy has held steady at around 1%, and a quarter of those patients have seizures that are not controlled, in spite of appropriate therapy.
While generalized and focal seizures remain the cornerstones of classification, the most recent theoretical advance is the network concept of epilepsy. By definition, a network must have nodes and connections. In generalized forms of epilepsy, these are recognized to be diffuse groupings of neurons and the fiber tracts that connect them. They are widely distributed and conducive to the rapid and bilateral spread of electrical abnormalities throughout the brain. In focal epilepsies, the abnormal electrical activity in the network is more constrained by traditional anatomic landmarks, but this does not preclude the possibility of secondary generalization. The elucidation of such networks by intracranial EEG and fMRI studies is a major triumph of the last 25 years.
All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
Looking Ahead
As they say, it is difficult to make predictions, especially about the future, but one can anticipate not only the identification of more gene mutations that cause epilepsy, but their correction with CRISPR/Cas9 and related technologies. Likewise, we can anticipate new antiepileptic drugs, but whether they will be broad-spectrum blockbusters like the cannabis derivatives are thought to be, or designer molecules tailored to specific types of seizures and epilepsy remains to be seen. In tuberous sclerosis, for example, drugs like tacrolimus that inhibit the mTOR pathway not only suppress abnormal cell proliferation, but also help with seizure control. Likewise, a small minority of epilepsies, now recognized to be autoimmune, will be treated with targeted immune suppression. A major goal is the discovery of drugs that will prevent the development of epilepsy or cure it in its early stages, as opposed to merely controlling the seizures.
Imaging of epileptic foci and networks of seizure spread will continue to improve with higher field strength MRI scans. EEG, MRI, and fMRI will probably coalesce, and PET scans will play a larger role. Combined images will guide epilepsy surgeons with regard to the boundaries of resections. The nature of EEG recording will also change. Until recently, owing to the properties of available amplifiers, we have looked at electrical oscillations between 1 Hz and 70 Hz. However, much higher frequencies are increasingly recognized as important in defining the epileptogenic zone and network. Epilepsy surgery that takes high-frequency oscillations into account will optimize the removal of epileptogenic lesions and the disruption of epileptic networks, while minimizing injury to normal brain functions.
Resective surgery may itself be rendered obsolete by cerebral stimulation, now in its infancy. Implanted devices such as Neuropace have shown promise in detecting seizures and delivering a counter-shock to abort them. Biologic stimulation is also on the horizon. In animal models, transplantation of GABA-producing cells has cured epilepsy, and optogenetic techniques may soon make it possible to activate particular classes of neurons that can turn off epileptic activity.
One can also anticipate a shift in treatment away from the exclusive emphasis on seizure control. We increasingly recognize that epilepsy is much more than seizures, and that patients with epilepsy may also have depression, impaired memory, and anxiety related to their illness. In the long run, the psychosocial problems of patients with epilepsy cannot be separated from social problems as a whole. Will, for example, the new, and doubtless expensive, treatments for epilepsy be made available to all who need them, or will we be obliged to work in a two-tier system? As health care providers, we can be cautiously optimistic regarding the medical aspects of epilepsy, but we will have to think in quite unanticipated ways to ensure equitable outcomes.
Vijay M. Thadani,
Dr. Thadani is Professor of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He reports no conflict of interest.
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of epilepsy care and research. Epilepsy is a disease whose earliest descriptions date back to Egypt and Mesopotamia 3,000 years ago. A modern understanding of epilepsy as an electrical disorder of the brain dates back perhaps 150 years. The last 25 years have seen considerable progress in diagnosis and treatment, but in the Western world, the prevalence of epilepsy has held steady at around 1%, and a quarter of those patients have seizures that are not controlled, in spite of appropriate therapy.
While generalized and focal seizures remain the cornerstones of classification, the most recent theoretical advance is the network concept of epilepsy. By definition, a network must have nodes and connections. In generalized forms of epilepsy, these are recognized to be diffuse groupings of neurons and the fiber tracts that connect them. They are widely distributed and conducive to the rapid and bilateral spread of electrical abnormalities throughout the brain. In focal epilepsies, the abnormal electrical activity in the network is more constrained by traditional anatomic landmarks, but this does not preclude the possibility of secondary generalization. The elucidation of such networks by intracranial EEG and fMRI studies is a major triumph of the last 25 years.
All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
Looking Ahead
As they say, it is difficult to make predictions, especially about the future, but one can anticipate not only the identification of more gene mutations that cause epilepsy, but their correction with CRISPR/Cas9 and related technologies. Likewise, we can anticipate new antiepileptic drugs, but whether they will be broad-spectrum blockbusters like the cannabis derivatives are thought to be, or designer molecules tailored to specific types of seizures and epilepsy remains to be seen. In tuberous sclerosis, for example, drugs like tacrolimus that inhibit the mTOR pathway not only suppress abnormal cell proliferation, but also help with seizure control. Likewise, a small minority of epilepsies, now recognized to be autoimmune, will be treated with targeted immune suppression. A major goal is the discovery of drugs that will prevent the development of epilepsy or cure it in its early stages, as opposed to merely controlling the seizures.
Imaging of epileptic foci and networks of seizure spread will continue to improve with higher field strength MRI scans. EEG, MRI, and fMRI will probably coalesce, and PET scans will play a larger role. Combined images will guide epilepsy surgeons with regard to the boundaries of resections. The nature of EEG recording will also change. Until recently, owing to the properties of available amplifiers, we have looked at electrical oscillations between 1 Hz and 70 Hz. However, much higher frequencies are increasingly recognized as important in defining the epileptogenic zone and network. Epilepsy surgery that takes high-frequency oscillations into account will optimize the removal of epileptogenic lesions and the disruption of epileptic networks, while minimizing injury to normal brain functions.
Resective surgery may itself be rendered obsolete by cerebral stimulation, now in its infancy. Implanted devices such as Neuropace have shown promise in detecting seizures and delivering a counter-shock to abort them. Biologic stimulation is also on the horizon. In animal models, transplantation of GABA-producing cells has cured epilepsy, and optogenetic techniques may soon make it possible to activate particular classes of neurons that can turn off epileptic activity.
One can also anticipate a shift in treatment away from the exclusive emphasis on seizure control. We increasingly recognize that epilepsy is much more than seizures, and that patients with epilepsy may also have depression, impaired memory, and anxiety related to their illness. In the long run, the psychosocial problems of patients with epilepsy cannot be separated from social problems as a whole. Will, for example, the new, and doubtless expensive, treatments for epilepsy be made available to all who need them, or will we be obliged to work in a two-tier system? As health care providers, we can be cautiously optimistic regarding the medical aspects of epilepsy, but we will have to think in quite unanticipated ways to ensure equitable outcomes.
Vijay M. Thadani,
Dr. Thadani is Professor of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He reports no conflict of interest.
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of epilepsy care and research. Epilepsy is a disease whose earliest descriptions date back to Egypt and Mesopotamia 3,000 years ago. A modern understanding of epilepsy as an electrical disorder of the brain dates back perhaps 150 years. The last 25 years have seen considerable progress in diagnosis and treatment, but in the Western world, the prevalence of epilepsy has held steady at around 1%, and a quarter of those patients have seizures that are not controlled, in spite of appropriate therapy.
While generalized and focal seizures remain the cornerstones of classification, the most recent theoretical advance is the network concept of epilepsy. By definition, a network must have nodes and connections. In generalized forms of epilepsy, these are recognized to be diffuse groupings of neurons and the fiber tracts that connect them. They are widely distributed and conducive to the rapid and bilateral spread of electrical abnormalities throughout the brain. In focal epilepsies, the abnormal electrical activity in the network is more constrained by traditional anatomic landmarks, but this does not preclude the possibility of secondary generalization. The elucidation of such networks by intracranial EEG and fMRI studies is a major triumph of the last 25 years.
All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
Looking Ahead
As they say, it is difficult to make predictions, especially about the future, but one can anticipate not only the identification of more gene mutations that cause epilepsy, but their correction with CRISPR/Cas9 and related technologies. Likewise, we can anticipate new antiepileptic drugs, but whether they will be broad-spectrum blockbusters like the cannabis derivatives are thought to be, or designer molecules tailored to specific types of seizures and epilepsy remains to be seen. In tuberous sclerosis, for example, drugs like tacrolimus that inhibit the mTOR pathway not only suppress abnormal cell proliferation, but also help with seizure control. Likewise, a small minority of epilepsies, now recognized to be autoimmune, will be treated with targeted immune suppression. A major goal is the discovery of drugs that will prevent the development of epilepsy or cure it in its early stages, as opposed to merely controlling the seizures.
Imaging of epileptic foci and networks of seizure spread will continue to improve with higher field strength MRI scans. EEG, MRI, and fMRI will probably coalesce, and PET scans will play a larger role. Combined images will guide epilepsy surgeons with regard to the boundaries of resections. The nature of EEG recording will also change. Until recently, owing to the properties of available amplifiers, we have looked at electrical oscillations between 1 Hz and 70 Hz. However, much higher frequencies are increasingly recognized as important in defining the epileptogenic zone and network. Epilepsy surgery that takes high-frequency oscillations into account will optimize the removal of epileptogenic lesions and the disruption of epileptic networks, while minimizing injury to normal brain functions.
Resective surgery may itself be rendered obsolete by cerebral stimulation, now in its infancy. Implanted devices such as Neuropace have shown promise in detecting seizures and delivering a counter-shock to abort them. Biologic stimulation is also on the horizon. In animal models, transplantation of GABA-producing cells has cured epilepsy, and optogenetic techniques may soon make it possible to activate particular classes of neurons that can turn off epileptic activity.
One can also anticipate a shift in treatment away from the exclusive emphasis on seizure control. We increasingly recognize that epilepsy is much more than seizures, and that patients with epilepsy may also have depression, impaired memory, and anxiety related to their illness. In the long run, the psychosocial problems of patients with epilepsy cannot be separated from social problems as a whole. Will, for example, the new, and doubtless expensive, treatments for epilepsy be made available to all who need them, or will we be obliged to work in a two-tier system? As health care providers, we can be cautiously optimistic regarding the medical aspects of epilepsy, but we will have to think in quite unanticipated ways to ensure equitable outcomes.
I’M NOT A PROVIDER
I am not sure when it occurred. I don’t know how it happened. I don’t think anyone took a vote on it. It happened gradually over the last decade. I think it happened when the administrative staff became larger than the medical staff. In order to include everyone under the same umbrella, everyone became a provider.
All those patients in our waiting room suddenly became consumers or clients. My grandfather ran a grocery store and had a lot of customers, and my father was a lawyer and had a lot of clients. None of those customers or clients would come to see me as their doctor with their illnesses today if I were a provider. The use of the terminology of “providers” and “customers” lowers all health care staff to the lowest common denominator and demeans the concerns of my patients.
I do not mean to diminish the role of the auto mechanic and salesperson, but they know and I know that our roles and are different and we are not just providers of a medical commodity. They do not expect me to deal with them as though they were coming to buy a car. They understand that we are actually trying to cure and treat worried patients and not to sell to customers in a show room.
This change in nomenclature that has permeated health care has had significant effects on how medical care is provided. Hospital care has been depersonalized in order to expedite hospital stays and maximize reimbursement. Gone is the hospital visit of your doctors when you need them the most.
Part of it is the complexity of contemporary care that requires the input from varying levels of expertise. Patients are often shuttled from one doctor to another. Communication is carried out through the web and rarely doctor to doctor. Often doctors are dealt with both at the patient level and the administrative level as commodities off the shelf, like buying a pair of shoes. And doctors in the hospital and in the clinic can be replaced by another one as the shift changes or the schedule dictates with little regard to the patient’s – or customer’s – choice.
Can we return to the days of yore? Probably not. All we can do now is try to inject some level of humanity and empathy as we see our patients in today’s world of mechanized medicine.
Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
I am not sure when it occurred. I don’t know how it happened. I don’t think anyone took a vote on it. It happened gradually over the last decade. I think it happened when the administrative staff became larger than the medical staff. In order to include everyone under the same umbrella, everyone became a provider.
All those patients in our waiting room suddenly became consumers or clients. My grandfather ran a grocery store and had a lot of customers, and my father was a lawyer and had a lot of clients. None of those customers or clients would come to see me as their doctor with their illnesses today if I were a provider. The use of the terminology of “providers” and “customers” lowers all health care staff to the lowest common denominator and demeans the concerns of my patients.
I do not mean to diminish the role of the auto mechanic and salesperson, but they know and I know that our roles and are different and we are not just providers of a medical commodity. They do not expect me to deal with them as though they were coming to buy a car. They understand that we are actually trying to cure and treat worried patients and not to sell to customers in a show room.
This change in nomenclature that has permeated health care has had significant effects on how medical care is provided. Hospital care has been depersonalized in order to expedite hospital stays and maximize reimbursement. Gone is the hospital visit of your doctors when you need them the most.
Part of it is the complexity of contemporary care that requires the input from varying levels of expertise. Patients are often shuttled from one doctor to another. Communication is carried out through the web and rarely doctor to doctor. Often doctors are dealt with both at the patient level and the administrative level as commodities off the shelf, like buying a pair of shoes. And doctors in the hospital and in the clinic can be replaced by another one as the shift changes or the schedule dictates with little regard to the patient’s – or customer’s – choice.
Can we return to the days of yore? Probably not. All we can do now is try to inject some level of humanity and empathy as we see our patients in today’s world of mechanized medicine.
Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
I am not sure when it occurred. I don’t know how it happened. I don’t think anyone took a vote on it. It happened gradually over the last decade. I think it happened when the administrative staff became larger than the medical staff. In order to include everyone under the same umbrella, everyone became a provider.
All those patients in our waiting room suddenly became consumers or clients. My grandfather ran a grocery store and had a lot of customers, and my father was a lawyer and had a lot of clients. None of those customers or clients would come to see me as their doctor with their illnesses today if I were a provider. The use of the terminology of “providers” and “customers” lowers all health care staff to the lowest common denominator and demeans the concerns of my patients.
I do not mean to diminish the role of the auto mechanic and salesperson, but they know and I know that our roles and are different and we are not just providers of a medical commodity. They do not expect me to deal with them as though they were coming to buy a car. They understand that we are actually trying to cure and treat worried patients and not to sell to customers in a show room.
This change in nomenclature that has permeated health care has had significant effects on how medical care is provided. Hospital care has been depersonalized in order to expedite hospital stays and maximize reimbursement. Gone is the hospital visit of your doctors when you need them the most.
Part of it is the complexity of contemporary care that requires the input from varying levels of expertise. Patients are often shuttled from one doctor to another. Communication is carried out through the web and rarely doctor to doctor. Often doctors are dealt with both at the patient level and the administrative level as commodities off the shelf, like buying a pair of shoes. And doctors in the hospital and in the clinic can be replaced by another one as the shift changes or the schedule dictates with little regard to the patient’s – or customer’s – choice.
Can we return to the days of yore? Probably not. All we can do now is try to inject some level of humanity and empathy as we see our patients in today’s world of mechanized medicine.
Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
Ureteral reimplantation for injuries not easily managed with stenting
The risk of lower urinary tract injury (bladder or ureters) at the time of benign gynecologic surgery is estimated to be between 0.3% and 4%. The majority are bladder injuries, with ureteral injuries occurring in 0.3%-1.8% of hysterectomies. While urologic procedures account for the majority of iatrogenic ureteral injuries, gynecologic surgery is the second leading cause, followed by general surgery and colorectal surgery.
With respect to hysterectomy in particular, the risk of ureteral injury is less than 1%. In a large prospective cohort of women undergoing hysterectomy for benign indications in 53 hospitals in Finland, rates of ureteral injury varied based on the route of hysterectomy, with laparoscopic and abdominal routes having an injury rate of 0.3% and the vaginal route having an injury rate of 0.04% (Human Reprod. 2011;26[7]:1741-51). The risk generally is higher with procedures for endometriosis, large fibroids, cancer, or pelvic organ prolapse.
During hysterectomy and with gynecologic surgery overall, ureteral injuries occur most commonly at three locations: at the level of the infundibulopelvic ligament and ovarian vessels, at the level of the uterine artery, and near the vaginal cuff. Identification and knowledge of the course of the ureter at these three locations is essential in preventing ureteral injury during pelvic surgery.
SOURCE: DR. MUELLER AND DR. KENTON
Perioperative ureteral stenting has been proposed as a method of preventing iatrogenic injury by allowing surgeons to more easily identify the ureters during surgery. Available reports suggest, however, that the actual risk of injury is not decreased and may even be increased by placing prophylactic ureteral stents, and most surgeons have moved away from this practice. The use of lighted ureteral stents during complex laparoscopic endometriosis resections may be helpful.
Many health care systems recommend intraoperative cystoscopy with bladder and ureteral survey to evaluate the integrity of the lower urinary tract at the time of all hysterectomies. A recent study of nearly 3,000 women undergoing benign hysterectomies at the University of Michigan, Ann Arbor, showed a significant decrease in the rate of delayed diagnosis of urinary tract injuries with implementation of a universal cystoscopy policy. While the rate of lower urinary tract injury was fairly consistent before and after implementation of the policy (2.6% and 1.8%, respectively), the rate of delayed detection of a lower urinary tract injury decreased from 0.7% before the policy to 0.1% after implementation (Obstet Gynecol. 2016;127[2]:369-75). The study also showed that hospital costs nearly doubled with a delayed detection of a lower urinary tract injury.
Unfortunately, even a normal postoperative cystoscopy does not ensure there is no lower urinary tract injury, especially considering that thermal injuries resulting from the use of energy devices typically do not present until 7-14 days after surgery. Overall, however, ureteral injury detection rates with universal cystoscopy approach 97% (Obstet Gynecol. 2009;113:6-10).
Identifying injuries
Intraoperative recognition and repair always is preferred, and when ureteral injuries are discovered or suspected in the operating room, cystoscopy and retrograde pyelography is the most helpful imaging tool. Contrast dye is injected during cystoscopy directly into the renal collecting system through the ureteral orifices; with fluoroscopy, the surgeon can visualize the integrity of the ureter from the bladder to the renal pelvis to diagnosis a ureteral injury, including ureteral transection, kinking, or ligation caused by a suture or sealing device.
If retrograde pyelography shows a transection or injury from a crushing clamp or sealing device, we recommend ureteroureteral anastomosis or urethral neocystostomy depending on the extent and location of the injury. If the ureter just appears kinked, sometime simply releasing the cuff sutures or uterosacral ligament sutures will resolve the obstruction. If there is extravasation of contrast suggesting a partial tear, placing a double-J ureteral stent for 6-8 weeks is frequently sufficient.
Patients with delayed iatrogenic ureteral injuries present with symptoms that often are nonspecific and that include abdominal or flank pain, fever, nausea, vomiting, back pain, and leukocytosis.
We recommend that patients with a history of surgery and symptoms suggestive of a ureteral injury be initially evaluated with CT urography that images the renal collecting system both as contrast dye is instilled and again several minutes later as it has progressed through the entire urinary tract. Alternatively, if CT urography is unavailable, a retrograde pyelogram can be performed as an emergency procedure to determine the location of renal injury.
Surgical management
Delayed ureteral injuries resulting in partial ureteral obstruction or extravasation of urine into the pelvis can sometimes be managed conservatively though placement of an internalized double J stent. The stent can be placed in a retrograde fashion via cystoscopy by a
We typically manage delayed ureteral injuries that are not amenable to, or do not heal with, ureteral stenting with ureteroneocystotomy, or ureteral reimplantation, into the bladder. This technique is effective for distal ureteral injuries that result in obstruction or fistula and are in close proximity to the bladder (most iatrogenic gynecologic injuries). We perform ureteroneocystotomy via an open, robotic, or laparoscopic route of access depending on the circumstance.
Our preferred route of access is minimally invasive with the da Vinci robot. A camera port is placed at the umbilicus, two robotic ports are placed on the patient’s left side at the level of the umbilicus, and one is placed on the patient’s right side at the level of the umbilicus with an additional assistant port on the right side. It is helpful if each port is at least 8 cm apart. If obstruction or transection is suspected to be more proximal, the ports may have been shifted above the umbilicus to optimally mobilize the ureter.
First, the ureter is identified and dissected. Regardless of the site of injury, which is usually identifiable with inflammation and scar tissue, it is always easiest to identify the ureter at the bifurcation of the common iliac vessels. The isolated ureter is inspected proximally and above the area of injury, and we find it helpful to place a vessel loop around the ureter for easy manipulation and counter traction. Care must be taken not to disturb the adventitia and blood supply. We do not transect the ureter until we’re ready to reimplant it in the bladder.
To mobilize the bladder and prepare for a tension-free anastomosis, an adequate retropubic dissection is performed, starting with an incision in the anterior abdominal wall peritoneum and taking it down to the level of the pubic bone and into the retropubic space. It is important to be mindful of the location of the obturator neurovascular bundle when performing this dissection.
Achieving a tension-free and water-tight anastomosis of the ureter to the bladder is critical. The bladder should be mobilized such that it reaches to above the injured portion of the ureter. The bladder is retrograde filled with approximately 300 mL and a reimplantation site of the posterior bladder is identified. When there is concern about tension, a psoas hitch suture can be placed to keep the bladder in a superior position with reduced tension. Because of high rates of the congenital absence of the psoas tendon minor, we advocate direct visualization of the genitofemoral nerve by incising the peritoneum; this will avoid nerve entrapment.
Once the bladder is mobilized and the ureter isolated, we perform an intentional cystotomy in the posterior lateral aspect of the bladder. The ureter, which is on the vessel loop, must be transected proximal to the site of injury. To facilitate this, we spatulate the ureter, making a vertical incision of often about 5 mm in length to increase our surface area for anastomosis. Placement of a suture at the apex of the spatulated ureter helps us maintain orientation.
Anastomosis of the ureter and bladder is achieved in a mucosa-to-mucosa fashion using a series of interrupted monofilament fine absorbable sutures; we use a 3-0 monocryl suture. The most posterior anastomotic sutures are placed first to allow for optimal visualization, and prior to completing the anastomosis, a guide wire is placed through the open ureter and a double-J stent is introduced into the renal pelvis. The wire is then removed and the distal end of the stent coiled in the bladder. This stent will protect the ureter for about 6 weeks while it heals. The anastomosis is then completed on the anterior aspect, with a watertight closure ensured.
Postoperatively, we routinely perform an x-ray to ensure proper placement of the stent in the reimplanted ureter. To determine correct stent placement, the last rib is identified at T12 vertebrae. The renal pelvis is located at the level of the L2-L3 with the left being slightly higher than the right. A Foley catheter is maintained in the bladder for approximately 2 weeks, and the stent is maintained for approximately 6 weeks. Both the catheter and the stent can be removed in the office with cystoscopic guidance.
Imaging at 4-6 weeks after removal of the stent is performed to rule out development of an obstruction or a stricture. In patients who did not have a dilated ureter and renal collecting system prior to reimplantation, a renal ultrasound is sufficient to identify hydroureter/hydronephrosis or a urinoma. Many patients with a markedly dilated renal-collecting system prior to ureteral reimplantation will have persistent hydroureter/hydronephrosis (similar to a latex balloon that does not return to its original size after it is blown up) after reimplantation. A Lasix renal scan is a better imaging modality in these patients because it can differentiate a ureter that is dilated from one that is dilated and obstructed.
It is important to note that prompt ureteroneocystotomy is feasible only when the delayed ureteral injury presents within approximately 7 days of surgery. If the patient presents more than a week after surgery, inflammation is so significant that conservative management is necessary with reevaluation for reimplantation in another 6 weeks. Decompression of the system prior to reimplantation can be achieved through either stent placement or placement of a percutaneous nephrostomy tube. We prefer the latter because it reduces inflammation around the ureter that may make subsequent dissection and surgery more difficult.
Dr. Kenton is chief of urogynecology, Northwestern University, Chicago, and Dr. Mueller also is in the division of female pelvic medicine and reconstructive surgery–urogynecology at Northwestern. Dr. Kenton discloses grant funding from Boston Scientific.
The risk of lower urinary tract injury (bladder or ureters) at the time of benign gynecologic surgery is estimated to be between 0.3% and 4%. The majority are bladder injuries, with ureteral injuries occurring in 0.3%-1.8% of hysterectomies. While urologic procedures account for the majority of iatrogenic ureteral injuries, gynecologic surgery is the second leading cause, followed by general surgery and colorectal surgery.
With respect to hysterectomy in particular, the risk of ureteral injury is less than 1%. In a large prospective cohort of women undergoing hysterectomy for benign indications in 53 hospitals in Finland, rates of ureteral injury varied based on the route of hysterectomy, with laparoscopic and abdominal routes having an injury rate of 0.3% and the vaginal route having an injury rate of 0.04% (Human Reprod. 2011;26[7]:1741-51). The risk generally is higher with procedures for endometriosis, large fibroids, cancer, or pelvic organ prolapse.
During hysterectomy and with gynecologic surgery overall, ureteral injuries occur most commonly at three locations: at the level of the infundibulopelvic ligament and ovarian vessels, at the level of the uterine artery, and near the vaginal cuff. Identification and knowledge of the course of the ureter at these three locations is essential in preventing ureteral injury during pelvic surgery.
SOURCE: DR. MUELLER AND DR. KENTON
Perioperative ureteral stenting has been proposed as a method of preventing iatrogenic injury by allowing surgeons to more easily identify the ureters during surgery. Available reports suggest, however, that the actual risk of injury is not decreased and may even be increased by placing prophylactic ureteral stents, and most surgeons have moved away from this practice. The use of lighted ureteral stents during complex laparoscopic endometriosis resections may be helpful.
Many health care systems recommend intraoperative cystoscopy with bladder and ureteral survey to evaluate the integrity of the lower urinary tract at the time of all hysterectomies. A recent study of nearly 3,000 women undergoing benign hysterectomies at the University of Michigan, Ann Arbor, showed a significant decrease in the rate of delayed diagnosis of urinary tract injuries with implementation of a universal cystoscopy policy. While the rate of lower urinary tract injury was fairly consistent before and after implementation of the policy (2.6% and 1.8%, respectively), the rate of delayed detection of a lower urinary tract injury decreased from 0.7% before the policy to 0.1% after implementation (Obstet Gynecol. 2016;127[2]:369-75). The study also showed that hospital costs nearly doubled with a delayed detection of a lower urinary tract injury.
Unfortunately, even a normal postoperative cystoscopy does not ensure there is no lower urinary tract injury, especially considering that thermal injuries resulting from the use of energy devices typically do not present until 7-14 days after surgery. Overall, however, ureteral injury detection rates with universal cystoscopy approach 97% (Obstet Gynecol. 2009;113:6-10).
Identifying injuries
Intraoperative recognition and repair always is preferred, and when ureteral injuries are discovered or suspected in the operating room, cystoscopy and retrograde pyelography is the most helpful imaging tool. Contrast dye is injected during cystoscopy directly into the renal collecting system through the ureteral orifices; with fluoroscopy, the surgeon can visualize the integrity of the ureter from the bladder to the renal pelvis to diagnosis a ureteral injury, including ureteral transection, kinking, or ligation caused by a suture or sealing device.
If retrograde pyelography shows a transection or injury from a crushing clamp or sealing device, we recommend ureteroureteral anastomosis or urethral neocystostomy depending on the extent and location of the injury. If the ureter just appears kinked, sometime simply releasing the cuff sutures or uterosacral ligament sutures will resolve the obstruction. If there is extravasation of contrast suggesting a partial tear, placing a double-J ureteral stent for 6-8 weeks is frequently sufficient.
Patients with delayed iatrogenic ureteral injuries present with symptoms that often are nonspecific and that include abdominal or flank pain, fever, nausea, vomiting, back pain, and leukocytosis.
We recommend that patients with a history of surgery and symptoms suggestive of a ureteral injury be initially evaluated with CT urography that images the renal collecting system both as contrast dye is instilled and again several minutes later as it has progressed through the entire urinary tract. Alternatively, if CT urography is unavailable, a retrograde pyelogram can be performed as an emergency procedure to determine the location of renal injury.
Surgical management
Delayed ureteral injuries resulting in partial ureteral obstruction or extravasation of urine into the pelvis can sometimes be managed conservatively though placement of an internalized double J stent. The stent can be placed in a retrograde fashion via cystoscopy by a
We typically manage delayed ureteral injuries that are not amenable to, or do not heal with, ureteral stenting with ureteroneocystotomy, or ureteral reimplantation, into the bladder. This technique is effective for distal ureteral injuries that result in obstruction or fistula and are in close proximity to the bladder (most iatrogenic gynecologic injuries). We perform ureteroneocystotomy via an open, robotic, or laparoscopic route of access depending on the circumstance.
Our preferred route of access is minimally invasive with the da Vinci robot. A camera port is placed at the umbilicus, two robotic ports are placed on the patient’s left side at the level of the umbilicus, and one is placed on the patient’s right side at the level of the umbilicus with an additional assistant port on the right side. It is helpful if each port is at least 8 cm apart. If obstruction or transection is suspected to be more proximal, the ports may have been shifted above the umbilicus to optimally mobilize the ureter.
First, the ureter is identified and dissected. Regardless of the site of injury, which is usually identifiable with inflammation and scar tissue, it is always easiest to identify the ureter at the bifurcation of the common iliac vessels. The isolated ureter is inspected proximally and above the area of injury, and we find it helpful to place a vessel loop around the ureter for easy manipulation and counter traction. Care must be taken not to disturb the adventitia and blood supply. We do not transect the ureter until we’re ready to reimplant it in the bladder.
To mobilize the bladder and prepare for a tension-free anastomosis, an adequate retropubic dissection is performed, starting with an incision in the anterior abdominal wall peritoneum and taking it down to the level of the pubic bone and into the retropubic space. It is important to be mindful of the location of the obturator neurovascular bundle when performing this dissection.
Achieving a tension-free and water-tight anastomosis of the ureter to the bladder is critical. The bladder should be mobilized such that it reaches to above the injured portion of the ureter. The bladder is retrograde filled with approximately 300 mL and a reimplantation site of the posterior bladder is identified. When there is concern about tension, a psoas hitch suture can be placed to keep the bladder in a superior position with reduced tension. Because of high rates of the congenital absence of the psoas tendon minor, we advocate direct visualization of the genitofemoral nerve by incising the peritoneum; this will avoid nerve entrapment.
Once the bladder is mobilized and the ureter isolated, we perform an intentional cystotomy in the posterior lateral aspect of the bladder. The ureter, which is on the vessel loop, must be transected proximal to the site of injury. To facilitate this, we spatulate the ureter, making a vertical incision of often about 5 mm in length to increase our surface area for anastomosis. Placement of a suture at the apex of the spatulated ureter helps us maintain orientation.
Anastomosis of the ureter and bladder is achieved in a mucosa-to-mucosa fashion using a series of interrupted monofilament fine absorbable sutures; we use a 3-0 monocryl suture. The most posterior anastomotic sutures are placed first to allow for optimal visualization, and prior to completing the anastomosis, a guide wire is placed through the open ureter and a double-J stent is introduced into the renal pelvis. The wire is then removed and the distal end of the stent coiled in the bladder. This stent will protect the ureter for about 6 weeks while it heals. The anastomosis is then completed on the anterior aspect, with a watertight closure ensured.
Postoperatively, we routinely perform an x-ray to ensure proper placement of the stent in the reimplanted ureter. To determine correct stent placement, the last rib is identified at T12 vertebrae. The renal pelvis is located at the level of the L2-L3 with the left being slightly higher than the right. A Foley catheter is maintained in the bladder for approximately 2 weeks, and the stent is maintained for approximately 6 weeks. Both the catheter and the stent can be removed in the office with cystoscopic guidance.
Imaging at 4-6 weeks after removal of the stent is performed to rule out development of an obstruction or a stricture. In patients who did not have a dilated ureter and renal collecting system prior to reimplantation, a renal ultrasound is sufficient to identify hydroureter/hydronephrosis or a urinoma. Many patients with a markedly dilated renal-collecting system prior to ureteral reimplantation will have persistent hydroureter/hydronephrosis (similar to a latex balloon that does not return to its original size after it is blown up) after reimplantation. A Lasix renal scan is a better imaging modality in these patients because it can differentiate a ureter that is dilated from one that is dilated and obstructed.
It is important to note that prompt ureteroneocystotomy is feasible only when the delayed ureteral injury presents within approximately 7 days of surgery. If the patient presents more than a week after surgery, inflammation is so significant that conservative management is necessary with reevaluation for reimplantation in another 6 weeks. Decompression of the system prior to reimplantation can be achieved through either stent placement or placement of a percutaneous nephrostomy tube. We prefer the latter because it reduces inflammation around the ureter that may make subsequent dissection and surgery more difficult.
Dr. Kenton is chief of urogynecology, Northwestern University, Chicago, and Dr. Mueller also is in the division of female pelvic medicine and reconstructive surgery–urogynecology at Northwestern. Dr. Kenton discloses grant funding from Boston Scientific.
The risk of lower urinary tract injury (bladder or ureters) at the time of benign gynecologic surgery is estimated to be between 0.3% and 4%. The majority are bladder injuries, with ureteral injuries occurring in 0.3%-1.8% of hysterectomies. While urologic procedures account for the majority of iatrogenic ureteral injuries, gynecologic surgery is the second leading cause, followed by general surgery and colorectal surgery.
With respect to hysterectomy in particular, the risk of ureteral injury is less than 1%. In a large prospective cohort of women undergoing hysterectomy for benign indications in 53 hospitals in Finland, rates of ureteral injury varied based on the route of hysterectomy, with laparoscopic and abdominal routes having an injury rate of 0.3% and the vaginal route having an injury rate of 0.04% (Human Reprod. 2011;26[7]:1741-51). The risk generally is higher with procedures for endometriosis, large fibroids, cancer, or pelvic organ prolapse.
During hysterectomy and with gynecologic surgery overall, ureteral injuries occur most commonly at three locations: at the level of the infundibulopelvic ligament and ovarian vessels, at the level of the uterine artery, and near the vaginal cuff. Identification and knowledge of the course of the ureter at these three locations is essential in preventing ureteral injury during pelvic surgery.
SOURCE: DR. MUELLER AND DR. KENTON
Perioperative ureteral stenting has been proposed as a method of preventing iatrogenic injury by allowing surgeons to more easily identify the ureters during surgery. Available reports suggest, however, that the actual risk of injury is not decreased and may even be increased by placing prophylactic ureteral stents, and most surgeons have moved away from this practice. The use of lighted ureteral stents during complex laparoscopic endometriosis resections may be helpful.
Many health care systems recommend intraoperative cystoscopy with bladder and ureteral survey to evaluate the integrity of the lower urinary tract at the time of all hysterectomies. A recent study of nearly 3,000 women undergoing benign hysterectomies at the University of Michigan, Ann Arbor, showed a significant decrease in the rate of delayed diagnosis of urinary tract injuries with implementation of a universal cystoscopy policy. While the rate of lower urinary tract injury was fairly consistent before and after implementation of the policy (2.6% and 1.8%, respectively), the rate of delayed detection of a lower urinary tract injury decreased from 0.7% before the policy to 0.1% after implementation (Obstet Gynecol. 2016;127[2]:369-75). The study also showed that hospital costs nearly doubled with a delayed detection of a lower urinary tract injury.
Unfortunately, even a normal postoperative cystoscopy does not ensure there is no lower urinary tract injury, especially considering that thermal injuries resulting from the use of energy devices typically do not present until 7-14 days after surgery. Overall, however, ureteral injury detection rates with universal cystoscopy approach 97% (Obstet Gynecol. 2009;113:6-10).
Identifying injuries
Intraoperative recognition and repair always is preferred, and when ureteral injuries are discovered or suspected in the operating room, cystoscopy and retrograde pyelography is the most helpful imaging tool. Contrast dye is injected during cystoscopy directly into the renal collecting system through the ureteral orifices; with fluoroscopy, the surgeon can visualize the integrity of the ureter from the bladder to the renal pelvis to diagnosis a ureteral injury, including ureteral transection, kinking, or ligation caused by a suture or sealing device.
If retrograde pyelography shows a transection or injury from a crushing clamp or sealing device, we recommend ureteroureteral anastomosis or urethral neocystostomy depending on the extent and location of the injury. If the ureter just appears kinked, sometime simply releasing the cuff sutures or uterosacral ligament sutures will resolve the obstruction. If there is extravasation of contrast suggesting a partial tear, placing a double-J ureteral stent for 6-8 weeks is frequently sufficient.
Patients with delayed iatrogenic ureteral injuries present with symptoms that often are nonspecific and that include abdominal or flank pain, fever, nausea, vomiting, back pain, and leukocytosis.
We recommend that patients with a history of surgery and symptoms suggestive of a ureteral injury be initially evaluated with CT urography that images the renal collecting system both as contrast dye is instilled and again several minutes later as it has progressed through the entire urinary tract. Alternatively, if CT urography is unavailable, a retrograde pyelogram can be performed as an emergency procedure to determine the location of renal injury.
Surgical management
Delayed ureteral injuries resulting in partial ureteral obstruction or extravasation of urine into the pelvis can sometimes be managed conservatively though placement of an internalized double J stent. The stent can be placed in a retrograde fashion via cystoscopy by a
We typically manage delayed ureteral injuries that are not amenable to, or do not heal with, ureteral stenting with ureteroneocystotomy, or ureteral reimplantation, into the bladder. This technique is effective for distal ureteral injuries that result in obstruction or fistula and are in close proximity to the bladder (most iatrogenic gynecologic injuries). We perform ureteroneocystotomy via an open, robotic, or laparoscopic route of access depending on the circumstance.
Our preferred route of access is minimally invasive with the da Vinci robot. A camera port is placed at the umbilicus, two robotic ports are placed on the patient’s left side at the level of the umbilicus, and one is placed on the patient’s right side at the level of the umbilicus with an additional assistant port on the right side. It is helpful if each port is at least 8 cm apart. If obstruction or transection is suspected to be more proximal, the ports may have been shifted above the umbilicus to optimally mobilize the ureter.
First, the ureter is identified and dissected. Regardless of the site of injury, which is usually identifiable with inflammation and scar tissue, it is always easiest to identify the ureter at the bifurcation of the common iliac vessels. The isolated ureter is inspected proximally and above the area of injury, and we find it helpful to place a vessel loop around the ureter for easy manipulation and counter traction. Care must be taken not to disturb the adventitia and blood supply. We do not transect the ureter until we’re ready to reimplant it in the bladder.
To mobilize the bladder and prepare for a tension-free anastomosis, an adequate retropubic dissection is performed, starting with an incision in the anterior abdominal wall peritoneum and taking it down to the level of the pubic bone and into the retropubic space. It is important to be mindful of the location of the obturator neurovascular bundle when performing this dissection.
Achieving a tension-free and water-tight anastomosis of the ureter to the bladder is critical. The bladder should be mobilized such that it reaches to above the injured portion of the ureter. The bladder is retrograde filled with approximately 300 mL and a reimplantation site of the posterior bladder is identified. When there is concern about tension, a psoas hitch suture can be placed to keep the bladder in a superior position with reduced tension. Because of high rates of the congenital absence of the psoas tendon minor, we advocate direct visualization of the genitofemoral nerve by incising the peritoneum; this will avoid nerve entrapment.
Once the bladder is mobilized and the ureter isolated, we perform an intentional cystotomy in the posterior lateral aspect of the bladder. The ureter, which is on the vessel loop, must be transected proximal to the site of injury. To facilitate this, we spatulate the ureter, making a vertical incision of often about 5 mm in length to increase our surface area for anastomosis. Placement of a suture at the apex of the spatulated ureter helps us maintain orientation.
Anastomosis of the ureter and bladder is achieved in a mucosa-to-mucosa fashion using a series of interrupted monofilament fine absorbable sutures; we use a 3-0 monocryl suture. The most posterior anastomotic sutures are placed first to allow for optimal visualization, and prior to completing the anastomosis, a guide wire is placed through the open ureter and a double-J stent is introduced into the renal pelvis. The wire is then removed and the distal end of the stent coiled in the bladder. This stent will protect the ureter for about 6 weeks while it heals. The anastomosis is then completed on the anterior aspect, with a watertight closure ensured.
Postoperatively, we routinely perform an x-ray to ensure proper placement of the stent in the reimplanted ureter. To determine correct stent placement, the last rib is identified at T12 vertebrae. The renal pelvis is located at the level of the L2-L3 with the left being slightly higher than the right. A Foley catheter is maintained in the bladder for approximately 2 weeks, and the stent is maintained for approximately 6 weeks. Both the catheter and the stent can be removed in the office with cystoscopic guidance.
Imaging at 4-6 weeks after removal of the stent is performed to rule out development of an obstruction or a stricture. In patients who did not have a dilated ureter and renal collecting system prior to reimplantation, a renal ultrasound is sufficient to identify hydroureter/hydronephrosis or a urinoma. Many patients with a markedly dilated renal-collecting system prior to ureteral reimplantation will have persistent hydroureter/hydronephrosis (similar to a latex balloon that does not return to its original size after it is blown up) after reimplantation. A Lasix renal scan is a better imaging modality in these patients because it can differentiate a ureter that is dilated from one that is dilated and obstructed.
It is important to note that prompt ureteroneocystotomy is feasible only when the delayed ureteral injury presents within approximately 7 days of surgery. If the patient presents more than a week after surgery, inflammation is so significant that conservative management is necessary with reevaluation for reimplantation in another 6 weeks. Decompression of the system prior to reimplantation can be achieved through either stent placement or placement of a percutaneous nephrostomy tube. We prefer the latter because it reduces inflammation around the ureter that may make subsequent dissection and surgery more difficult.
Dr. Kenton is chief of urogynecology, Northwestern University, Chicago, and Dr. Mueller also is in the division of female pelvic medicine and reconstructive surgery–urogynecology at Northwestern. Dr. Kenton discloses grant funding from Boston Scientific.
The diagnosis and treatment of ureteral injury
A gynecologic surgeon learns very early in his/her career to respect the ureter. Whether from the procedure being performed (endometriosis surgery, hysterectomy, myomectomy for ligamentous fibroids, salpingo-oophorectomy, excision of ovarian remnants, adhesiolysis), blood loss that obscures visualization and must be controlled, or use of energy for cutting, desiccation, and coagulation leading to potential lateral tissue damage, ureteral injury is a well-known complication. Even normal anatomic variations may put some women at greater risk; according to Hurd et al. (Am J Obstet Gynecol. 2001;184:336-9). In a small subset of women, the distance between the cervix and the ureter may be less than 0.5 cm.
As a practicing minimally invasive gynecologic surgeon for the past 30 years, and an early adapter to laparoscopic hysterectomy, I remember quite well the recommendation to always dissect out ureters at time of the procedure. At present, most will agree that selective dissection is safe and thus, more desirable, as bleeding, damage secondary to desiccation, and ureter devascularization with subsequent necrosis are all increased with ureterolysis.
I agree with Dr. Kenton and Dr. Mueller that ureteral stenting has not been shown to significantly decrease ureteral injury rates. Often times, with loss of peristalsis secondary to stent placement, locating the ureter may be even more difficult. Recent advances using lighted stents or indocyanine green, which fluoresces in response to near-infrared laser and can be injected into the ureter via the ureteral catheter tip, are still in the feasibility phase of evaluation and can be costly.
As most urogenital fistulae are secondary to unrecognized injuries at time of surgery, and due to the fact that intraoperative recognition of the injury allows for primary repair, thus, decreasing the rate of secondary surgery and the associated increased morbidity, I recommend cystoscopy to check for ureteral jets (ureteral efflux) be performed when there is concern regarding ureter compromise.
Currently, I utilize a 70° cystoscope to visualize the ureters. While in the past, I have used intravenous indigo carmine, methylene blue, or fluorescein sodium, I currently use Pyridium (phenazopyridine) 200 mg taken by mouth 1 hour prior to the procedure.
Unfortunately, ureteral jetting still may be noted despite partial ligation, laceration, or desiccation of the ureter.
If ureteral injury is not recognized at time of surgery, it can lead to various postoperative symptoms. If there is a ureteral defect, the patient may note profuse wound leakage, increased abdominal fluid, or a urinoma, ileus, fever, peritonitis, or hematuria. With ureteral obstruction, flank or abdominal pain or anuria can be noted; while, with fistula formation, the patient will likely present with urinary incontinence or watery vaginal discharge.
Dr. Miller is a minimally invasive gynecologic surgeon in Naperville, Ill., and a past president of the AAGL.
A gynecologic surgeon learns very early in his/her career to respect the ureter. Whether from the procedure being performed (endometriosis surgery, hysterectomy, myomectomy for ligamentous fibroids, salpingo-oophorectomy, excision of ovarian remnants, adhesiolysis), blood loss that obscures visualization and must be controlled, or use of energy for cutting, desiccation, and coagulation leading to potential lateral tissue damage, ureteral injury is a well-known complication. Even normal anatomic variations may put some women at greater risk; according to Hurd et al. (Am J Obstet Gynecol. 2001;184:336-9). In a small subset of women, the distance between the cervix and the ureter may be less than 0.5 cm.
As a practicing minimally invasive gynecologic surgeon for the past 30 years, and an early adapter to laparoscopic hysterectomy, I remember quite well the recommendation to always dissect out ureters at time of the procedure. At present, most will agree that selective dissection is safe and thus, more desirable, as bleeding, damage secondary to desiccation, and ureter devascularization with subsequent necrosis are all increased with ureterolysis.
I agree with Dr. Kenton and Dr. Mueller that ureteral stenting has not been shown to significantly decrease ureteral injury rates. Often times, with loss of peristalsis secondary to stent placement, locating the ureter may be even more difficult. Recent advances using lighted stents or indocyanine green, which fluoresces in response to near-infrared laser and can be injected into the ureter via the ureteral catheter tip, are still in the feasibility phase of evaluation and can be costly.
As most urogenital fistulae are secondary to unrecognized injuries at time of surgery, and due to the fact that intraoperative recognition of the injury allows for primary repair, thus, decreasing the rate of secondary surgery and the associated increased morbidity, I recommend cystoscopy to check for ureteral jets (ureteral efflux) be performed when there is concern regarding ureter compromise.
Currently, I utilize a 70° cystoscope to visualize the ureters. While in the past, I have used intravenous indigo carmine, methylene blue, or fluorescein sodium, I currently use Pyridium (phenazopyridine) 200 mg taken by mouth 1 hour prior to the procedure.
Unfortunately, ureteral jetting still may be noted despite partial ligation, laceration, or desiccation of the ureter.
If ureteral injury is not recognized at time of surgery, it can lead to various postoperative symptoms. If there is a ureteral defect, the patient may note profuse wound leakage, increased abdominal fluid, or a urinoma, ileus, fever, peritonitis, or hematuria. With ureteral obstruction, flank or abdominal pain or anuria can be noted; while, with fistula formation, the patient will likely present with urinary incontinence or watery vaginal discharge.
Dr. Miller is a minimally invasive gynecologic surgeon in Naperville, Ill., and a past president of the AAGL.
A gynecologic surgeon learns very early in his/her career to respect the ureter. Whether from the procedure being performed (endometriosis surgery, hysterectomy, myomectomy for ligamentous fibroids, salpingo-oophorectomy, excision of ovarian remnants, adhesiolysis), blood loss that obscures visualization and must be controlled, or use of energy for cutting, desiccation, and coagulation leading to potential lateral tissue damage, ureteral injury is a well-known complication. Even normal anatomic variations may put some women at greater risk; according to Hurd et al. (Am J Obstet Gynecol. 2001;184:336-9). In a small subset of women, the distance between the cervix and the ureter may be less than 0.5 cm.
As a practicing minimally invasive gynecologic surgeon for the past 30 years, and an early adapter to laparoscopic hysterectomy, I remember quite well the recommendation to always dissect out ureters at time of the procedure. At present, most will agree that selective dissection is safe and thus, more desirable, as bleeding, damage secondary to desiccation, and ureter devascularization with subsequent necrosis are all increased with ureterolysis.
I agree with Dr. Kenton and Dr. Mueller that ureteral stenting has not been shown to significantly decrease ureteral injury rates. Often times, with loss of peristalsis secondary to stent placement, locating the ureter may be even more difficult. Recent advances using lighted stents or indocyanine green, which fluoresces in response to near-infrared laser and can be injected into the ureter via the ureteral catheter tip, are still in the feasibility phase of evaluation and can be costly.
As most urogenital fistulae are secondary to unrecognized injuries at time of surgery, and due to the fact that intraoperative recognition of the injury allows for primary repair, thus, decreasing the rate of secondary surgery and the associated increased morbidity, I recommend cystoscopy to check for ureteral jets (ureteral efflux) be performed when there is concern regarding ureter compromise.
Currently, I utilize a 70° cystoscope to visualize the ureters. While in the past, I have used intravenous indigo carmine, methylene blue, or fluorescein sodium, I currently use Pyridium (phenazopyridine) 200 mg taken by mouth 1 hour prior to the procedure.
Unfortunately, ureteral jetting still may be noted despite partial ligation, laceration, or desiccation of the ureter.
If ureteral injury is not recognized at time of surgery, it can lead to various postoperative symptoms. If there is a ureteral defect, the patient may note profuse wound leakage, increased abdominal fluid, or a urinoma, ileus, fever, peritonitis, or hematuria. With ureteral obstruction, flank or abdominal pain or anuria can be noted; while, with fistula formation, the patient will likely present with urinary incontinence or watery vaginal discharge.
Dr. Miller is a minimally invasive gynecologic surgeon in Naperville, Ill., and a past president of the AAGL.
The FDA’s novel drugs approved in 2017
Novel drugs are innovative new products that have never before been used in clinical practice. Among the 46 that the Food and Drug Administration approved in 2017, 45 could be used in pregnancy. One, cerliponase alfa (Brineura), is indicated for pediatric patients 3 years of age or older, for treatment of late infantile neuronal ceroid lipofuscinosis type 2. It is doubtful that this drug would be used in pregnancy or during breastfeeding.
With the two exceptions noted below, there are no human pregnancy data for these drugs. It is important to consider that although high molecular weight (MW) drugs (for example, greater than 1,000) probably do not usually cross the placenta in the first half of pregnancy, they may do so in late pregnancy. The cited MWs are shown as the nearest whole number. Animal reproductive data are also cited because, although not definitive, they can provide some measure of the human embryo-fetal risk.
Anti-infectives
Benznidazole (same trade name) (MW 441), given orally, is indicated for pediatric patients aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. However, there are international reports describing its use in pregnancy and breastfeeding. No fetal harm from these exposures were noted. Nevertheless, because of the low MW and the reported animal risk, avoiding the drug during the first half of pregnancy appears to be the best choice. Delafloxacin (Baxdela) (MW 441), a fluoroquinolone antimicrobial given intravenously or orally, is indicated for acute bacterial skin infections. The animal data suggest low risk. However, like other fluoroquinolones, it is contraindicated in pregnancy and should be used only if there are no other alternatives.
Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) (MWs 529, 883, 869), a fixed oral dose combination of three antivirals, is indicated for the treatment of hepatitis C virus infection. The MWs suggest that all three will cross the human placenta. The animal data suggest low risk. Secnidazole (Solosec) (MW 185), given orally, is indicated for the treatment of bacterial vaginosis. It is closely related to metronidazole. No evidence of embryo-fetal toxicity was observed in rats and rabbits, suggesting that the human risk is low. In a report from Brazil, 134 pregnant women with bacterial vaginosis were treated with secnidazole, metronidazole, or tinidazole in the second and third trimesters. Treatment significantly decreased the incidence of premature rupture of membranes, preterm labor, preterm birth, and low birth weight. No fetal harm was reported.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, in pregnancy and breastfeeding.]
Abemaciclib (Verzenio) (MW 507), an oral inhibitor of cyclin-dependent kinases, is indicated for the treatment of breast cancer. The drug is teratogenic in rats. Acalabrutinib (Calquence) (MW 466) is an oral kinase inhibitor indicated for mantle cell lymphoma. The drug had no effect on the rat embryo-fetus but caused decreased fetal body weights and delayed skeletal ossification in rabbits. Avelumab (Bavencio) (MW 147,000) is given intravenously for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma. Animal reproduction studies have not been conducted. However, based on its mechanism of action, fetal exposure may increase the risk of developing immune-related disorders or altering the normal immune response.
Brigatinib (Alunbrig) (MW 584) is given orally for the treatment of metastatic non–small-cell lung cancer. In rats, doses less than or slightly above the human exposure caused multiple anomalies in the fetuses of pregnant rats. Copanlisib (Aliqopa) (MW 553) is a kinase inhibitor that is given intravenously for relapsed follicular lymphoma. In rats during organogenesis, doses based on body surface area that were a fraction of the human dose caused embryo-fetal death and fetal defects. Durvalumab (Imfinzi) (MW 146,000), given intravenously, is indicated for the treatment of metastatic urothelial carcinoma and non–small-cell lung cancer. Monkeys given the drug from organogenesis through delivery experienced increased premature birth, fetal loss, and premature neonatal death. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
Enasidenib (Idhifa) (MW 569), given orally, is indicated for the treatment of myeloid leukemia. The drug caused maternal toxicity and adverse embryo-fetal effects (postimplantation loss, resorptions, decrease viable fetuses, lower fetal birth weights, and skeletal variations) in rats and spontaneous abortions in rabbits. Inotuzumab ozogamicin (Besponsa) (MW 160,000), given intravenously, is indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug caused fetal harm in rats but not in rabbits. Midostaurin (Rydapt) (MW 571) is an oral kinase inhibitor indicated for myeloid leukemia. In rats, a dose given during the first week of pregnancy that was a small fraction of the human exposure caused pre- and postimplantation loss. When very small doses were given during organogenesis to rats and rabbits there was significant maternal and fetal toxicity.
Neratinib (Nerlynx) (MW 673) is an oral kinase inhibitor for breast cancer. Although the drug did not cause embryo-fetal toxicity in rats, it did cause this toxicity in rabbits. Doses that resulted in exposures that were less than the human exposure caused maternal toxicity, abortions, and embryo-fetal death. Lower doses caused multiple fetal anomalies. Niraparib (Zejula) (MW 511) is indicated for treatment of epithelial ovarian, fallopian, or peritoneal cancer. Because of the potential human embryo-fetal risk based on its mechanism of action, pregnant animal studies were not conducted. Women with reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Ribociclib (Kisqali) (MW 553) is an oral kinase inhibitor indicated for postmenopausal women with breast cancer. In rats, the drug cause reduced fetal weights and skeletal changes. Increased incidences of fetal abnormalities and lower fetal weights were observed in rabbits.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046) is a naturally occurring peptide hormone given as an intravenous infusion. It is indicated as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. Animal reproduction studies have not been conducted. Because septic or other distributive shock is a medical emergency that can be fatal, the use of this agent in pregnancy should not be withheld.
Central nervous system
Deutetrabenazine (Austedo) (MW 324) is an oral drug indicated for the treatment of chorea associated with Huntington’s disease and for tardive dyskinesia. When given to rats during organogenesis there was no clear effect on embryo-fetal development.
Edaravone (Radicava) (MW 174), given as an intravenous infusion, is indicated for the treatment of amyotrophic lateral sclerosis. Doses that were not maternal toxic did not cause embryo-fetal toxicity in rats and rabbits. However, the no-effect dose for developmental toxicity was less than the recommended human dose. Naldemedine (Symproic) (MW 743) is an opioid antagonist indicated for the treatment of opioid-induced constipation. The drug crosses the human placenta and may precipitate opioid withdrawal in the fetus. The drug caused no embryo-fetal adverse effects, even at high doses, in pregnant rats and rabbits.
Ocrelizumab (Ocrevus) (MW 145,000), an intravenous agent, is used to treat patients with multiple sclerosis. The MW is high but immunoglobulins are known to cross the placenta. When given to monkeys at doses similar to or greater than the human dose, there was increased perinatal mortality, depletion of B-cell populations, and renal, bone marrow, and testicular toxicity in the offspring in the absence of maternal toxicity. Safinamide (Xadago) (MW 399) is an oral drug indicated as adjunctive treatment to levodopa/carbidopa in Parkinson’s disease. In rats, the drug was teratogenic (mainly urogenital defects) at all doses. When it was combined with levodopa/carbidopa or used alone, increased rates of fetal visceral and skeletal defects occurred at all doses studied. In rabbits, given the combination throughout organogenesis, there was an increased incidence of embryo-fetal death and cardiac and skeletal defects. Based on these data, avoiding the drug in pregnancy appears to be the best course.
Valbenazine (Ingrezza) (MW 419) is indicated for the treatment of tardive dyskinesia. The drug caused no malformations in rats and rabbits. However, in rats given the drug during organogenesis through lactation, an increase in the number of stillborn pups and postnatal pup mortalities was observed.
Dermatologic
Brodalumab (Siliq) (MW 144,000), given subcutaneously, is indicated for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In monkeys, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from mothers given weekly subcutaneous doses of the drug. Dupilumab (Dupixent) (MW 144,000) is given subcutaneously for the treatment of atopic dermatitis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age.
Guselkumab (Tremfya) (MW 143,600) is given subcutaneously for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age. However, neonatal deaths were observed in three monkeys given six times the maximum recommended human dose.
Endocrine/metabolic
Deflazacort (Emflaza) (MW 442) is an oral corticosteroid prodrug indicated for the treatment of Duchenne muscular dystrophy. The drug is converted in vivo to an active metabolite. The drug readily crosses the placenta. Although animal reproduction studies have not been conducted, such studies with other corticosteroids in various animal species have shown an increased incidence of cleft palate. In some species, there was an increase in embryo-fetal death, intrauterine growth restriction, and constriction of the ductus arteriosus.
Ertugliflozin (Steglatro) (MW 566) is an oral drug indicated to improve glycemic control in adults with type 2 diabetes mellitus. In juvenile rats, doses that were about 13 times the human dose caused increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization. These effects occurred during periods of rat renal development that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. Etelcalcetide (Parsabiv) (MW 1,048), an intravenous calcium-sensing receptor agonist, is indicated for patients on hemodialysis who have secondary hyperparathyroidism. In rats and rabbits given the drug during organogenesis, there was reduced fetal growth. In rats given the drug during organogenesis through birth and weaning, there was a slight increase in pup mortality, delay in parturition, and transient effects on pup growth, but there were no effects on sexual maturation, neurobehavioral, or reproductive function. Macimorelin (Macrilen) (MW 535) is an oral growth hormone secretagogue receptor agonist. It is indicated for adult growth hormone deficiency. Animal reproduction studies have not been conducted.
Semaglutide (Ozempic) (MW 4,114), given subcutaneously, is a glucagon-like peptide indicated to improve glycemic control in type 2 diabetes mellitus. In rats given the drug during organogenesis, embryo-fetal death, structural defects, and alterations in growth were observed. In rabbits and monkeys given the drug during organogenesis, there were early pregnancy losses and structural abnormalities. In addition, there was marked maternal body weight loss in both animal species. Vestronidase alfa-vjbk (Mepsevii) is given intravenously. It is indicated for the treatment of Mucopolysaccharidosis VII (Sly syndrome). The calculated average MW of each nonglycosylated peptide chain is 72,562. In rats and rabbits given the drug during organogenesis, there was no maternal toxicity or adverse developmental outcomes.
Gastrointestinal
Plecanatide (Trulance) (MW 1,682) is an oral drug indicated for the treatment of constipation. The drug and its active metabolite are negligibly absorbed systemically and fetal exposure to the drug is not expected. In mice and rabbits given the oral drug during organogenesis, no effects on embryo-fetal development were observed. Telotristat ethyl (Xermelo) (MW 754) is an oral drug indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (MW not specified) therapy in adults not controlled by somatostatin analog. When given during organogenesis in rats, there was no effect on embryo-fetal development at doses that were about nine times the recommended human dose. However, an increased incidence of mortality in rat offspring was observed when the drug was given from organogenesis through lactation. During organogenesis in rabbits, the drug had no embryo-fetal effects at doses that were 10 or more times the human dose.
Hematologics
Betrixaban (Bevyxxa) (MW 568) is an oral factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism. The drug was not associated with adverse developmental fetal outcomes in rats and rabbits. However, maternal hemorrhage did occur. In humans, there is an increased risk of hemorrhage during pregnancy and delivery. Emicizumab (Hemlibra) (MW 145,600), given subcutaneously, is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding in patients with hemophilia A with factor VIII inhibitors. Animal reproduction studies have not been conducted. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta.
Immunologic
Sarilumab (Kevzara) (MW 150,000) is given subcutaneously. It is indicated for patients with moderate to severe rheumatoid arthritis. Reproduction studies were conducted in pregnant monkeys. There was no evidence of embryo toxicity or fetal malformations. Based on this data, the human pregnancy risk is low.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508) is a prostaglandin analog that is indicated to reduce intraocular pressure. No quantifiable plasma concentrations of latanoprostene bunod were detected in nonpregnant patients. However, very low levels of latanoprost acid (51-59 pg/mL), the active metabolite, were detected with the maximal plasma concentration occurring 5 minutes after administration. When given intravenously to pregnant rabbits, the drug was shown to be abortifacient and teratogenic, but these effects were not observed in pregnant rats. Netarsudil (Rhopressa) (MW 454) is a kinase inhibitor indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. No quantifiable plasma concentrations of netarsudil were detected in 18 subjects. For the active metabolite, a plasma level of 0.11 ng/mL was found in one subject. Intravenous doses to pregnant rats and rabbits during organogenesis did not cause embryo-fetal adverse effects at clinically relevant systemic exposures.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3,961), given subcutaneously, is a human parathyroid hormone related peptide analog that is indicated for postmenopausal women with osteoporosis at high risk for fracture. Reproduction studies in animals have not been conducted. Because of the indication, it is doubtful if the agent will be used in pregnancy or during breastfeeding.
Respiratory
Benralizumab (Fasenra) (MW 150,000), given subcutaneously, is indicated for the add-on maintenance treatment of severe eosinophilic asthma. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta. Studies in monkeys found no evidence of fetal harm with intravenous doses throughout pregnancy that produced exposures up to about 310 times the exposure at the maximum recommended human dose.
The potential adverse effects in an infant when the mother is taking one of the above drugs while breastfeeding will be covered in my next column.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Novel drugs are innovative new products that have never before been used in clinical practice. Among the 46 that the Food and Drug Administration approved in 2017, 45 could be used in pregnancy. One, cerliponase alfa (Brineura), is indicated for pediatric patients 3 years of age or older, for treatment of late infantile neuronal ceroid lipofuscinosis type 2. It is doubtful that this drug would be used in pregnancy or during breastfeeding.
With the two exceptions noted below, there are no human pregnancy data for these drugs. It is important to consider that although high molecular weight (MW) drugs (for example, greater than 1,000) probably do not usually cross the placenta in the first half of pregnancy, they may do so in late pregnancy. The cited MWs are shown as the nearest whole number. Animal reproductive data are also cited because, although not definitive, they can provide some measure of the human embryo-fetal risk.
Anti-infectives
Benznidazole (same trade name) (MW 441), given orally, is indicated for pediatric patients aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. However, there are international reports describing its use in pregnancy and breastfeeding. No fetal harm from these exposures were noted. Nevertheless, because of the low MW and the reported animal risk, avoiding the drug during the first half of pregnancy appears to be the best choice. Delafloxacin (Baxdela) (MW 441), a fluoroquinolone antimicrobial given intravenously or orally, is indicated for acute bacterial skin infections. The animal data suggest low risk. However, like other fluoroquinolones, it is contraindicated in pregnancy and should be used only if there are no other alternatives.
Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) (MWs 529, 883, 869), a fixed oral dose combination of three antivirals, is indicated for the treatment of hepatitis C virus infection. The MWs suggest that all three will cross the human placenta. The animal data suggest low risk. Secnidazole (Solosec) (MW 185), given orally, is indicated for the treatment of bacterial vaginosis. It is closely related to metronidazole. No evidence of embryo-fetal toxicity was observed in rats and rabbits, suggesting that the human risk is low. In a report from Brazil, 134 pregnant women with bacterial vaginosis were treated with secnidazole, metronidazole, or tinidazole in the second and third trimesters. Treatment significantly decreased the incidence of premature rupture of membranes, preterm labor, preterm birth, and low birth weight. No fetal harm was reported.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, in pregnancy and breastfeeding.]
Abemaciclib (Verzenio) (MW 507), an oral inhibitor of cyclin-dependent kinases, is indicated for the treatment of breast cancer. The drug is teratogenic in rats. Acalabrutinib (Calquence) (MW 466) is an oral kinase inhibitor indicated for mantle cell lymphoma. The drug had no effect on the rat embryo-fetus but caused decreased fetal body weights and delayed skeletal ossification in rabbits. Avelumab (Bavencio) (MW 147,000) is given intravenously for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma. Animal reproduction studies have not been conducted. However, based on its mechanism of action, fetal exposure may increase the risk of developing immune-related disorders or altering the normal immune response.
Brigatinib (Alunbrig) (MW 584) is given orally for the treatment of metastatic non–small-cell lung cancer. In rats, doses less than or slightly above the human exposure caused multiple anomalies in the fetuses of pregnant rats. Copanlisib (Aliqopa) (MW 553) is a kinase inhibitor that is given intravenously for relapsed follicular lymphoma. In rats during organogenesis, doses based on body surface area that were a fraction of the human dose caused embryo-fetal death and fetal defects. Durvalumab (Imfinzi) (MW 146,000), given intravenously, is indicated for the treatment of metastatic urothelial carcinoma and non–small-cell lung cancer. Monkeys given the drug from organogenesis through delivery experienced increased premature birth, fetal loss, and premature neonatal death. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
Enasidenib (Idhifa) (MW 569), given orally, is indicated for the treatment of myeloid leukemia. The drug caused maternal toxicity and adverse embryo-fetal effects (postimplantation loss, resorptions, decrease viable fetuses, lower fetal birth weights, and skeletal variations) in rats and spontaneous abortions in rabbits. Inotuzumab ozogamicin (Besponsa) (MW 160,000), given intravenously, is indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug caused fetal harm in rats but not in rabbits. Midostaurin (Rydapt) (MW 571) is an oral kinase inhibitor indicated for myeloid leukemia. In rats, a dose given during the first week of pregnancy that was a small fraction of the human exposure caused pre- and postimplantation loss. When very small doses were given during organogenesis to rats and rabbits there was significant maternal and fetal toxicity.
Neratinib (Nerlynx) (MW 673) is an oral kinase inhibitor for breast cancer. Although the drug did not cause embryo-fetal toxicity in rats, it did cause this toxicity in rabbits. Doses that resulted in exposures that were less than the human exposure caused maternal toxicity, abortions, and embryo-fetal death. Lower doses caused multiple fetal anomalies. Niraparib (Zejula) (MW 511) is indicated for treatment of epithelial ovarian, fallopian, or peritoneal cancer. Because of the potential human embryo-fetal risk based on its mechanism of action, pregnant animal studies were not conducted. Women with reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Ribociclib (Kisqali) (MW 553) is an oral kinase inhibitor indicated for postmenopausal women with breast cancer. In rats, the drug cause reduced fetal weights and skeletal changes. Increased incidences of fetal abnormalities and lower fetal weights were observed in rabbits.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046) is a naturally occurring peptide hormone given as an intravenous infusion. It is indicated as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. Animal reproduction studies have not been conducted. Because septic or other distributive shock is a medical emergency that can be fatal, the use of this agent in pregnancy should not be withheld.
Central nervous system
Deutetrabenazine (Austedo) (MW 324) is an oral drug indicated for the treatment of chorea associated with Huntington’s disease and for tardive dyskinesia. When given to rats during organogenesis there was no clear effect on embryo-fetal development.
Edaravone (Radicava) (MW 174), given as an intravenous infusion, is indicated for the treatment of amyotrophic lateral sclerosis. Doses that were not maternal toxic did not cause embryo-fetal toxicity in rats and rabbits. However, the no-effect dose for developmental toxicity was less than the recommended human dose. Naldemedine (Symproic) (MW 743) is an opioid antagonist indicated for the treatment of opioid-induced constipation. The drug crosses the human placenta and may precipitate opioid withdrawal in the fetus. The drug caused no embryo-fetal adverse effects, even at high doses, in pregnant rats and rabbits.
Ocrelizumab (Ocrevus) (MW 145,000), an intravenous agent, is used to treat patients with multiple sclerosis. The MW is high but immunoglobulins are known to cross the placenta. When given to monkeys at doses similar to or greater than the human dose, there was increased perinatal mortality, depletion of B-cell populations, and renal, bone marrow, and testicular toxicity in the offspring in the absence of maternal toxicity. Safinamide (Xadago) (MW 399) is an oral drug indicated as adjunctive treatment to levodopa/carbidopa in Parkinson’s disease. In rats, the drug was teratogenic (mainly urogenital defects) at all doses. When it was combined with levodopa/carbidopa or used alone, increased rates of fetal visceral and skeletal defects occurred at all doses studied. In rabbits, given the combination throughout organogenesis, there was an increased incidence of embryo-fetal death and cardiac and skeletal defects. Based on these data, avoiding the drug in pregnancy appears to be the best course.
Valbenazine (Ingrezza) (MW 419) is indicated for the treatment of tardive dyskinesia. The drug caused no malformations in rats and rabbits. However, in rats given the drug during organogenesis through lactation, an increase in the number of stillborn pups and postnatal pup mortalities was observed.
Dermatologic
Brodalumab (Siliq) (MW 144,000), given subcutaneously, is indicated for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In monkeys, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from mothers given weekly subcutaneous doses of the drug. Dupilumab (Dupixent) (MW 144,000) is given subcutaneously for the treatment of atopic dermatitis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age.
Guselkumab (Tremfya) (MW 143,600) is given subcutaneously for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age. However, neonatal deaths were observed in three monkeys given six times the maximum recommended human dose.
Endocrine/metabolic
Deflazacort (Emflaza) (MW 442) is an oral corticosteroid prodrug indicated for the treatment of Duchenne muscular dystrophy. The drug is converted in vivo to an active metabolite. The drug readily crosses the placenta. Although animal reproduction studies have not been conducted, such studies with other corticosteroids in various animal species have shown an increased incidence of cleft palate. In some species, there was an increase in embryo-fetal death, intrauterine growth restriction, and constriction of the ductus arteriosus.
Ertugliflozin (Steglatro) (MW 566) is an oral drug indicated to improve glycemic control in adults with type 2 diabetes mellitus. In juvenile rats, doses that were about 13 times the human dose caused increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization. These effects occurred during periods of rat renal development that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. Etelcalcetide (Parsabiv) (MW 1,048), an intravenous calcium-sensing receptor agonist, is indicated for patients on hemodialysis who have secondary hyperparathyroidism. In rats and rabbits given the drug during organogenesis, there was reduced fetal growth. In rats given the drug during organogenesis through birth and weaning, there was a slight increase in pup mortality, delay in parturition, and transient effects on pup growth, but there were no effects on sexual maturation, neurobehavioral, or reproductive function. Macimorelin (Macrilen) (MW 535) is an oral growth hormone secretagogue receptor agonist. It is indicated for adult growth hormone deficiency. Animal reproduction studies have not been conducted.
Semaglutide (Ozempic) (MW 4,114), given subcutaneously, is a glucagon-like peptide indicated to improve glycemic control in type 2 diabetes mellitus. In rats given the drug during organogenesis, embryo-fetal death, structural defects, and alterations in growth were observed. In rabbits and monkeys given the drug during organogenesis, there were early pregnancy losses and structural abnormalities. In addition, there was marked maternal body weight loss in both animal species. Vestronidase alfa-vjbk (Mepsevii) is given intravenously. It is indicated for the treatment of Mucopolysaccharidosis VII (Sly syndrome). The calculated average MW of each nonglycosylated peptide chain is 72,562. In rats and rabbits given the drug during organogenesis, there was no maternal toxicity or adverse developmental outcomes.
Gastrointestinal
Plecanatide (Trulance) (MW 1,682) is an oral drug indicated for the treatment of constipation. The drug and its active metabolite are negligibly absorbed systemically and fetal exposure to the drug is not expected. In mice and rabbits given the oral drug during organogenesis, no effects on embryo-fetal development were observed. Telotristat ethyl (Xermelo) (MW 754) is an oral drug indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (MW not specified) therapy in adults not controlled by somatostatin analog. When given during organogenesis in rats, there was no effect on embryo-fetal development at doses that were about nine times the recommended human dose. However, an increased incidence of mortality in rat offspring was observed when the drug was given from organogenesis through lactation. During organogenesis in rabbits, the drug had no embryo-fetal effects at doses that were 10 or more times the human dose.
Hematologics
Betrixaban (Bevyxxa) (MW 568) is an oral factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism. The drug was not associated with adverse developmental fetal outcomes in rats and rabbits. However, maternal hemorrhage did occur. In humans, there is an increased risk of hemorrhage during pregnancy and delivery. Emicizumab (Hemlibra) (MW 145,600), given subcutaneously, is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding in patients with hemophilia A with factor VIII inhibitors. Animal reproduction studies have not been conducted. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta.
Immunologic
Sarilumab (Kevzara) (MW 150,000) is given subcutaneously. It is indicated for patients with moderate to severe rheumatoid arthritis. Reproduction studies were conducted in pregnant monkeys. There was no evidence of embryo toxicity or fetal malformations. Based on this data, the human pregnancy risk is low.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508) is a prostaglandin analog that is indicated to reduce intraocular pressure. No quantifiable plasma concentrations of latanoprostene bunod were detected in nonpregnant patients. However, very low levels of latanoprost acid (51-59 pg/mL), the active metabolite, were detected with the maximal plasma concentration occurring 5 minutes after administration. When given intravenously to pregnant rabbits, the drug was shown to be abortifacient and teratogenic, but these effects were not observed in pregnant rats. Netarsudil (Rhopressa) (MW 454) is a kinase inhibitor indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. No quantifiable plasma concentrations of netarsudil were detected in 18 subjects. For the active metabolite, a plasma level of 0.11 ng/mL was found in one subject. Intravenous doses to pregnant rats and rabbits during organogenesis did not cause embryo-fetal adverse effects at clinically relevant systemic exposures.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3,961), given subcutaneously, is a human parathyroid hormone related peptide analog that is indicated for postmenopausal women with osteoporosis at high risk for fracture. Reproduction studies in animals have not been conducted. Because of the indication, it is doubtful if the agent will be used in pregnancy or during breastfeeding.
Respiratory
Benralizumab (Fasenra) (MW 150,000), given subcutaneously, is indicated for the add-on maintenance treatment of severe eosinophilic asthma. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta. Studies in monkeys found no evidence of fetal harm with intravenous doses throughout pregnancy that produced exposures up to about 310 times the exposure at the maximum recommended human dose.
The potential adverse effects in an infant when the mother is taking one of the above drugs while breastfeeding will be covered in my next column.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Novel drugs are innovative new products that have never before been used in clinical practice. Among the 46 that the Food and Drug Administration approved in 2017, 45 could be used in pregnancy. One, cerliponase alfa (Brineura), is indicated for pediatric patients 3 years of age or older, for treatment of late infantile neuronal ceroid lipofuscinosis type 2. It is doubtful that this drug would be used in pregnancy or during breastfeeding.
With the two exceptions noted below, there are no human pregnancy data for these drugs. It is important to consider that although high molecular weight (MW) drugs (for example, greater than 1,000) probably do not usually cross the placenta in the first half of pregnancy, they may do so in late pregnancy. The cited MWs are shown as the nearest whole number. Animal reproductive data are also cited because, although not definitive, they can provide some measure of the human embryo-fetal risk.
Anti-infectives
Benznidazole (same trade name) (MW 441), given orally, is indicated for pediatric patients aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. However, there are international reports describing its use in pregnancy and breastfeeding. No fetal harm from these exposures were noted. Nevertheless, because of the low MW and the reported animal risk, avoiding the drug during the first half of pregnancy appears to be the best choice. Delafloxacin (Baxdela) (MW 441), a fluoroquinolone antimicrobial given intravenously or orally, is indicated for acute bacterial skin infections. The animal data suggest low risk. However, like other fluoroquinolones, it is contraindicated in pregnancy and should be used only if there are no other alternatives.
Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) (MWs 529, 883, 869), a fixed oral dose combination of three antivirals, is indicated for the treatment of hepatitis C virus infection. The MWs suggest that all three will cross the human placenta. The animal data suggest low risk. Secnidazole (Solosec) (MW 185), given orally, is indicated for the treatment of bacterial vaginosis. It is closely related to metronidazole. No evidence of embryo-fetal toxicity was observed in rats and rabbits, suggesting that the human risk is low. In a report from Brazil, 134 pregnant women with bacterial vaginosis were treated with secnidazole, metronidazole, or tinidazole in the second and third trimesters. Treatment significantly decreased the incidence of premature rupture of membranes, preterm labor, preterm birth, and low birth weight. No fetal harm was reported.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, in pregnancy and breastfeeding.]
Abemaciclib (Verzenio) (MW 507), an oral inhibitor of cyclin-dependent kinases, is indicated for the treatment of breast cancer. The drug is teratogenic in rats. Acalabrutinib (Calquence) (MW 466) is an oral kinase inhibitor indicated for mantle cell lymphoma. The drug had no effect on the rat embryo-fetus but caused decreased fetal body weights and delayed skeletal ossification in rabbits. Avelumab (Bavencio) (MW 147,000) is given intravenously for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma. Animal reproduction studies have not been conducted. However, based on its mechanism of action, fetal exposure may increase the risk of developing immune-related disorders or altering the normal immune response.
Brigatinib (Alunbrig) (MW 584) is given orally for the treatment of metastatic non–small-cell lung cancer. In rats, doses less than or slightly above the human exposure caused multiple anomalies in the fetuses of pregnant rats. Copanlisib (Aliqopa) (MW 553) is a kinase inhibitor that is given intravenously for relapsed follicular lymphoma. In rats during organogenesis, doses based on body surface area that were a fraction of the human dose caused embryo-fetal death and fetal defects. Durvalumab (Imfinzi) (MW 146,000), given intravenously, is indicated for the treatment of metastatic urothelial carcinoma and non–small-cell lung cancer. Monkeys given the drug from organogenesis through delivery experienced increased premature birth, fetal loss, and premature neonatal death. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
Enasidenib (Idhifa) (MW 569), given orally, is indicated for the treatment of myeloid leukemia. The drug caused maternal toxicity and adverse embryo-fetal effects (postimplantation loss, resorptions, decrease viable fetuses, lower fetal birth weights, and skeletal variations) in rats and spontaneous abortions in rabbits. Inotuzumab ozogamicin (Besponsa) (MW 160,000), given intravenously, is indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug caused fetal harm in rats but not in rabbits. Midostaurin (Rydapt) (MW 571) is an oral kinase inhibitor indicated for myeloid leukemia. In rats, a dose given during the first week of pregnancy that was a small fraction of the human exposure caused pre- and postimplantation loss. When very small doses were given during organogenesis to rats and rabbits there was significant maternal and fetal toxicity.
Neratinib (Nerlynx) (MW 673) is an oral kinase inhibitor for breast cancer. Although the drug did not cause embryo-fetal toxicity in rats, it did cause this toxicity in rabbits. Doses that resulted in exposures that were less than the human exposure caused maternal toxicity, abortions, and embryo-fetal death. Lower doses caused multiple fetal anomalies. Niraparib (Zejula) (MW 511) is indicated for treatment of epithelial ovarian, fallopian, or peritoneal cancer. Because of the potential human embryo-fetal risk based on its mechanism of action, pregnant animal studies were not conducted. Women with reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Ribociclib (Kisqali) (MW 553) is an oral kinase inhibitor indicated for postmenopausal women with breast cancer. In rats, the drug cause reduced fetal weights and skeletal changes. Increased incidences of fetal abnormalities and lower fetal weights were observed in rabbits.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046) is a naturally occurring peptide hormone given as an intravenous infusion. It is indicated as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. Animal reproduction studies have not been conducted. Because septic or other distributive shock is a medical emergency that can be fatal, the use of this agent in pregnancy should not be withheld.
Central nervous system
Deutetrabenazine (Austedo) (MW 324) is an oral drug indicated for the treatment of chorea associated with Huntington’s disease and for tardive dyskinesia. When given to rats during organogenesis there was no clear effect on embryo-fetal development.
Edaravone (Radicava) (MW 174), given as an intravenous infusion, is indicated for the treatment of amyotrophic lateral sclerosis. Doses that were not maternal toxic did not cause embryo-fetal toxicity in rats and rabbits. However, the no-effect dose for developmental toxicity was less than the recommended human dose. Naldemedine (Symproic) (MW 743) is an opioid antagonist indicated for the treatment of opioid-induced constipation. The drug crosses the human placenta and may precipitate opioid withdrawal in the fetus. The drug caused no embryo-fetal adverse effects, even at high doses, in pregnant rats and rabbits.
Ocrelizumab (Ocrevus) (MW 145,000), an intravenous agent, is used to treat patients with multiple sclerosis. The MW is high but immunoglobulins are known to cross the placenta. When given to monkeys at doses similar to or greater than the human dose, there was increased perinatal mortality, depletion of B-cell populations, and renal, bone marrow, and testicular toxicity in the offspring in the absence of maternal toxicity. Safinamide (Xadago) (MW 399) is an oral drug indicated as adjunctive treatment to levodopa/carbidopa in Parkinson’s disease. In rats, the drug was teratogenic (mainly urogenital defects) at all doses. When it was combined with levodopa/carbidopa or used alone, increased rates of fetal visceral and skeletal defects occurred at all doses studied. In rabbits, given the combination throughout organogenesis, there was an increased incidence of embryo-fetal death and cardiac and skeletal defects. Based on these data, avoiding the drug in pregnancy appears to be the best course.
Valbenazine (Ingrezza) (MW 419) is indicated for the treatment of tardive dyskinesia. The drug caused no malformations in rats and rabbits. However, in rats given the drug during organogenesis through lactation, an increase in the number of stillborn pups and postnatal pup mortalities was observed.
Dermatologic
Brodalumab (Siliq) (MW 144,000), given subcutaneously, is indicated for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In monkeys, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from mothers given weekly subcutaneous doses of the drug. Dupilumab (Dupixent) (MW 144,000) is given subcutaneously for the treatment of atopic dermatitis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age.
Guselkumab (Tremfya) (MW 143,600) is given subcutaneously for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age. However, neonatal deaths were observed in three monkeys given six times the maximum recommended human dose.
Endocrine/metabolic
Deflazacort (Emflaza) (MW 442) is an oral corticosteroid prodrug indicated for the treatment of Duchenne muscular dystrophy. The drug is converted in vivo to an active metabolite. The drug readily crosses the placenta. Although animal reproduction studies have not been conducted, such studies with other corticosteroids in various animal species have shown an increased incidence of cleft palate. In some species, there was an increase in embryo-fetal death, intrauterine growth restriction, and constriction of the ductus arteriosus.
Ertugliflozin (Steglatro) (MW 566) is an oral drug indicated to improve glycemic control in adults with type 2 diabetes mellitus. In juvenile rats, doses that were about 13 times the human dose caused increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization. These effects occurred during periods of rat renal development that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. Etelcalcetide (Parsabiv) (MW 1,048), an intravenous calcium-sensing receptor agonist, is indicated for patients on hemodialysis who have secondary hyperparathyroidism. In rats and rabbits given the drug during organogenesis, there was reduced fetal growth. In rats given the drug during organogenesis through birth and weaning, there was a slight increase in pup mortality, delay in parturition, and transient effects on pup growth, but there were no effects on sexual maturation, neurobehavioral, or reproductive function. Macimorelin (Macrilen) (MW 535) is an oral growth hormone secretagogue receptor agonist. It is indicated for adult growth hormone deficiency. Animal reproduction studies have not been conducted.
Semaglutide (Ozempic) (MW 4,114), given subcutaneously, is a glucagon-like peptide indicated to improve glycemic control in type 2 diabetes mellitus. In rats given the drug during organogenesis, embryo-fetal death, structural defects, and alterations in growth were observed. In rabbits and monkeys given the drug during organogenesis, there were early pregnancy losses and structural abnormalities. In addition, there was marked maternal body weight loss in both animal species. Vestronidase alfa-vjbk (Mepsevii) is given intravenously. It is indicated for the treatment of Mucopolysaccharidosis VII (Sly syndrome). The calculated average MW of each nonglycosylated peptide chain is 72,562. In rats and rabbits given the drug during organogenesis, there was no maternal toxicity or adverse developmental outcomes.
Gastrointestinal
Plecanatide (Trulance) (MW 1,682) is an oral drug indicated for the treatment of constipation. The drug and its active metabolite are negligibly absorbed systemically and fetal exposure to the drug is not expected. In mice and rabbits given the oral drug during organogenesis, no effects on embryo-fetal development were observed. Telotristat ethyl (Xermelo) (MW 754) is an oral drug indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (MW not specified) therapy in adults not controlled by somatostatin analog. When given during organogenesis in rats, there was no effect on embryo-fetal development at doses that were about nine times the recommended human dose. However, an increased incidence of mortality in rat offspring was observed when the drug was given from organogenesis through lactation. During organogenesis in rabbits, the drug had no embryo-fetal effects at doses that were 10 or more times the human dose.
Hematologics
Betrixaban (Bevyxxa) (MW 568) is an oral factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism. The drug was not associated with adverse developmental fetal outcomes in rats and rabbits. However, maternal hemorrhage did occur. In humans, there is an increased risk of hemorrhage during pregnancy and delivery. Emicizumab (Hemlibra) (MW 145,600), given subcutaneously, is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding in patients with hemophilia A with factor VIII inhibitors. Animal reproduction studies have not been conducted. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta.
Immunologic
Sarilumab (Kevzara) (MW 150,000) is given subcutaneously. It is indicated for patients with moderate to severe rheumatoid arthritis. Reproduction studies were conducted in pregnant monkeys. There was no evidence of embryo toxicity or fetal malformations. Based on this data, the human pregnancy risk is low.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508) is a prostaglandin analog that is indicated to reduce intraocular pressure. No quantifiable plasma concentrations of latanoprostene bunod were detected in nonpregnant patients. However, very low levels of latanoprost acid (51-59 pg/mL), the active metabolite, were detected with the maximal plasma concentration occurring 5 minutes after administration. When given intravenously to pregnant rabbits, the drug was shown to be abortifacient and teratogenic, but these effects were not observed in pregnant rats. Netarsudil (Rhopressa) (MW 454) is a kinase inhibitor indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. No quantifiable plasma concentrations of netarsudil were detected in 18 subjects. For the active metabolite, a plasma level of 0.11 ng/mL was found in one subject. Intravenous doses to pregnant rats and rabbits during organogenesis did not cause embryo-fetal adverse effects at clinically relevant systemic exposures.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3,961), given subcutaneously, is a human parathyroid hormone related peptide analog that is indicated for postmenopausal women with osteoporosis at high risk for fracture. Reproduction studies in animals have not been conducted. Because of the indication, it is doubtful if the agent will be used in pregnancy or during breastfeeding.
Respiratory
Benralizumab (Fasenra) (MW 150,000), given subcutaneously, is indicated for the add-on maintenance treatment of severe eosinophilic asthma. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta. Studies in monkeys found no evidence of fetal harm with intravenous doses throughout pregnancy that produced exposures up to about 310 times the exposure at the maximum recommended human dose.
The potential adverse effects in an infant when the mother is taking one of the above drugs while breastfeeding will be covered in my next column.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.