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
Showing posts with label clinical trials. Show all posts
Showing posts with label clinical trials. Show all posts
Thursday, December 2, 2010
Tuesday, August 31, 2010
The Miscarriage Study: 400 vs 800 mcg misoprostol
Mater Mother’s Hospital in Queensland has been conducting a randomized controlled trial comparing two doses of misoprostol (800 mcg versus 400 mcg) for the medical management of miscarriage. More information can be found in the brochure for The Miscarriage Study on their website:
http://brochures.mater.org.au/Home/Brochures/Mater-Mothers--Hospitals/Miscarriage
Medical management is only available to women participating in the Miscarriage Study. Surgery or expectant management is offered as standard care options to women who choose not to participate.
The web brochure explains that the study is being carried out because currently there is no agreement on the most effective dose for misoprostol use in miscarriage. However it points out that 800mcg is the most common dose used in studies. While it is true that researchers have not determined a dosage/regimen which is as effective as D&C i.e. the ‘optimum’ protocol for medical management using misoprostol, preliminary guidelines based on hundreds of studies have been produced by the expert group convened by WHO in Bellagio in February 2007. They are published in a supplement to the International Journal of Gynecology and Obstetrics (2007, vol. 99) and can be read here. According to these guidelines, 600-800 mcg misoprostol is the recommended dose for first trimester miscarriage. The guidelines for misoprostol use according to indication and gestational age are also available at: http://www.misoprostol.org/ This website also provides excellent resources to clinicians interested in information about misoprostol use and the misoprostol debate.
The researchers have chosen to study quite a low dosage of misoprostol to reduce side effects. However, it has already been established that even 600-800 mcg is not as effective for first trimester miscarriage as the standard care D&C (it remains questionable as to why it is imperative for medical management to be equally as effective as D&C for it to be used when medical management offers the advantages of being non-invasive, cheap, free of anesthetics and safer for future fertility than D&C).The drug is inexpensive, so cost is evidently not an issue. Furthermore, the optimum dose for use in termination up to 7 weeks is 800 mcg (in combination with mifepristone). A recent study found that this dose should not be lowered (link). Apparently misoprostol side effects for termination are not a concern for women. One would imagine the same for women who miscarry.
Misoprostol is listed in the Standard Drug List of Queensland Hospitals for use in miscarriage and is currently used in this hospital for the treatment of other pregnancy complications. The Therapeutic Goods Administration (TGA), which is the Australian equivalent of the FDA in the US, has not approved of its use in pregnancy in Australia.
However, the Queensland Health and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists support its use in the treatment of miscarriage. Despite this, misoprostol use for first trimester miscarriage remains uncommon in Australia. The drug is quite commonly used for miscarriage management in European countries. In contrast, a combined misoprostol/mifepristone regimen is offered by most if not all services in Australia specializing in pregnancy termination. It has also become common practice for labour induction despite the fact that there is not more evidence to support its use for this indication than for miscarriage. Interestingly, expectant management is considered acceptable although it is not more effective than for miscarriage management in clinical trials. Health professionals excuse the restricted access to misoprostol for miscarriage management with the pretext that misoprostol is not TGA approved, yet misoprostol use in ALL obstetric/gynecologic indications is not approved (misoprostol was developed for the treatment and prevention of ulcers). The unlicensed use of misoprostol for terminations is cunningly circumvented by a legal loophole which allows its use in combination with mifepristone which is only TGA approved for use in pregnancy termination. Unlicensed use of misoprostol in labour induction, curiously, does not seem to hinder clinicians from using it for labour induction even though substantially less is known about the short and long term effects it may have on infants exposed to it. Misoprostol is also used in the treatment of osteoarthritis and marketed under the name Arthrotec. Curiously, there is no debate over the unlicensed use of misoprostol for arthritis. Yet none of the above has lead to questioning the objective validity behind the selective use of misoprostol for some unlicensed obstetric (or other) indications but not for miscarriage management. Why is it that the only people who seem to be prevented from using misoprostol are women who miscarry?
Most women who miscarry have no choice but to undergo a costly D&C, potentially leading to long term adverse effects on fertility (Asherman’s syndrome) and a host of possible future obstetric complications (placenta accreta, percreta, previa, IUGR, pre eclampsia, preterm birth, cervical insufficiency leading to second trimester loss, and uterine rupture). It is ironic that the very women who desire a pregnancy most are also those who are exposed to iatrogenic infertility and/or pregnancy complications arising from surgical management. Disappointing overall reproductive outcomes (40%) and associated healthcare costs (not to mention patient discontent) do not make the approach of relying on treatment of Asherman’s syndrome a paradigm. The restriction of a safe, inexpensive and non-invasive alternative such as misoprostol for miscarriage management can be considered unethical and perhaps even discriminatory as it is available to other populations of women for unlicensed obstetric/gynecological indications.
The Mater Mother’s Hospital webpage mentions potential complications from surgical management (D&C) without specifically naming Asherman’s syndrome (intrauterine adhesions and/or fibrosis) or cervical insufficiency (from cervical dilation). It also quotes the risk of complications from D&C as 1:200-500 surgeries, a greatly underestimated frequency (see Frequency of intrauterine adhesions after curettage).
It is encouraging to see local studies on misoprostol for miscarriage management. Even if 400 ug will turn out to have a significantly lower success rate than 800 ug, exposure to women and clinicians could help promote awareness about it and increase its demand/use. Perhaps it is a sign that Australia is finally ready to implement medical management as a routine care option.
http://brochures.mater.org.au/Home/Brochures/Mater-Mothers--Hospitals/Miscarriage
Medical management is only available to women participating in the Miscarriage Study. Surgery or expectant management is offered as standard care options to women who choose not to participate.
The web brochure explains that the study is being carried out because currently there is no agreement on the most effective dose for misoprostol use in miscarriage. However it points out that 800mcg is the most common dose used in studies. While it is true that researchers have not determined a dosage/regimen which is as effective as D&C i.e. the ‘optimum’ protocol for medical management using misoprostol, preliminary guidelines based on hundreds of studies have been produced by the expert group convened by WHO in Bellagio in February 2007. They are published in a supplement to the International Journal of Gynecology and Obstetrics (2007, vol. 99) and can be read here. According to these guidelines, 600-800 mcg misoprostol is the recommended dose for first trimester miscarriage. The guidelines for misoprostol use according to indication and gestational age are also available at: http://www.misoprostol.org/ This website also provides excellent resources to clinicians interested in information about misoprostol use and the misoprostol debate.
The researchers have chosen to study quite a low dosage of misoprostol to reduce side effects. However, it has already been established that even 600-800 mcg is not as effective for first trimester miscarriage as the standard care D&C (it remains questionable as to why it is imperative for medical management to be equally as effective as D&C for it to be used when medical management offers the advantages of being non-invasive, cheap, free of anesthetics and safer for future fertility than D&C).The drug is inexpensive, so cost is evidently not an issue. Furthermore, the optimum dose for use in termination up to 7 weeks is 800 mcg (in combination with mifepristone). A recent study found that this dose should not be lowered (link). Apparently misoprostol side effects for termination are not a concern for women. One would imagine the same for women who miscarry.
Misoprostol is listed in the Standard Drug List of Queensland Hospitals for use in miscarriage and is currently used in this hospital for the treatment of other pregnancy complications. The Therapeutic Goods Administration (TGA), which is the Australian equivalent of the FDA in the US, has not approved of its use in pregnancy in Australia.
However, the Queensland Health and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists support its use in the treatment of miscarriage. Despite this, misoprostol use for first trimester miscarriage remains uncommon in Australia. The drug is quite commonly used for miscarriage management in European countries. In contrast, a combined misoprostol/mifepristone regimen is offered by most if not all services in Australia specializing in pregnancy termination. It has also become common practice for labour induction despite the fact that there is not more evidence to support its use for this indication than for miscarriage. Interestingly, expectant management is considered acceptable although it is not more effective than for miscarriage management in clinical trials. Health professionals excuse the restricted access to misoprostol for miscarriage management with the pretext that misoprostol is not TGA approved, yet misoprostol use in ALL obstetric/gynecologic indications is not approved (misoprostol was developed for the treatment and prevention of ulcers). The unlicensed use of misoprostol for terminations is cunningly circumvented by a legal loophole which allows its use in combination with mifepristone which is only TGA approved for use in pregnancy termination. Unlicensed use of misoprostol in labour induction, curiously, does not seem to hinder clinicians from using it for labour induction even though substantially less is known about the short and long term effects it may have on infants exposed to it. Misoprostol is also used in the treatment of osteoarthritis and marketed under the name Arthrotec. Curiously, there is no debate over the unlicensed use of misoprostol for arthritis. Yet none of the above has lead to questioning the objective validity behind the selective use of misoprostol for some unlicensed obstetric (or other) indications but not for miscarriage management. Why is it that the only people who seem to be prevented from using misoprostol are women who miscarry?
Most women who miscarry have no choice but to undergo a costly D&C, potentially leading to long term adverse effects on fertility (Asherman’s syndrome) and a host of possible future obstetric complications (placenta accreta, percreta, previa, IUGR, pre eclampsia, preterm birth, cervical insufficiency leading to second trimester loss, and uterine rupture). It is ironic that the very women who desire a pregnancy most are also those who are exposed to iatrogenic infertility and/or pregnancy complications arising from surgical management. Disappointing overall reproductive outcomes (40%) and associated healthcare costs (not to mention patient discontent) do not make the approach of relying on treatment of Asherman’s syndrome a paradigm. The restriction of a safe, inexpensive and non-invasive alternative such as misoprostol for miscarriage management can be considered unethical and perhaps even discriminatory as it is available to other populations of women for unlicensed obstetric/gynecological indications.
The Mater Mother’s Hospital webpage mentions potential complications from surgical management (D&C) without specifically naming Asherman’s syndrome (intrauterine adhesions and/or fibrosis) or cervical insufficiency (from cervical dilation). It also quotes the risk of complications from D&C as 1:200-500 surgeries, a greatly underestimated frequency (see Frequency of intrauterine adhesions after curettage).
It is encouraging to see local studies on misoprostol for miscarriage management. Even if 400 ug will turn out to have a significantly lower success rate than 800 ug, exposure to women and clinicians could help promote awareness about it and increase its demand/use. Perhaps it is a sign that Australia is finally ready to implement medical management as a routine care option.
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.
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