Steps in the right direction

Since first starting this blog in 2009, medical management of miscarriage has become more accessible in Australia. To my knowledge, the Royal Prince Alfred Hospital routinely offers medical management as an alternative to surgical and expectant management. The Royal Hospital for Women also mentions it as one the services it provides (link to protocol). Also, during a course I took as part of my degree, lectures by fertility specialists have included the topic of intrauterine adhesions/Asherman’s syndrome and the use of medical management for miscarriage. A study on the prevalence of IUA after repeat curettage (D&C) has been awarded funding by the Australasian Gynaecological Endoscopy Society. These are all positive steps, and signs that the condition and medical management of miscarriage are gaining awareness. Of course, further awareness by the public and non-specialist doctors is still necessary, that is why this site exists. I will no longer be blogging except to complete older posts, but this site will continue to be available as a source of information for clinicians, patients and all women faced with a decision about whether to undergo a D&C or those who are experiencing symptoms of IUA and are looking for an answer.

Good bye and good luck.             

When EBM is not really EBM

This post might seem a bit off-topic, but it's relevant to anyone who is interested in any type of human research. As you might be aware of, I'm a strong believer in evidence based medicine (EBM) and am currently studying for a Masters in Clinical Epidemiology. I find it scary that there even exist doctors who are against the concept of EBM (see http://www.kevinmd.com/blog/2011/10/evidence-based-medicine-removes-physicians-autonomy.html). However, I've also become aware of the highjacking of EBM to suit researchers' or governments' agendas. I have sometimes been stuck by the contradiction between what I am being taught and what is being touted as 'accepted evidence' or a 'valid' study the next minute. Of course researchers are human and we all have our opinions and beliefs (not to mention prejudices) that will spill over into research. Many researchers become interested in a topic because of a personal experience which sparked an interest in contributing to or improving research in that area because they had gained a personal insight into the problem that previous researchers missed. Improving patient care is a great reason to support human research and EBM. On the other hand, there are researchers who, motivated by personal gain whether this is career advancement, religious/'moral' beliefs, or financial gain, manipulate research using their credentials as 'evidence based researchers' to bias research outcomes. This is the complete opposite of what they are claiming to be doing, to the great detriment of EBM. Sometimes fear underlies their motivations because their research or investigation could show something the government or their peers did not want to acknowledge, resulting in law suits, medical scandals, or ridicule and it could spell the end of their career.  The following article from the Indian Journal of Medical Ethics outlines some of the ways research can be exploited to 'prove' what the researchers want it to prove:

Evidence based medicine: can the evidence be trusted? by Prathap Tharyan
Indian J Med Ethics.2011 Oct-Dec;8(4)

Link to full text article:

http://www.issuesinmedicalethics.org/194ed203.html

No one can claim to have no agendas whatsoever when it comes to conducting their particular research. One could argue that researchers should be able to design and analyse their own research according to what they have been taught about EBM to reduce bias and to critically appraise research undertaken by others by those standards. I'm not sure all researchers are able to do this, particularly if they have been taught about scientific thinking after their formal education, not as part of it. It takes a special mind to question what professors may be teaching you are established 'facts' and no one wants to be accused of 'arrogance'. However, not everyone is capable of scientific thinking, lateral thinking or thinking outside the box, no matter how successful, experienced, skilled or well-respected they may be.

For some areas of Gynecology and Obstetrics (such as Asherman's syndrome) it has not even reached the stage where EBM is being used much at all, so its manipulation is not the biggest problem. The first hurdle is to actually apply EBM to the field, which is desperately needed. There are however some areas where I can see some manipulation (not necessarily machiavellian) already, for example studies about misoprostol where low doses and short periods for assessing outcome are being used to 'prove' how poorly it performs compared to D&C. Another pitfall I see is something called 'intention to treat' or ITT. Although ITT is a non-controversial and accepted concept in EBM and I agree with all other aspects of EBM, this is one area that I question. ITT means that in a randomized controlled trial (RCT) those assigned to the experimental group (new treatment being tested) should be analyzed according to belonging to that group, and those assigned to the control (no treatment or standard treatment) should be analyzed according to the control group, REGARDLESS of whether they actually undergo those treatments. The rationale behind this is that, if for example 80% of the people in the experimental group decide not to take the new medicine, the drug will not be a success no matter how well it works because of patient non-compliance. This could be due to severe side-effects or inconvenience (you have to inject it whereas the standard drug can be taken orally). While I can understand its usefulness in assessing feasability of a treatment, it can be very misleading about actual outcomes, efficacy and even causal mechanisms. Imagine a study comparing the outcome of intrauterine adhesions (IUA) following miscarriage management by misoprostol or surgical curettage (D&C). If a low ineffective dose of misoprostol is dictated by the study design, or if the researchers decide that treatment will be evaluated after 48 hours instead of a week or two, or if they mistakenly diagnose retained products of conception by ultrasound (a common occurrence) after misoprostol treatment in a large portion of participants, these women will automatically be given the standard treatment which is D&C- in this case, the exact same treatment as the 'control' group! This means that study results according to ITT could inaccurately find that misoprostol 'causes' IUA and infertility, rather than that the misoprostol regimen was not given a fair go of success. In fact, even with irreproachable statistical methods, ITT can find that there is either 'no significant difference' or a significantly 'higher' rate of IUA among women in the misoprostol treatment group than in the D&C group depending on chance or on inclusion criteria (they may have included women with past D&Cs in both groups. See the MIST study). Although the logic is flawed, researchers could probably get away with arguing that this was 'proof' that IUA was not necessarily caused by instrumental injury to the endometrium and draw other naive conclusions, preventing progress in the field or prevention of the condition.

The point of this post is to highlight that there is yet a long way to go in achieving trustworthy EBM, but it should remain the goal of all medical research and practice. Another important thing to note is that what may be accepted as medically 'sound' today (due to poorly designed studies masquerading as evidence based research) could appear ridiculous in a century- and vice versa. A good example of this is the Hungarian Obstetrician Ignaz Semmelweis, who first understood that the cause of 'childbed fever' (puerperal fever) was contamination by Obstetricians with unclean hands. How did this observation he proved affect his career? He was shunned by his peers who were 'offended' by the suggestion they wash their hands ("the nerve of him!"), and his views were dismissed ironically as being 'unscientific' (despite his experimental evidence that washing hands reduced mortality rates to below 1%) only because he was unable to explain why. It was only after his death that knowledge about microorganisms explained the association (the germ theory of disease), and his ideas about hand hygiene became understood and accepted into practice. He is one of the doctors whose rationale led to the emergence EBM, but he died alone  (ironically of septicemia) with no glory, in a mental asylum (because of course anyone who rallied against accepted dogma was 'mentallly ill', see Foucault's biopower theory) and betrayed by all. I can see why some researchers would rather go with the flow, but to me Semmelweis was a courageous hero, ahead of his time in his thinking, while his detractors thought they were being scientific by parroting ideas they didn't fully comprehend ...or simply were not brave or caring enough about their patients.

Insights from an Asherman's syndrome expert (Part II)

Apologies for the long delay... To recap, in my last blog post I gave a brief background about Dr Charles March of California Fertility Partners and his vast experience on Asherman’s syndrome (AS), which he summarizes in his last review, Management of Asherman’s syndrome (1). Dr March’s article emphasizes many important issues that are often overlooked and reconsiders the validity of accepted beliefs. It’s clear throughout that he has given a lot of critical as well as practical thought to different aspects of Asherman’s syndrome.  The review starts off with a background including the epidemiology of AS, symptoms and diagnosis, then management, which he summarizes by the acronym PRACTICE, for prevention, anticipation, comprehensive therapy, timely surveillance of subsequent pregnancies, investigation (potential treatments like anti-adhesive gels and vitamin supplementation to improve blood flow), and continuing education (continuing medical education courses and literature).

I’ll focus on the parts of the review containing relevant insights which I have not encountered in other reviews, or which are important enough that repeating them is warranted.

General

1.       Asherman’s syndrome is not rare. He points out that most physicians believe that AS occurs  rarely and fail to diagnose it even when a patients exhibits obvious symptoms. Table 1. (page 64 of the article) displays convincingly that AS is not rare by showing the prevalence of AS in different populations of women undergoing hysteroscopy, and the incidence of AS after various procedures

2.       The term ‘syndrome’ does not correctly describe the condition. This is because the condition has varying symptoms and pathology, from endometrial sclerosis without intrauterine adhesions (IUA), to IUA without endometrial sclerosis. However, he points out that Asherman’s syndrome encompasses all of the different possible manifestations of endometrial injury, from all possible causes and varying symptoms. For this reason he continues using the term instead of IUA or traumatic amenorrhea.

Etiology

3.       AS most commonly occurs after dilation and curettage during or shortly after a pregnancy. However, diagnostic curettage may also lead to AS. Ignorance about this continues. I’ve heard several doctors who are not experts on AS and probably haven’t read the literature on it claim that the condition only occurs where there has been pregnancy and never in its absence. This old belief has been proven to be untrue. Interestingly, Dr March mentions that curettage used to be used during laparoscopy to investigate infertility, observing that this probably caused more harm than good. It is very refreshing to hear doctors reflect on their predecessors’ or colleagues’ mistakes and admitting that sometimes what seems like a progressive approach turns out to be a step backwards.

4.       There is no evidence that uterine malformations such as Mullerian anomalies are more prone to developing adhesions, even though there is very strong evidence that the two are associated. He points out that the correlation can be explained by the high miscarriage rate- and subsequent D&Cs- among this group of women. Another reminder that correlation is not evidence of causation. The bottom line is that injury from surgical trauma (or TB in some countries) is what causes AS, and there is a tendency for some authors to mystify the condition by neglecting the obvious associated risk factor i.e. women with Mullerian anomalies tend to have more D&Cs which lead to AS.

5.       There is no evidence that infection leads to AS. Dr March notes that infections occurred in less than 1% of his patients. The Polishuk case series (2) showed that among 171 women who underwent C-sections, of the 28 who had severe endometritis, none developed de-novo adhesions (the one patient who did develop cervical adhesions already had a previous history of AS from several miscarriages treated by D&C (her AS was also ‘treated’ by D&C).  Furthermore, there are no studies whatsoever that show any evidence that endometritis alone leads to AS.

6.       Endometriosis may develop in AS with outflow obstruction and patent fallopian tube(s) if treatment is delayed. This is an important point that isn’t mentioned enough in my opinion. It’s also another good reason why AS should be prevented or if it's too late, treated to prevent further problems: it can lead to 2 fertility problems for the price of one (a bargain nobody wants).

7.       Inexperienced operators can inadvertently cause uterine damage. New instrumentation and technologies for intrauterine surgeries are proven to be safe by experts, however they may not be so harmless if inexperienced operators use them.

Diagnosis

8.       Menstruation and withdrawal bleeding cannot rule out AS. Some women with IUA have normal periods (‘eumenorrhea’) and some women with amenorrhea have withdrawal bleeding after hormone administration. Therefore hysteroscopy is the gold standard for diagnosis. (HSG and SIS can lead to false positives). However, the opposite is true: women with hypomenorrhea or amenorrhea after intrauterine surgery are likely to have IUA.

9.       HSG and SIS can rule out IUA, but cannot rule out endometrial sclerosis, which can be diagnosed by hysteroscopy. On the other hand, one important advantage of HSG is that it provides information on the patency of fallopian tubes, which hysteroscopy does not. Single or bilateral tubal obstruction is in some cases caused by AS if adhesions occlude the ostia/ostium, so it is important to confirm after corrective surgery that the adhesions have not reformed. A partial or complete obstruction of one or both ostium can lead to tubal pregnancy or infertility.

Next time: Dr March’s advice about prevention, treatment and monitoring of post-AS pregnancies.

References

March C. Management of Asherman’s syndrome Reprod Biomed Online. 2011 Jul;23(1):63-76.

Polishuk WZ, Anteby SO, Weinstein D. Puerperal endometritis and intrauterine adhesions. Int Surg. 1975 Aug;60(8):418-20.

When available studies are limited, expert opinions count

As a strong believer in evidence-based medicine, the lack of the highest quality of studies and sometimes of sound scientific interpretation in articles about Asherman’s syndrome is disappointing. It can be difficult to accurately assess information on AS from different sources when primary studies may be deficient in study design, use outdated techniques of diagnosis or treatment,  have small sample sizes, are carried out retrospectively, randomization/allocation concealment are absent and when comparisons between primary studies is impossible due to differences in methods of treatment. Unfortunately some of these limitations are difficult, if not impossible to overcome. However, there is still room for improvement in studies about AS. There is also a lot we can learn about AS by correctly interpreting data that is already available, and by taking note of the knowledge acquired from specialists with extensive expertise on the topic. To be knowledgible about AS requires more than having the letters MD behind your name, learning about AS through a 10 minute lecture at University and skimming through a few papers on it. To be an expert requires decades of experience with diagnosing and treating it and the ability to think scientifically (objectively), something doctors are not actually taught routinely which is only really pertinent to doctors that are involved in research.

Dr Charles March of California Fertility Partners is a respected authority on Asherman’s syndrome. He is board certified in Obstetrics and Gynecology and fellowship trained in Reproductive Endocrinology and Infertility and was a Professor at University of Southern California. Not only is he a great surgeon who is popular with patients, but I believe he is currently the doctor with the most knowledge about Asherman’s syndrome. This is probably due to the fact that he has over 30 years of experience in dealing with patients that have Asherman’s syndrome and that he is additionally a fertility specialist and obstetrician which enables him to clearly see the causes and repercussions of the condition. He also has a particular interest in the condition and clearly enjoys talking and educating others about it.

His most recent review article,‘Management of Asherman’s syndrome’, appeared in Reproductive Biomedicine Online this year. His articles show that he is a wealth of information on all aspects of AS. Anyone can write a narrative review by consolidating previous data and supporting their arguments with cherry-picked information they have read, sometimes from old or inaccurate sources, but only those who have strong critical appraisal skills and the know-how that comes from decades of experience can offer so much valuable insight and advice on a topic. My next blog will focus on the relevant discussions and kernels of wisdom found in Dr March’s review on Asherman’s syndrome.

Indispensable technique becomes disposable to boost its use

A new single-use disposable hysteroscope (http://hcp.obgyn.net/conference-insider/aagl2011/content/article/1760982/1976908 and http://hcp.obgyn.net/conference-insider/aagl2011/content/article/1760982/1980724) is being investigated by Dr Paul Indman in hopes that, once FDA-approved for commercial use, it will encourage more gynecologists to carry out diagnostic hysteroscopy in an office setting. Dr Indman believes that it is just as important for a gynaecologist to be able to look inside the uterus as it is for an ear doctor to look inside the ear. While nothing seems more evident, fewer than 10% of Obgyns in the US are trained to perform in-office hysteroscopy. This is due to a number of factors including the lengthy preparation and costs of setting up traditional hysteroscopy. Conventional ones are large and cumbersome, and need to be sterilised before each use. Besides the actual hysteroscope, a video camera, monitor and lighting are necessary to perform the procedure. The new hysteroscope is hand-held with a plastic disposable hysteroscope and a reusable handle that has a monitor, light source and a high resolution camera the size of a pin-head incorporated into it. Currently, plastic disposable curettes are used for D&C, so there is no basis for the concern that this will increase pollution to the environment. Hopefully it will be available in the near future and more gynaecologists and fertility specialists will take an interest in using this less-invasive technology to improve diagnosis of women’s health problems. Note: There is another similar device that is available for ~ 300 USD: http://medgadget.com/2007/01/femsuites_femey.html

(Disclaimer:  It is up to medical professionals who are trained in hysteroscopy to assess the performance of these products. I am not in a position to endorse them).

Hysteroscopy is gold-standard method for the evaluation of the uterine cavity to diagnose conditions such as intrauterine adhesions, endometrial polyps and fibroids and structural malformations such as septate uterus. Operative hysteroscopy is used for treating the diagnosed condition where microscissors or other instruments are used for tissue dissection. A resectoscope is a hysteroscope which is equipped with loop that uses electrical energy for cutting, although the loop can be used without thermal energy as a mechanical cutting tool.

Operative hysteroscopy is also used by some gynecologists to remove retained products of conception in select patients and/or situations. It may raise eyebrows among some medicaI professionals who have been trained to rely on blind curettage (D&C) for a wide range of diagnostic and therapeutic indications, but there should be no reason why it is not routinely used in Gynecology, including for ERPC when expectant or medical management fail to completely empty the uterus after a miscarriage, instead of blind curettage. There are a number of publications describing hysteroscopic curettage (1-7) for removing RPOC. Blind curettage is the most common cause of intrauterine adhesions (Asherman’s syndrome), which leads to infertility necessitating corrective surgery. The lack of Obgyns suitably trained in hysteroscopy is another reason why hysteroscopy has not replaced the D&C. Unfortunately, the use of hysteroscopy in Gynecology is even declining from the time it was first invented in the 1980s. Hysteroscopy is the logical progression from blind scraping invented over a century ago. It’s hard to believe that over a century later this comparatively rudimentary technique for women is still being used. Minimally invasive techniques are routinely used in Urology (e.g. in-office cytoscopy). Women also need to empower themselves and support more precise and safer methods by choosing hysteroscopy over blind curettage. Most gynaecologists perform blind curettage without giving a second thought to any long term risks involved. They may not be aware of the future problems it has caused their patients unless the patient specifically contacts them to tell them.  

Finally, this article by Dr Keith Isaacson(8) is not new, but it outlines the uses of hysteroscopy, compares office and hospital hysteroscopy and dispels the common misconceptions about it that are hindering its widespread use, such as poor reimbursements and a difficult learning curve. http://www.obpmedical.com/v/vspfiles/assets/images/office%20hysteroscopy%20-%20a%20valuable%20but%20under-%20utilized%20technique.pdf

REFERENCES

1. Nicopoullos JDM, Treharne A, Raza A and Richardson R. The use of a hysteroscopic resectoscope for repeat evacuation of retained products of conception procedures: a case series. Gynecological Surgery. 2010; 7(2):163-6. Abstract http://www.springerlink.com/content/384125gp81055401/  
2. M.H. Emanuel, F.W. Jansen and D. Schoot The Hysteroscopic Morcellator, an Effective Technique for the Removal of Residual Trophoblastic Tissue Journal of Minimally Invasive Gynecology Volume 16, Issue 6, Supplement 1, 2009, Page S85. 
3. Faivre E, Deffieux X, Mrazguia C, Gervaise A, Chauveaud-Lambling A, Frydman R, Fernandez H. Hysteroscopic management of residual trophoblastic tissue and reproductive outcome: a pilot study. J Minim Invasive Gynecol. 2009 Jul-Aug;16(4):487-90. Abstract www.ncbi.nlm.nih.gov/pubmed/19573826
4. T. Dankert & M. Vleugels. Hysteroscopic resection of retained placental tissue:a feasibility study Gynecol Surg . 2008; 5:121–124. Free article www.springerlink.com/index/w4021j484l211057.pdf  
5. F. Leone, T. Bignardi, C. Marciante, E. Bertazzoli, P. Mustoni, E. Ferrazzi and L. DSC 74: Hysteroscopy for Selective Removal of Residual Trophoblastic Tissue. Journal of Minimally Invasive Gynecology 2005;12(5), Supplement 1: 30-1.
6. Cohen SB, Kalter-Ferber A, Weisz BS, Zalel Y, Seidman DS, Mashiach S, Lidor AL, Zolti M and Goldenberg M. Hysteroscopy May Be the Method of Choice for Management of Residual Trophoblastic Tissue. The Journal of the American Association of Gynecologic Laparoscopists 2001;8(2):199-202. Abstract
7. 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. Abstract www.ncbi.nlm.nih.gov/pubmed/9018641
8. Isaacson K. Office hysteroscopy: a valuable but under-utilized technique.Current Opinion in Obstetrics and Gynecology 2002, 14:381-385. Free article http://www.obpmedical.com/v/vspfiles/assets/images/office%20hysteroscopy%20-%20a%20valuable%20but%20under-%20utilized%20technique.pdf

Endometrial injury subfertility and superfertility: a decidual link.

Miscarriages occur in approximately 20% of pregnancies. Recurrent pregnancy loss (RPL), affects 1-2% of couples and is defined as three or more consecutive miscarriages. Broadly speaking, the most common cause is chromosomal abnormalities of the embryo. Other causes of RPL include immunological factors (e.g. Lupus), blood clotting disorders a.k.a. thrombophilias (e.g. antiphospholipid syndrome) and uterine factors which are less well understood. The authors of the review article, The molecular basis of recurrent pregnancy loss: impaired natural embryo selection, examine uterine factor infertility and its relation to recurrent miscarriage. 

Researchers have noted that many women with recurrent and consecutive miscarriages, have unusually high pregnancy rates, conceiving within an average of 3 months or less. These women are dubbed ‘superfertile’, though the concept of superfertility in humans is anecdotal and not based on clinical diagnostic testing. Three percent of the population is estimated to be superfertile, compared to 18% estimated to be subfertile (Tietz, 1950; Evers, 2002). It has already been hypothesized that recurrent miscarriage is a consequence of impaired natural embryo selection, in other words, the inability of the uterus to filter out poor quality embryos destined to miscarry (Quenby, 2002). In their review, Teklenburg et al examine the biological plausibility of superfertility as a pathological entity leading to apparent infertility. They use results from their own studies and others to lead to the hypothesis that cyclic changes in the endometrium ensure normal implantation, and that a dysfunctional endometrium associated with superfertility will lead to perturbations in the endometrial decidual response, delayed implantation and poor embryo selection resulting in defective placental formation and miscarriage, regardless of embryo karyotype. This would explain why karyotype analysis of miscarried embryos from superfertile women reveal both chromosomally normal and abnormal embryos. 

To arrive at this theory, they examined the implantation window of the embryo and its coordination with endometrial development. There is clinical evidence that an unresponsive endometrium during the window of implantation is a cause of subfertility. Thus, one would expect that persistent endometrial receptivity will result in higher implantation rates but would also include embryos of poor quality (i.e. superfertility). Central to the process of implantation is decidualization, which occurs about 10 days after ovulation regardless of pregnancy status. This is the process by which endometrial stromal cells differentiate into decidual cells giving the endometrium properties necessary for placenta formation. Inadequate decidualization leads to miscarriage or obstetric complications such as preterm birth. Underlying implantation is a complex molecular cross-talk between the embryo and the endometrium, a process triggered by the hormone progesterone which is responsible for maintaining the endometrium’s integrity during a viable pregnancy. Several types of molecular regulators including growth hormones, transcription factors, and cytokines are needed to mediate the implantation process. The window during which the endometrium is receptive to embryo implantation occurs approximately 6 days after ovulation, lasting for around 5 days. The proposals that miscarriages may be caused by impaired embryo selection or conception outside of the normal implantation window are not new. There is already some evidence from studies to support that impaired embryo selection underlying a short time to pregnancy is a cause of sporadic miscarriages.

Cyclic decidualization in the absence of pregnancy results in menstruation. Researchers have tried to explain from an evolutionary standpoint, why a process which results in the ‘punitive’ occurrence of repeated menstruation arose. One possible explanation is uterine preconditioning which protects the uterine tissues from hyperinflammation and oxidative stress resulting from deep trophoblast invasion during pregnancy.  Another possible explanation put forth by Teklenburg et al in this review is embryo natural selection.  In human co-culture studies, their group recently observed that blastocysts were unable to trigger a maternal response in endometrial stromal cells which had not been decidualized, yet they were able to in decidualizing cells. This led them to hypoethsize that an important function of decidualization is to provide endometrial stromal cells the ability to act as biosensors of embryo quality (Teklenburg et al, 2010a). Therefore the failure of the endometrial stromal cells to undergo an appropriate decidualization would lead not only to late implantation of poorer quality embryos but also to early placental failure regardless of embryonic karyotype. Thus, the ability of the decidualized endometrium to terminate the window of implantation could be just as important for a viable pregnancy as its ability to become receptive.

They propose that this instrinsic failure of endometrial stromal cells to mount an appropriate decidual response is due to a reversible programming of endometrial cells, most likely epigenetic changes such as DNA methylation. 

Implications for Asherman's syndrome?

This hypothesis can potentially explain many causes of uterine factor infertility as well as their current treatments. For example, inflammatory signals are important epigenetic modifiers (Backdahl et al, 2009). Although the review does not mention Asherman's syndrome, it could be speculated that tissue injury from D&Cs resulting in inflammation can lead to epigenetic modification that underlies recurrent miscarriage. Of course this may happen even if the injury does not lead to intrauterine adhesion formation. The persistence of epigenetic modification from the initial trauma could also explain why even after corrective surgery women who had Asherman's syndrome may continue to experience miscarriage or perhaps even become ‘superfertile’ from a defective decidual response. Although superfertility in Asherman’s syndrome has not been previously reported to my knowledge, it is biologically plausible if the theory about epigenetic modification subsequent to endometrial injury is correct. It could also explain why women may become infertile even in the presence of few intrauterine adhesions. Conversely, local injury using endometrial biopsy has been used to improve pregnancy rates in subfertile women, lending support to the theory that tissue injury can modify the decidual response (for the better in this case). How injury can increase fertility in some cases or reduce it in others is unclear, but would probably be related to the extent and location of the injury and baseline fertility characteristics specific to the woman. An interesting study would be to compare decidualization in women with and without Asherman’s syndrome through the expression of uterine proteins and factors involved in decidualization. The potential link between endometrial injury and superfertility may also explain the obstetric complications encountered in women with a history of Asherman’s syndrome such as placenta accreta and percreta, intrauterine growth restriction and preterm birth since these are all related to impaired placental function. 

If the above hypothesis is correct, the bad news is that prenatal genetic diagnosis (PGD) and comparative genomic hybridization (CGH) would not be effective treatments for recurrent miscarriage since even chromosomally normal embryos would abort in the presence of a defective decidual response. Variations in the prevalence of superfertile versus subfertile or infertile patients in different studies could explain the conflicting  efficacies reported for these techniques. There is at least some hope for women with recurrent miscarriage; the authors point out that even after 3 consecutive miscarriages many women with RPL go on to have a successful pregnancy. (Rai and Regan, 2006). The authors also noted that many of the drugs used in the management of RPL (progesterone, DHEA, glucocorticoids and heparin) directly modulate the decidual response and that the timing of their administration could be the critical factor in their outcome.

A better understanding of the endometrium and its decidual response may hold the key to preventing recurrent miscarriage and future obstetric complications. Perhaps the confirmation of an association between endometrial injury, defective decidualization and recurrent pregnancy loss would further support the need to switch to non-invasive and minimally invasive gynecological and obstetric treatments. 

REFERENCES  

Backdahl L, Bushell A, Beck S. Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation. Int J Biochem Cell Biol 2009;41:176 – 184.

Evers JL. Female subfertility. Lancet 2002;360:151 – 159.

Quenby S, Vince G, Farquharson R, Aplin J. Recurrent miscarriage: a defect in nature’s quality control? Hum Reprod 2002;17:1959 – 1963.

Rai R, Regan L. Recurrent miscarriage. Lancet 2006;368:601 – 611.

a. Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C et al. Natural selection of human embryos: decidualizing endometrial stromal cells serve as
sensors of embryo quality upon implantation. PLoS ONE 2010;5:e10258.

Teklenburg G, Salker M, Heijnen C, Macklon NS, Brosens JJ. The Molecular basis of recurrent pregnancy loss: impaired natural embryo selection. Mol Human Reprod. 2010;16(12): 886-895.

Tietze C, Guttmacher AF, Rubin S. Time required for conception in 1727 planned pregnancies. Fertil Steril 1950;1:338– 346.

Articles on Asherman's syndrome: Reproductive outcomes and Obstetric complications

The final section on references to peer-reviewed publications on Asherman's syndrome have been uploaded under pages (please see relevant tab above or click here). It includes case reports, studies and reviews of reproductive outcomes (pregnancy rates, live birth rates), obstetric complications in women with a past history of Asherman's syndrome (e.g. placenta accreta, IUGR etc.), as well as in women who have untreated intrauterine adhesions at the time of pregnancy. I also included some articles on fertility complications in women who have had Asherman's syndrome, such as thin endometrium. I will continue updating all pages with new articles when they are published. I also intend to add other articles such as those on stem cells, uterine transplantation, hysteroscopy, treatment of thin endometrium, and general articles on misoprostol and the risks of D&C, so stay tuned.

A genetic predisposition: from speculation to opinion to 'fact' without any data (Part II)

In my last blog post I presented the ‘evidence’ (or lack thereof) on which the theory of a genetic/constitutional predisposition for Asherman's syndrome was based. To recap the gist of these observations which pass for proof:

a) some women develop a severe form of IUA after undergoing the ‘same’ traumatic procedures as others who do not acquire AS, and 

b) some women respond more ‘favourably’ to treatment than others who suffer from recurrent adhesions. 

Before deconstructing these observations, the most obvious argument against a genetic basis is the lack of familial clustering of the ‘pathology’. Assuming a polygenic mode of inheritance (as opposed to a Mendelian one) it would be expected that those with a first degree relative with Asherman’s syndrome would have a higher risk of  developing AS than those without a close relative who has the condition. I have yet to read a study of identical twins with Asherman’s syndrome, let alone any study showing the sisters or daughters of patients having a higher risk. In over a century since its first report, there is no evidence of familial clustering to lend support to this theory. Nor is there any evidence that women with scarring defects (eg. keloids) or connective tissue disorders (Marfan’s syndrome, Ehlers-Danlos syndrome) are more prone to AS as one might expect. 

How can trauma be quantified when surgery is blind?

As for the ‘evidence’ above, with regards to a), what proof is there that the women who develop severe IUA actually underwent the exact same trauma as those who did not acquire it? This is a an unfounded statement given differences in doctor’s skill, technique and more importantly, the mis- or under-diagnosis of AS and the blind nature of D&Cs- the number one cause of AS. The problem with bind surgery is that one relies on guess work and instinct to not scrape too deeply. ‘Too deeply’ can be one millimeter too much. How is it possible to detect this difference when not even an ultrasound is used during the procedure? Even with visualization it is not possible to tell where the functional endometrium ends and the basal endometrium begins. However, techniques which utilize visualization for intrauterine surgery (i.e. hysteroscopy) are inherently less risky with regards to instrumental injury because they allow the surgeon to only scrape/dissect/remove parts of the endometrium which need to be treated thus sparing underlying and adjacent tissue from potential injury. Furthermore, each woman has a different anatomy, and different location of retained products of conception. Some have retroverted uteri, others have Mullerian malformations, and the shape, widths and lengths of uteri vary enough between women to be a significant factor with regards to acquiring an injury during a blind procedure. A D&C consists of blindly scraping away the top layer of the endometrium (the functional layer) which can vary in thickness between women but is often not thicker than a few millimeters in most parts. It is simply impossible for a clinician or midwife to know whether they have scraped into the basal endometrium, particularly when no visual guidance is used. 

In summary, the above argument is akin to saying that not all smokers develop lung cancer therefore lung cancer is not caused by cigarettes. Why not theorize that those who develop lung cancer have a genetic predisposition instead? (Note: this comment was intended to highlight the absurdity of believing that cigarette smoking does not cause lung cancer, and hence the absurdity of believing that the fact that all women who have D&Cs do not acquire Asherman's syndrome proves that the condition is not caused by D&Cs but is instead genetic. I later learned that the famous statistician RA Fisher actually theorized half a century ago that people who are genetically predisposed to lung cancer are also genetically predisposed to becoming smokers. Of course this theory was refuted by a study of monozygotic twins versus dizygotic twins who were discordant for cigarette smoking, and it turns out,  lung cancer risk. This example points out how easily theories can be taken seriously just because an expert, or in this case, a genius put it forth, and that experts too have biases which affect their views (he smoked and was a consultant for the tobacco industry!). These theories, will not hold up against evidence from well-designed studies, but until these are done, they impede medical progress).

Recurrence depends on initial severity and treatment methods

With respect to the second part of the argument, the fact that some women respond more ‘favourably’ to treatment than others who suffer from recurrent adhesions can be rationally explained in other ways.

Firstly, it is not surprising that some women need more than one hysteroscopic adhesiolysis surgeries than others, depending on severity. This has been known for many years and reported in the literature. The more damage incurred on the endometrium, the higher the rate of IUA recurrence, and the more surgeries needed for correction, although at some point, damage is too great to allow for endometrial regeneration resulting in recurrent adhesions or fibrotic endometrium.

Another important point to consider is that hysteroscopy was not used for diagnosis or treatment when the observation about treatment outcomes was made. Asherman’s syndrome was still ‘treated’ with blind D&C, the same procedure which is responsible for most cases of AS. This would understandably result in inconsistent outcomes. The absence of accurate diagnosis (and hence classification) in those days also distorted the correlation between severity and outcome. A patient with seemingly severe AS presenting with total amenorrhea may ‘inexplicably’ have had a better outcome after surgery than someone with supposedly less severe AS who had some menstrual flow. We now know that amenorrhea is not always due to severe and widespread adhesions. It can be due to cervical adhesions alone. As the rest of the uterus may be intact in such cases, the reproductive prognosis is better than a patient who has deep adhesions in part of her uterus but no outflow obstruction (and thus has menstrual bleeding, albeit reduced flow). 

With regards to treatment, estrogen therapy was not carried out as part of post surgical therapy in the past. It is generally accepted that estrogen supplementation plays an important role in the prevention of adhesion recurrence following surgery/adhesioloysis by stimulating endometrial regeneration. Thus in the absence of hysteroscopic adhesiolysis, uterine stents and estrogen therapy, more severe cases were less treatable than they are today. 

It is well known that the functional endometrium is regenerated from the underlying basal endometrial layer. As a simple analogy, imagine the lining of the uterus as a lawn. The grass seeds would be the stem cells from which the grass grew with the addition of water (i.e. estrogen). The functional layer would be the grass, and the roots would be the basal endometrium. If someone came along to trim the lawn (i.e. D&C) and accidentally dug out the roots of the grass, the grass would regrow after watering only in the areas where there were either some residual roots, or seeds. Imagining that the seeds are in a slightly deeper layer of soil (for the purpose of this analogy), if the gardener dug very deeply so that even the seeds were removed, no amount of watering would regrow the grass. This could happen in a patch of grass or the whole lawn. In this simple analogy the bald patches would be endometrial sclerosis (unstuck Asherman’s), but adhesions would result if two bald patches came into contact with eachother in the uterus.

More recently, the presence of endometrial stem cells at the myometrial junction was reported. These should be able to transform into endometrial stem cells with the right stimulation. The discovery of the existence of endometrial stem cells could explain why in some cases an apparently denuded endometrium (ie.no visible endometrium) will regenerate while in other cases it will not. Or why some women have recurring adhesions while others do not. This would explain why estrogen therapy after hysteroscopic adhesiolysis can in some cases stimulate the regerenation of endometrium while other cases of IUA are recurrent no matter the dose of estrogen therapy and the length of uterine barrier therapy. Endometrium is what keeps the myometrial layer of the uterus from adhering to opposing walls of the uterus. Once again, it is imposible to observe with the naked eye whether stem cells have been removed by curettage or not which would give rise to ‘paradoxical’ outcomes between patients with the ‘same’ severity of injury. In addition, differences in methods for dissecting adhesions can account for differing outcomes. Mechanical methods for adhesion dissection may also be preferable to methods which utilize thermal energy as the latter may damage adjacent tissue.

A modern perspective on an old problem

Authors need to re-evaluate the validity of assumptions, speculations and theories made in publications written when conditions and standards differed greatly to those of today, taking into consideration medical progress.   Although older papers are still important and interesting to read, they need to be interpreted carefully and in the context of limitations in medical technology and critical thinking, lower standards needed for proof and gaps in scientific understanding at the time they were written. Blind repetition of theories cited from papers that were published decades ago without any questioning is simply archaic, unrigorous and unscientific. If there is a case for a genetic or constitutional basis for AS, data from well designed studies would be more persuasive than citing theories which lack any experimental support of any kind. In what seems to be a recurring theme in AS, absence of evidence may not be evidence of absence, but by today’s standards in medicine only presence of evidence is evidence of presence.

A genetic predisposition: from speculation to opinion to 'fact' without any data (Part I)

The theory that Asherman’s syndrome has a ‘constitutional’ or ‘genetic’ basis has been making rounds for a while. It is time to critical appraise this idea with a view of our understanding of modern medicine.

From where did this theory originate and is there any evidence to support it? From my own thorough research of the literature on Asherman’s syndrome, having read most of the peer reviewed publications dating back to the early 60s, the first mention of the possibility of a hypothetical constitutional factor comes from a publication by Foix et al in 1966 (1). They write: (page 1028): "Besides the above-mentioned presidposing factors, there appears sometimes to be a constitutional element, for some of our patients treated for adhesions after each of several induced abortions, always developed new ones.” Thus they give no supporting references or evidence other than their own subjective observations.

Most reviews or studies mentioning this theory cite a review paper by Schenker and Margoliath in 1982 (2). In it they elaborate on the same ideas, citing a case series by Polishuk and Sadovsky in 1973 (3) as ‘support’. Schenker and Margoliath’s rationale was that:

a) some women develop a severe form of IUA after undergoing the ‘same’ traumatic procedures as others who do not acquire AS, and

b) some women respond more ‘favourably’ to treatment than others who suffer from recurrent adhesions.

They go further and conjecture that 28 women plucked from studies they compiled from the literature ‘may have possessed this predisposing factor, which might have been the reason for the development of IUA after normal delivery or following abortion without subsequent curettage, or even when lacking any attributable trauma.” This is a very bold, if not preposterous assertion to make about patients they have never examined or treated. Needless to say, diagnosis from a distance by third party observers is not a credible source of evidence.

The Polishuk and Sadovsky paper also fails to provide any proof. In fact, Polishuk and Sadovsky themselves never mentioned the idea of a genetic predisposition in their paper or set out to prove such a theory. Instead, they present a case series of 11 patients who have recurrent adhesions, one of three types of adhesions, they explain. Adhesions recurred in all cases after curettage for removal of adhesions or following abortion in a new pregnancy. They suggest that the patients in their study may have had extensive endometrial ‘repair’ i.e. fibrosis, where the endometrium is replaced by connective tissue, which they attempted to treat by removing it. Their understanding of cellular physiology, like their contemporaries, is incorrect but excusable given what was known at the the time it was written. They conclude that their treatment was not encouraging. It should not be surprising to doctors today that blind lysis using curettage is not a successful treatment for IUA or that the removal of fibrotic tissue does not result in endometrial regeneration. I will explain later...(Part II)

Since the speculation by Foix et al and later Schenker and Margoliath, numerous authors have subsequenty made it a habit to include this under etiology of AS, apparently without much thought. The theory also seems to have gained credibility with authors stating it as a fact rather than a hypothesis without any further ‘evidence’. The quality of referencing in many articles about Asherman’s syndrome is lacking. Some authors even cite other reviews which never made the speculation. Clearly, many authors simply copy references from other papers without ever reading the original article to confirm or verify what was actually written.

Back in 1948 Asherman himself seemed to have understood that the underlying cause of IUA are usually trauma from instrumentation (although severe infection, especially endometrial tuberculosis can also cause physical injury to the lining) when he named the condition ‘traumatic amenorrhea’ (4). Unfortunately, the medical community has since been trying to attribute other causes or factors necessary for its development (another example of this is ‘subclinical infection’) perhaps to redeem their dependence on blind curettage as a standard procedure, and also to compensate for their lack of understanding about cellular physiology and insight into the condition. The condition has also been renamed (or misnomered) ‘Asherman’s syndrome’ which distances it from an iatrogenic cause. The word ‘traumatic’ made some doctors feel uncomfortable (5):

(See Discussion Dr John Morton LA California): “The nomenclature also is objectionable. The “traumatic” part of the phrase indicates an iatrogenic lesion, which may not always be justified. (my edit: This is true, but many if not most cases are actually iatrogenic since surgery is involved).

(…)

Dr Jones (closing):It is true that the term “traumatic” is not wholly satisfactory, but it is the term most frequently used in current literature to describe the abnormality under discussion. H W Jones Jr has suggested that the term “postcurettage atresia of the endometrial cavity” is more descriptive, and this may avoid the iatrogenic connotation of the word “traumatic”.

(…)

Thus, there must be an inflammatory factor in the etiology of intrauterine adhesions (my edit: Trauma to the tissue causes inflammation-not to be confused with infection). Parenthetically this too underlines Dr Morton’s objection to the term ‘traumatic’.”

I won’t go into why the above reasoning is incorrect here, my point was to display the obvious discomfort doctors felt in acknowledging an iatrogenic etiology, which probably contributed to its eventual name change as well as the reason why the medical community is so willing to accommodate other unproven causes of Asherman’s syndrome. It’s as if the mentality with regards to Asherman’s syndrome is caught in a time warp where principles of modern medicine such as using modern techniques, well designed studies, objectivie interpretation of data and the requirement of evidence have been temporarily waived.

Although it is natural to consider the possibility that any condition may have a genetic basis, a current understanding of adhesions, the advent of hysteroscopy and techniques to view inside the uterus, a century of observations and plain common sense suggest that such an explanation is not only based on speculation and flawed thinking, and cannot obscure the lack of even the weakest level of research evidence (eg. a case study) exists to support it. Next time I will explain exactly why.

We know now that adhesions (whether intra unterine or intra abdominal) are not a pathological response: they are a normal physiological response to injury adjacent mucosa. Adhesions are only pathological in the sense that they can lead to pathologies such as infertility, bowel obstruction and pain, depending on their location. They are the end result of normal wound healing, of which inflammation (not to be confused with infection) is an inherent process. They occur very commonly in intraabdominal surgery because there is no regenerative layer unlike the uterus which is lined with a regenerative endometrium. Yet no intraabdominal surgeon has attempted to label the condition as ‘genetic’ or ‘constitutional. However, not surprisingly, the endometrium will not regenerate if it is entirely removed, which should not occur during curettage, but which may happen unintentionally due to the blind nature of the procedure. The situation in the uterus then becomes analogous to that in the peritoneum, and adhesion formation ensues.

Lastly, with regards to Polishuk and Sadovsky’s paper, if anything, these cases should highlight the dangers of blind curettage as a method of treating Asherman’s syndrome and miscarriage, the latter particularly in women who have had Asherman’s syndrome. It would appear that endometrial damage leading to AS predisposes to further adhesions probably by facilitating injury, even after previous treatment to restore an open cavity. This is consistent with the observation that even after corrective surgery, women who have a history of Asherman’s syndrome are at an increased risk of specific obstetric complications. It is therefore of no surprise that the common underlying characteristic of these complications is a defective utero-placental interface.

REFERENCES

1.  Foix A, Bruno RO, Davison T, Baltasar L. The pathology of postcurettage intrauterine adhesions. Am J Obst & Gynec.1966; 96(7):1027-33.
2. Schenker JG, Margoliath EJ. Intrauterine adhesions: an updated appraisal. 1982; 37(5):593-610.
3. Polishuk WZ, Sadovsky E. A syndrome of recurrent intrauterine adhesions. Am J Obstet Gynecol 1975 151-8.
4. Asherman J, Amenorrhoea traumatic (Atretica). J Obstet Gynecol 1948; Br Emp 55:23.
5. Jones W. Traumatic Intrauterine adhesion; a report of 8 cases with emphasis on therapy. Am J Obstet & Gynec 1964; 89(3):304-13.

Articles on Asherman's syndrome Diagnosis, Classification and Treatment

Further publications on Asherman's syndrome have been added to the site. These include those on the Diagnosis, Classification and Treatment of Asherman's syndrome. Please click here or on the relevant tab in the menu above to view these references.

Previously a page with references to studies on the Etiology, Incidence and Prevention of Asherman's syndrome was added. Click here or on the relevant tab in the menu above for more.

Further references to publications on Asherman's syndrome by topic will be added to the site in the near future.

Alternative perspectives?

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.

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