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

Failed medical management or a failure to comply with accepted guidelines?

Only 4 months after an in utero fetal demise at 14 weeks, I had a first trimester miscarriage at 8 weeks. I had conceived (naturally again) after only a month of trying and the pregnancy was suspected by chance at a follow up for my previous miscarriage only a few days after implantation. I’d had my next ultrasounds at 5 weeks, just under 8 weeks-where a heart rate of 151 bpm was detected- and then at 9 weeks, where there was no longer any cardiac activity.
 As if this was not bad enough, I was again faced with how to cope with the physical side of this loss without incurring damage to my previously scarred uterus. Misoprostol was of course my method of choice. I learned that I would have to be admitted as an in-patient according to this hospital’s treatment protocol, although I know that in other countries misoprostol management of first trimester miscarriage (and abortion) are routinely done on an out-patient basis. This of course would increase the cost of the procedure. Once I was admitted, I learned that I would be given the same protocol as for second trimester terminations. This is because the hospital only has protocols in place using misoprostol for late abortions.


I should clarify that in Australia, misoprostol is rarely used for first trimester miscarriage. This was an exception for them and I am relieved that I was not forced into having a D&C which caused this whole debacle to begin with.

What worried me was that the accepted dosage for second trimester terminations (400 mcg every 3 hours up to 5 times) is lower per administration than that recommended for first trimester miscarriage. According to guidelines published in a supplement to the International Journal of Gynecology and Obstetrics (2007, vol. 99) a woman with a first trimester miscarriage should be given 2 doses of 800 mcg of misoprostol (vaginally) 3 hours apart. This is because early in a pregnancy, there are fewer prostaglandin receptors to which misoprostol binds than later in pregnancy.


While I received the same protocol for my previous second trimester miscarriage as for second trimester abortion, the accepted protocols for these two indications are much more similar and was thus it was more effective. However, this dosage is not considered effective for first trimester pregnancy failure and with good reason, as I subsequently found out: it simply does not work. On the first day I received 5 doses but none of them produced contractions that were strong enough to evacuate the uterus. There seemed to be less uterine contractions and bleeding after the first few administrations as though the effects were wearing off. I was given a 12 hour break before starting again. I requested that the drug be given orally instead this time. I had even less of a reaction, not even nausea or diarrhea which are commonly reported side effects of oral misoprostol. The following day, I agreed to hysteroscopic removal with my Asherman’s syndrome specialist.


According to this specialist, my cervix was slightly dilated but not enough for the gestational sac to pass through. The gestational sac had implanted slightly low in the uterine cavity (future placenta previa?), and in the anterior wall, in a region where I’d had scarring from my D&C and adhesions. Tissue obtained during the hysteroscopy did not grow in culture so I was unable to find out the karyotype of the embryo, or subsequently, the gender. It is possible that I miscarried because by chance the embryo implanted in a region where I’d had previous scarring and possible fibrosis, and the blood supply was not sufficient to maintain the pregnancy. If so, this is much more upsetting than if the baby was chromosomally abnormal and would not have survived anyway. I will never know for sure what caused this miscarriage, but an Asherman’s related cause cannot be either confirmed or ruled out.


It is quite possible that I would have required hysteroscopy to remove retained products, as I had previous uterine scarring from Asherman's syndrome, and the embryo also implanted in the area of the previous scarring. However, had I been given the correct dosage, I may not have needed to wait another day to respond to a drug which was given in too low a quantity to be effective anyway.


I noticed that on my hysteroscopic surgery report written under ‘reason for hysteroscopy’ was ‘failed medical management of miscarriage.’ This made me wonder if doctors and nurses would look at my file and incorrectly conclude that misoprostol was an ineffective drug for miscarriage, rather than realizing that the dose I had been given was inappropriate and not officially recommended for my stage of pregnancy. I wonder how many other women who claim their miscarriage management with misoprostol was a ‘failure’ were also given a dose not suited to their gestational age. From a patient perspective, I wonder why it is not possible for my hospital to provide treatment according to published recommendations for that indication (rather than according to a protocol used for another indication ie. second trimester abortion)? What is the logic in applying a protocol which goes against evidence-based medicine? I hope that instead of discouraging doctors, my experience will go towards persuading this hospital to broaden the current protocol so that women with first trimester miscarriage will benefit from misoprostol. For misoprostol to be effective and safe, it needs to be used according to established guidelines which take into account factors such as gestational age and indication.

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

presentation about hysteroscopy, the debate about the use of hysteroscopy is outlined with studies. Provided the doctor performing hysteroscopy is properly trained and experienced (in my opinion many more gynaecologists need to be) the benefits of hysteroscopy in women with infertility or recurrent miscarriage may far outweigh the risks.

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.

5. 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.

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
uterine cavity in recurrent aborters. Fertil Steril 1994;62(5):1080-2.

9. Preutthipan, S and Linasmita, V. Reproductive outcome following hysteroscopic
lysis of intrauterine adhesions: a result of 65 cases at Ramathibodi Hospital. J Med
Assoc Thai 2000;83(1):42-6.

10. Ventolini, G, Zhang, M, and Gruber, J. Hysteroscopy in the evaluation of patients
with recurrent pregnancy loss:

11. Dendrinos, S, Grigoriou, O, Sakkas, EG, Makrakis, E, and Creatsas, G.
Hysteroscopy in the evaluation of habitual abortions. Eur J Contracept Reprod
Health Care 2008;13(2):198-200.