Some months ago, a fellow Asherman’s syndrome (AS) sufferer who writes the blog Alternative Asherman’s had a missed miscarriage after AS and wrote of her experience (Three steps backwards) using misoprostol, linking it to the blog about my own experience using misoprostol. I feel it is necessary to clarify certain points in her experience as they may be inadvertantly misleading and appear to implicate misoprostol in what apparently ensued. She has also since updated her blog to clarify her interpretation of her experience.
Misoprostol is a non-invasive uterotonic drug that expels the uterine contents in a way that is analogous to a natural miscarriage. Scarring and subsequent adhesions are the result of physical injury (or severe infection) to the basal endometrium. In fact management of miscarriage with misoprostol has been shown to prevent adhesion formation compared to blind D&C (Tam WH, Lau WC, Cheung LP, Yuen PM, Chung TK. J Am Assoc Gynecol Laparosc.2002; 9 (2): 182–185.). Misoprostol can be used to expel the contents of the uterus for either pregnancy termination, after a missed or incomplete miscarriage has occured or for labour induction. It also dilates the cervix and is useful prior to hysteroscopic surgery. Unfortunately, misoprostol is often referred to as a 'pregnancy termination drug' despite its various uses.
With regards to misoprostol's efficacy it should be noted that she obtained Chinese herbs from her accupuncturist to help 'prepare her body for miscarriage'. (See her comment below). This is unnecessary. It is not advised to mix Chinese or any other alternative or over the counter drug/herb with the treatment prescribed by your qualified ObGyn. Any responsible qualified homeopath/alternative medicine practitioner (some are MDs) would not dispense drugs whose effects and interactions with drugs prescribed by another specialist is not known and has not been vigorously trialed. There is no regulation or standardization of alternative drugs (herbs, extracts, etc.) so their concentrations, compositions quality and therefore effects and interactions vary greatly. We don't know if using these herbs could have interfered with misoprostol's effect in some way (for example, reducing its efficacy by blocking the same receptors targeted by misoprostol).
She was told that she developed IUA after using misoprostol and prior to hysteroscopic surgery to remove retained products. Her hysteroscopic surgeon said that the RPOC from an incomplete evacuation led to fibrous scar tissue formation. While I have heard about this anecdotally, I have not seen any reports of women developing IUA from RPOC in the absence of severe infection. It is also difficult to reconcile the observation of dense scar tissue with products retained for just 5 weeks when scar tissue is not complete until about 8 weeks. Anecdotally, I personally had substantial retained products for 3 weeks after my second trimester miscarriage treated with misoprostol and did not develop IUA. RPOC and retained placenta can be managed conservatively (under medical supervision).
However, she does mention that she may have already had some recurrence of IUA before her pregnancy as her Obstetrician noticed what appeared to be synechiae on ultrasound. This appears to be an important clue.
She says that there were dense adhesions whereas she previously had had only mild adhesions at initial diagnosis.One possible way to explain the deterioration of her condition could lie in the initial treatment of her AS: she had a uterine cook balloon inserted following adhesiolysis. While I underwent the same procedure without any apparent complications like hundreds of others (a proportion of whom have gone on to have children), it is possible that if the stent was not removed properly, or if it somehow adhered to raw surfaces in the uterus, it could have caused damage on removal (the balloon is deflated and simply pulled out). This explanation would also be consistent with her ObGyn's observation of scar tissue during a prenatal scan. Note also that there is limited data from studies on the benefits of using the Foley catheter and IUDs after surgical lysis and no controlled or comparative trials on the Cook balloon. Some Asherman’s syndrome specialists even believe that stents can stunt endometrial regrowth.
A well researched and routinely used drug like misoprostol should not be treated with suspicion compared to many other medical and even pseudo medical treatments the same women undergo without questioning, from unproven and potentially harmful altnernative drugs to contraversial fertility therapies to treatments of Asherman’s syndrome on which there are comparatively less data and of a lower quality. This leads me to wonder whether it is the attitude of the treating doctor(s) which influences patients' perceptions of treatments. I agree that more doctors need to be trained in the use of misoprostol for miscarriage (and in particular among women with a history of AS) and that a followup hysteroscopy may be needed depending on clinical symptoms and gestational age at time of miscarriage to ensure there are no retained products of conception. Followup hysteroscopy may also be necessary in women with a history of AS if the miscarriage passed naturally as there is a possible tendency towards retained tissue from scarring. We already know that women with past AS are at an increased risk of abnormally invasive placentation such as placenta accreta. Retained tissue and placenta accreta may be different ends of a spectrum of abnormalities associated with placental invasion in a defective endometrium. Whether misoprostol is necessary to evacuate miscarriages that occur very early on in the pregnancy (prior to 7 weeks) is also questionable. These can be managed expectantly. It is especially risky to perform a blind D&C in women who already have suffered damage to their uterine lining. It is time for miscarriage management as a whole to be reviewed in light of advances in medical therapy and hysterosopic alternatives.
Showing posts with label intrauterine adhesions. Show all posts
Showing posts with label intrauterine adhesions. Show all posts
Tuesday, January 4, 2011
Thursday, December 2, 2010
Update Dec '10: Clinical trials and patents relevant to Asherman's syndrome
Clinical trials:
There are a number of trials involving the use of misoprostol for miscarriage management (note: I am not including studies on misoprostol use for pregnancy terminations because this choice is already routinely available to women who abort. It is not routinely- let alone occasionally-available to those who miscarry). As a blog which promotes prevention, these are naturally included. Below is more information and links to the studies.
Optimal Treatment of Miscarriage OR
Which is the Optimal Treatment for Miscarriage With a Gestational ac in the Uterus and Which Factors Can Predict if the Treatment Will be Successful?Region Skane, Kvinnokliniken, University Hopsital MAS Malmo Sweden.
Study type: Open labelled randomized trial (parallel assignment).
Aim: To compare the number of women with a complete miscarriage after 10 days between expectant management versus treatment with 800 micrograms of misoprostol intravaginally in women with an an incomplete miscarriage before 14 weeks and a gestational sac retained in the uterus.
link: http://clinicaltrials.gov/ct2/show/NCT01033903?term=miscarriage&rank=5
A Randomized Trial of Two Regimens of Misoprostol for Second Trimester Termination for Intrauterine Fetal DeathAmerican University of Beirut Medical Center
Study type: Open labelled, randomized controlled crossover trial.
Aim: To compare the safety, efficacy and patient satisfaction of vaginal versus sublingual administration of misoprostol (400 mcg every 4 hours until delivery. Time frame=24 hours)
link: http://clinicaltrials.gov/ct2/show/NCT00141895?term=misoprostol&rank=7
Sublingual Misoprostol Versus Standard Surgical Care for the Treatment of Incomplete AbortionGynuity Health Projects, Egypt, Mauritania, Niger.
Study type: Open labeled randomized controlled trial.
Aim: To compare the safety and efficacy of 400 mcg sublingual misoprostol to standard surgical curretage (D&C or MVA) for incomplete abortion (ie. retained products of conception). Presumably either spontaneous or induced.
link: http://clinicaltrials.gov/ct2/show/NCT00466999?term=misoprostol&rank=50
Non Surgical Management for Uterine Residua After Pregnancy Termination, Abortion or DeliveryHaEmek Medical Center, Israel
Study type: open labelled randomized trial (parallel assignment)
Aim:To compare the outcome of misoprostol treatment (intravaginal, 800 mcg) and expectant management in the case of intrauterine residua after completion of pregnancy.
link: http://clinicaltrials.gov/ct2/show/NCT01134926?term=misoprostol&rank=56
Misoprostol for Treatment of Fetal Death at 14-28 Weeks of PregnancyGynuity, California, Illinois, Boston, New York.
Study type: Double blinded randomized trial, parallel assignment.
Aim: To establish the safety and effectiveness of two different doses of the prostaglandin E1 analogue misoprostol administered buccally as a treatment for fetal death at 14 - 28 weeks, inclusive, of pregnancy.
link: http://clinicaltrials.gov/ct2/show/NCT00671060?term=misoprostol&rank=24
Effect of Colony Stimulating Factor on Poor Endometrial Development During IVF
Official Title: G-CSF and Endometrial Growth, Embryo Implantation and Pregnancy Following FET or Donor ET
The Center for Human Reproduction (CHR) is conducting a double-blind, randomized cross over trial to investigate the effect of G-CSF on endometrial thickness in women who have failed reaching minimal endometrial thickness by standard treatments. Outcome measures will include endometrial thickness (must be >7mm for transfer), implantation and pregnancy rates compared to control patients. The study will be conducted in women undergoing transfer of previously cryopreserved embryos or transfer of embryos from donor eggs.
There are published studies on the use of Vitamin E (tocopherol), Pentoxyfilline, and Sildenafil in women with a thin endometrium (some of whom have a history of Asherman’s syndrome (1-4)). To my knowledge this is the first trial using G-CSF for this purpose.
For more information see:
http://clinicaltrials.gov/ct2/show/NCT01202643?term=asherman+syndrome&rank=1
Safety of Leaving Cook Balloon Uterine Stent in Uterus for One Month
The Department of Obstetrics and Gynecology, Shin-Kong Wu-Ho-Su Memorial Hospital in Taiwan is conducting an open label randomized controlled trial to investigate the feasibility of leaving an intrauterine Cook balloon in the uterus for 1 month. The experimental arm of the study will be fitted with a uterine Cook stent while the control will not. Both groups will have swabs taken for culture just before hysteroscopic adhesiolysis and 30 days later, during second look hysteroscopy to evaluate the outcome of surgery.
The practice of leaving a Cook Balloon stent in the uterus for this length of time is used by some Asherman’s syndrome specialists in cases of severe and recurrent intrauterine adhesions (personal communication). In the above study there is no mention of antibiotic use, however the specialists that use the Cook balloon or Foley catheter prescribe antibiotic prophylaxy during the entire therapy to prevent the potential infection. The results of the study will also reveal the effectiveness of the Cook balloon in preventing adhesion recurrence compared to no stent. Previously there was a study comparing the IUD (3 cycles) to the Foley catheter (10 days), however the method of ‘adhesiolysis’ was blind D&C, not dissection of adhesions under direct hysteroscopic view (5). As blind D&C is the most common cause of intrauterine adhesions, it is difficult to know if the previous findings are due to the barrier method used or to fortuitous variations in the success of ‘surgery’ which is carried out blindly.
For more information see: http://clinicaltrials.gov/ct2/show/NCT01167296?term=uterine+adhesions&rank=2
SIGnificance of Routine Hysteroscopy Prior to a First 'in Vitro Fertilization'(IVF) Treatment Cycle (inSIGHT)
A multicenter single-blinded (caregiver) randomized intervention trial is being undertaken in the Netherlands to assess the cost effectiveness of screening women for intauterine abnormalities using hysteroscopy and SIS (saline infusion sonography) prior to fertility treatment (IVF/ICSI). If abnormalities are found (defined as the existence of a septum, endometrial polyp, submucous myoma, adhesions or endometritis) these will be treated on the spot, using scissors, Versapoint, grasping forceps, polypsnare or antibiotics. The primary outcome measure is cumulative ongoing pregnancy rate and live birth after randomization within 18 months of IVF/ICSI. Secondary outcome measures include cumulative implantation rates, miscarriage rates, and comparative cost calculations.
Studies have shown that minor intrauterine abnormalities can be found in 11-40% of infertile women with a normal tranvaginal sonography. Detection and treatment of these abnormalities by office hysteroscopy have led to a 9-13% increase in pregnancy rate. Therefore, it is increasingly advised to screen all infertile women on intracavitary pathology prior to the start of IVF/ICSI.
Note that women with recurrent miscarriage are excluded from the study, when it is known that women with uterine abnormalities (congenital or acquired) are at a risk of repeated pregnancy loss. This exclusion is perhaps added in order to eliminate women who have other causes of infertility that are not due to anatomical anomalies and which cannot be diagnosed and corrected via hysteroscopy. However, this possible bias could have been avoided by excluding women who tested positive for other conditions known to cause recurrent miscarriage. I also wonder how effective outcomes will be in the experimental arm if IVF/ICSI is commenced immediately after treatment, without assessing the state of the cavity (IUA often recur, and IUA are a common consequence of septum correction and myomectomy). Furthermore, would it not be possible to answer this clinical question by reviewing the prevalence of uterine abnormalities in infertile and subfertile women, the cumulative implantation, pregnancy and live birth rates following treatment of these conditions, and analyzing the costs versus benefits ratio? For example, if past studies have shown that more than 10% of infertile women have an intrauterine pathology, and 40% of these women have a live birth after treatment, is it not justified to perform a diagnostic hysteroscopy prior to IVF/ICSI?
For more information: http://clinicaltrials.gov/ct2/show/NCT01242852?term=uterine+adhesions&rank=8
Note: There appears to be an error in the table describing the intervention and control arms of the study.
Patents
Patent Applications:
WO 2010/05/054068 A2 Cyclic adenosine monophosphates (cAMPs) for reducing the formation of adhesions. This world patent application claims the use of various derivatives of cAMPs for the reduction of adhesion formation for reducing inflammation or tissue damage after abdominal or pelvic surgery.
Jackson, EK. Cyclic adenosine monophosphates for reducing the formation of adhesions. 14 May 2010.
More info http://www.ibridgenetwork.org/university-of-pittsburgh/cyclic-adenosine-monophosphates-for-reducing-the-formation-of
In contrast to adhesion barriers, the invention would not involve placing a foreign body in the surgical cavity. Present adhesion barriers can cause immunological reactions. Also, the cyclic adenosine monophosphates are naturally-occuring substances and therefore should be quite safe. The cyclic adenosine monophosphates can be quickly and easily administered with a syringe. It can be used in minimally-invasive surgery, the future of surgery, and should be effective even if blood is in the surgical field. It is likely that the invention will be more efficacious than existing adhesion barriers.
Theoretically it could also be useful for intrauterine adhesions as many of the gel barriers used for pelvic surgery are also being used/trialled post adhesiolysis in Asherman’s syndrome treatment.So far there are only limited data on the efficacy of gel barriers in the treatment of Asherman’s syndrome (6-8). One of the difficulties of using gels is that they do not stay in a fixed position which is essential for them to be effective.
Granted Patents:
2005/0084,508 A61K Topical anesthesia formulation for bodily cavities
Innovators: Vancaillie, Thierry G; Hewitt, Alan Ernest
A topical anesthetic used for in-office hysteroscopy has recently been patented. The pH is adjusted to that of the body’s to optimize the effectiveness of the anesthetic.One of the inventors is an Asherman’s syndrome specialist. He has also developed a device for administering the anesthetic.
More info: http://www.patentbuddy.com/patentdetails/2402425
References
1. Acharya S, Yasmin E, & Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies – a report of 20 cases Human Fertility, December 2009; 12(4): 198–203.
2. Batailles N, Oliviennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Rep 2002;17(5):1249-53.
3. Sher G, Fisch D. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril. 2002 Nov;78(5):1073-6.
4. Zinger M, Liu Thomas JH, MA. Successful Use of Vaginal Sildenafil Citrate in Two Infertility Patients with Asherman’s Syndrome. JOURNAL OF WOMEN’S HEALTH 2006;15(4):,442-4.
5. Orhue AA, Aziken ME, Igbefoh JO. A comparison of two adjunctive treatments for intrauterine adhesions following lysis. Int J Gynaecol Obstet; 2003;82:49-56.
6. Abbott J, Thomson A, Vancaillie T. SprayGel following surgery for Asherman’s syndrome may improve pregnancy outcome. J Obstet Gynaecol 2004;24:710-1.
7. Acunzo G, Guida M, Pellicano M, Tommaselli GA, Di Spiezio Sardo A, Bifulco G, et al. Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Hum Reprod2003;18:1918-21.
8. Metwally M, Watson A, Lilford R, Vandekerckhove P. Fluid and pharmacological agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev2006;(2): CD001298. doi: 10.1002/14651858.CD001298.pub3.
Relevant links:
Understanding Clinical Trials
There are a number of trials involving the use of misoprostol for miscarriage management (note: I am not including studies on misoprostol use for pregnancy terminations because this choice is already routinely available to women who abort. It is not routinely- let alone occasionally-available to those who miscarry). As a blog which promotes prevention, these are naturally included. Below is more information and links to the studies.
Optimal Treatment of Miscarriage OR
Which is the Optimal Treatment for Miscarriage With a Gestational ac in the Uterus and Which Factors Can Predict if the Treatment Will be Successful?Region Skane, Kvinnokliniken, University Hopsital MAS Malmo Sweden.
Study type: Open labelled randomized trial (parallel assignment).
Aim: To compare the number of women with a complete miscarriage after 10 days between expectant management versus treatment with 800 micrograms of misoprostol intravaginally in women with an an incomplete miscarriage before 14 weeks and a gestational sac retained in the uterus.
link: http://clinicaltrials.gov/ct2/show/NCT01033903?term=miscarriage&rank=5
A Randomized Trial of Two Regimens of Misoprostol for Second Trimester Termination for Intrauterine Fetal DeathAmerican University of Beirut Medical Center
Study type: Open labelled, randomized controlled crossover trial.
Aim: To compare the safety, efficacy and patient satisfaction of vaginal versus sublingual administration of misoprostol (400 mcg every 4 hours until delivery. Time frame=24 hours)
link: http://clinicaltrials.gov/ct2/show/NCT00141895?term=misoprostol&rank=7
Sublingual Misoprostol Versus Standard Surgical Care for the Treatment of Incomplete AbortionGynuity Health Projects, Egypt, Mauritania, Niger.
Study type: Open labeled randomized controlled trial.
Aim: To compare the safety and efficacy of 400 mcg sublingual misoprostol to standard surgical curretage (D&C or MVA) for incomplete abortion (ie. retained products of conception). Presumably either spontaneous or induced.
link: http://clinicaltrials.gov/ct2/show/NCT00466999?term=misoprostol&rank=50
Non Surgical Management for Uterine Residua After Pregnancy Termination, Abortion or DeliveryHaEmek Medical Center, Israel
Study type: open labelled randomized trial (parallel assignment)
Aim:To compare the outcome of misoprostol treatment (intravaginal, 800 mcg) and expectant management in the case of intrauterine residua after completion of pregnancy.
link: http://clinicaltrials.gov/ct2/show/NCT01134926?term=misoprostol&rank=56
Misoprostol for Treatment of Fetal Death at 14-28 Weeks of PregnancyGynuity, California, Illinois, Boston, New York.
Study type: Double blinded randomized trial, parallel assignment.
Aim: To establish the safety and effectiveness of two different doses of the prostaglandin E1 analogue misoprostol administered buccally as a treatment for fetal death at 14 - 28 weeks, inclusive, of pregnancy.
link: http://clinicaltrials.gov/ct2/show/NCT00671060?term=misoprostol&rank=24
Effect of Colony Stimulating Factor on Poor Endometrial Development During IVF
Official Title: G-CSF and Endometrial Growth, Embryo Implantation and Pregnancy Following FET or Donor ET
The Center for Human Reproduction (CHR) is conducting a double-blind, randomized cross over trial to investigate the effect of G-CSF on endometrial thickness in women who have failed reaching minimal endometrial thickness by standard treatments. Outcome measures will include endometrial thickness (must be >7mm for transfer), implantation and pregnancy rates compared to control patients. The study will be conducted in women undergoing transfer of previously cryopreserved embryos or transfer of embryos from donor eggs.
There are published studies on the use of Vitamin E (tocopherol), Pentoxyfilline, and Sildenafil in women with a thin endometrium (some of whom have a history of Asherman’s syndrome (1-4)). To my knowledge this is the first trial using G-CSF for this purpose.
For more information see:
http://clinicaltrials.gov/ct2/show/NCT01202643?term=asherman+syndrome&rank=1
Safety of Leaving Cook Balloon Uterine Stent in Uterus for One Month
The Department of Obstetrics and Gynecology, Shin-Kong Wu-Ho-Su Memorial Hospital in Taiwan is conducting an open label randomized controlled trial to investigate the feasibility of leaving an intrauterine Cook balloon in the uterus for 1 month. The experimental arm of the study will be fitted with a uterine Cook stent while the control will not. Both groups will have swabs taken for culture just before hysteroscopic adhesiolysis and 30 days later, during second look hysteroscopy to evaluate the outcome of surgery.
The practice of leaving a Cook Balloon stent in the uterus for this length of time is used by some Asherman’s syndrome specialists in cases of severe and recurrent intrauterine adhesions (personal communication). In the above study there is no mention of antibiotic use, however the specialists that use the Cook balloon or Foley catheter prescribe antibiotic prophylaxy during the entire therapy to prevent the potential infection. The results of the study will also reveal the effectiveness of the Cook balloon in preventing adhesion recurrence compared to no stent. Previously there was a study comparing the IUD (3 cycles) to the Foley catheter (10 days), however the method of ‘adhesiolysis’ was blind D&C, not dissection of adhesions under direct hysteroscopic view (5). As blind D&C is the most common cause of intrauterine adhesions, it is difficult to know if the previous findings are due to the barrier method used or to fortuitous variations in the success of ‘surgery’ which is carried out blindly.
For more information see: http://clinicaltrials.gov/ct2/show/NCT01167296?term=uterine+adhesions&rank=2
SIGnificance of Routine Hysteroscopy Prior to a First 'in Vitro Fertilization'(IVF) Treatment Cycle (inSIGHT)
A multicenter single-blinded (caregiver) randomized intervention trial is being undertaken in the Netherlands to assess the cost effectiveness of screening women for intauterine abnormalities using hysteroscopy and SIS (saline infusion sonography) prior to fertility treatment (IVF/ICSI). If abnormalities are found (defined as the existence of a septum, endometrial polyp, submucous myoma, adhesions or endometritis) these will be treated on the spot, using scissors, Versapoint, grasping forceps, polypsnare or antibiotics. The primary outcome measure is cumulative ongoing pregnancy rate and live birth after randomization within 18 months of IVF/ICSI. Secondary outcome measures include cumulative implantation rates, miscarriage rates, and comparative cost calculations.
Studies have shown that minor intrauterine abnormalities can be found in 11-40% of infertile women with a normal tranvaginal sonography. Detection and treatment of these abnormalities by office hysteroscopy have led to a 9-13% increase in pregnancy rate. Therefore, it is increasingly advised to screen all infertile women on intracavitary pathology prior to the start of IVF/ICSI.
Note that women with recurrent miscarriage are excluded from the study, when it is known that women with uterine abnormalities (congenital or acquired) are at a risk of repeated pregnancy loss. This exclusion is perhaps added in order to eliminate women who have other causes of infertility that are not due to anatomical anomalies and which cannot be diagnosed and corrected via hysteroscopy. However, this possible bias could have been avoided by excluding women who tested positive for other conditions known to cause recurrent miscarriage. I also wonder how effective outcomes will be in the experimental arm if IVF/ICSI is commenced immediately after treatment, without assessing the state of the cavity (IUA often recur, and IUA are a common consequence of septum correction and myomectomy). Furthermore, would it not be possible to answer this clinical question by reviewing the prevalence of uterine abnormalities in infertile and subfertile women, the cumulative implantation, pregnancy and live birth rates following treatment of these conditions, and analyzing the costs versus benefits ratio? For example, if past studies have shown that more than 10% of infertile women have an intrauterine pathology, and 40% of these women have a live birth after treatment, is it not justified to perform a diagnostic hysteroscopy prior to IVF/ICSI?
For more information: http://clinicaltrials.gov/ct2/show/NCT01242852?term=uterine+adhesions&rank=8
Note: There appears to be an error in the table describing the intervention and control arms of the study.
Patents
Patent Applications:
WO 2010/05/054068 A2 Cyclic adenosine monophosphates (cAMPs) for reducing the formation of adhesions. This world patent application claims the use of various derivatives of cAMPs for the reduction of adhesion formation for reducing inflammation or tissue damage after abdominal or pelvic surgery.
Jackson, EK. Cyclic adenosine monophosphates for reducing the formation of adhesions. 14 May 2010.
More info http://www.ibridgenetwork.org/university-of-pittsburgh/cyclic-adenosine-monophosphates-for-reducing-the-formation-of
In contrast to adhesion barriers, the invention would not involve placing a foreign body in the surgical cavity. Present adhesion barriers can cause immunological reactions. Also, the cyclic adenosine monophosphates are naturally-occuring substances and therefore should be quite safe. The cyclic adenosine monophosphates can be quickly and easily administered with a syringe. It can be used in minimally-invasive surgery, the future of surgery, and should be effective even if blood is in the surgical field. It is likely that the invention will be more efficacious than existing adhesion barriers.
Theoretically it could also be useful for intrauterine adhesions as many of the gel barriers used for pelvic surgery are also being used/trialled post adhesiolysis in Asherman’s syndrome treatment.So far there are only limited data on the efficacy of gel barriers in the treatment of Asherman’s syndrome (6-8). One of the difficulties of using gels is that they do not stay in a fixed position which is essential for them to be effective.
Granted Patents:
2005/0084,508 A61K Topical anesthesia formulation for bodily cavities
Innovators: Vancaillie, Thierry G; Hewitt, Alan Ernest
A topical anesthetic used for in-office hysteroscopy has recently been patented. The pH is adjusted to that of the body’s to optimize the effectiveness of the anesthetic.One of the inventors is an Asherman’s syndrome specialist. He has also developed a device for administering the anesthetic.
More info: http://www.patentbuddy.com/patentdetails/2402425
References
1. Acharya S, Yasmin E, & Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies – a report of 20 cases Human Fertility, December 2009; 12(4): 198–203.
2. Batailles N, Oliviennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Rep 2002;17(5):1249-53.
3. Sher G, Fisch D. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril. 2002 Nov;78(5):1073-6.
4. Zinger M, Liu Thomas JH, MA. Successful Use of Vaginal Sildenafil Citrate in Two Infertility Patients with Asherman’s Syndrome. JOURNAL OF WOMEN’S HEALTH 2006;15(4):,442-4.
5. Orhue AA, Aziken ME, Igbefoh JO. A comparison of two adjunctive treatments for intrauterine adhesions following lysis. Int J Gynaecol Obstet; 2003;82:49-56.
6. Abbott J, Thomson A, Vancaillie T. SprayGel following surgery for Asherman’s syndrome may improve pregnancy outcome. J Obstet Gynaecol 2004;24:710-1.
7. Acunzo G, Guida M, Pellicano M, Tommaselli GA, Di Spiezio Sardo A, Bifulco G, et al. Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Hum Reprod2003;18:1918-21.
8. Metwally M, Watson A, Lilford R, Vandekerckhove P. Fluid and pharmacological agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev2006;(2): CD001298. doi: 10.1002/14651858.CD001298.pub3.
Relevant links:
Understanding Clinical Trials
Thursday, November 18, 2010
Articles on Asherman's syndrome Etiology, Incidence, Prevention
A selection of publications about Asherman's syndrome including reviews and journal articles on its etiology, incidence and prevention is being added to the site. It can be found here or alternatively, click on the relevant tab in tab menu at the top of the page. There will be another page with articles on Diagnosis, Classification, Treatment, Reproductive Outcomes and Obstetric Complications soon.
Thursday, October 21, 2010
When infertility or recurrent miscarriage persist after treatment of Asherman's syndrome
For many women who have had Asherman's syndrome, the journey to having a baby is not over with the removal of adhesions. While many doctors will use this to support their theory that they had other underlying fertility problems to begin with, it is equally possible that in some cases, Asherman's syndrome has lasting effects on fertility. Sometimes these are obvious such as inaccessible ostia (adhesions are sometimes too risky to remove) or thin endometrium. Most doctors agree that a lining of at least 8 mm at the time of ovulation is ideal for implantation. There could be other defects that persist after surgical correction such as reduced blood flow to the uterus. There is some disagreement as to whether procedures which reduce blood flow to the uterus, such as uterine artery embolization (UAE) can reduce fertility by affecting ovarian reserve. There is another intriguing link between blood flow and egg quality: it is known that endometriosis reduces egg quality although the mechanism is unknown. This makes me wonder whether I have endometriosis (I've never had a laparoscopy). There is something incongruent about having so many eggs of such poor quality. Unfortunately there is little research and few artifical reproductive techniques which focus on the quality of the endometrium. These few studies will be the topic of a future blog. There is also little research on improving egg quality as most fertility specialists are skeptical that this is possible due to currently accepted dogma on egg development.
Many women with a history of AS end up undergoing fertility treatments. Personally, I experienced infertility for 1.5 years even after AS correction (surgery and estrogen therapy) when I had had no problems conceiving to begin with. Then I went from being infertile to now conceiving once every two months but miscarrying. I have had 5 miscarriages in one year. All of my pregnancies have been naturally conceived. The last 3 have been very early miscarriages. Of course my first thought was that I might have some recurrence adhesions from my last hysteroscopic removal of RPOC in March. An in-office diagnostic hysteroscopy ruled out this possibility. I had molecular karyotyping (MLPA) of my last miscarriage which revealed trisomy 9, 20 and triallelic markers on the X chromosome. This indicates problems with egg quality. The first pregnancy after AS occurred a few months after 2 cycles of unsuccessful IVF. I wonder whether the effect of IVF hormones had a beneficial effect on my endometrium and egg development. My plan is to now find a fertility specialist who is willing to work with me on a protocol that does not include egg retrieval and in vitro fertilization (since I conceive very easily without it), but rather one that concentrates on improving the uterine environment. My idea is to use low dose aspirin (to improve blood flow to the uterus) and low doses of FSH to stimulate about 2 follicles (to double my chances of a healthy embryo) , undergo 'in vivo' fertilization and start taking progesterone pessaries after ovulation (for luteal phase support). FSH stimulates follicles to grow which in turn secrete estrogen to thicken the endometrial lining. Some women with past AS find that their endometrium responds more favourably to this ovarian stimulation than to estrogen pills. I'm also considering the use of DHEA, a controversial hormone which is alleged to improve ovarian reserve and quality, resulting in fewer miscarriages (and presumably aneuploidies).
Unfortunately, a few of the fertility specialists I have seen in the past have been very unflexible and biased in their thinking. Many have their own 'pet' theories about what works and what doesn't without the backup of proper studies. While they are happy to point out that my suggestions have no rigorous evidence of efficacy, they seem oblivious to the fact that their own suggestions also lack robust data and in addition, are often expensive, time consuming, painful and with possible adverse effects on health. When I once pointed this out, a well respected specialist told me to stop thinking like a scientist! He also told me that if I 'really' wanted a baby I would be willing to try risky treatments! There are still many unknowns in the area of infertility and fertility doctors don't know everything (even if some of them think they do!). For instance, this specialist convinced me that my inability to conceive was due to my low AMH levels (an indicator of poor ovarian reserve in my case due to being over 40) and in his words, I would never conceive without IVF, although he couldn't explain how IVF would improve ovarian reserve or egg quality. As an aside, I have very low FSH levels (3 when I was 42) which are meant to indicate excellent ovarian reserve. I didn't know it at the time he said this, but I was already pregnant. I went on to have 4 more pregnancies afterwards. Unfortunately my problem now is recurrent miscarriage, but his statement is still untrue. No one has been able to give me a reasonable explanation as to why I have gone from being unable to conceive for 1.5 years despite treatment for IUA, to conceiving every 2 months.
Below is a link to a chart detailing which tests and treatments are scientifically supported and which are not. Most have not been proven to be useful, although it is possible that in future there will be evidence to support them. It is up to the individual to decide, after considering risks and benefits, whether to proceed with them.
Infertility Tests and Therapies Questioned (Bupa)
More information on the validity of tests and therapies for infertility/recurrent miscarriage:
Cochrane Reviews: Immunotherapy for recurrent miscarriage (Full article: click here)
Note that this systematic review is comprised of studies where exclusion criteria included women with abnormal immune tests (eg. auto-antibody, cytotoxic antibodies, IgA deficiency etc.). Bascially, this review found that in women with recurrent miscarriage without any demonstrated abnormal immune function, there is no significant evidence that immunotherapy is useful (which one would expect). Still, many fertility specialists are eager to use these therapies on such patients.
RCOG: Implantation and Early Development - study group statement.
Miscarriage, Infertility, Antibodies and the Immune System Dr Licciardi's Infertility Blog
Many women with a history of AS end up undergoing fertility treatments. Personally, I experienced infertility for 1.5 years even after AS correction (surgery and estrogen therapy) when I had had no problems conceiving to begin with. Then I went from being infertile to now conceiving once every two months but miscarrying. I have had 5 miscarriages in one year. All of my pregnancies have been naturally conceived. The last 3 have been very early miscarriages. Of course my first thought was that I might have some recurrence adhesions from my last hysteroscopic removal of RPOC in March. An in-office diagnostic hysteroscopy ruled out this possibility. I had molecular karyotyping (MLPA) of my last miscarriage which revealed trisomy 9, 20 and triallelic markers on the X chromosome. This indicates problems with egg quality. The first pregnancy after AS occurred a few months after 2 cycles of unsuccessful IVF. I wonder whether the effect of IVF hormones had a beneficial effect on my endometrium and egg development. My plan is to now find a fertility specialist who is willing to work with me on a protocol that does not include egg retrieval and in vitro fertilization (since I conceive very easily without it), but rather one that concentrates on improving the uterine environment. My idea is to use low dose aspirin (to improve blood flow to the uterus) and low doses of FSH to stimulate about 2 follicles (to double my chances of a healthy embryo) , undergo 'in vivo' fertilization and start taking progesterone pessaries after ovulation (for luteal phase support). FSH stimulates follicles to grow which in turn secrete estrogen to thicken the endometrial lining. Some women with past AS find that their endometrium responds more favourably to this ovarian stimulation than to estrogen pills. I'm also considering the use of DHEA, a controversial hormone which is alleged to improve ovarian reserve and quality, resulting in fewer miscarriages (and presumably aneuploidies).
Unfortunately, a few of the fertility specialists I have seen in the past have been very unflexible and biased in their thinking. Many have their own 'pet' theories about what works and what doesn't without the backup of proper studies. While they are happy to point out that my suggestions have no rigorous evidence of efficacy, they seem oblivious to the fact that their own suggestions also lack robust data and in addition, are often expensive, time consuming, painful and with possible adverse effects on health. When I once pointed this out, a well respected specialist told me to stop thinking like a scientist! He also told me that if I 'really' wanted a baby I would be willing to try risky treatments! There are still many unknowns in the area of infertility and fertility doctors don't know everything (even if some of them think they do!). For instance, this specialist convinced me that my inability to conceive was due to my low AMH levels (an indicator of poor ovarian reserve in my case due to being over 40) and in his words, I would never conceive without IVF, although he couldn't explain how IVF would improve ovarian reserve or egg quality. As an aside, I have very low FSH levels (3 when I was 42) which are meant to indicate excellent ovarian reserve. I didn't know it at the time he said this, but I was already pregnant. I went on to have 4 more pregnancies afterwards. Unfortunately my problem now is recurrent miscarriage, but his statement is still untrue. No one has been able to give me a reasonable explanation as to why I have gone from being unable to conceive for 1.5 years despite treatment for IUA, to conceiving every 2 months.
Below is a link to a chart detailing which tests and treatments are scientifically supported and which are not. Most have not been proven to be useful, although it is possible that in future there will be evidence to support them. It is up to the individual to decide, after considering risks and benefits, whether to proceed with them.
Infertility Tests and Therapies Questioned (Bupa)
More information on the validity of tests and therapies for infertility/recurrent miscarriage:
Cochrane Reviews: Immunotherapy for recurrent miscarriage (Full article: click here)
Note that this systematic review is comprised of studies where exclusion criteria included women with abnormal immune tests (eg. auto-antibody, cytotoxic antibodies, IgA deficiency etc.). Bascially, this review found that in women with recurrent miscarriage without any demonstrated abnormal immune function, there is no significant evidence that immunotherapy is useful (which one would expect). Still, many fertility specialists are eager to use these therapies on such patients.
RCOG: Implantation and Early Development - study group statement.
Miscarriage, Infertility, Antibodies and the Immune System Dr Licciardi's Infertility Blog
Friday, July 2, 2010
FAQs Asherman's syndrome
Please see the new page on frequently asked questions about Asherman's syndrome. You can also click on the relevant tab button in the tab bar at the top of the page to view it.
Friday, May 14, 2010
Doctor’s orders: in support of Ashermans syndrome prevention and/or alternatives to D&C.
Here's what the doctors have written over the years in support of preventing Asherman's syndrome from occuring and more recently, in support of alternative methods to D&C for miscarriage management. This list is not exhaustive and I may add to it in future. There is so much evidence in the medical literature and knowledge among some doctors at least, that it is difficult to reconcile it with current medical practices. 'Translational research' might be the current buzz word at research centers, hospitals and universities, but how quickly this progress is incorporated into routine or widespread practice is entirely another matter. This is where patients need to speak up to encourage change, and why patients need to educate themselves and others first. Reading the research is the only way to get an overall view of the established facts rather than relying only on second hand information from others who may have vested interests or other agendas.
(my additions are in blue)
1. Toaf and Ballas, 1978 (1):
"Peurperal curettage…was discontinued in Israel after publication of Asherman’s observations.”
This is not so in the US, UK, Australia and many other countries. Also, curettage remains standard care for treating miscarriage in many countries (while abortion is now usually carried out medically).
2. Li et al, 2001 (2):
After vaginal delivery, a retained placenta may cause a risk to maternal health because of hemorrhage or infection. …manual removal of the retained placenta is a routine procedure. ..This invasive procedure increases risk of trauma*, rupture of uterus, hemorrhage, postpartum infection, and anesthetic complications.”
* Asherman’s syndrome may result
“In all 18 parturients, spontaneous expulsion of the placenta developed in an average interval of 12 min (range from 5 to 35 min) after rectal insertion of misoprostol.”
3. Friedler et al, 1993 (3):
“The incidence of IUA might be lower following medical evacuation of the uterus, thus avoiding any intra-uterine instrumentation; however, use of progesterone antagonists (ie, mifepristone) for this purpose is not yet approved by the Israeli Ministry of Health.”
4. Chapman and Chapman, 1990 (4):
“One must also note that the suction curette is capable of causing synechiae, usually, however in the region of the internal os.”
“It is noteworthy that, of the 11 patients with isthmus stenosis, six of them were attributable to termination of pregnancy, of which all but one had been performed by suction curettage”
“It goes without saying that, in view of the seriousness of the sequelae, the best management is prevention…”
3. Tam et al, 2002 (5):
“No cases of IUA were found in patients managed conservatively or by medical evacuation, whereas 2 cases (7.7%) of filmy IUA were detected in those managed by surgical evacuation.”
“We therefore recommend expectant management and medical evacuation as first-line treatment for complete abortion* and incomplete abortion*, respectively. Surgical evacuation should be the treatment of choice when {these methods} fails or is contraindicated.”
*ie miscarriage
6. Goldenberg et al, 1997 (6):
“Selective curettage of residual trophoblastic tissue directed by hysteroscopy is an easy and short procedure and might be preferable to conventional, nonselective, blind curettage.”
“…areas not covered by residual tissue…are not subject to surgical trauma during the selective procedure and presumably are therefore exposed to lower risks of inflammation, scarring and adhesion formation”
“Incomplete removal of the residua is more likely to occur during repeated conventional curettage, even if guided by ultrasonography, as had occurred in two of our patients. Direct visualization of the cavity allows…the exact location and extent of the residual tissue to be resected.”
7. Yu et al, 2008 (7):
“Prevention of Asherman Syndrome
Prevention is always better than cure. To prevent the formation of endometrial fibrosis and adhesions, it is essential that any trauma to the uterus be avoided, especially in the pregnant or postpartum state.”
They go on to recommend:
“Avoid postpartum or postabortion curettage”
“Diagnosis of retained products of conception …present a clinical challenge.
…Saline infusion sonohysterography (SHG) has enhanced our ability to diagnose retained products of conception (8)”
“…transvaginal B-mode ultrasonography combined with color velocity imaging and pulsed Doppler to detect retained trophoblastic tissue…could be useful to…select patients suitable for conservative management.(9)”
“Transvaginal duplex Doppler ultrasonography is also an effective noninvasive method for evaluating patients with persistent postpartum hermorrhage (10).”
"…hysteroscopy should be considered an effective method for diagnosis and treatment of retained products of conception." They cite the Goldenberg et al (6) study (see above).
…
“Select medical management of miscarriages
When termination of early pregnancy is necessary, medical treatment should be considered instead of surgical options.”
They cite the Tam et al study (5)(see above).
“Since its introduction, the uptake of medical abortion has been steadily increasing in countries where it has been available for routine use….Similarly, in the management of incomplete miscarriage or delayed miscarriage, expectant or medical treatment should be considered.”
7. Chung et al, 1995 (11):
“The accepted management of spontaneous abortion has not changed substantially in 60-70 years.”
“The policy of routine, universal evacuation of retained products of conception (ERPC) became the accepted form of management around the 1930s to combat [these*] complications. However, this approach may no longer be appropriate in all cases.”
*hemorrhage, infection.
“…in the United Kingdom, 90% of spontaneous abortions are managed [by ERPC] (12). Confidence in routine ERPC as the unquestioned ‘gold standard’ may no longer be justified. There may be alternative approaches that are less invasive but equally effective without incurring greater morbidity.”
“Transvaginal sonography can identify approximately one in three women with a spontaneous abortion who do not have a significant amount of retained tissue in the uterus.”
“Surgical intervention in {women who do not have a significant amount of retained tissue in the uterus} may unnecessarily incur iatrogenic complications without therapeutic gain.”
8. Demetroulis et al, 2001 (13):
“Surgical curettage under anaesthesia accounts for almost three-quarters of emergency gynaecological operations performed in the UK (14). However, dilatation and suction evacuation of the uterus under anaesthesia has certain morbidity, such as the risk of anaesthesia, uterine perforation, intrauterine adhesions, cervical trauma, and infections leading to infertility, pelvic pain and increased chance of ectopic pregnancy.”
9. Moodliar et al, 2005 (15):
“Moreover, surgical evacuation of retained products of conception (ERPC) is performed in the operating room, which significantly increases costs. Inherent in the procedure are the possible complications of perforation, hemorrhage, cervical trauma, intrauterine adhesions and postinstrumentation endometritis.”
“As an alternative, medical management has been found to be cost-effective and associated with fewer complications…Yet in South Africa*, incomplete abortion is still being managed by surgical evacuation.”
*in Australia and in many other countries too!
10. Muffley et al, 2002 (16):
“Curettage has been traditionally used as the surgical method of treatment. It has been estimated that approximately 100,000 uterine curettages are performed annually in the United States, at a total yearly cost of >100 million (17). Uterine curettage is associated with …hemorrhage and infection. Uterine adhesions, impaired future fertility, cervical trauma, uterine perforation, and anesthesia errors are also other potential sequelae of curettage.”
“In the late 1980s single-dose methotrexate therapy was introduced for the treatment of unruptured ampullary ectopic gestations (18). Nearly 10 years later, this medical therapy has replaced laparotomy or laparoscopy in many circumstances (19). At this time, however, medical treatment of early pregnancy failure is still in its infancy in the United States. On completion of multicenter randomized clinical trials, we believe that medical treatment will replace surgical therapy as the initial treatment of early pregnancy failure.”
(I hope so!)
Comment by Dr Lisa Fall:
“Firstly, as the trend toward later childrearing continues, we are faced with an increased incidence of pregnancy failure because of advancing gestational [ sic maternal] age. Our patients are interested in noninvasive options for treatment to avoid possible complications that may have an impact on future fertility.”
(Yup, that was me, but I was refused)
11. Zhang et al, 2005 (20):
“For most of the 20th century, dilatation and curettage was the commonly accepted approach to early pregnancy failure. This practice can be traced back to the late 19th and early 20th centuries, when illegally induced abortions commonly resulted in hemorrhage and sepsis (21). With the legalization of abortion and the availability of antibiotics, these problems have become rare. In more recent years, the medical community began to question whether immediate evacuation by surgical intervention was necessary for uncomplicated cases of early pregnancy failure (12,17).”
12. Stockheim et al, 2006 (22):
“Over the past decade, elective medical termination of pregnancy using a protocol that includes mifepristone and misoprostol was accepted into wide practice. This drug regimen was consistently shown to be associated with high success rates of 90-95% (23-26). However, medical treatment of pregnancy failure (blighted ovum or spontaneous abortion) has not yet gained wide acceptance.”
“Misoprostol is an effective and safe treatment for early pregnancy failure and could replace surgical curettage in over two-thirds of the patients.”
13. Creinin et al, 2006 (27):
“As clinicians and researchers, we must ask why women with an undesired normal pregnancy can receive a treatment regimen that is more effective than that tested for women with a desired abnormal pregnancy. The information presented in this analysis will allow us to better tailor misoprostol treatment for early pregnancy failure.”
I would also add, why women with an undesired normal pregnancy only have access to the mifepristone/misoprostol regimen which preserves fertility while those who miscarry do not.
14. Pang et al, 2001 (28):
“Misoprostol is justified as a first line treatment in the management of miscarriage in all cases because firstly it will avoid surgical intervention altogether in a proportion and secondly, in those who need it, misoprostol reduces surgery-related morbidity, mainly by priming the cervix (29.)”
15. Blanchard et al, 2004 (30):
“A growing body of research evidence indicates that medical treatment of incomplete abortion with misoprostol is an effective alternative to surgical intervention. Misoprostol could be an important alternative to dilatation and curettage or manual vacuum aspiration for treatment of incomplete abortion, allowing women to avoid surgical intervention and the attendant risks. Misoprostol is inexpensive and widely available and may also be more acceptable to women than the current standard of care.”
16. Shaw D, The International Federation of Gynecology and Obstetrics (FIGO) President (31):
“Furthermore, women have the right to benefit from advances in scientific knowledge and since women brought unapproved, reproductive health use of misoprostol to the attention of health professionals, it is especially fitting that they now benefit from the research into such use.”
17. The American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, 2009 (32):
“In addition, there is increasing evidence that misoprostol is a safe, effective,and acceptable method to achieve uterine evacuation for women needing postabortion* care.”
“Misoprostol may be used to treat women with an incomplete and missed abortion.”
* Postabortion care: “… refers to a specific set of services for women experiencing problems from all types of spontaneous or induced abortions.”
REFERENCES
1. Toaff R, Ballas S (1978). Traumatic hypomenorrhea-amenorrhea (Asherman's syndrome). Fertil. Steril. 30 (4): 379–87.
2. Li YT, Yin CS, Chen FM. Rectal administration of misoprostol for the management of retained placenta- a preliminary report. Chinese Medical Journal (Taipei) 2001;64:721-4.
3. Friedler S, Margalioth EJ, Kafka I, Yaffe H. (1993). Incidence of postabortion intra-uterine adhesions evaluated by hysteroscopy: a prospective study. Hum Reprod 8 (3): 442–444.
4. K Chapman and R Chapman. Asherman's syndrome: a review of the literature, and a husband and wife's 20-year world-wide experience. J R Soc Med. 1990 September; 83(9): 576–580.
5. Tam WH, Lau WC, Cheung LP, Yuen PM, Chung TK. (2002). Intrauterine adhesions after conservative and surgical management of spontaneous abortion. J Am Assoc Gynecol Laparosc. 9 (2): 182–185.
6. Goldenberg, M., Schiff, E.' Achiron, R.' Lipitz, S.' Mashiach, S. Managing residual trophoblastic tissue. Hysteroscopy for directing curettage. J Reprod Med. 1997;42(1)26-8.
7. Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome-one century later. Fertil Steril 2008;89(4):759-779.
8. Wolman I, Gordon D, Yaron Y, Kupferminc M, Lessing JB, Jaffa AJ. Transvaginal sonohysterography for the evaluation and treatment of retained products of conception. Gynecol Obstet Invest 2000;50:73-6.
9. Alcazar JL. Transvaginal ultrasonography combined with color velocity imaging an dpulsed Doppler to detect residual trophoblastic tissue. Ultrasound Obstet Gynecol 1998; 11:54-8.
10. Achiron R, Goldenberg M, Lipitz S, Mashiach S. Transvaginal duplex Doppler ultrasonography in bleeding patients suspected of having residual trophoblastic tissue. Obstet Gynecol1993;81:507-11.
11. Chung, TK, Cheung, LP, Leung, TY, Haines, CJ, and Chang, AM. Misoprostol in
the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102(10):832-
5.
12. Macrow, P and Elstein, M. Managing miscarriage medically. BMJ 1993;306(6882):876.
13. Demetroulis, C, Saridogan, E, Kunde, D, and Naftalin, AA. A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure. Hum Reprod 2001;16(2):365-9.
14. McKee M, Priest P, Ginzlet M et al. Can out-of-hours operating in gynecology be reduced? Arch Emerg Med 1992;9:290-8.
15. Moodliar S, Bagratee JS, Moodley J. Medical vs surgical evacuation of first-trimester spontaneous abortion. Int J Gynecol Obstet 2005;91:21-6.
16. Muffley, PE, Stitely, ML, and Gherman, RB. Early intrauterine pregnancy failure: a randomized trial of medical versus surgical treatment. Am J Obstet Gynecol 2002;187(2):321-5; discussion 325-6.
17. Ballagh SA, Harris HA, Demasio K.Is curettage needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279-82.
18. Stovall, TG, Ling, FW, and Buster, JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51(3):435-8.
19. Lipscomb, GH, Bran, D, McCord, ML, Portera, JC, and Ling, FW. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998;178(6):1354-8.
20. Zhang, J, Gilles, JM, Barnhart, K, Creinin, MD, Westhoff, C, and Frederick, MM. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353(8):761-9.
21. Hertig AT, Livingstone RG. Spontaneous, threatened and habitual abortion: their pathogenesis and treatment. N Engl J Med 1944;230:797-806.
22. Stockheim D, Machtinger R, Wiser A, Dulitzky M, Soriano D, Goldenberg M, Schiff E, Seidman D. A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril 86(4):956-60.
23. World Health Organization Task Force on post-ovulatory methods of fertility regulation. Comparison of two doses of two doses of mifepristone in combination with misoprostol for early medical abortion: a randomized trial. BJOG 2000;107:524-30.
24. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537-40.
25. Peyron R, Auberny E, Targosz V, Silvestre L, Renault M, Elkik F et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993;328:1509-13.
26. Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misprostol in the United States. N Engl J Med 1998;338:1241-7.
27. Creinin MD, Huang X, Westhoff C, Barnhart K, Gilles JM, Zhang JZ. Factors related to successful misoprostol treatment for early pregnancy failure. Obstet Gynecol 2006; 107(4):901-907.
28. Pang MW, Lee TS, Chung TKH. Incomplete miscarriage: a randomized controlled trial comparing oral with vaginal misoprostol for medical evacuation. Hum Rep 2001;16(11):2283-7.
29. Chung TKH, Cheung LP, Sahota DS et al. Spontaneous abortion: short term complications following either conservative or surgical management. Aust NZ J Obstet Gynaecol 2001; 38:61-4.
30. Blanchard K, Taneepanichskul S, Kiriwat O, Sirimai K, Svirirojana N, Mavimbela N, Winikoff B. Two regimens of misoprostol for treatment of incomplete abortion. Obstetrics & Gynecology 2004;103(5 Pt1): 860-5.
31. Shaw, D. Misoprostol for reproductive health: Dosage recommendations. International Journal of Gynecology and Obstetrics 2007; 99:S155.
32. ACOG Committee on International Affairs. Committee Opinion: Misoprostol for postabortion care. Obstetrics & Gynecology 2009; 113(2) Part I:465-8.
(my additions are in blue)
1. Toaf and Ballas, 1978 (1):
"Peurperal curettage…was discontinued in Israel after publication of Asherman’s observations.”
This is not so in the US, UK, Australia and many other countries. Also, curettage remains standard care for treating miscarriage in many countries (while abortion is now usually carried out medically).
2. Li et al, 2001 (2):
After vaginal delivery, a retained placenta may cause a risk to maternal health because of hemorrhage or infection. …manual removal of the retained placenta is a routine procedure. ..This invasive procedure increases risk of trauma*, rupture of uterus, hemorrhage, postpartum infection, and anesthetic complications.”
* Asherman’s syndrome may result
“In all 18 parturients, spontaneous expulsion of the placenta developed in an average interval of 12 min (range from 5 to 35 min) after rectal insertion of misoprostol.”
3. Friedler et al, 1993 (3):
“The incidence of IUA might be lower following medical evacuation of the uterus, thus avoiding any intra-uterine instrumentation; however, use of progesterone antagonists (ie, mifepristone) for this purpose is not yet approved by the Israeli Ministry of Health.”
4. Chapman and Chapman, 1990 (4):
“One must also note that the suction curette is capable of causing synechiae, usually, however in the region of the internal os.”
“It is noteworthy that, of the 11 patients with isthmus stenosis, six of them were attributable to termination of pregnancy, of which all but one had been performed by suction curettage”
“It goes without saying that, in view of the seriousness of the sequelae, the best management is prevention…”
3. Tam et al, 2002 (5):
“No cases of IUA were found in patients managed conservatively or by medical evacuation, whereas 2 cases (7.7%) of filmy IUA were detected in those managed by surgical evacuation.”
“We therefore recommend expectant management and medical evacuation as first-line treatment for complete abortion* and incomplete abortion*, respectively. Surgical evacuation should be the treatment of choice when {these methods} fails or is contraindicated.”
*ie miscarriage
6. Goldenberg et al, 1997 (6):
“Selective curettage of residual trophoblastic tissue directed by hysteroscopy is an easy and short procedure and might be preferable to conventional, nonselective, blind curettage.”
“…areas not covered by residual tissue…are not subject to surgical trauma during the selective procedure and presumably are therefore exposed to lower risks of inflammation, scarring and adhesion formation”
“Incomplete removal of the residua is more likely to occur during repeated conventional curettage, even if guided by ultrasonography, as had occurred in two of our patients. Direct visualization of the cavity allows…the exact location and extent of the residual tissue to be resected.”
7. Yu et al, 2008 (7):
“Prevention of Asherman Syndrome
Prevention is always better than cure. To prevent the formation of endometrial fibrosis and adhesions, it is essential that any trauma to the uterus be avoided, especially in the pregnant or postpartum state.”
They go on to recommend:
“Avoid postpartum or postabortion curettage”
“Diagnosis of retained products of conception …present a clinical challenge.
…Saline infusion sonohysterography (SHG) has enhanced our ability to diagnose retained products of conception (8)”
“…transvaginal B-mode ultrasonography combined with color velocity imaging and pulsed Doppler to detect retained trophoblastic tissue…could be useful to…select patients suitable for conservative management.(9)”
“Transvaginal duplex Doppler ultrasonography is also an effective noninvasive method for evaluating patients with persistent postpartum hermorrhage (10).”
"…hysteroscopy should be considered an effective method for diagnosis and treatment of retained products of conception." They cite the Goldenberg et al (6) study (see above).
…
“Select medical management of miscarriages
When termination of early pregnancy is necessary, medical treatment should be considered instead of surgical options.”
They cite the Tam et al study (5)(see above).
“Since its introduction, the uptake of medical abortion has been steadily increasing in countries where it has been available for routine use….Similarly, in the management of incomplete miscarriage or delayed miscarriage, expectant or medical treatment should be considered.”
7. Chung et al, 1995 (11):
“The accepted management of spontaneous abortion has not changed substantially in 60-70 years.”
“The policy of routine, universal evacuation of retained products of conception (ERPC) became the accepted form of management around the 1930s to combat [these*] complications. However, this approach may no longer be appropriate in all cases.”
*hemorrhage, infection.
“…in the United Kingdom, 90% of spontaneous abortions are managed [by ERPC] (12). Confidence in routine ERPC as the unquestioned ‘gold standard’ may no longer be justified. There may be alternative approaches that are less invasive but equally effective without incurring greater morbidity.”
“Transvaginal sonography can identify approximately one in three women with a spontaneous abortion who do not have a significant amount of retained tissue in the uterus.”
“Surgical intervention in {women who do not have a significant amount of retained tissue in the uterus} may unnecessarily incur iatrogenic complications without therapeutic gain.”
8. Demetroulis et al, 2001 (13):
“Surgical curettage under anaesthesia accounts for almost three-quarters of emergency gynaecological operations performed in the UK (14). However, dilatation and suction evacuation of the uterus under anaesthesia has certain morbidity, such as the risk of anaesthesia, uterine perforation, intrauterine adhesions, cervical trauma, and infections leading to infertility, pelvic pain and increased chance of ectopic pregnancy.”
9. Moodliar et al, 2005 (15):
“Moreover, surgical evacuation of retained products of conception (ERPC) is performed in the operating room, which significantly increases costs. Inherent in the procedure are the possible complications of perforation, hemorrhage, cervical trauma, intrauterine adhesions and postinstrumentation endometritis.”
“As an alternative, medical management has been found to be cost-effective and associated with fewer complications…Yet in South Africa*, incomplete abortion is still being managed by surgical evacuation.”
*in Australia and in many other countries too!
10. Muffley et al, 2002 (16):
“Curettage has been traditionally used as the surgical method of treatment. It has been estimated that approximately 100,000 uterine curettages are performed annually in the United States, at a total yearly cost of >100 million (17). Uterine curettage is associated with …hemorrhage and infection. Uterine adhesions, impaired future fertility, cervical trauma, uterine perforation, and anesthesia errors are also other potential sequelae of curettage.”
“In the late 1980s single-dose methotrexate therapy was introduced for the treatment of unruptured ampullary ectopic gestations (18). Nearly 10 years later, this medical therapy has replaced laparotomy or laparoscopy in many circumstances (19). At this time, however, medical treatment of early pregnancy failure is still in its infancy in the United States. On completion of multicenter randomized clinical trials, we believe that medical treatment will replace surgical therapy as the initial treatment of early pregnancy failure.”
(I hope so!)
Comment by Dr Lisa Fall:
“Firstly, as the trend toward later childrearing continues, we are faced with an increased incidence of pregnancy failure because of advancing gestational [ sic maternal] age. Our patients are interested in noninvasive options for treatment to avoid possible complications that may have an impact on future fertility.”
(Yup, that was me, but I was refused)
11. Zhang et al, 2005 (20):
“For most of the 20th century, dilatation and curettage was the commonly accepted approach to early pregnancy failure. This practice can be traced back to the late 19th and early 20th centuries, when illegally induced abortions commonly resulted in hemorrhage and sepsis (21). With the legalization of abortion and the availability of antibiotics, these problems have become rare. In more recent years, the medical community began to question whether immediate evacuation by surgical intervention was necessary for uncomplicated cases of early pregnancy failure (12,17).”
12. Stockheim et al, 2006 (22):
“Over the past decade, elective medical termination of pregnancy using a protocol that includes mifepristone and misoprostol was accepted into wide practice. This drug regimen was consistently shown to be associated with high success rates of 90-95% (23-26). However, medical treatment of pregnancy failure (blighted ovum or spontaneous abortion) has not yet gained wide acceptance.”
“Misoprostol is an effective and safe treatment for early pregnancy failure and could replace surgical curettage in over two-thirds of the patients.”
13. Creinin et al, 2006 (27):
“As clinicians and researchers, we must ask why women with an undesired normal pregnancy can receive a treatment regimen that is more effective than that tested for women with a desired abnormal pregnancy. The information presented in this analysis will allow us to better tailor misoprostol treatment for early pregnancy failure.”
I would also add, why women with an undesired normal pregnancy only have access to the mifepristone/misoprostol regimen which preserves fertility while those who miscarry do not.
14. Pang et al, 2001 (28):
“Misoprostol is justified as a first line treatment in the management of miscarriage in all cases because firstly it will avoid surgical intervention altogether in a proportion and secondly, in those who need it, misoprostol reduces surgery-related morbidity, mainly by priming the cervix (29.)”
15. Blanchard et al, 2004 (30):
“A growing body of research evidence indicates that medical treatment of incomplete abortion with misoprostol is an effective alternative to surgical intervention. Misoprostol could be an important alternative to dilatation and curettage or manual vacuum aspiration for treatment of incomplete abortion, allowing women to avoid surgical intervention and the attendant risks. Misoprostol is inexpensive and widely available and may also be more acceptable to women than the current standard of care.”
16. Shaw D, The International Federation of Gynecology and Obstetrics (FIGO) President (31):
“Furthermore, women have the right to benefit from advances in scientific knowledge and since women brought unapproved, reproductive health use of misoprostol to the attention of health professionals, it is especially fitting that they now benefit from the research into such use.”
17. The American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, 2009 (32):
“In addition, there is increasing evidence that misoprostol is a safe, effective,and acceptable method to achieve uterine evacuation for women needing postabortion* care.”
“Misoprostol may be used to treat women with an incomplete and missed abortion.”
* Postabortion care: “… refers to a specific set of services for women experiencing problems from all types of spontaneous or induced abortions.”
REFERENCES
1. Toaff R, Ballas S (1978). Traumatic hypomenorrhea-amenorrhea (Asherman's syndrome). Fertil. Steril. 30 (4): 379–87.
2. Li YT, Yin CS, Chen FM. Rectal administration of misoprostol for the management of retained placenta- a preliminary report. Chinese Medical Journal (Taipei) 2001;64:721-4.
3. Friedler S, Margalioth EJ, Kafka I, Yaffe H. (1993). Incidence of postabortion intra-uterine adhesions evaluated by hysteroscopy: a prospective study. Hum Reprod 8 (3): 442–444.
4. K Chapman and R Chapman. Asherman's syndrome: a review of the literature, and a husband and wife's 20-year world-wide experience. J R Soc Med. 1990 September; 83(9): 576–580.
5. Tam WH, Lau WC, Cheung LP, Yuen PM, Chung TK. (2002). Intrauterine adhesions after conservative and surgical management of spontaneous abortion. J Am Assoc Gynecol Laparosc. 9 (2): 182–185.
6. Goldenberg, M., Schiff, E.' Achiron, R.' Lipitz, S.' Mashiach, S. Managing residual trophoblastic tissue. Hysteroscopy for directing curettage. J Reprod Med. 1997;42(1)26-8.
7. Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome-one century later. Fertil Steril 2008;89(4):759-779.
8. Wolman I, Gordon D, Yaron Y, Kupferminc M, Lessing JB, Jaffa AJ. Transvaginal sonohysterography for the evaluation and treatment of retained products of conception. Gynecol Obstet Invest 2000;50:73-6.
9. Alcazar JL. Transvaginal ultrasonography combined with color velocity imaging an dpulsed Doppler to detect residual trophoblastic tissue. Ultrasound Obstet Gynecol 1998; 11:54-8.
10. Achiron R, Goldenberg M, Lipitz S, Mashiach S. Transvaginal duplex Doppler ultrasonography in bleeding patients suspected of having residual trophoblastic tissue. Obstet Gynecol1993;81:507-11.
11. Chung, TK, Cheung, LP, Leung, TY, Haines, CJ, and Chang, AM. Misoprostol in
the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102(10):832-
5.
12. Macrow, P and Elstein, M. Managing miscarriage medically. BMJ 1993;306(6882):876.
13. Demetroulis, C, Saridogan, E, Kunde, D, and Naftalin, AA. A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure. Hum Reprod 2001;16(2):365-9.
14. McKee M, Priest P, Ginzlet M et al. Can out-of-hours operating in gynecology be reduced? Arch Emerg Med 1992;9:290-8.
15. Moodliar S, Bagratee JS, Moodley J. Medical vs surgical evacuation of first-trimester spontaneous abortion. Int J Gynecol Obstet 2005;91:21-6.
16. Muffley, PE, Stitely, ML, and Gherman, RB. Early intrauterine pregnancy failure: a randomized trial of medical versus surgical treatment. Am J Obstet Gynecol 2002;187(2):321-5; discussion 325-6.
17. Ballagh SA, Harris HA, Demasio K.Is curettage needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279-82.
18. Stovall, TG, Ling, FW, and Buster, JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51(3):435-8.
19. Lipscomb, GH, Bran, D, McCord, ML, Portera, JC, and Ling, FW. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998;178(6):1354-8.
20. Zhang, J, Gilles, JM, Barnhart, K, Creinin, MD, Westhoff, C, and Frederick, MM. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353(8):761-9.
21. Hertig AT, Livingstone RG. Spontaneous, threatened and habitual abortion: their pathogenesis and treatment. N Engl J Med 1944;230:797-806.
22. Stockheim D, Machtinger R, Wiser A, Dulitzky M, Soriano D, Goldenberg M, Schiff E, Seidman D. A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril 86(4):956-60.
23. World Health Organization Task Force on post-ovulatory methods of fertility regulation. Comparison of two doses of two doses of mifepristone in combination with misoprostol for early medical abortion: a randomized trial. BJOG 2000;107:524-30.
24. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537-40.
25. Peyron R, Auberny E, Targosz V, Silvestre L, Renault M, Elkik F et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993;328:1509-13.
26. Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misprostol in the United States. N Engl J Med 1998;338:1241-7.
27. Creinin MD, Huang X, Westhoff C, Barnhart K, Gilles JM, Zhang JZ. Factors related to successful misoprostol treatment for early pregnancy failure. Obstet Gynecol 2006; 107(4):901-907.
28. Pang MW, Lee TS, Chung TKH. Incomplete miscarriage: a randomized controlled trial comparing oral with vaginal misoprostol for medical evacuation. Hum Rep 2001;16(11):2283-7.
29. Chung TKH, Cheung LP, Sahota DS et al. Spontaneous abortion: short term complications following either conservative or surgical management. Aust NZ J Obstet Gynaecol 2001; 38:61-4.
30. Blanchard K, Taneepanichskul S, Kiriwat O, Sirimai K, Svirirojana N, Mavimbela N, Winikoff B. Two regimens of misoprostol for treatment of incomplete abortion. Obstetrics & Gynecology 2004;103(5 Pt1): 860-5.
31. Shaw, D. Misoprostol for reproductive health: Dosage recommendations. International Journal of Gynecology and Obstetrics 2007; 99:S155.
32. ACOG Committee on International Affairs. Committee Opinion: Misoprostol for postabortion care. Obstetrics & Gynecology 2009; 113(2) Part I:465-8.
Wednesday, April 21, 2010
The DO’s and DON’T's (and maybe’s) of Managing Intrauterine Adhesions.
Based on: AAGL: Practice Report: Practice Guidelines for Management of Intrauterine Synechiae, The Journal of Minimally Invasive Gynecology Vol. 17, No.1 2010.
Practice committee members:
Malcolm Munro MD, FRCS(C), FACOG
Rafaele F.Valle,MD
Jason A. Abbott, PhD,FRANZCOG,MRCOG
Angus J.M. Thompson, MRCOG
Keith B. Isaacson, MD
Adolf Gallinat, MD
Volker R. Jacobs, MD, PhD, MBA
Fred M. Howard MD
Andrew I. Sokol, MD
Linda D. Bradley, MD
Recently, the Practice Committee of the AAGL developed guidelines for the management of intrauterine adhesions (IUA), published in the Journal of Minimally Invasive Gynecology (2010). This is a welcome initiative, and long-awaited, with over one century passing since the first description of Asherman’s syndrome in the literature (1). Although these guidelines were based on studies published in peer-reviewed medical journals, there are limitations and room for more specific guidelines, as the authors themselves acknowledge, due to a lack of comparative studies and rigorous medical evidence from randomized controlled trials (RCTs). For example, studies were conducted using different surgical modalities, surgical tools, adjunctive therapies, and hormone therapy protocols. Many studies are also old and/or conducted retrospectively. One of the difficulties of studying IUA is that it is under diagnosed so that many women may not realize they have it. This results in a small sample size for studies, especially when patient treatment is spread between different centers. Additionally, the skills of the surgeon are important in influencing outcome which makes comparisons between different studies difficult. Consequently, drawing meaningful conclusions on treatment is problematic. To circumvent these shortcomings, the authors classified data based on the highest level of evidence found in the data and graded them according to a system outlined by the US Preventive Services Task Force. In most cases the evidence is based primarily on consensus and expert opinion (Level C). Hopefully trials will be forthcoming which meet today’s strict standards of clinical research, and recommendations which are stronger and more specific will result from them.
The goal of IUA management is to restore the volume and architecture of the uterine cavity and its communication with the fallopian tubes and cervical canal by removing IUA, preventing their recurrence and regenerating deficient endometrial growth.
Below is a summary of the recommendations of the article. My additional comments are in blue font.DIAGNOSISHysteroscopy is the most accurate method for diagnosis of IUA and should be chosen over HSG and SHG (although the latter are reasonable alternatives if hysteroscopy is not available).
(Grade B)
CLASSIFICATION
Although there are several classification systems, none is considered superior over the other, probably reflecting inadequacies in all current systems. (Grade C)
An accurate and universal classification system for IUA is important for enabling the comparison of studies and providing prognostic indicators of fertility outcome. (Grade B)
TREATMENT
DO's:
Only expert hysteroscopists familiar with IUA treatment should attempt to treat extensive or dense adhesions. (Level C)(Surgeons who are inexperienced may inadvertantly cause further irreparable damage).
Direct visualization of the uterus during hysteroscopic lysis of adhesions using a tool for dissection is the treatment of choice for IUA which underlies infertility, recurrent pregnancy loss, pain or other related symptoms. (Level C).
In some women expectant management may be acceptable. (Level C)
(ie. if adhesions are thin and filmy and/or cover a small surface area treatment benefits may not outweigh treatment risks).
Estrogen therapy with or without progestin may reduce reformation of IUAs. (Level B)(Estrogen therapy dose and length will depend on severity. See also Recommendations for Future Research).
MAYBE's:
Gel barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel may reduce IUA recurrence follow surgical correction, however there is not enough data on pregnancy outcomes following their use, so should not be used without more rigorous trials. (Level A)
(Potential problems with gel barriers are that they are difficult to keep in place, become less viscous at body temperature, draining out of the uterus. See also Recommendations for Future Research).
Foley catheter or IUD should not be used routinely after corrective surgery without further data from trials supporting their benefit. This is because they may increase the risk for infection. (Level C)
(There have been reports of IUDs puncturing the uterus. Also, some doctors also believe that intrauterine pressure from balloons can hinder endometrial regeneration. However, both the Foley catheter and the Cook stent-which curiously was not mentioned in the article-have been used successfully (2)).
Supporting or refuting the use of prophylactic antibiotics before, during or after surgical adhesiolysis. (Level C)
(However, antibiotic prophylaxis should be used in the case of barriers, as a foreign object inside the uterus increases the risk of infection. See also Recommendations for Future Research).
Medications to improve blood flow to the endometrium should be used only after being supported by rigorous research. (Level C)(These include low-dose aspirin, Coenzyme Q-10, vitamin E, and Sildenafil citrate.ie. Viagra, and even herbal remedies such as raspberry leaf tea).
Prevention of complications (eg. perforation) or improved outcomes with the use of external imaging techniques or laparoscopy, however these techniques may have advantages in case perforation does occur. (Level B)(Another advantage is that laparoscopy allows the surgeon to view the pelvic cavity where there may be endometriosis (3), especially in the more severe cases where laparoscopy is often used).
DON’T's:
There is no evidence to support blind D&C or blind cervical probing in the treatment of IUA (Level C)(The authors state that D&C should not be used because it does not permit accurate diagnosis and classification. The bigger concern should be that blind curettage may cause further and irreversible damage and is the underlying cause of most IUA (4)).
Copper (inflammatory), progestin-releasing (suppress endometrium) and T-shaped IUDs (small surface area) should not be used after adhesiolysis. (Level C)
Laparotomy should be considered as a last resort (eg. when hysteroscopic surgery fails) (Level C)
Electrosurgery/laser: There is some disagreement over which tools are best suited for adhesiolysis. Some surgeons prefer to use microscissors and stress that thermal energy tools offer no advantage over scissor dissection with regards to either speed or hemostasis (2). Furthermore, these modalities (including resectoscope, Nd:YAG laser, monopolar/bipolar electrode) deliver energy that can cause injury to surrounding tissues and therefore some believe it is prudent to avoid them for the treatment of IUA (2). Indeed, electrosurgical tools are normally used for endometrial ablation which burns away endometrium and intentionally induces Asherman’s syndrome in women with excessive bleeding. However, other doctors claim that in experienced hands these tools are safe. Which ever the case, this is an issue which probably needs to be further examined to refute any safety concerns.POSTOPERATIVE ASSESSMENT:Follow-up evaluation of the uterine cavity is recommended after treatment of IUA. (Level B).(This is an important factor in determining outcome as adhesions may reform and further surgery may be needed. If a pregnancy occurs in a uterus with IUA, there is a higher likelihood of infertility, miscarriage and pregnancy complications (5). Patients should undergo either HSG, SHG, or in-office hysteroscopy (with as narrow cervical dilation as possible) in order to verify the uterine cavity is free of adhesions. A mid-cycle scan should also be used to measure the endometrial thickness at ovulation. Ideally this should measure 7-8 mm for implantation to be successful. Some women with corrected IUA have thin endometrium which may require hormone treatment to thicken. If adhesions blocking the ostium are present, natural conception is not possible and IVF will be recommended).
RECOMMENDATIONS FOR FUTURE RESEARCH:
1. Prospective trials on the effect of intraoperative and postoperative antibiotic prophylaxis on surgical and fertility outcome.(I don’t know of doctors who do not use antibiotics during or after operative hysteroscopy. Also, the article states: “…it has been proposed that infection may be a primary cause of IUAs…” Antibiotic prophylaxis is wise for preventing infections whether or not they lead to IUA. However, at this stage, there is actually no evidence to support that most IUAs result from infection, whether frank or subclinical. In fact, there is limited evidence to the contrary (6,7). Also see The subclinical infection myth).2. Prospective trials of adjunctive hormone therapy efficacy with respect to surgical and fertility outcome.(The optimum dosage of estrogen (E2 with or without progestin, P4) and length of treatment have not been studied. Progynova (Estradiol valerate) a synthetic version of a naturally occurring estrogen or Premarin, a combination of around 11 conjugated equine estrogens extracted from pregnant mare urine, are usually used. These compounds have not been compared to each other in trials).
3. Prospective trials of barrier method (IUD, Foley catheter and gel adhesion barriers) efficacy with respect to surgical and fertility outcome.
(Presumably the Cook stent, which is used by some doctors (2), should also be included in trials. Regarding the use of gel adhesion barriers which are potentially the least invasive and risky type of barrier, one questions why there is not more research on their use to prevent IUA from occurring in the first place. If gel barriers are therapeutic for reducing IUA reformation after hysteroscopic adhesiolysis perhaps their use after D&C and other primary intrauterine surgery would reduce the incidence of IUA. There is so far only one study and results show only 10% of women who received Seprafilm after curettage for miscarriage developed IUA vs 50% amongst controls (8)).
4. Stem cells for future treatment: As discussed in a previous blog, some cases are currently not treatable because the extent of damage to the basal endometrium (sometimes curettage even removes part of the underlying myometrium) from which the functional layer regenerates. This leads to persistently thin endometrium or reformation of IUA after corrective surgery and excludes the possibility of carrying a pregnancy. Surrogacy is the only option in such cases. However Dr Chaitanya Nagori and Dr Sonal Panchal of Nagori Institute of Infertility in India claim to have used stem cell technology to thicken the endometrium in women who underwent excessive ‘cleaning’ up of the uterus (ie. a euphemism for D&C), although they do not mention the presence of IUA. The process involved isolating adult stem cells from the bone marrow of the patient, transplanting the purified stem cells into the patient’s uterine cavity under transvaginal sonographic guidance, and stimulating the production of endometrial angiogenic stem cells by administering estrogen before IVF treatment. Using this technique they reportedly were able to increase ‘negligible’ endometrial growth to 6mm three months after the transfer and estrogen therapy. Although they assert that IVF drugs alone did not increase the patient’s endometrial measurement, it remains to be proven whether this effect is due to the post-transplant estrogen treatment or from the stem cell therapy. Nonetheless, the concept of using stem cells for tissue repair in the uterus is intriguing, and possibly the best hope in future for very severe cases of IUA (uterine transplant is another future possibility). This could be more convincing if recurrent IUA was prevented with stem cells following hysteroscopic adhesiolysis. Definitive proof would be obtained if the stem cells and their progeny were biochemically labeled so as to be identifiable from the original tissue. This could be done in animal studies, for example. The great advantage of stem cells is that they have the capacity to differentiate into a range of cells that are necessary to rebuild a normal uterus, from myometrium and endometrium to the blood vessels which supply them with blood and hormones. Furthermore, as the stem cells are derived from the patient’s own bone marrow ie. autologous adult stem cells, there is no risk of either rejection or ethical controversy (as with embryonic stem cells). Unfortunately at this stage there are no published studies on this treatment.
REFERENCES
1. Fritsch H, Ein Fall von volligem Schwaund der Gebormutterhohle nach Auskratzung. Zentralbl Gynaekol 1894; 18:1337-1342.
2. March, CM; Miller, CE. Hysteroscopic lysis of intrauterine adhesions. Ob.Gyn. News 2006; 41(23):36-37. Abstract
3. Palter. SF, High Rates of Endometriosis in Patients With Intrauterine Synechiae (Asherman's Syndrome). Fertility and Sterility 2005; 86 (null):S471-S471. Link
4. Palter S, Spyrou P. Asherman’s syndrome: Etiologic factors, patterns of pregnancy loss, and treatment results. Results from an international registry. Fertility and Sterility 2003; 80(3):36-7. Link
5. March CM. Intrauterine adhesions. Obstet Gynecol Clin N Am 1995;22(3):491-505. Abstract
6. Jensen, P.A. and Stromme, W.B. Amenorrhea secondary to puerperal curettage (Asherman's syndrome). Am J Obstet Gynecol 1972; 113: 150–4.
7. Polishuk, SO Anteby and D Weinstein, Puerperal endometritis and intrauterine adhesions, Int Surg 1975;60:418–420. Abstract
8. Tsapanos VS, Stathopoulou LP, Papathanassopoulou VS, Tzingounis VA. The role of Seprafilm bioresorbable membrane in the prevention and therapy of endometrial synechiae. Biomed Material Res. 2002;63:10-14. Abstract
Related Links:Good news: Grow endometrium by stem cells. (Times of India)
Recommendation Grading:
Level A: Recommendations are based on good and consistent scientific evidence.
Level B: Recommendations are based on limited or incomsistent scientific evidence.
Level C: Recommendations are based primarily on consensus and expert opinion.
Practice committee members:
Malcolm Munro MD, FRCS(C), FACOG
Rafaele F.Valle,MD
Jason A. Abbott, PhD,FRANZCOG,MRCOG
Angus J.M. Thompson, MRCOG
Keith B. Isaacson, MD
Adolf Gallinat, MD
Volker R. Jacobs, MD, PhD, MBA
Fred M. Howard MD
Andrew I. Sokol, MD
Linda D. Bradley, MD
Recently, the Practice Committee of the AAGL developed guidelines for the management of intrauterine adhesions (IUA), published in the Journal of Minimally Invasive Gynecology (2010). This is a welcome initiative, and long-awaited, with over one century passing since the first description of Asherman’s syndrome in the literature (1). Although these guidelines were based on studies published in peer-reviewed medical journals, there are limitations and room for more specific guidelines, as the authors themselves acknowledge, due to a lack of comparative studies and rigorous medical evidence from randomized controlled trials (RCTs). For example, studies were conducted using different surgical modalities, surgical tools, adjunctive therapies, and hormone therapy protocols. Many studies are also old and/or conducted retrospectively. One of the difficulties of studying IUA is that it is under diagnosed so that many women may not realize they have it. This results in a small sample size for studies, especially when patient treatment is spread between different centers. Additionally, the skills of the surgeon are important in influencing outcome which makes comparisons between different studies difficult. Consequently, drawing meaningful conclusions on treatment is problematic. To circumvent these shortcomings, the authors classified data based on the highest level of evidence found in the data and graded them according to a system outlined by the US Preventive Services Task Force. In most cases the evidence is based primarily on consensus and expert opinion (Level C). Hopefully trials will be forthcoming which meet today’s strict standards of clinical research, and recommendations which are stronger and more specific will result from them.
The goal of IUA management is to restore the volume and architecture of the uterine cavity and its communication with the fallopian tubes and cervical canal by removing IUA, preventing their recurrence and regenerating deficient endometrial growth.
Below is a summary of the recommendations of the article. My additional comments are in blue font.DIAGNOSISHysteroscopy is the most accurate method for diagnosis of IUA and should be chosen over HSG and SHG (although the latter are reasonable alternatives if hysteroscopy is not available).
(Grade B)
CLASSIFICATION
Although there are several classification systems, none is considered superior over the other, probably reflecting inadequacies in all current systems. (Grade C)
An accurate and universal classification system for IUA is important for enabling the comparison of studies and providing prognostic indicators of fertility outcome. (Grade B)
TREATMENT
DO's:
Only expert hysteroscopists familiar with IUA treatment should attempt to treat extensive or dense adhesions. (Level C)(Surgeons who are inexperienced may inadvertantly cause further irreparable damage).
Direct visualization of the uterus during hysteroscopic lysis of adhesions using a tool for dissection is the treatment of choice for IUA which underlies infertility, recurrent pregnancy loss, pain or other related symptoms. (Level C).
In some women expectant management may be acceptable. (Level C)
(ie. if adhesions are thin and filmy and/or cover a small surface area treatment benefits may not outweigh treatment risks).
Estrogen therapy with or without progestin may reduce reformation of IUAs. (Level B)(Estrogen therapy dose and length will depend on severity. See also Recommendations for Future Research).
MAYBE's:
Gel barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel may reduce IUA recurrence follow surgical correction, however there is not enough data on pregnancy outcomes following their use, so should not be used without more rigorous trials. (Level A)
(Potential problems with gel barriers are that they are difficult to keep in place, become less viscous at body temperature, draining out of the uterus. See also Recommendations for Future Research).
Foley catheter or IUD should not be used routinely after corrective surgery without further data from trials supporting their benefit. This is because they may increase the risk for infection. (Level C)
(There have been reports of IUDs puncturing the uterus. Also, some doctors also believe that intrauterine pressure from balloons can hinder endometrial regeneration. However, both the Foley catheter and the Cook stent-which curiously was not mentioned in the article-have been used successfully (2)).
Supporting or refuting the use of prophylactic antibiotics before, during or after surgical adhesiolysis. (Level C)
(However, antibiotic prophylaxis should be used in the case of barriers, as a foreign object inside the uterus increases the risk of infection. See also Recommendations for Future Research).
Medications to improve blood flow to the endometrium should be used only after being supported by rigorous research. (Level C)(These include low-dose aspirin, Coenzyme Q-10, vitamin E, and Sildenafil citrate.ie. Viagra, and even herbal remedies such as raspberry leaf tea).
Prevention of complications (eg. perforation) or improved outcomes with the use of external imaging techniques or laparoscopy, however these techniques may have advantages in case perforation does occur. (Level B)(Another advantage is that laparoscopy allows the surgeon to view the pelvic cavity where there may be endometriosis (3), especially in the more severe cases where laparoscopy is often used).
DON’T's:
There is no evidence to support blind D&C or blind cervical probing in the treatment of IUA (Level C)(The authors state that D&C should not be used because it does not permit accurate diagnosis and classification. The bigger concern should be that blind curettage may cause further and irreversible damage and is the underlying cause of most IUA (4)).
Copper (inflammatory), progestin-releasing (suppress endometrium) and T-shaped IUDs (small surface area) should not be used after adhesiolysis. (Level C)
Laparotomy should be considered as a last resort (eg. when hysteroscopic surgery fails) (Level C)
Electrosurgery/laser: There is some disagreement over which tools are best suited for adhesiolysis. Some surgeons prefer to use microscissors and stress that thermal energy tools offer no advantage over scissor dissection with regards to either speed or hemostasis (2). Furthermore, these modalities (including resectoscope, Nd:YAG laser, monopolar/bipolar electrode) deliver energy that can cause injury to surrounding tissues and therefore some believe it is prudent to avoid them for the treatment of IUA (2). Indeed, electrosurgical tools are normally used for endometrial ablation which burns away endometrium and intentionally induces Asherman’s syndrome in women with excessive bleeding. However, other doctors claim that in experienced hands these tools are safe. Which ever the case, this is an issue which probably needs to be further examined to refute any safety concerns.POSTOPERATIVE ASSESSMENT:Follow-up evaluation of the uterine cavity is recommended after treatment of IUA. (Level B).(This is an important factor in determining outcome as adhesions may reform and further surgery may be needed. If a pregnancy occurs in a uterus with IUA, there is a higher likelihood of infertility, miscarriage and pregnancy complications (5). Patients should undergo either HSG, SHG, or in-office hysteroscopy (with as narrow cervical dilation as possible) in order to verify the uterine cavity is free of adhesions. A mid-cycle scan should also be used to measure the endometrial thickness at ovulation. Ideally this should measure 7-8 mm for implantation to be successful. Some women with corrected IUA have thin endometrium which may require hormone treatment to thicken. If adhesions blocking the ostium are present, natural conception is not possible and IVF will be recommended).
RECOMMENDATIONS FOR FUTURE RESEARCH:
1. Prospective trials on the effect of intraoperative and postoperative antibiotic prophylaxis on surgical and fertility outcome.(I don’t know of doctors who do not use antibiotics during or after operative hysteroscopy. Also, the article states: “…it has been proposed that infection may be a primary cause of IUAs…” Antibiotic prophylaxis is wise for preventing infections whether or not they lead to IUA. However, at this stage, there is actually no evidence to support that most IUAs result from infection, whether frank or subclinical. In fact, there is limited evidence to the contrary (6,7). Also see The subclinical infection myth).2. Prospective trials of adjunctive hormone therapy efficacy with respect to surgical and fertility outcome.(The optimum dosage of estrogen (E2 with or without progestin, P4) and length of treatment have not been studied. Progynova (Estradiol valerate) a synthetic version of a naturally occurring estrogen or Premarin, a combination of around 11 conjugated equine estrogens extracted from pregnant mare urine, are usually used. These compounds have not been compared to each other in trials).
3. Prospective trials of barrier method (IUD, Foley catheter and gel adhesion barriers) efficacy with respect to surgical and fertility outcome.
(Presumably the Cook stent, which is used by some doctors (2), should also be included in trials. Regarding the use of gel adhesion barriers which are potentially the least invasive and risky type of barrier, one questions why there is not more research on their use to prevent IUA from occurring in the first place. If gel barriers are therapeutic for reducing IUA reformation after hysteroscopic adhesiolysis perhaps their use after D&C and other primary intrauterine surgery would reduce the incidence of IUA. There is so far only one study and results show only 10% of women who received Seprafilm after curettage for miscarriage developed IUA vs 50% amongst controls (8)).
4. Stem cells for future treatment: As discussed in a previous blog, some cases are currently not treatable because the extent of damage to the basal endometrium (sometimes curettage even removes part of the underlying myometrium) from which the functional layer regenerates. This leads to persistently thin endometrium or reformation of IUA after corrective surgery and excludes the possibility of carrying a pregnancy. Surrogacy is the only option in such cases. However Dr Chaitanya Nagori and Dr Sonal Panchal of Nagori Institute of Infertility in India claim to have used stem cell technology to thicken the endometrium in women who underwent excessive ‘cleaning’ up of the uterus (ie. a euphemism for D&C), although they do not mention the presence of IUA. The process involved isolating adult stem cells from the bone marrow of the patient, transplanting the purified stem cells into the patient’s uterine cavity under transvaginal sonographic guidance, and stimulating the production of endometrial angiogenic stem cells by administering estrogen before IVF treatment. Using this technique they reportedly were able to increase ‘negligible’ endometrial growth to 6mm three months after the transfer and estrogen therapy. Although they assert that IVF drugs alone did not increase the patient’s endometrial measurement, it remains to be proven whether this effect is due to the post-transplant estrogen treatment or from the stem cell therapy. Nonetheless, the concept of using stem cells for tissue repair in the uterus is intriguing, and possibly the best hope in future for very severe cases of IUA (uterine transplant is another future possibility). This could be more convincing if recurrent IUA was prevented with stem cells following hysteroscopic adhesiolysis. Definitive proof would be obtained if the stem cells and their progeny were biochemically labeled so as to be identifiable from the original tissue. This could be done in animal studies, for example. The great advantage of stem cells is that they have the capacity to differentiate into a range of cells that are necessary to rebuild a normal uterus, from myometrium and endometrium to the blood vessels which supply them with blood and hormones. Furthermore, as the stem cells are derived from the patient’s own bone marrow ie. autologous adult stem cells, there is no risk of either rejection or ethical controversy (as with embryonic stem cells). Unfortunately at this stage there are no published studies on this treatment.
REFERENCES
1. Fritsch H, Ein Fall von volligem Schwaund der Gebormutterhohle nach Auskratzung. Zentralbl Gynaekol 1894; 18:1337-1342.
2. March, CM; Miller, CE. Hysteroscopic lysis of intrauterine adhesions. Ob.Gyn. News 2006; 41(23):36-37. Abstract
3. Palter. SF, High Rates of Endometriosis in Patients With Intrauterine Synechiae (Asherman's Syndrome). Fertility and Sterility 2005; 86 (null):S471-S471. Link
4. Palter S, Spyrou P. Asherman’s syndrome: Etiologic factors, patterns of pregnancy loss, and treatment results. Results from an international registry. Fertility and Sterility 2003; 80(3):36-7. Link
5. March CM. Intrauterine adhesions. Obstet Gynecol Clin N Am 1995;22(3):491-505. Abstract
6. Jensen, P.A. and Stromme, W.B. Amenorrhea secondary to puerperal curettage (Asherman's syndrome). Am J Obstet Gynecol 1972; 113: 150–4.
7. Polishuk, SO Anteby and D Weinstein, Puerperal endometritis and intrauterine adhesions, Int Surg 1975;60:418–420. Abstract
8. Tsapanos VS, Stathopoulou LP, Papathanassopoulou VS, Tzingounis VA. The role of Seprafilm bioresorbable membrane in the prevention and therapy of endometrial synechiae. Biomed Material Res. 2002;63:10-14. Abstract
Related Links:Good news: Grow endometrium by stem cells. (Times of India)
Recommendation Grading:
Level A: Recommendations are based on good and consistent scientific evidence.
Level B: Recommendations are based on limited or incomsistent scientific evidence.
Level C: Recommendations are based primarily on consensus and expert opinion.
Friday, February 19, 2010
How AS causes infertility or miscarriages
Asherman’s syndrome (AS) can lead infertility in a number of ways. No two cases are identical and it can manifest as infertility according to how and which parts of the reproductive anatomy is affected. AS is characterized by intrauterine adhesions (IUA) and/or fibrosis (non-functional scar tissue).
Infertility may be caused by adhesions occluding the tubal ostia, uterine cavity, or the cervix, thereby interfering with the migration of sperm or implantation of the embryo (1). The presence of defective endometrium in the fundus and ostia which are partially obliterated by the adhesions may also predispose women to tubal and cervical pregnancies (2,3). Partial obstruction of tubes can lead to pregnancy complications such as ectopic pregnancy because the fertilized egg may be physically impeded from migrating to the uterus for implantation. If ostial obstruction is so extensive that it cannot be corrected through hysteroscopic adhesiolysis, in vitro fertilization is the only possibility for a biological offspring (providing that the rest of the uterus is functional and adhesion free). Cervical pregnancy (another form of ectopic pregnancy) may occur if the embryo implants in the cervix. Adhesions involving the cervix may result in the cervix being closed (outlet obstruction). This obviously prevents the sperm from encountering the egg. It has also been noted that in women with outlet obstruction due to adhesions blocking the lower uterus or cervix, endometrial measures are thinner than in women where adhesions are limited to the upper uterus (4). It is thought that the underlying cause of this is a feedback loop to prevent haematometra from occurring. Haematometra is the formation of a large clot of blood from trapped menstrual debris and it very rarely occurs in the former subgroup of women.
Another possible way Asherman’s syndrome can result in infertility is by causing endometriosis. Some authors have noted that women with extensive adhesions either in the uterus or cervix, blocking menstrual flow, later develop endometriosis (5). This was discovered because laparoscopic (keyhole) surgery is sometimes carried out at the same time as hysteroscopy when performing adhesiolysis of IUA. Laparoscopy helps to prevent uterine perforation in severe cases where it may be difficult to judge the limits of the uterine cavity. Endometriosis is the growth of endometrial lining outside of the uterus. It can occur anywhere in the body, though most commonly occurs in the abdomen. Although the cause(s) of endometriosis remain unknown, one of the theories put forth by John A. Sampson is known as the theory of retrograde menstruation. It speculates that a back flow of blood and debris through the fallopian tubes and into the abdomen enables its implantation to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as endometriosis. (As an aside to those who practice yoga, this is why inverted positions such as headstands are avoided during menstruation). Endometriosis itself can lead to infertility by causing pelvic adhesions (Note: not to be confused with intrauterine adhesions which occur INSIDE the uterus). Pelvic adhesions (or extrauterine adhesions) can twist and distort the fallopian tubes and prevent fertilization or implantation.
Many women who have had Asherman’s syndrome develop a thin endometrium even after surgical correction and hormonal therapy to stimulate endometrial regeneration. An optimal thickness of the endometrium (>8mm) is considered to be one of the prerequisites for successful implantation of the embryo. Thin endometrium can be caused by either too much of the endometrium having been removed during D&C (or other uterine surgery) or cervical obstruction (as described above). A thin endometrium may be unresponsive to hormones (6) and may lead to infertility in the form of implantation failure or early miscarriages known as ‘chemical pregnancies’ due to a lack of blood supply and poor placental perfusion. Thin endometrium can also occur in women who have had D&Cs, even if they did not develop Asherman’s syndrome. In fact, a recent study found that the endometrium of women is thinner for about 6 months after a D&C (7). A recent study suggests that treatment with tocopherol (ie. vitamin E) and pentoxifylline may help to thicken the endometrium (8), improving implantation. Of course IUA must be removed before pregnancy can be attempted.
The exact mechanisms by which IUA predispose to miscarriages are unknown, however, it is suspected that constrictions of the uterine cavity by adhesions, lack of adequate functional endometrium to support implantation and defective vascularisation of the residual endometrial tissue due to fibrosis may account for repeated pregnancy loss (9). If an embryo implants in an adhesion or a fibrotic region, it will not grow successfully because it will not have an adequate blood supply, essential for providing the growing embryo with oxygen and nutrients. This can lead to miscarriage. Interestingly, this is analogous to the situation where women with Mullerian malformations such as septate uterus often undergo miscarriage when the embryo implants in the septum (10). If IUAs obstruct the openings of one or both of the fallopian tubes (known as ostia) this prevents the sperm from fertilizing the egg (which normally happens in the fallopian tubes after ovulation).
There is another potential cause of second trimester miscarriage which has been often reported in women with a past history of Asherman’s syndrome: cervical incompetence, also known and cervical insufficiency, however, I will write about this under a future blog topic, post-Asherman’s syndrome obstetric complications, since these miscarriages are not due to adhesions or fibrosis per se but to previous dilations of the cervix during surgeries.
As a consequence of the above, many women who have untreated Asherman’s syndrome are either unable to conceive, or suffer from repeated miscarriages. However, depending on the location, extent and severity of IUA/fibrosis, patients may conceive and carry a pregnancy without treatment. This is not recommended and is usually a chance finding on ultrasound when an adhesion or synechia is detected. There have been isolated case reports of successful and uncomplicated pregnancies in the presence of IUA (11). In the best case scenario, the adhesions are minimal and thin, stretching with the pregnancy such that it does not impinge on the growth of the fetus or uterus. However, women are strongly advised to use contraception to avoid pregnancy until surgical correction of adhesions to avoid pregnancy complications. In women who conceive without removal of adhesions, the reproductive outcome is usually poor: in one well known study, it was reported that of the 46% of patients with untreated IUA who conceived, 40% of the pregnancies ended in spontaneous miscarriage, 12% of which were ectopic. Of the viable pregnancies, 23% delivered prematurely and 13% had placenta accreta with only 53% delivering viable infants (12). Obviously, the more severe the classification of AS, the more likely complications are to occur if a pregnancy occurs. On the other hand, pregnancy itself is probably less likely to occur in more severe cases. Note that these complications may also occur in women after treatment of Asherman’s syndrome, however not as frequently. This will be covered in a future blog.
The moral of the story is: get treated by a trusted Asherman’s specialist if you have Asherman’s syndrome and make sure the uterine cavity is clear (via a follow up hysteroscopy or HSG) and that adhesions have not recurred before trying to conceive. Even better, avoid getting Asherman’s syndrome by using alternatives to D&C.
References
1.Yu, D, Wong, YM, Cheong, Y, Xia, E, and Li, TC. Asherman syndrome--one century later. Fertil Steril 2008;89(4):759-79.
2. Dicker, D, Feldberg, D, Samuel, N, and Goldman, JA. Etiology of cervical pregnancy. Association with abortion, pelvic pathology, IUDs and Asherman's syndrome. J Reprod Med 1985;30(1):25-7.
3. Forssman, L. Posttraumatic intrauterine synechiae and pregnancy. Obstet Gynecol 1965;26(5):710-3.
4. Lo ST, Ramsay P, Pierson R, Manconi F, Munro MG, Fraser IS. Endometrial thickness measured by ultrasound scan in women with uterine outlet obstruction due to intrauterine or upper cervical adhesions.Hum Reprod. 2008 ;23(2):306-9. Link
5. Palter. SF, High Rates of Endometriosis in Patients With Intrauterine Synechiae (Asherman's Syndrome). Fertility and Sterility 2005; 86 (null):S471-S471. Link
6. Shufaro, Y, Simon, A, Laufer, N, and Fatum, M. Thin unresponsive endometrium--a possible complication of surgical curettage compromising ART outcome. J Assist Reprod Genet 2008;25(8):421-5.
7. Moon KS, Richter KS, Levy MJ, Widra EA. Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development? Fertil Steril. 2009;92(5):1776-9. PMID 19560759
8. Acharya S, Yasmin E, Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies--a report of 20 cases. Hum Fertil (Camb). 2009;12(4):198-203. Link
9. Polishuk, WZ and Sadovsky, E. A syndrome of recurrent intrauterine adhesions. Am J Obstet Gynecol 1975;123(2):151-8.
10. Golan, A, Schneider, D, Avrech, O, Raziel, A, Bukovsky, I, and Caspi, E.
Hysteroscopic findings after missed abortion. Fertil Steril 1992;58(3):508-10.
11. Klatsky PC, Tran ND, Strachowski L. A pregnancy complicated by endometrial scarring. Fertil Steril. 2009;91(6):2707-8.
12. Schenker, JG and Margalioth, EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril 1982;37(5):593-610.
Infertility may be caused by adhesions occluding the tubal ostia, uterine cavity, or the cervix, thereby interfering with the migration of sperm or implantation of the embryo (1). The presence of defective endometrium in the fundus and ostia which are partially obliterated by the adhesions may also predispose women to tubal and cervical pregnancies (2,3). Partial obstruction of tubes can lead to pregnancy complications such as ectopic pregnancy because the fertilized egg may be physically impeded from migrating to the uterus for implantation. If ostial obstruction is so extensive that it cannot be corrected through hysteroscopic adhesiolysis, in vitro fertilization is the only possibility for a biological offspring (providing that the rest of the uterus is functional and adhesion free). Cervical pregnancy (another form of ectopic pregnancy) may occur if the embryo implants in the cervix. Adhesions involving the cervix may result in the cervix being closed (outlet obstruction). This obviously prevents the sperm from encountering the egg. It has also been noted that in women with outlet obstruction due to adhesions blocking the lower uterus or cervix, endometrial measures are thinner than in women where adhesions are limited to the upper uterus (4). It is thought that the underlying cause of this is a feedback loop to prevent haematometra from occurring. Haematometra is the formation of a large clot of blood from trapped menstrual debris and it very rarely occurs in the former subgroup of women.
Another possible way Asherman’s syndrome can result in infertility is by causing endometriosis. Some authors have noted that women with extensive adhesions either in the uterus or cervix, blocking menstrual flow, later develop endometriosis (5). This was discovered because laparoscopic (keyhole) surgery is sometimes carried out at the same time as hysteroscopy when performing adhesiolysis of IUA. Laparoscopy helps to prevent uterine perforation in severe cases where it may be difficult to judge the limits of the uterine cavity. Endometriosis is the growth of endometrial lining outside of the uterus. It can occur anywhere in the body, though most commonly occurs in the abdomen. Although the cause(s) of endometriosis remain unknown, one of the theories put forth by John A. Sampson is known as the theory of retrograde menstruation. It speculates that a back flow of blood and debris through the fallopian tubes and into the abdomen enables its implantation to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as endometriosis. (As an aside to those who practice yoga, this is why inverted positions such as headstands are avoided during menstruation). Endometriosis itself can lead to infertility by causing pelvic adhesions (Note: not to be confused with intrauterine adhesions which occur INSIDE the uterus). Pelvic adhesions (or extrauterine adhesions) can twist and distort the fallopian tubes and prevent fertilization or implantation.
Many women who have had Asherman’s syndrome develop a thin endometrium even after surgical correction and hormonal therapy to stimulate endometrial regeneration. An optimal thickness of the endometrium (>8mm) is considered to be one of the prerequisites for successful implantation of the embryo. Thin endometrium can be caused by either too much of the endometrium having been removed during D&C (or other uterine surgery) or cervical obstruction (as described above). A thin endometrium may be unresponsive to hormones (6) and may lead to infertility in the form of implantation failure or early miscarriages known as ‘chemical pregnancies’ due to a lack of blood supply and poor placental perfusion. Thin endometrium can also occur in women who have had D&Cs, even if they did not develop Asherman’s syndrome. In fact, a recent study found that the endometrium of women is thinner for about 6 months after a D&C (7). A recent study suggests that treatment with tocopherol (ie. vitamin E) and pentoxifylline may help to thicken the endometrium (8), improving implantation. Of course IUA must be removed before pregnancy can be attempted.
The exact mechanisms by which IUA predispose to miscarriages are unknown, however, it is suspected that constrictions of the uterine cavity by adhesions, lack of adequate functional endometrium to support implantation and defective vascularisation of the residual endometrial tissue due to fibrosis may account for repeated pregnancy loss (9). If an embryo implants in an adhesion or a fibrotic region, it will not grow successfully because it will not have an adequate blood supply, essential for providing the growing embryo with oxygen and nutrients. This can lead to miscarriage. Interestingly, this is analogous to the situation where women with Mullerian malformations such as septate uterus often undergo miscarriage when the embryo implants in the septum (10). If IUAs obstruct the openings of one or both of the fallopian tubes (known as ostia) this prevents the sperm from fertilizing the egg (which normally happens in the fallopian tubes after ovulation).
There is another potential cause of second trimester miscarriage which has been often reported in women with a past history of Asherman’s syndrome: cervical incompetence, also known and cervical insufficiency, however, I will write about this under a future blog topic, post-Asherman’s syndrome obstetric complications, since these miscarriages are not due to adhesions or fibrosis per se but to previous dilations of the cervix during surgeries.
As a consequence of the above, many women who have untreated Asherman’s syndrome are either unable to conceive, or suffer from repeated miscarriages. However, depending on the location, extent and severity of IUA/fibrosis, patients may conceive and carry a pregnancy without treatment. This is not recommended and is usually a chance finding on ultrasound when an adhesion or synechia is detected. There have been isolated case reports of successful and uncomplicated pregnancies in the presence of IUA (11). In the best case scenario, the adhesions are minimal and thin, stretching with the pregnancy such that it does not impinge on the growth of the fetus or uterus. However, women are strongly advised to use contraception to avoid pregnancy until surgical correction of adhesions to avoid pregnancy complications. In women who conceive without removal of adhesions, the reproductive outcome is usually poor: in one well known study, it was reported that of the 46% of patients with untreated IUA who conceived, 40% of the pregnancies ended in spontaneous miscarriage, 12% of which were ectopic. Of the viable pregnancies, 23% delivered prematurely and 13% had placenta accreta with only 53% delivering viable infants (12). Obviously, the more severe the classification of AS, the more likely complications are to occur if a pregnancy occurs. On the other hand, pregnancy itself is probably less likely to occur in more severe cases. Note that these complications may also occur in women after treatment of Asherman’s syndrome, however not as frequently. This will be covered in a future blog.
The moral of the story is: get treated by a trusted Asherman’s specialist if you have Asherman’s syndrome and make sure the uterine cavity is clear (via a follow up hysteroscopy or HSG) and that adhesions have not recurred before trying to conceive. Even better, avoid getting Asherman’s syndrome by using alternatives to D&C.
References
1.Yu, D, Wong, YM, Cheong, Y, Xia, E, and Li, TC. Asherman syndrome--one century later. Fertil Steril 2008;89(4):759-79.
2. Dicker, D, Feldberg, D, Samuel, N, and Goldman, JA. Etiology of cervical pregnancy. Association with abortion, pelvic pathology, IUDs and Asherman's syndrome. J Reprod Med 1985;30(1):25-7.
3. Forssman, L. Posttraumatic intrauterine synechiae and pregnancy. Obstet Gynecol 1965;26(5):710-3.
4. Lo ST, Ramsay P, Pierson R, Manconi F, Munro MG, Fraser IS. Endometrial thickness measured by ultrasound scan in women with uterine outlet obstruction due to intrauterine or upper cervical adhesions.Hum Reprod. 2008 ;23(2):306-9. Link
5. Palter. SF, High Rates of Endometriosis in Patients With Intrauterine Synechiae (Asherman's Syndrome). Fertility and Sterility 2005; 86 (null):S471-S471. Link
6. Shufaro, Y, Simon, A, Laufer, N, and Fatum, M. Thin unresponsive endometrium--a possible complication of surgical curettage compromising ART outcome. J Assist Reprod Genet 2008;25(8):421-5.
7. Moon KS, Richter KS, Levy MJ, Widra EA. Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development? Fertil Steril. 2009;92(5):1776-9. PMID 19560759
8. Acharya S, Yasmin E, Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies--a report of 20 cases. Hum Fertil (Camb). 2009;12(4):198-203. Link
9. Polishuk, WZ and Sadovsky, E. A syndrome of recurrent intrauterine adhesions. Am J Obstet Gynecol 1975;123(2):151-8.
10. Golan, A, Schneider, D, Avrech, O, Raziel, A, Bukovsky, I, and Caspi, E.
Hysteroscopic findings after missed abortion. Fertil Steril 1992;58(3):508-10.
11. Klatsky PC, Tran ND, Strachowski L. A pregnancy complicated by endometrial scarring. Fertil Steril. 2009;91(6):2707-8.
12. Schenker, JG and Margalioth, EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril 1982;37(5):593-610.
Saturday, January 30, 2010
A hidden cause of ‘unexplained’ infertility and miscarriages: ignorance about AS
Asherman’s syndrome remains a cause of infertility –ie. the inability to conceive or carry a pregnancy- the latter sometimes resulting in repeat miscarriages- which is often overlooked. This is because both doctors and women alike are often unaware of this ‘syndrome’ which rarely gets a mention outside of infrequent gynecological journal articles or anti-abortion propaganda (which ignores the fact that a D&C for any reason or intrauterine surgery can cause the condition). Furthermore, it may be difficult to make a link between a surgery and problems or complications which may occur years later. Another reason is that it is incorrectly thought of as being a rare condition, despite reports of up to 30% of women developing intrauterine adhesions (IUA) after D&C for missed miscarriage and 25% if D&C is performed following delivery (1,2).
Ironically, perhaps another reason it remains so hidden is due to its very symptoms: infertility and miscarriages. Unfortunately, even among highly educated medical professionals, there remains a tendency to consider women who exhibit these as having other fertility flaws rather than to contemplate that problems could be the result of a routine procedure they or a colleague carried out. I was dismayed to have read so many peer-reviewed medical articles where this view is expressed. In fact, Dr. Joseph Asherman, the doctor who described the condition in detail in 1948 and whose name the condition was coined after, quite strangely believed that "adhesions are certainly not to blame for the incapacity to conceive" (3). Of course, this view is certainly refuted today. I will write about this and other errors Dr Asherman (and others) made in a future blog. With all due respect, one should keep in mind that his speculations were based on what he could extrapolate from the imaging techniques and medical and scientific knowledge available in the 1940s and 1950s. Today we are in a much better position to analyze medical conditions. However many study authors continue to suggest that any failure to achieve pregnancy or live birth after 'successful' treatment of IUA as ‘evidence’ of other additional underlying fertility issues even though there could be endometrial dysfunction due to fibrosis for which there are currently no accurate tests. Current live birth outcomes are around 40% at best. This means that they attribute at least 60% of post AS infertility to hypothetical additional infertility factors. Therefore, secondary infertility is often incorrectly labeled as primary infertility.
It is of no surprise that Asherman's syndrome was first noted in a woman who developed amenorrhea after a postpartum curettage (6). If she had not 'proven' her fertility by giving birth her infertility would surely be ascribed to some other undefined cause. Thus, if a childless woman who has a D&C to treat a miscarriage and develops AS, many doctors are less likely to investigate it and put down her future infertility (and prior miscarriage) to other 'unknown' fertility problems. It does not help that the older a woman, the more likely she is to have a miscarriage and therefore undergo a D&C- and develop AS. Age-related infertility can then be the excuse, and if you are a woman aged 40 or over and have ever been to see a fertility specialist as I have, you will have this drummed into you like a mantra. (On a personal note, this is why it especially sucks to get AS after the miscarriage of a first pregnancy when you are an older woman!!!). Most D&Cs are carried out for miscarriage, and proportionally more miscarriages occur in older women at the same time as their natural fertility is declining.
Also unfortunate is that the indirect association between women who do have other fertility problems and AS is often thought to be a direct association. The correlation is due to the fact that women with fertility problems are more likely to miscarry, and therefore have D&Cs-the cause of AS- however unfortunately some doctors will only look at the simplest assocation. There is a review article (4) which misleadingly describes Mullerian defects (eg. septate uterus) as a cause of AS due to 'stagnation of menstrual debris or old blood inside the uterine cavity'. This assertion has no basis whatsoever, nor have I read any similar claim in any other peer-reviewed medical article. (Note: incidentally, that article which is ironically titled 'Ashermans syndrome (IUA): Has there been any progress over the last 20 years?' is undoubtedly the most unconventional review on Asherman's syndrome I have ever come across. Perhaps I can go into the details of this in a blog of its own). In fact it has already been noted that women with Mullerian defects often have had several miscarriages and D&Cs, and it is the latter which increases their risk of developing AS (5). Furthermore, it doesn't take a rocket scientist to realize that blindly scraping in any uterus, let alone an unusually shaped uterus with a wall in the middle, is likely to result in injury leading to IUA. In reality, the only female population that is ‘predisposed’ to AS is anyone who is likely to undergo D&C or intrauterine surgery more frequently than the 'normal' population, whatever the reason might be. No wonder there is so little sympathy or admission of responsibility by the medical community when it is in their interest to blame the patient’s age or other undefined fertility issues for infertility instead of standard medical care.
Even when menstrual disturbances -which are hallmarks of AS- are reported by patients they are either brushed aside as imaginary, explained as normal for one’s age or following miscarriage, or put down to other ‘proof’ of other fertility problems.
The sayings:
“Science progresses best when observations force us to alter our preconceptions.” (Vera Rubin)
“Those who have excess faith in their theories or in their ideas are not only poorly disposed to make discoveries, but they also make very poor observations.” (Claude Bernard)
come to mind.
The bad news is that if Gyns/ObGyns are missing (intentionally or not) the link between cause and effect (ie. D&C and infertility/miscarriages) and making biased and incorrect assumptions about other causes of infertility to ‘explain’ reproductive outcome failure, this gives less incentive for doctors to replace the current standard of care for miscarriage with drugs such as misoprostol or hysteroscopic removal of retained tissue instead. Instead, these attitudes help to maintain the status quo and enables D&Cs to continue to be used widely and indiscrimminately, ignoring the risks.
The most accurate method for diagnosis of IUA is hysteroscopy because it allows a direct view of the inside of the uterus however it is not routinely carried out during infertility workups. Couples considering artificial reproductive technology (ART) are referred for other diagnostic procedures such as ultrasound and HSG however these may not accurately detect the presence of IUA. Also, there is currently no test available for endometrial function which is essential to proper embryo implantation and successful pregnancy. Unfortunately there are few gynecologists who are trained to perform hysteroscopy. Only 15% of US doctors perform office hysteroscopy (7). In comparison, 100% of urologists use office cytoscopy to evaluate bladder pathology. I find it disconcerting that hysteroscopy is such an underutilized technique and question if this would be the case if those likely to benefit from it were men (similarly, would D&C continue to be used if it caused male infertility?). Perhaps our own inaction and passivity as women are in part to blame. Undergoing IVF in the presence of AS is a very expensive waste of time and once again, it is the patient (and broader community if fertility treatment is government subsidized, as in some countries) who suffers most from it, not the fertility specialists! (on the contrary...) IVF is bound to fail if the cavity is not suited for embryo implantation/growth. Even if a patient has other fertility problems such as blocked tubes or her husband has poor sperm quality, the patient must first correct IUA, if present, to enable her to conceive and carry a pregnancy through IVF.
Prospective studies in women with infertility and/or recurrent miscarriages who underwent diagnostic hysteroscopy revealed AS rates of 19-23.6% (8)(9)(10)(11). In other words, 1 in 4 to 1 in 5 women who are infertile or suffer repeat miscarriages have been shown to have IUA. For this reason, diagnostic hysteroscopy should be considered by any woman with unexplained infertility especially if she has ever had a D&C or intrauterine surgery for ANY reason. It especially makes sense to investigate the cavity further if she is either considering IVF or has had unsuccessful IVF treatments. The recommendation to use hysteroscopy in infertility workups appears to be controversial. Interestingly, diagnostic D&Cs are far more commonly used in gynecology even though they carry more risks and provide zero information about the presence of IUA. In the following
Quoting from the presentation:
“It is no more acceptable for a gynecologist to insert a sharp curette into a uterine cavity blindly to discover and remove suspected pathology than it is for an orthopedist to insert a curette into a knee joint blindly.”
REFERENCES
1. Adoni, A, Palti, Z, Milwidsky, A, and Dolberg, M. The incidence of intrauterine
adhesions following spontaneous abortion. Int J Fertil 1982;27(2):117-8.
2. Eriksen, J and Kaestel, C. The incidence of uterine atresia after post-partum
curettage. A follow-up examination of 141 patients. Dan Med Bull 1960;7:50-1.
3. Asherman J. Traumatic intrauterine adhesions and their effect on fertility. Int J Fertil 2:49, 1957.
4. Panayotidis C, Weyers S, Bosteels J, van Herendael B.5. Intrauterine adhesions (IUA): has there been progress in understanding and treatment over the last 20 years? (2009) Gynecol Surg 6(3):197-211.
Hysteroscopic findings after missed abortion. Fertil Steril 1992;58(3):508-10.
6. Fritsch, H. Ein Fall von volligem Schwaund der Gebormutterhohle nach
Auskratzung Zentralbl Gynaekol 1894;18:1337-1342.
7. Isaacson, K. Office hysteroscopy: a valuable but under-utilized technique. Curr
Opin Obstet Gynecol 2002;14(4):381-5.
8. Raziel, A, Arieli, S, Bukovsky, I, Caspi, E, and Golan, A. Investigation of the
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