Currently the gold standard for treatment of Asherman’s syndrome is surgery to remove/cut adhesions (hysteroscopic adhesiolysis or synechiolysis) and hormonal therapy to regenerate any residual endometrium. One of the challenges in treating Asherman’s syndrome is the propensity of intrauterine adhesions to reform again during the healing process. To try to overcome this, some doctors place a saline-filled stent (Foley or Cook) or an IUD in the uterus after surgery in order to keep the walls of the uterus and cervix apart during the healing process. If there is little endometrium regrowth adhesions will continue forming again in the same areas. Hormone therapy (2-4mg/day estrogen for up to 2 months followed by progestin (P) to induce a withdrawal bleed) is also used in addition to surgery to prevent adhesions from reforming by promoting regrowth of endometrium. It is also thought that it generally improves the thickness and quality of endometrium- some patients end up with thin endometrium or fibrosis (scar tissue with no viable endometrium) after instrumental trauma from surgery precipitating Asherman’s syndrome (usually a D&C). Adhesion reformation following corrective surgery correlates with the severity of adhesions. According to one study adhesion reformation occurs in 50% of severe cases and 21.6% of moderate cases (1). Sometimes multiple surgeries are needed to correct uterine architecture.
The problem is that if one does not have enough endometrium because it has been scraped away, either adhesions or fibrosis will continue to be a problem no matter how many surgeries are undertaken or how much hormonal stimulation is given.
As you can see from a previous post, the live birth rates after corrective surgery are not very high for moderate to severe cases. To understand why this treatment is not effective in all patients one needs to understand the physiology of the endometrium and adhesion formation. The outermost layer of the uterus is lined by the endometrium which sits above the muscle layer, the myometrium. The endometrium itself is comprised of two layers. The functional layer is outermost and is shed on a monthly basis during menstruation. The underlying basal layer is necessary to produce the functional layer each month. If permanent damage is incurred to the basal layer, the functional layer will not be able to regenerate. Without the regeneration of endometrium the bare myometrium underlying the endometrium will begin to stick to other areas devoid of endometrium as soon as the injury occurs. Adhesion formation is the normal physiogical response to injury whether this is in the uterus or elsewhere in the abdominal cavity. Adhesion formation begins immediately after scar formation from instrumental injury and will be complete by 8 weeks. Any area where injured tissue can come into contact with other injured tissue, adhesions form. Adhesions are a serious health problem related to surgery, not just in the uterus but also in the abdomen and intestines. However abdominal or intestinal surgery does not have alternatives whereas uterine evacuation does. In other words, D&C is not the only available method for effectively emptying the uterus after miscarriage or delivery, however staggeringly, it remains standard care for the former in many advanced countries.
So the problem comes down to endometrial regeneration (or the lack of it). Some tissue in the body is able to regenerate. For example, cells in the the gut and bone marrow regularly divide to repair damaged or worn out tissue. In other tissues such as the heart and brain, cells are only stimulated to divide under special circumstances. Endometrium is another such tissue. Tissue regeneration is due to the activity of stem cells which have special properties. Initially it was thought that only embryonic stem cells had the capacity to differentiate. More recently the existence of adult stem cells was discovered. Adult stem cells are undifferentiated cells usually found in little islands or "niches" in tissues and organs. They are generally thought to have a more limited ability to differentiate than embryonic stem cells which can develop into any type of cell in the body. Adult stem cells, on the other hand, are already partially committed to certain cell lineages. Adult stem cells are thought to play a role in tissue maintenance and reparation in the tissues they are found.
Recently the existence of endometrial adult stem cells was reported in the scientific literature (2). However, if all of the basal and stem cells have been removed from a large part of the uterus, it is impossible to resolve the problem of recurrent adhesion formation and/or fibrosis. Sadly, current therapy can only remove bands of scar tissue and promote endometrial regeneration in areas where there is some remaining basal cells or even perhaps stem cells. Put simply, current treatment will not be successful if the patient does not have enough residual endometrium to regenerate. In theory, the identification of endometrial stem cells in the junction between the endometrium and myometrium opens the possibility of future therapy for damaged endometrium. Stem cells can be introduced either from a donor, or better yet, from the same patient whose stem cells have proliferated in a culture medium. Once inside the right tissue and with the appropriate stimulation, they will be able to differentiate into basal endometrial cells and fill in any 'bald' patches of endometrium. Adhesion formation or sclerosis should no longer be a problem. The advantage of using the patients own cells is that it will avoid immune rejection. The use of adult stem cells also avoids any obstacles from those citing ethical problems in using embryonic stem cells. Note that I have greatly simplified the process in the scenario above.
Stem cell research, both adult and embryonic, are still in their infancy. Most stem cell researchers are focusing on regeneration of heart tissue or other major organs as an alternative to organ transplantation. The problem is that there is little if any research on endometrial regeneration and in particular for the treatment of Asherman’s syndrome. In the past basic research was carried out to improve endometrial growth in animals where AS was artificially produced. This type of research no longer seems to exist. Instead, there is research on uterus transplantation which is much more complex and difficult to achieve. As long as endometrial research remains stalled there is little hope that treatment will continue to progress much beyond what has been attained today- which leaves much to be desired if treatment is regarded as the primary solution to the problem of Asherman’s syndrome.
REFERENCES
1. Valle RF, Sciarra JJ. Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. Am J Obstet Gynecol. 1988 Jun;158(6 Pt 1):1459-70.
Abstract
2. Gargett BE, Chan RW. Endometrial stem/progenitor cells and proliferative disorders of the endometrium. Minerva Ginecol. 2006 Dec;58(6):511-26.
Abstract
Tuesday, September 22, 2009
Tuesday, September 15, 2009
‘Victims’ in miscarriage headlines are luckier than they think
Oh no. Not another story about a woman who goes to hospital emergency with an impending miscarriage and gets given painkillers and told to go home (click here for 'story'). Or miscarries in the hospital toilet. I don’t know why, but Sydney newspapers abound with such stories. It started off with the famous Jana Horska story. Yesterday I read in the Sydney Morning Herald that women will now be offered D&Cs straight away. OK, I’ve kept silent long enough. When women think that miscarriage and the pain that goes with it are the worst things than can happen to them, I must enlighten them about Asherman’s syndrome. Especially when their complaints have prompted hospitals to consider carrying out even more D&Cs, the number one cause of Asherman’s syndrome.
One in four pregnancies ends in miscarriage. I too had a miscarriage so I know what I’m talking about. I was around 14 weeks into the pregnancy. Mine was a missed miscarriage detected via ultrasound at 11 weeks. The fetus either died (fetal demise) and was resorbed or stopped developing very early on (anembryonic gestation). I was offered a D&C straight away by my ObGyn. I recalled vaguely hearing about the risks of D&C and future fertility. I was 39 and was not about to take a chance. My ObGyn insisted that Asherman’s syndrome and uterine perforation were ‘extremely rare’ (see what the real incidence rates are. Not rare at all!). Still, if there was a chance I could avoid it altogether by waiting to miscarry naturally, I would take that option. I had no other choice as he flatly refused to give me medication (misoprostol). The ObGyn was visibly irritated and disappointed in my choice to avoid a D&C.
The shock and sadness of losing the pregnancy was soon replaced with impatience to miscarry naturally so I could avoid a D&C, and start trying to conceive again with my fertility intact. My goal was to avoid a D&C at all costs. I was relieved when one Sunday morning about 3 weeks later, I finally began to bleed. At first it was like a normal period. As the day progressed the bleeding got heavier, and so did the cramps. By 11 PM I could no longer contain my cries of pain. My husband shut the windows, worried the neighbours might think he was beating me! Finally around midnight when I could no longer stand the pain I sent my husband to an all night pharmacy to get the strongest painkiller available without prescription. He tried to convince me to go to the hospital instead. “Are you nuts?” I retorted. “They’ll just tell me to have a D&C”. Not only that, but I’d have to stifle my moans and sit upright in uncomfortable clothes, surrounded by strangers and without access to a clean toilet. At home I could make as much noise as I wanted in my loose nighty and stand on all fours if that was the most comfortable position. The toilet was less than a meter from my bed and I wouldn’t have to compete with 50 other patients for it while waiting in emergency. He came back with a box of Panadeine forte containing codeine and that took the edge off the labour-like cramps. At some point after midnight I felt a ‘pop’ and instantaneous relief. Instinctively I knew the gestational sac must have burst and I rushed to the toilet. I continued to bleed heavily but was glad everything was coming out.
Later that day I had an appointment with the ObGyn who seemed rather disappointed that I miscarried by myself. Somewhat wistfully, he said that on ultrasound it appeared that there was no remaining tissue. What a relief that was to hear. But for some reason, he insisted I return a few days later to make sure everything was OK. When I returned later that week his story changed. This time he said it appeared that I had large ‘products of conception’ and that I had no other choice than to have a D&C. What??? I asked about drugs again. He refused again, saying they would be ‘ineffective.’ Reluctantly, I had the D&C, got stage 3 Asherman’s syndrome and the rest is history. (Here’s my story).
I’m convinced that the D&C was needless. I lost my fertility for no reason at all.
I wonder if these women who are sent home without a D&C realize how lucky they are to not go through what I did? Instead of noticing something is wrong with their periods, or are no longer able to conceive or miscarry repeatedly… instead of having to find a doctor who believes them and who is aware about the existence of Asherman’s syndrome and is trained to diagnose it with hysteroscopy… instead of having to undergo hysteroscopic surgery and hormone therapy to remove adhesions and salvage any viable endometrium in the hope that they will be able to have a baby in future… they get to try to conceive again right away with any complications whatsoever! And they’re the ones who are complaining! As a victim of D&C, I guarantee you, a miscarriage is nothing compared to the pain of possible loss of fertility and serious future pregnancy complications from D&C.
I wonder, do these women realize that there is absolutely nothing any hospital or doctor can do to stop the miscarriage from happening? They probably miscarried because the babies were not normal and there is unfortunately nothing that can change that. If they really want to be of help, they should insist that hospitals offer medical management with misoprostol and mifepristone in addition to expectant management, which also evacuates the uterus safely. Instead, I fear their indignant cries have resulted in a policy to systematically use D&C to manage miscarriage and will result in an increase in Asherman’s syndrome cases.
When will the lesson be learned? What is the world coming to when no one says a word about the risks of reproductive mutilation from systematic blind D&C, yet C-sections and male circumcision are made out to be the most dangerous,needless and wicked surgery known to humankind?!
Related link:
Here is a youtube clip I made about miscarriage management
This is another website which aims to raise awareness about the risks of D&C: http://www.dandcnow.info/
One in four pregnancies ends in miscarriage. I too had a miscarriage so I know what I’m talking about. I was around 14 weeks into the pregnancy. Mine was a missed miscarriage detected via ultrasound at 11 weeks. The fetus either died (fetal demise) and was resorbed or stopped developing very early on (anembryonic gestation). I was offered a D&C straight away by my ObGyn. I recalled vaguely hearing about the risks of D&C and future fertility. I was 39 and was not about to take a chance. My ObGyn insisted that Asherman’s syndrome and uterine perforation were ‘extremely rare’ (see what the real incidence rates are. Not rare at all!). Still, if there was a chance I could avoid it altogether by waiting to miscarry naturally, I would take that option. I had no other choice as he flatly refused to give me medication (misoprostol). The ObGyn was visibly irritated and disappointed in my choice to avoid a D&C.
The shock and sadness of losing the pregnancy was soon replaced with impatience to miscarry naturally so I could avoid a D&C, and start trying to conceive again with my fertility intact. My goal was to avoid a D&C at all costs. I was relieved when one Sunday morning about 3 weeks later, I finally began to bleed. At first it was like a normal period. As the day progressed the bleeding got heavier, and so did the cramps. By 11 PM I could no longer contain my cries of pain. My husband shut the windows, worried the neighbours might think he was beating me! Finally around midnight when I could no longer stand the pain I sent my husband to an all night pharmacy to get the strongest painkiller available without prescription. He tried to convince me to go to the hospital instead. “Are you nuts?” I retorted. “They’ll just tell me to have a D&C”. Not only that, but I’d have to stifle my moans and sit upright in uncomfortable clothes, surrounded by strangers and without access to a clean toilet. At home I could make as much noise as I wanted in my loose nighty and stand on all fours if that was the most comfortable position. The toilet was less than a meter from my bed and I wouldn’t have to compete with 50 other patients for it while waiting in emergency. He came back with a box of Panadeine forte containing codeine and that took the edge off the labour-like cramps. At some point after midnight I felt a ‘pop’ and instantaneous relief. Instinctively I knew the gestational sac must have burst and I rushed to the toilet. I continued to bleed heavily but was glad everything was coming out.
Later that day I had an appointment with the ObGyn who seemed rather disappointed that I miscarried by myself. Somewhat wistfully, he said that on ultrasound it appeared that there was no remaining tissue. What a relief that was to hear. But for some reason, he insisted I return a few days later to make sure everything was OK. When I returned later that week his story changed. This time he said it appeared that I had large ‘products of conception’ and that I had no other choice than to have a D&C. What??? I asked about drugs again. He refused again, saying they would be ‘ineffective.’ Reluctantly, I had the D&C, got stage 3 Asherman’s syndrome and the rest is history. (Here’s my story).
I’m convinced that the D&C was needless. I lost my fertility for no reason at all.
I wonder if these women who are sent home without a D&C realize how lucky they are to not go through what I did? Instead of noticing something is wrong with their periods, or are no longer able to conceive or miscarry repeatedly… instead of having to find a doctor who believes them and who is aware about the existence of Asherman’s syndrome and is trained to diagnose it with hysteroscopy… instead of having to undergo hysteroscopic surgery and hormone therapy to remove adhesions and salvage any viable endometrium in the hope that they will be able to have a baby in future… they get to try to conceive again right away with any complications whatsoever! And they’re the ones who are complaining! As a victim of D&C, I guarantee you, a miscarriage is nothing compared to the pain of possible loss of fertility and serious future pregnancy complications from D&C.
I wonder, do these women realize that there is absolutely nothing any hospital or doctor can do to stop the miscarriage from happening? They probably miscarried because the babies were not normal and there is unfortunately nothing that can change that. If they really want to be of help, they should insist that hospitals offer medical management with misoprostol and mifepristone in addition to expectant management, which also evacuates the uterus safely. Instead, I fear their indignant cries have resulted in a policy to systematically use D&C to manage miscarriage and will result in an increase in Asherman’s syndrome cases.
When will the lesson be learned? What is the world coming to when no one says a word about the risks of reproductive mutilation from systematic blind D&C, yet C-sections and male circumcision are made out to be the most dangerous,needless and wicked surgery known to humankind?!
Related link:
Here is a youtube clip I made about miscarriage management
This is another website which aims to raise awareness about the risks of D&C: http://www.dandcnow.info/
Friday, September 11, 2009
The cycle of Asherman's syndrome needs to be broken with prevention
In my next blog I will explain why it is that current treatment (surgery and hormone therapy) can never be a cure for all women who have been diagnosed with Asherman’s syndrome (AS). However I also want to explain why my position on prevention as the best approach is unwavering. I’ve always maintained that I would continue to spread my word about prevention even if I was lucky enough to have a baby after AS treatment. This is because I realize that I would be one of the lucky minority if I did. Just because I may be fortunate enough to have a child after my diagnosis and treatment doesn’t mean I should forget about all of the others who didn’t. It’s not about how ‘hard’ you try or how ‘deserving’ you are- one has to understand that the body has its limits according to the damage that was incurred and other factors. I would realize that my case may not have necessary been as severe or my situation not as dire as others who were inflicted with this condition. It would be unfair to the women who have done all they possibly could to achieve a live birth but didn’t succeed to not acknowledge that each case is different not only in severity but also the circumstances in which it happens. As a PhD scientist (molecular microbiology) I know there are no hidden Asherman’s experts out there: all of the ones who are truly experts have peer reviewed published papers on outcomes in their patients following treatment. That is the nature of these careers. One is judged and recognized according to their publication record. And I have read those papers and know what the outcomes are. I would feel daft to go around telling other women not to worry about getting Asherman's syndrome because it can be treated when a) according to statistics from the best doctors, the majority of women will not have a live birth after AS, and b) it doesn't have to happen in the first place. I know also that personally, I could never forget what happened to me for no justifiable reason. Imagine if someone almost accidentally killed you through a preventable and routine careless act but you were saved by a treatment which has a 50% failure rate at best- would you think it was better to promote the treatment , or would you want to do something to prevent another person from possibly losing their life? If I will ever be fortunate to have a child after Asherman’ s syndrome it doesn’t mean that it is still acceptable to damage women through the systematic use of D&C when alternatives exist. I cannot forget the years of suffering, of fearing I will never have a child, the sleepless nights, the tears, the time lost waiting for treatment as I now had to race against my biological clock, the negative pregnancy tests month after month, the failed IVF, the worries that even if I were to become pregnant post AS pregnancies are high risk, none of that will ever be ‘worth it’. For me, to say something is ‘worth it’, it has to be something challenging that I chose for myself, not what someone (ie a treating Dr) did to me. For example, my PhD- those were some of the most difficult and challenging years of my life, performing experiments until late at night and on weekends, reading hundreds of papers, spending months writing my thesis. But I wanted to do, and it was worth it! Without all that hard work I wouldn't have achieved it. On the other hand, it should not be a struggle to have a child when nothing is wrong with you in the first place. Isn't there enough infertility and heartache in the world without doctors causing Asherman's syndrome?
As women we are expected to be martyrs and put up with all kinds of assaults on our bodies without complaining. It’s supposed to be the very essence of being a caring, nurturing Madonna, to put ourselves last. I prefer to be proactive and warn women about the dangers of D&C, and let doctors know it is not OK to perform D&Cs at the drop of a hat. It’s not acceptable to pretend there are no alternatives and to keep silent when prolife activists prevent drug companies from seeking FDA approval for drugs which can prevent fertility loss and even mortality because they also happen to be used for abortion.
You see, it’s not just about me. Of course I’m angry that it happened to me, especially given the particular circumstances- I was 39 and it was my first pregnancy that ended in miscarriage. Given my age I was extremely concerned about future fertility. I had asked about the risks of D&C and in particular about AS only to be told it was rare, I had asked for alternatives like misoprostol only to be told it was ineffective and refused. I had put up a brave stand to avoid D&C by waiting to miscarry myself (which I did) and after all of that I was told that I had RPOC and had to have a D&C or risked getting AS from an infection (balogna!). The pathology report showed that I only had a blood clot and some tiny fragments and no infection. But it's not that I am a disgruntled, childless older woman: even if I were to have a child, it’s the principle that I find objectionable- that women are continuing to go through this needless suffering because doctors will not give up an archaic surgery even when other safer and cheaper medical options have been developed.
Once again, to be clear, I encourage all women who have been diagnosed with Asherman’s syndrome: please seek help from an expert for treatment if you want to have a chance of having a child. I won’t ever regret having treatment even if I don’t succeed in having a child because I know without it there would be no possibility of it. I gave myself the best odds that I could in a situation which never should have happened to me in the first place. But just because it happened to me it doesn’t mean it should continue happening to others! There is nothing I gain out of pain and suffering of other women. It makes me somewhat angry that other women who have had it before me have done nothing to prevent it from happening to me and others. It makes me somewhat resentful that the information I was after about D&C risks and alternatives for miscarriage management were not readily available to me at the time that I needed it. And I refuse to continue that cycle which is why I am doing everything possible to warn and educate women about the big coverup about Asherman’s syndrome and D&C risks and the existence of cheaper and safer alternatives. Not to mention the exaggeration of treatment success to patients as an excuse to hinder prevention. Of course, anything that promotes further dependence on doctors is encouraged and supported by the medical community while prevention is ignored. It’s time to break the cycle-now.
Some women speak of the spiritual journey AS has given them in a way where they almost sound thankful that it happened to them! All I can say it that I don' t understand people who are thankful for unnecessary damage to be inflicted upon themselves. Only someone who didn’t feel they were worthy or seriously deluded would think it was a blessing in disguise. Asherman’s syndrome was never ‘meant to be’. It only happens because many doctors are unwilling to offer alternatives to D&Cs and nothing is being done about it.
In my ‘journey’ I have learned a lot from having Asherman’s syndrome. I have learned that there is an urgent need for women to speak out against the routine use of D&C for miscarriage. I have learned that women should at the very least be given the right to choose which treatment option they prefer. I have learned that women must pressure doctors and the government to approve of all drugs which can help to safely evacuate the uterus and that these should be the first line of therapy for miscarriage and other indications instead of D&C. I have learned that not all doctors act in the best interest of their patients so patient activism is required for change.
As women we are expected to be martyrs and put up with all kinds of assaults on our bodies without complaining. It’s supposed to be the very essence of being a caring, nurturing Madonna, to put ourselves last. I prefer to be proactive and warn women about the dangers of D&C, and let doctors know it is not OK to perform D&Cs at the drop of a hat. It’s not acceptable to pretend there are no alternatives and to keep silent when prolife activists prevent drug companies from seeking FDA approval for drugs which can prevent fertility loss and even mortality because they also happen to be used for abortion.
You see, it’s not just about me. Of course I’m angry that it happened to me, especially given the particular circumstances- I was 39 and it was my first pregnancy that ended in miscarriage. Given my age I was extremely concerned about future fertility. I had asked about the risks of D&C and in particular about AS only to be told it was rare, I had asked for alternatives like misoprostol only to be told it was ineffective and refused. I had put up a brave stand to avoid D&C by waiting to miscarry myself (which I did) and after all of that I was told that I had RPOC and had to have a D&C or risked getting AS from an infection (balogna!). The pathology report showed that I only had a blood clot and some tiny fragments and no infection. But it's not that I am a disgruntled, childless older woman: even if I were to have a child, it’s the principle that I find objectionable- that women are continuing to go through this needless suffering because doctors will not give up an archaic surgery even when other safer and cheaper medical options have been developed.
Once again, to be clear, I encourage all women who have been diagnosed with Asherman’s syndrome: please seek help from an expert for treatment if you want to have a chance of having a child. I won’t ever regret having treatment even if I don’t succeed in having a child because I know without it there would be no possibility of it. I gave myself the best odds that I could in a situation which never should have happened to me in the first place. But just because it happened to me it doesn’t mean it should continue happening to others! There is nothing I gain out of pain and suffering of other women. It makes me somewhat angry that other women who have had it before me have done nothing to prevent it from happening to me and others. It makes me somewhat resentful that the information I was after about D&C risks and alternatives for miscarriage management were not readily available to me at the time that I needed it. And I refuse to continue that cycle which is why I am doing everything possible to warn and educate women about the big coverup about Asherman’s syndrome and D&C risks and the existence of cheaper and safer alternatives. Not to mention the exaggeration of treatment success to patients as an excuse to hinder prevention. Of course, anything that promotes further dependence on doctors is encouraged and supported by the medical community while prevention is ignored. It’s time to break the cycle-now.
Some women speak of the spiritual journey AS has given them in a way where they almost sound thankful that it happened to them! All I can say it that I don' t understand people who are thankful for unnecessary damage to be inflicted upon themselves. Only someone who didn’t feel they were worthy or seriously deluded would think it was a blessing in disguise. Asherman’s syndrome was never ‘meant to be’. It only happens because many doctors are unwilling to offer alternatives to D&Cs and nothing is being done about it.
In my ‘journey’ I have learned a lot from having Asherman’s syndrome. I have learned that there is an urgent need for women to speak out against the routine use of D&C for miscarriage. I have learned that women should at the very least be given the right to choose which treatment option they prefer. I have learned that women must pressure doctors and the government to approve of all drugs which can help to safely evacuate the uterus and that these should be the first line of therapy for miscarriage and other indications instead of D&C. I have learned that not all doctors act in the best interest of their patients so patient activism is required for change.
Tuesday, September 8, 2009
Treatment of Asherman's syndrome is not a panacea, Part III
Continued from Part II
In my last post in this series on treatment of Asherman's syndrome I posted the actual live birth rate outcomes according to studies published peer reviewed medical journals to show why it is not the promising solution that it is often promoted as, and why prevention would be a better approach. The gold standard for treatment of intrauterine adhesions (Asherman’s syndrome) is hysteroscopic adhesiolysis (synechiolysis) and hormonal therapy. Most studies so far focus on fertility outcomes following a particular treatment method.
Yet one needs to be cautious when evaluating outcomes because some studies are presented in ways which may mislead the inexperienced or lay reader into believing that the success rates are higher than they actually are. If you have read some of the original abstracts or papers I cited in the references of my last post, you may notice that some of the results I have given differ from those apparently reported by the authors. This is because I gave live birth rates as total number of births per total number of patients treated, which gives a complete and accurate picture of the outcomes. As I explained before, the reason I did this is to include women who may never have conceived as it is very possible that surgery did not restore their fertility. Below are some other examples of how data presentation can be misleading.
Data Presentation
'Success rates’ after surgery may not be what you had in mind. I think most patients like myself are interested in achieving a live birth. Sometimes the author is referring to menstrual outcome. Yasmin et al (1), report that 95% of women in their study resumed normal menstruation. Unfortunately, this is not closely correlated to live birth rate. Accordingly, only 1 patient out of 20 treated ie.5% went on to have a live birth (although followup was short). Restoration of menses is known to be an unreliable criteria for future fertility. In my view this is partly because it is self-reported.
Even pregnancy or conception rates per patients treated or live birth rates per total pregnancies do not necessarily reflect live birth outcomes realistically because not only do 1 in 4-5 pregnancies end in miscarriage under the best of circumstances, women with a history of Asherman’s syndrome are also prone to second trimester pregnancy loss and preterm delivery (2). Other women with residual scarring may conceive but repeatedly miscarry with no live births.
In one study (3) the abstract says that live birth rate was 86.1%. Not only was this an overall rate in a study group where mild and moderate cases greatly outnumbered severe cases (71 vs 18), it is also calculated per pregnancy (instead of per patients treated). This can be gleaned from Table 3 where a 66.6% live birth rate was given among women with severe condition at presentation. In other words, two thirds of the women with severe Asherman’s who were able to conceive after treatment went on to deliver a live baby. This is good but not that inspiring when you consider that most women in this group were not able to conceive. In fact, only 4 out of 18 (22%) women with severe AS in this study had a live birth. Another example of this occurs in Table 6 of Yu et al, 2008 (4) review where outcomes are given in terms of live births/pregnancies.
Perhaps reporting data in this way is seen as acceptable by some because doctors are all too eager to put down the inability to conceive after treatment to ‘other fertility issues’, particularly in women who have had the cruel misfortune of being inflicted with Asherman’s syndrome before having a child. The ridiculous premise is that unless women have a live birth prior to developing this iatrogenic condition, they cannot 'prove' they were ever fertile (infertile unless proven otherwise). Unless these ‘other causes of infertility’ are clearly described and (depending on the cause) pre-existing, there is no evidence to suggest that these women were infertile to begin with and should be discarded from outcomes. If the studies were conducted according to the highest standards, women with ‘other fertility issues’ would be excluded from studies to begin with and not after the fertility results are known. This brings me to…
Study design
Besides data presentation, it is also important to take into account how the study was conducted because this too has important implications on outcomes. Unfortunately, studies on Asherman’s syndrome have not been conducted to meet most rigorous scientific methodology-RCTs, making it difficult to assess the exact outcomes. I have mentioned the lack of RCTs in an earlier post. It follows that there are currently no systematic reviews or meta-analyses of the studies either since they are not conducted to stringent standards.
RCTs are clinical trials which have to meet certain criteria in order for the results to be considered unbiased, accurate and of statistical significance. In summary, studies must be done prospectively, they must be randomized with respect to treatment strategies depending on the outcome measure(s), there must be blinding of the doctors, investigators with regard to diagnoses/assessment of outcome with regards to treatment, a clear definition of exclusion and inclusion criteria for patients must be set in order to avoid outcome bias, and there must be enough participants in the/each study group(s) such that statistical analyses can be deemed to have significant value.
RCTs can be carried out to test the efficacy of a particular treatment, or to compare the efficacies of two or more different treatments. Most Asherman's studies focus on fertility outcomes following a given treatment protocol. The risk for potential bias comes mainly from unclearly defined patient inclusion/exclusion criteria, retrospective analyses and sample size and composition.
With regards to study design, the most blatant weakness is when studies are done retrospectively. This means that the doctor/investigator chooses the data to present after they already know the outcomes. This approach introduces the possibility of bias in outcomes because they may select, for example, all of the patients who went on to have live births after treatment, but leave out a portion of those who did not regain their fertility from the study without ever mentioning it. This would obviously make the success rate of treatment appear to be higher than in actuality. Most studies are now carried out prospectively.
Even if a study is done prospectively there are ways in which the outcome can be premeditatingly skewed to enhance outcomes. This is why in proper RCTs everything about the study (except for the results and conclusions) is decided in detail in advance and recorded in a repository. This leaves little space for modifications which can incorporate bias.
If exclusion/inclusion criteria are not stringent from the outset, some of the women who did not achieve a pregnancy could still be discounted on account that they had ‘other' fertility problems. Some authors write their study before allowing a reasonable followup time (1,5) and suggest that the success rate is potentially higher because at the time of writing it was too soon for X number of patients to try to conceive. Others may include patients with ongoing pregnancies (4,6,7,8) which may later not eventuate in live birth on complete followup. In one study, (9) live birth rates were reported as 83% a figure that sticks out like a sore thumb compared to other studies. It turns out that the study, which was done on 365 women, only included 186 patients in the live birth rate outcome. The justification for this was the 179 patients who were left out did not desire a pregnancy. Call me skeptical but I find it hard to believe that 179 women would undergo surgery just to get their periods back. If you include all 365 women in the study the live birth rates don’t look quite as remarkable -42.7%- blending in with the rates recorded by other studies.
Another thing to keep in mind is patient composition: how many have mild, moderate and severe disease? Since an increase in disease severity is associated with a poorer prognosis in terms of live births, a study group consisting of proportionally fewer severe cases could artificially bump up the live birth rate. Therefore it is important to either indicate this by giving a breakdown of outcomes according to disease severity, or to carry out studies where there are equal numbers of patients of the different disease classifications. Many studies will report overall birth rates among patients without giving a breakdown according to disease severity at presentation. It is up to the reader to do their own calculations.
I think the above examples show why proper RCTs are needed to not just to compare different methods of treatment, but to give accurate data regarding live birth outcomes. It would also be of help if there was a more standard way of reporting outcomes such as live births per total patients treated.
REFERENCES
1. Yasmin H, Nasir A, Noorani KJ. Hystroscopic management of Asherman’s syndromeJ Pak Med Assoc. 2007 Nov;57(11):553-5.
2. Capella-Allouc, S, Morsad, F, Rongieres-Bertrand, C, Taylor, S, and Fernandez, H. Hysteroscopic treatment of severe Asherman's syndrome and subsequent fertility. Hum Reprod 1999;14(5):1230-3.
3. Roy KK, Baruah J, Sharma JB, Kumar S, Kachawa G, Singh N.Reproductive outcome following hysteroscopic adhesiolysis in patients with infertility due to Asherman's syndrome. Arch Gynecol Obstet. 2009
4. Yu, D, Li, TC, Xia, E, Huang, X, Liu, Y, and Peng, X. Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman's syndrome. Fertil Steril 2008;89(3):715-22.
5. A. Thomson, J. Abbott, A. Kingston, M. Lenart, T. Vancaillie. Fluoroscopically guided synechiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Fertil Steril, 2007; Volume 87(2):405-410
6. Goldenberg, M, Sivan, E, Sharabi, Z, Mashiach, S, Lipitz, S, and Seidman, DS. Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions. Hum Reprod 1995;10(10):2663-5.
7. Robinson, JK, Colimon, LM, and Isaacson, KB. Postoperative adhesiolysis therapy for intrauterine adhesions (Asherman's syndrome). Fertil Steril 2008;90(2):409-14.
8. Protopapas, A, Shushan, A, and Magos, A. Myometrial scoring: a new technique for the management of severe Asherman's syndrome. Fertil Steril 1998;69(5):860-4.
9. Feng, Z, Yang, B, Shao, J, and Liu, S. Diagnostic and therapeutic hysteroscopy for traumatic intrauterine adhesions after induced abortions: clinical analysis of 365 cases. Gynaecol Endosc 1999;8(2):95-98.
In my last post in this series on treatment of Asherman's syndrome I posted the actual live birth rate outcomes according to studies published peer reviewed medical journals to show why it is not the promising solution that it is often promoted as, and why prevention would be a better approach. The gold standard for treatment of intrauterine adhesions (Asherman’s syndrome) is hysteroscopic adhesiolysis (synechiolysis) and hormonal therapy. Most studies so far focus on fertility outcomes following a particular treatment method.
Yet one needs to be cautious when evaluating outcomes because some studies are presented in ways which may mislead the inexperienced or lay reader into believing that the success rates are higher than they actually are. If you have read some of the original abstracts or papers I cited in the references of my last post, you may notice that some of the results I have given differ from those apparently reported by the authors. This is because I gave live birth rates as total number of births per total number of patients treated, which gives a complete and accurate picture of the outcomes. As I explained before, the reason I did this is to include women who may never have conceived as it is very possible that surgery did not restore their fertility. Below are some other examples of how data presentation can be misleading.
Data Presentation
'Success rates’ after surgery may not be what you had in mind. I think most patients like myself are interested in achieving a live birth. Sometimes the author is referring to menstrual outcome. Yasmin et al (1), report that 95% of women in their study resumed normal menstruation. Unfortunately, this is not closely correlated to live birth rate. Accordingly, only 1 patient out of 20 treated ie.5% went on to have a live birth (although followup was short). Restoration of menses is known to be an unreliable criteria for future fertility. In my view this is partly because it is self-reported.
Even pregnancy or conception rates per patients treated or live birth rates per total pregnancies do not necessarily reflect live birth outcomes realistically because not only do 1 in 4-5 pregnancies end in miscarriage under the best of circumstances, women with a history of Asherman’s syndrome are also prone to second trimester pregnancy loss and preterm delivery (2). Other women with residual scarring may conceive but repeatedly miscarry with no live births.
In one study (3) the abstract says that live birth rate was 86.1%. Not only was this an overall rate in a study group where mild and moderate cases greatly outnumbered severe cases (71 vs 18), it is also calculated per pregnancy (instead of per patients treated). This can be gleaned from Table 3 where a 66.6% live birth rate was given among women with severe condition at presentation. In other words, two thirds of the women with severe Asherman’s who were able to conceive after treatment went on to deliver a live baby. This is good but not that inspiring when you consider that most women in this group were not able to conceive. In fact, only 4 out of 18 (22%) women with severe AS in this study had a live birth. Another example of this occurs in Table 6 of Yu et al, 2008 (4) review where outcomes are given in terms of live births/pregnancies.
Perhaps reporting data in this way is seen as acceptable by some because doctors are all too eager to put down the inability to conceive after treatment to ‘other fertility issues’, particularly in women who have had the cruel misfortune of being inflicted with Asherman’s syndrome before having a child. The ridiculous premise is that unless women have a live birth prior to developing this iatrogenic condition, they cannot 'prove' they were ever fertile (infertile unless proven otherwise). Unless these ‘other causes of infertility’ are clearly described and (depending on the cause) pre-existing, there is no evidence to suggest that these women were infertile to begin with and should be discarded from outcomes. If the studies were conducted according to the highest standards, women with ‘other fertility issues’ would be excluded from studies to begin with and not after the fertility results are known. This brings me to…
Study design
Besides data presentation, it is also important to take into account how the study was conducted because this too has important implications on outcomes. Unfortunately, studies on Asherman’s syndrome have not been conducted to meet most rigorous scientific methodology-RCTs, making it difficult to assess the exact outcomes. I have mentioned the lack of RCTs in an earlier post. It follows that there are currently no systematic reviews or meta-analyses of the studies either since they are not conducted to stringent standards.
RCTs are clinical trials which have to meet certain criteria in order for the results to be considered unbiased, accurate and of statistical significance. In summary, studies must be done prospectively, they must be randomized with respect to treatment strategies depending on the outcome measure(s), there must be blinding of the doctors, investigators with regard to diagnoses/assessment of outcome with regards to treatment, a clear definition of exclusion and inclusion criteria for patients must be set in order to avoid outcome bias, and there must be enough participants in the/each study group(s) such that statistical analyses can be deemed to have significant value.
RCTs can be carried out to test the efficacy of a particular treatment, or to compare the efficacies of two or more different treatments. Most Asherman's studies focus on fertility outcomes following a given treatment protocol. The risk for potential bias comes mainly from unclearly defined patient inclusion/exclusion criteria, retrospective analyses and sample size and composition.
With regards to study design, the most blatant weakness is when studies are done retrospectively. This means that the doctor/investigator chooses the data to present after they already know the outcomes. This approach introduces the possibility of bias in outcomes because they may select, for example, all of the patients who went on to have live births after treatment, but leave out a portion of those who did not regain their fertility from the study without ever mentioning it. This would obviously make the success rate of treatment appear to be higher than in actuality. Most studies are now carried out prospectively.
Even if a study is done prospectively there are ways in which the outcome can be premeditatingly skewed to enhance outcomes. This is why in proper RCTs everything about the study (except for the results and conclusions) is decided in detail in advance and recorded in a repository. This leaves little space for modifications which can incorporate bias.
If exclusion/inclusion criteria are not stringent from the outset, some of the women who did not achieve a pregnancy could still be discounted on account that they had ‘other' fertility problems. Some authors write their study before allowing a reasonable followup time (1,5) and suggest that the success rate is potentially higher because at the time of writing it was too soon for X number of patients to try to conceive. Others may include patients with ongoing pregnancies (4,6,7,8) which may later not eventuate in live birth on complete followup. In one study, (9) live birth rates were reported as 83% a figure that sticks out like a sore thumb compared to other studies. It turns out that the study, which was done on 365 women, only included 186 patients in the live birth rate outcome. The justification for this was the 179 patients who were left out did not desire a pregnancy. Call me skeptical but I find it hard to believe that 179 women would undergo surgery just to get their periods back. If you include all 365 women in the study the live birth rates don’t look quite as remarkable -42.7%- blending in with the rates recorded by other studies.
Another thing to keep in mind is patient composition: how many have mild, moderate and severe disease? Since an increase in disease severity is associated with a poorer prognosis in terms of live births, a study group consisting of proportionally fewer severe cases could artificially bump up the live birth rate. Therefore it is important to either indicate this by giving a breakdown of outcomes according to disease severity, or to carry out studies where there are equal numbers of patients of the different disease classifications. Many studies will report overall birth rates among patients without giving a breakdown according to disease severity at presentation. It is up to the reader to do their own calculations.
I think the above examples show why proper RCTs are needed to not just to compare different methods of treatment, but to give accurate data regarding live birth outcomes. It would also be of help if there was a more standard way of reporting outcomes such as live births per total patients treated.
REFERENCES
1. Yasmin H, Nasir A, Noorani KJ. Hystroscopic management of Asherman’s syndromeJ Pak Med Assoc. 2007 Nov;57(11):553-5.
2. Capella-Allouc, S, Morsad, F, Rongieres-Bertrand, C, Taylor, S, and Fernandez, H. Hysteroscopic treatment of severe Asherman's syndrome and subsequent fertility. Hum Reprod 1999;14(5):1230-3.
3. Roy KK, Baruah J, Sharma JB, Kumar S, Kachawa G, Singh N.Reproductive outcome following hysteroscopic adhesiolysis in patients with infertility due to Asherman's syndrome. Arch Gynecol Obstet. 2009
4. Yu, D, Li, TC, Xia, E, Huang, X, Liu, Y, and Peng, X. Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman's syndrome. Fertil Steril 2008;89(3):715-22.
5. A. Thomson, J. Abbott, A. Kingston, M. Lenart, T. Vancaillie. Fluoroscopically guided synechiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Fertil Steril, 2007; Volume 87(2):405-410
6. Goldenberg, M, Sivan, E, Sharabi, Z, Mashiach, S, Lipitz, S, and Seidman, DS. Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions. Hum Reprod 1995;10(10):2663-5.
7. Robinson, JK, Colimon, LM, and Isaacson, KB. Postoperative adhesiolysis therapy for intrauterine adhesions (Asherman's syndrome). Fertil Steril 2008;90(2):409-14.
8. Protopapas, A, Shushan, A, and Magos, A. Myometrial scoring: a new technique for the management of severe Asherman's syndrome. Fertil Steril 1998;69(5):860-4.
9. Feng, Z, Yang, B, Shao, J, and Liu, S. Diagnostic and therapeutic hysteroscopy for traumatic intrauterine adhesions after induced abortions: clinical analysis of 365 cases. Gynaecol Endosc 1999;8(2):95-98.
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