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.

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.

Treatment of Asherman's syndrome is not a panacea, Part II

Continued from Part I

One century after its first description, treatment of Asherman’s syndrome (1) has not progressed enough to ensure that a high percentage of patients will regain fertility. I hope that one day it will be 100% treatable but it seems that this is a long way off and not a top priority for researchers or funding bodies. As important as treatment is for the women who have been diagnosed with Asherman’s syndrome, it is still difficult to justify why so little is being done to prevent it in the first place. Not all cases are preventable depending on the cause, but most are. Most cases (over 90% according to one study) (2) are caused by D&C and yet there are alternatives to D&C for every indication for which it is used. When D&C continues to be standard care for miscarriage management most cases of Asherman’s syndrome will continue to occur in women who have miscarried.

Asherman’s syndrome was first described in 1894 (1) and later further characterized in 1948(3). In those days there were no other options to D&C so naturally treatment (or more selective use of D&C) was the only solution to the problem. The situation today is very different with the discovery of drugs and hysteroscopy to replace D&C. These approaches would undoubtedly reduce the incidence of Asherman’s syndrome.


Unfortunately treatment is not a panacea. The outcomes of studies speak for themselves (see below). They range from 27% to 43% and include women of different classification severities (so presumably this rate is even less inspiring for women with more severe presentation). Note that all of these studies are recent. The most accurate way to present these results is to report number of live births per total patients treated because some women will either never conceive or give birth after treatment. Reporting live births per pregnancy is deceptive because the women who never got pregnant are discounted from the outcomes. It is very possible that some women never conceived because the endometrial damage they sustained and which led to Asherman’s syndrome was permanent and not able to be repaired by treatment enough to allow for successful implantation. Absence of adhesions does not imply that the endometrium is functioning properly- there could be fibrosis or very thin unresponsive endometrium. Unfortunately, to this date, there is no test which can ensure that the entire endometrium is functional. In the next part of this discussion about treatment (Part III), I will discuss in further detail the results from studies and difficulties in conducting studies on Asherman's syndrome.

Studies of modern success rates (#live births/#patients treated) after treatment of Asherman’s syndrome:

STUDY	REF	BIRTHS/PATIENTS	BIRTH RATE
1. Zikopoulos et al, 2004	(4)	20/46	43.5%
2. Fernandez et al, 2006	(5)	21/64	32.8%
3. Thomson et al, 2007	(6)	8/27	29.6%*
4. Yu et al, 2008	(7)	25/85	29%
5. Robinson et al, 2008	(8)	4/15	27% **
6. Pabuccu et al, 2008	(9)	22/71	31%

* the paper itself quotes a 47% live birth rate but excludes 10 women ie. one third of the patient sample size from the calculation on the basis that they were not trying for pregnancy.

**the paper quotes a 46% (7/15) live birth rate, however 3 of those pregnancies were still ongoing at the time of publication.


The real outcomes, including the results of treatment by the best doctors in the field according to the Asherman's Syndrome International Support Group don’t look as inspirational in statistics as they do when presented as personal success stories.

Are these live birth rates high enough to justify treatment as the best solution to the problem of iatrogenic Asherman’s syndrome? Or that D&C should continue to be used routinely or as ‘standard care’?

I will not get into the serious obstetric complications sometimes encountered in future pregnancies (should patients be fortunate enough to be able to conceive and carry a pregnancy). I have saved this for another post as it is a whole other area that needs to be discussed in detail.

There is another very important reason for women to told the true success rates of treatment (and about future obstetric complications): awareness will undoubtedly create a push among patients and and more importantly women, in general, for prevention by using alternatives to D&C…

Continued in Part III

REFERENCES

1. Fritsch, H. Ein Fall von volligem Schwaund der Gebormutterhohle nach Auskratzung Zentralbl Gynaekol 1894;18:1337-1342.

2. Schenker, JG and Margalioth, EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril 1982;37(5):593-610.

3. Asherman, JG. Amenorrhea traumatica (atretica). J Obstet Gynaec Brit Emp 1948;55(23).

4. Zikopoulos, KA, Kolibianakis, EM, Platteau, P, de Munck, L, Tournaye, H, Devroey, P et al. Live delivery rates in subfertile women with Asherman's syndrome after hysteroscopic adhesiolysis using the resectoscope or the Versapoint system. Reprod Biomed Online 2004;8(6):720-5. Abstract

5. Fernandez, H, Al-Najjar, F, Chauveaud-Lambling, A, Frydman, R, and Gervaise, A. Fertility after treatment of Asherman's syndrome stage 3 and 4. J Minim Invasive Gynecol 2006;13(5):398-402. Abstract

6. Thomson Angus J M; Abbott Jason A; Kingston Ashley; Lenart Meegan; Vancaillie Thierry G. Fluoroscopically guided synechiolysis for patients with Asherman's syndrome: menstrual and fertility outcomes. Fertility and sterility 2007;87(2):405-10. Abstract

7. Robinson, JK, Colimon, LM, and Isaacson, KB. Postoperative adhesiolysis therapy for intrauterine adhesions (Asherman's syndrome). Fertil Steril 2008;90(2):409-14. Abstract

8. 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. Abstract

9. Pabuccu Recai; Onalan Gogsen; Kaya Cemil; Selam Belgin; Ceyhan Temel; Ornek Turkan; Kuzudisli Ebru. Efficiency and pregnancy outcome of serial intrauterine device-guided hysteroscopic adhesiolysis of intrauterine synechiae. Fertility and sterility 2008;90(5):1973-7.
Abstract

Treatment of Asherman's syndrome is not a panacea (Part I)

Not all that long ago Asherman’s syndrome patients may have been told to forget about ever having a(nother) child. Treatment has come a long way with the advent of hysteroscopy, hormonal treatment, stents and adhesive barriers. It’s not surprising that before these were available, success rates were very low and often more damage was incurred from ‘treatment’ resulting in worse outcomes. One of the reasons for this is that some doctors used to treat Asherman’s syndrome by performing a blind D&C to break apart intrauterine adhesions they couldn’t even see. It’s hard to imagine why anyone would think that performing the same procedure as the one which usually causes the condition could fix things, but lots of doctors did- and some continue to do so with disastrous consequences.

Some doctors might still have the attitude that anyone whom they cannot treat successfully should give up hope, even if they are not highly skilled or experienced in the treatment of intrauterine adhesions. However, a new and equally detrimental view is being encouraged among sufferers: that treatment has come so far that anyone who is diagnosed stands a very good chance of conceiving and delivering a healthy baby (provided they go to the right doctors). While it’s true that some doctors have much more training, experience and expertise in the treatment of Asherman’s syndrome, the harsh reality is that the overall success rate is not above 50% (and lower for the moderate to severe cases)- even with the best doctors. If anyone tells you that there are doctors who have higher success rates with moderate to severe cases than 50%, they are either not being truthful or simply don’t know (or prefer not to accept) the reality.

It’s a bitter pill to swallow, but women need to be made aware of this fact. Not to crush any optimism, but to give realistic expectations, and perhaps to avoid the costs and heartbreak of ‘unexplained infertility’ following ‘successful’ treatment. There is a very fine line between giving encouragement and creating false hope. You may read of success stories, you may hear of women overcoming seemingly astonishing odds, and photos of women beaming with their babies, praising their ‘miracle’ doctors, but make no mistake: these are the faces and stories of less than 50% of women who are diagnosed with IUA and get treatment by the best doctors. But they do not reflect the reality for more than half of women diagnosed with Asherman’s syndrome. The latter are the women who fade into the background, the ones doctors and patients alike would like to forget about, or blame the lack of success on other reasons. Let us not underestimate the significance of the initial trauma underlying the Asherman’s syndrome. Some of us got a worse deal than the others. Worst of all, there is no clear way of predicting whether treatment will be successful or even knowing if it was successful. The only way to know is to try to conceive. If you do have a baby, your treatment was successful. If you don’t, your treatment may not have fully restored your fertility (or you have other causes of unexplained infertility). But let’s not exaggerate the likelihood of the latter- why would someone who was previously capable of getting pregnant suddenly have ‘unexplained infertility’ after having had Asherman’s syndrome? Fibrosis from Asherman’s syndrome can affect blood flow to the endometrium and reduce the chance of implantation or maintaining a pregnancy. I’m not saying one should not seek treatment. By all means, please do whatever is necessary to improve your chances of regaining your fertility! But don’t be too surprised if you don’t end up with a success story.

The attitude of the medical community is also to blame for encouraging the view that treatment is the best answer to the problem. For reasons which evade me, they seem to think it is more logical to subject all women to blind surgery causing Asherman's syndrome in a non-negligible proportion of them, and then to attempt surgical correction and hormonal therapy on those who do develop IUA in the hope that at most 50% of them will have a child (30-40% with moderate to severe IUA, 80% with mild IUA). Not to mention that these future pregnancies are at risk of serious complications, like placenta accreta, preterm delivery, intrauterine growth restriction, cervical incompetence etc. How logical is this? What is the advantage or logic in performing two (or more) expensive, difficult and potentially risky uterine surgeries- one which can cause damage, and one (or more) to repair the damage of the first surgery? Why not nip it at the bud and not cause damage to begin with?

Why not simply use drugs or hysteroscopy to empty the uterus, preventing scarring in the first place? When you consider that there are ways of emptying the uterus without blind surgery (either by using drugs like misoprostol or mifepristone, or visually guided hysteroscopy) the surgical approach makes no sense whatsoever. Is the approach of D&C followed by corrective surgery in the best interest of patients? Absolutely not.

In my next post I will include modern studies on outcomes of treatment as evidence.

Continued in Part II