Focus on the medical literature: Misoprostol for early pregnancy failure is underused despite efficacy and safety .

Article: Provider knowledge, attitudes, and treatment preferences for early pregnancy failure.

Dalton VK, Harris LH, Gold KJ, Kane-Low L, Schulkin J, Guire K, Fendrick AM. Am J Obstet Gynecol. 2010 Jun;202(6):531.e1-8. Epub 2010


The American Journal of Obstetrics & Gynecology has recently published an article, ‘Provider knowledge, attitudes and treatment preferences for early pregnancy failure’ (EPF),which explores the relationship between health provider attitudes and associated factors and the methods they use for treating miscarriage. Ever since acquiring Asherman’s syndrome from a D&C for an incomplete miscarriage because I was spuriously denied medical management, I have been curious to find out what proportion of Obstetricians offer misoprostol to their patients. This will vary from country to country. My understanding is that many countries in continental Europe are more progressive in adopting misoprostol use than the US, England, Australia and New Zealand. I know from personal experience that in Australia the use of misoprostol for first trimester or early second trimester miscarriage management is rare. I have also learned that even when it is used, the hospital protocols are strict and dosages are in accordance with only second trimester termination, as illogical and ineffective as this may be for other gestational ages.


My interest in the article of course stems from an angle of Asherman’s syndrome prevention, whereas cost effectiveness was the main interest of the study. For this reason, the researchers were focused on the frequency of misoprostol and office uterine evacuations, both of which are far less expensive than operating room (OR) surgical evacuations. This is mainly due to operating room and anesthesiologist costs of OR D&C (the patient is awake during in-office D&C). Thus, the authors consider all treatment options (expectant or medical management, office, and OR procedures) to be reasonable, and that patient preferences should be the deciding factor in treatment choice. It should be mentioned that the same group authored case reports alerting that even gentle manual vacuum aspiration (MVA) (a type of office uterine evacuation) can lead to symptomatic IUA ie. Asherman’s syndrome (1). This is not surprising given that blind instrumentation is involved.


There is a plethora of clinical studies in the medical literature supporting the efficacy and safety of misoprostol (click here) for treatment of early pregnancy failure (2,3) as well as for abortion. Yet there is a discrepancy between the established research findings and its level of use in practice. Although the problem of failing to adopt evidence-based treatments is a common problem it is especially so in women’s health (4,5,6). Therefore, practitioners are usually slow to offer new treatment methods, even when these are known to be effective, safe, and offer advantages to traditional treatments. Thus, clinicians have the power to influence patient treatment, rather than letting the patient choose how her miscarriage is managed (7,8). It is unclear whether all treatment options are routinely offered or available to women who experience early pregnancy failure (9).


The study hypothesized that most providers do not routinely offer patients all acceptable treatment options, and that factors such as knowledge and perceived obstacles to adopting new methods might be associated with sex, specialty, years of practice, and training.


In particular they sought answers from health providers with respect to each treatment method regarding :


-attitudes about treatment safety (and I would add efficacy) (Treatment Preference)
-perceptions of patient acceptance of options (Perception of patient preferences)
-provider comfort with the options (Use of treatments)



For misoprostol and office uterine evacuations they looked at additional factors.


The study was carried out as a written survey which was sent out to Obstetrician-gynecologists (‘Obgyns’), certified nurse midwives/midwives (‘nurses/midwives’), and family physicians (‘GPs’) in the United States.


From the point of view of Asherman’s syndrome prevention, the focus will be on the paper’s relevant outcomes with regards to use of the non-invasive alternatives misoprostol and expectant management compared to OR surgical evacuation (ie. D&C). Also, I am adding a few interpretations which were not mentioned in the article. These are in blue font.

D&C Treatment preference-Obgyns preferred uterine evacuation in the operating room over other methods (45.7%)(No surprise there…) Perception of patient preferences -Interestingly, Obgyns believed OR D&C was the more preferable treatment than their patients (28.4% vs 15.5%; P<.001, perceived Obgyn and patient rank, respectively). It is unclear whether this reflects a higher level of confidence than their patients in the procedure or if the preference is influenced by financial factors. Note that 21.8% of Obgyns in the study expressed concern regarding reimbursement for in office uterine evacuations- the identical procedure to their self-declared preferred method, the much costlier operating room D&C including anesthesiologist. Use of treatments -Obgyns reported using OR D&C more than the other options and nurses/midwives and GPs. -38.9% of Obgyns used D&C in over half of all patients in the past 6 months.

Expectant management Treatment preference -Nurses/midwives and GPs were the most likely to prefer expectant management (55.2% and 64.5% , respectively) -Obgyns were the least likely to report expectant management as their most preferred treatment Perception of patient preferences -Health provider’s belief regarding patient preference of expectant management mirrored their own. Use of treatments -Obgyns were less likely than the others to use expectant management (12.3% compared to 30.4% and 43.4% for nurses/midwives and GPs, respectively).

Misoprostol Treatment preference -Obgyns, nurses/midwives and GPs chose misoprostol as the second preferred treatment method (33.2%, 61.8% and 60.7% respectively). Perception of patient preferences -Health provider’s belief regarding patient preference of misoprostol management mirrored their own. Use of treatments Misoprostol (along with office uterine evacuations) were the least commonly used treatment options. -Most providers had not used misoprostol at all in the past 6 months for EPF treatment. - Over the last 6 months, 52.7% of Obgyns reported not using it even once. - Obgyns were still more likely than the others to use misoprostol but only 5% of them reported using it in over half of their patients in the last 6 months. -67.9% and 84.1% of nurses/midwives and GPs, respectively, reported not ever using misoprostol in the last 6 months.

Provider factors influence on use of misoprostol -sex and race: Not associated with use of misoprostol -Safety: providers who believed that misoprostol is safe used it more than those that did not. Disturbingly, 29.7% of Obgyns, 36.2% of nurses/midwives, and 37.8% of GPs did not agree with the statement “Misoprostol is safe.” (This mindset counters evidence-based medicine and requires further examining). -Low patient demand: 34.7% of GPs claimed little patient demand was a barrier, versus 18.2% of Obgyns and 15.7% of nurses/midwives. (Is this really a valid excuse not to at least offer it?) -prior induced abortion training: Not significantly associated with misoprostol use. (I wonder if training in misoprostol use specifically for EPF management exists) -Other perceived obstacles to using misoprostol included lack of surgical or nursing backup/support. (Paradoxically these do not appear to hinder the preference of nurses/midwives or GPs for expectant management).

Conclusions
-EPF management is still largely dominated by operating room uterine evacuations (Obgyns) and expectant management (nurses/midwives and GPs) even though the efficacy and safety of misoprostol is well established.


-targeting inaccurate beliefs about the safety of misoprostol and clarifying patient preferences may increase the willingness of providers to adopt new practices to meet patient needs.


Note: -This study does not delineate how much patient preferences account for current treatment patterns, however: 

-Women vary in their treatment preferences, therefore providing access to a wide range of services will improve care.


-clinical trials suggest that misoprostol is acceptable and may be preferred by many women over surgical evacuation especially when successful and when surgery is performed without anesthesia eg. in office (10,11,12,13).


-Improvements in services for EPF, one of the most common clinical problems encountered by women of reproductive age, will have a strong impact on patient experience and satisfaction (I would add also from the point of view of Asherman’s syndrome prevention).


REFERENCES

1. Dalton, VK, Saunders, NA, Harris, LH, Williams, JA, and Lebovic, DI. Intrauterine
adhesions after manual vacuum aspiration for early pregnancy failure. Fertil Steril
2006;85(6):1823 e1-3.

2. Zhang, J, Gilles, JM, Barnhart, K, Creinin, MD, Westhoff, C, and Frederick, MM.
A comparison of medical management with misoprostol and surgical management
for early pregnancy failure. N Engl J Med 2005;353(8):761-9.

3. Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical, or surgical? Results of randomized controlled trial (miscarriage treatment (MIST) trial). BMJ 2006;332:1235-40.

4. Cabana MD, Kim C. Physician adherence to preventive cardiology guidelines for women. Women’s Health Issues 2003;13:142-9.

5. Haagen EC, Nelen WL, Hermens RP, Braat DD, Grol RP, Kremer JA. Barriers to physician adherence to a subfertility guideline. Hum Reprod 2005;20:3301-6.

6. Harper CC, Blum M, de Bocanegra HT, et al. Challenges in translating evidence to practice: the provision of intrauterine contraception. Obstet Gynecol 2008;111:1359-69.

7. Gurmankin AD, Baron J, Hershey JC, Ubel PA. The role of physicians’ recommendations in medical treatment decisions. Med Decis Making 2002;22:262-71.

8. Molnar AM, Oliver LM, Geyman JP. Patient preferences for management of first-trimester incomplete spontaneous abortion. J Am Board Fam Pract 2000;13:333-7.

9. Dalton VK, Harris LH, Clark SJ, Cohn L, Guire K, Fendrick AM. Treatment patterns for early pregnancy failure in Michigan. J Women’s Health 2009;18:1-7.

10. Moodliar, S, Bagratee, JS, and Moodley, J. Medical vs. surgical evacuation of firsttrimester spontaneous abortion. Int J Gynaecol Obstet 2005;91(1):21-6.

11. Bique, C, Usta, M, Debora, B, Chong, E, Westheimer, E, and Winikoff, B. Comparison of misoprostol and manual vacuum aspiration for the treatment of incomplete abortion. Int J Gynaecol Obstet 2007;98(3):222-6.

12. Lee, DT, Cheung, LP, Haines, CJ, Chan, KP, and Chung, TK. A comparison of the psychologic impact and client satisfaction of surgical treatment with medical treatment of spontaneous abortion: a randomized controlled trial. Am J Obstet Gynecol 2001;185(4):953-8.

13. Graziosi GC, Bruinse HW, Reuwer PJ, Mol BW. Women’s preferences for misoprostol in case of early pregnancy failure. Eur J Obstet Gynecol Reprod Biol 2005;124:184-6.

Cochrane review: Medical treatments for incomplete miscarriage (less than 24 weeks)

This systematic review was published in January. I'm adding a link to it in the RELEVANT LINKS section to the right. Or click here to have access to the complete article (then click on a link in the left window).

"Women experiencing miscarriage at less than 13 weeks should be offered an informed choice." (from the abstract)

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

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


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

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


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


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


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


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

Doctor’s orders: in support of Ashermans syndrome prevention and/or alternatives to D&C.

Here's what the doctors have written over the years in support of preventing Asherman's syndrome from occuring and more recently, in support of alternative methods to D&C for miscarriage management. This list is not exhaustive and I may add to it in future. There is so much evidence in the medical literature and knowledge among some doctors at least, that it is difficult to reconcile it with current medical practices. 'Translational research' might be the current buzz word at research centers, hospitals and universities, but how quickly this progress is incorporated into routine or widespread practice is entirely another matter. This is where patients need to speak up to encourage change, and why patients need to educate themselves and others first. Reading the research is the only way to get an overall view of the established facts rather than relying only on second hand information from others who may have vested interests or other agendas.

(my additions are in blue)


1. Toaf and Ballas, 1978 (1):

"Peurperal curettage…was discontinued in Israel after publication of Asherman’s observations.”

This is not so in the US, UK, Australia and many other countries. Also, curettage remains standard care for treating miscarriage in many countries (while abortion is now usually carried out medically).

2. Li et al, 2001 (2):

After vaginal delivery, a retained placenta may cause a risk to maternal health because of hemorrhage or infection. …manual removal of the retained placenta is a routine procedure. ..This invasive procedure increases risk of trauma*, rupture of uterus, hemorrhage, postpartum infection, and anesthetic complications.”

* Asherman’s syndrome may result

“In all 18 parturients, spontaneous expulsion of the placenta developed in an average interval of 12 min (range from 5 to 35 min) after rectal insertion of misoprostol.”

3. Friedler et al, 1993 (3):

“The incidence of IUA might be lower following medical evacuation of the uterus, thus avoiding any intra-uterine instrumentation; however, use of progesterone antagonists (ie, mifepristone) for this purpose is not yet approved by the Israeli Ministry of Health.”

4. Chapman and Chapman, 1990 (4):

“One must also note that the suction curette is capable of causing synechiae, usually, however in the region of the internal os.”
“It is noteworthy that, of the 11 patients with isthmus stenosis, six of them were attributable to termination of pregnancy, of which all but one had been performed by suction curettage”
“It goes without saying that, in view of the seriousness of the sequelae, the best management is prevention…”

3. Tam et al, 2002 (5):

“No cases of IUA were found in patients managed conservatively or by medical evacuation, whereas 2 cases (7.7%) of filmy IUA were detected in those managed by surgical evacuation.”

“We therefore recommend expectant management and medical evacuation as first-line treatment for complete abortion* and incomplete abortion*, respectively. Surgical evacuation should be the treatment of choice when {these methods} fails or is contraindicated.”
*ie miscarriage

6. Goldenberg et al, 1997 (6):
“Selective curettage of residual trophoblastic tissue directed by hysteroscopy is an easy and short procedure and might be preferable to conventional, nonselective, blind curettage.”

“…areas not covered by residual tissue…are not subject to surgical trauma during the selective procedure and presumably are therefore exposed to lower risks of inflammation, scarring and adhesion formation”

“Incomplete removal of the residua is more likely to occur during repeated conventional curettage, even if guided by ultrasonography, as had occurred in two of our patients. Direct visualization of the cavity allows…the exact location and extent of the residual tissue to be resected.”

7. Yu et al, 2008 (7):

“Prevention of Asherman Syndrome
Prevention is always better than cure. To prevent the formation of endometrial fibrosis and adhesions, it is essential that any trauma to the uterus be avoided, especially in the pregnant or postpartum state.”

They go on to recommend:
“Avoid postpartum or postabortion curettage”
“Diagnosis of retained products of conception …present a clinical challenge.
…Saline infusion sonohysterography (SHG) has enhanced our ability to diagnose retained products of conception (8)”
“…transvaginal B-mode ultrasonography combined with color velocity imaging and pulsed Doppler to detect retained trophoblastic tissue…could be useful to…select patients suitable for conservative management.(9)”
“Transvaginal duplex Doppler ultrasonography is also an effective noninvasive method for evaluating patients with persistent postpartum hermorrhage (10).”

"…hysteroscopy should be considered an effective method for diagnosis and treatment of retained products of conception." They cite the Goldenberg et al (6) study (see above).
…
“Select medical management of miscarriages
When termination of early pregnancy is necessary, medical treatment should be considered instead of surgical options.”
They cite the Tam et al study (5)(see above).

“Since its introduction, the uptake of medical abortion has been steadily increasing in countries where it has been available for routine use….Similarly, in the management of incomplete miscarriage or delayed miscarriage, expectant or medical treatment should be considered.”

7. Chung et al, 1995 (11):

“The accepted management of spontaneous abortion has not changed substantially in 60-70 years.”

“The policy of routine, universal evacuation of retained products of conception (ERPC) became the accepted form of management around the 1930s to combat [these*] complications. However, this approach may no longer be appropriate in all cases.”
*hemorrhage, infection.

“…in the United Kingdom, 90% of spontaneous abortions are managed [by ERPC] (12). Confidence in routine ERPC as the unquestioned ‘gold standard’ may no longer be justified. There may be alternative approaches that are less invasive but equally effective without incurring greater morbidity.”

“Transvaginal sonography can identify approximately one in three women with a spontaneous abortion who do not have a significant amount of retained tissue in the uterus.”

“Surgical intervention in {women who do not have a significant amount of retained tissue in the uterus} may unnecessarily incur iatrogenic complications without therapeutic gain.”


8. Demetroulis et al, 2001 (13):

“Surgical curettage under anaesthesia accounts for almost three-quarters of emergency gynaecological operations performed in the UK (14). However, dilatation and suction evacuation of the uterus under anaesthesia has certain morbidity, such as the risk of anaesthesia, uterine perforation, intrauterine adhesions, cervical trauma, and infections leading to infertility, pelvic pain and increased chance of ectopic pregnancy.”

9. Moodliar et al, 2005 (15):

“Moreover, surgical evacuation of retained products of conception (ERPC) is performed in the operating room, which significantly increases costs. Inherent in the procedure are the possible complications of perforation, hemorrhage, cervical trauma, intrauterine adhesions and postinstrumentation endometritis.”

“As an alternative, medical management has been found to be cost-effective and associated with fewer complications…Yet in South Africa*, incomplete abortion is still being managed by surgical evacuation.”

*in Australia and in many other countries too!

10. Muffley et al, 2002 (16):

“Curettage has been traditionally used as the surgical method of treatment. It has been estimated that approximately 100,000 uterine curettages are performed annually in the United States, at a total yearly cost of >100 million (17). Uterine curettage is associated with …hemorrhage and infection. Uterine adhesions, impaired future fertility, cervical trauma, uterine perforation, and anesthesia errors are also other potential sequelae of curettage.”

“In the late 1980s single-dose methotrexate therapy was introduced for the treatment of unruptured ampullary ectopic gestations (18). Nearly 10 years later, this medical therapy has replaced laparotomy or laparoscopy in many circumstances (19). At this time, however, medical treatment of early pregnancy failure is still in its infancy in the United States. On completion of multicenter randomized clinical trials, we believe that medical treatment will replace surgical therapy as the initial treatment of early pregnancy failure.”

(I hope so!)

Comment by Dr Lisa Fall:
“Firstly, as the trend toward later childrearing continues, we are faced with an increased incidence of pregnancy failure because of advancing gestational [ sic maternal] age. Our patients are interested in noninvasive options for treatment to avoid possible complications that may have an impact on future fertility.”
(Yup, that was me, but I was refused)
11. Zhang et al, 2005 (20):

“For most of the 20th century, dilatation and curettage was the commonly accepted approach to early pregnancy failure. This practice can be traced back to the late 19th and early 20th centuries, when illegally induced abortions commonly resulted in hemorrhage and sepsis (21). With the legalization of abortion and the availability of antibiotics, these problems have become rare. In more recent years, the medical community began to question whether immediate evacuation by surgical intervention was necessary for uncomplicated cases of early pregnancy failure (12,17).”

12. Stockheim et al, 2006 (22):

“Over the past decade, elective medical termination of pregnancy using a protocol that includes mifepristone and misoprostol was accepted into wide practice. This drug regimen was consistently shown to be associated with high success rates of 90-95% (23-26). However, medical treatment of pregnancy failure (blighted ovum or spontaneous abortion) has not yet gained wide acceptance.”

“Misoprostol is an effective and safe treatment for early pregnancy failure and could replace surgical curettage in over two-thirds of the patients.”

13. Creinin et al, 2006 (27):

“As clinicians and researchers, we must ask why women with an undesired normal pregnancy can receive a treatment regimen that is more effective than that tested for women with a desired abnormal pregnancy. The information presented in this analysis will allow us to better tailor misoprostol treatment for early pregnancy failure.”

I would also add, why women with an undesired normal pregnancy only have access to the mifepristone/misoprostol regimen which preserves fertility while those who miscarry do not.

14. Pang et al, 2001 (28):

“Misoprostol is justified as a first line treatment in the management of miscarriage in all cases because firstly it will avoid surgical intervention altogether in a proportion and secondly, in those who need it, misoprostol reduces surgery-related morbidity, mainly by priming the cervix (29.)”

15. Blanchard et al, 2004 (30):

“A growing body of research evidence indicates that medical treatment of incomplete abortion with misoprostol is an effective alternative to surgical intervention. Misoprostol could be an important alternative to dilatation and curettage or manual vacuum aspiration for treatment of incomplete abortion, allowing women to avoid surgical intervention and the attendant risks. Misoprostol is inexpensive and widely available and may also be more acceptable to women than the current standard of care.”

16. Shaw D, The International Federation of Gynecology and Obstetrics (FIGO) President (31):

“Furthermore, women have the right to benefit from advances in scientific knowledge and since women brought unapproved, reproductive health use of misoprostol to the attention of health professionals, it is especially fitting that they now benefit from the research into such use.”

17. The American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, 2009 (32):

“In addition, there is increasing evidence that misoprostol is a safe, effective,and acceptable method to achieve uterine evacuation for women needing postabortion* care.”

“Misoprostol may be used to treat women with an incomplete and missed abortion.”

* Postabortion care: “… refers to a specific set of services for women experiencing problems from all types of spontaneous or induced abortions.”
 REFERENCES

1. Toaff R, Ballas S (1978). Traumatic hypomenorrhea-amenorrhea (Asherman's syndrome). Fertil. Steril. 30 (4): 379–87.
 2. Li YT, Yin CS, Chen FM. Rectal administration of misoprostol for the management of retained placenta- a preliminary report. Chinese Medical Journal (Taipei) 2001;64:721-4.
 3. Friedler S, Margalioth EJ, Kafka I, Yaffe H. (1993). Incidence of postabortion intra-uterine adhesions evaluated by hysteroscopy: a prospective study. Hum Reprod 8 (3): 442–444.
 4. K Chapman and R Chapman. Asherman's syndrome: a review of the literature, and a husband and wife's 20-year world-wide experience. J R Soc Med. 1990 September; 83(9): 576–580.

5. Tam WH, Lau WC, Cheung LP, Yuen PM, Chung TK. (2002). Intrauterine adhesions after conservative and surgical management of spontaneous abortion. J Am Assoc Gynecol Laparosc. 9 (2): 182–185.

6. 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.
 7. Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome-one century later. Fertil Steril 2008;89(4):759-779.

8. Wolman I, Gordon D, Yaron Y, Kupferminc M, Lessing JB, Jaffa AJ. Transvaginal sonohysterography for the evaluation and treatment of retained products of conception. Gynecol Obstet Invest 2000;50:73-6.
 9. Alcazar JL. Transvaginal ultrasonography combined with color velocity imaging an dpulsed Doppler to detect residual trophoblastic tissue. Ultrasound Obstet Gynecol 1998; 11:54-8.

10. Achiron R, Goldenberg M, Lipitz S, Mashiach S. Transvaginal duplex Doppler ultrasonography in bleeding patients suspected of having residual trophoblastic tissue. Obstet Gynecol1993;81:507-11.
 11. Chung, TK, Cheung, LP, Leung, TY, Haines, CJ, and Chang, AM. Misoprostol in
the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102(10):832-
5.

12. Macrow, P and Elstein, M. Managing miscarriage medically. BMJ 1993;306(6882):876.
 13. Demetroulis, C, Saridogan, E, Kunde, D, and Naftalin, AA. A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure. Hum Reprod 2001;16(2):365-9.

14. McKee M, Priest P, Ginzlet M et al. Can out-of-hours operating in gynecology be reduced? Arch Emerg Med 1992;9:290-8.
 15. Moodliar S, Bagratee JS, Moodley J. Medical vs surgical evacuation of first-trimester spontaneous abortion. Int J Gynecol Obstet 2005;91:21-6.

16. Muffley, PE, Stitely, ML, and Gherman, RB. Early intrauterine pregnancy failure: a randomized trial of medical versus surgical treatment. Am J Obstet Gynecol 2002;187(2):321-5; discussion 325-6.
 17. Ballagh SA, Harris HA, Demasio K.Is curettage needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279-82.
 18. Stovall, TG, Ling, FW, and Buster, JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51(3):435-8.
 19. Lipscomb, GH, Bran, D, McCord, ML, Portera, JC, and Ling, FW. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998;178(6):1354-8.
 20. Zhang, J, Gilles, JM, Barnhart, K, Creinin, MD, Westhoff, C, and Frederick, MM. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353(8):761-9.

21. Hertig AT, Livingstone RG. Spontaneous, threatened and habitual abortion: their pathogenesis and treatment. N Engl J Med 1944;230:797-806.

22. Stockheim D, Machtinger R, Wiser A, Dulitzky M, Soriano D, Goldenberg M, Schiff E, Seidman D. A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril 86(4):956-60.
 23. World Health Organization Task Force on post-ovulatory methods of fertility regulation. Comparison of two doses of two doses of mifepristone in combination with misoprostol for early medical abortion: a randomized trial. BJOG 2000;107:524-30.
 24. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537-40.
 25. Peyron R, Auberny E, Targosz V, Silvestre L, Renault M, Elkik F et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993;328:1509-13.
 26. Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misprostol in the United States. N Engl J Med 1998;338:1241-7.
 27. Creinin MD, Huang X, Westhoff C, Barnhart K, Gilles JM, Zhang JZ. Factors related to successful misoprostol treatment for early pregnancy failure. Obstet Gynecol 2006; 107(4):901-907.

28. Pang MW, Lee TS, Chung TKH. Incomplete miscarriage: a randomized controlled trial comparing oral with vaginal misoprostol for medical evacuation. Hum Rep 2001;16(11):2283-7.
 29. Chung TKH, Cheung LP, Sahota DS et al. Spontaneous abortion: short term complications following either conservative or surgical management. Aust NZ J Obstet Gynaecol 2001; 38:61-4.
 30. Blanchard K, Taneepanichskul S, Kiriwat O, Sirimai K, Svirirojana N, Mavimbela N, Winikoff B. Two regimens of misoprostol for treatment of incomplete abortion. Obstetrics & Gynecology 2004;103(5 Pt1): 860-5.
 31. Shaw, D. Misoprostol for reproductive health: Dosage recommendations. International Journal of Gynecology and Obstetrics 2007; 99:S155.

32. ACOG Committee on International Affairs. Committee Opinion: Misoprostol for postabortion care. Obstetrics & Gynecology 2009; 113(2) Part I:465-8.

Ashermans syndrome in the news: The secret syndrome leaving women infertile

A recent article on Asherman’s syndrome (AS) appeared in the UK Daily mirror. It was about Sophie Blake, a TV presenter in the UK, who acquired Asherman’s syndrome as a result of two D&Cs to remove retained placenta after giving birth. It is unfortunate that her situation was not handled differently, as postpartum D&C has been reported to result in Asherman’s syndrome in 25% of cases (1). There are usually alternatives, and in some countries such as Israel, post partum D&C is no longer performed because of AS risks (2).

Toaff and Ballas, 1978
“Puerperal curettage….was discontinued in Israel after publication of Asherman’s observations*”.
*1948!!

Publicity about Asherman’s syndrome is important, and it always helps to have a public figure bring awareness to an overlooked condition. However, according to the article, the moral of the story is to seek early treatment when there is actually no evidence that fertility is more likely to be restored if treatment is sought early. Studies have shown that fertility outcomes are correlated with severity of adhesions (3), however there have been no studies on the effect of length of the condition on fertility. Sometimes damage is too great to be corrected and the uterus will rescar at every attempt to surgically remove adhesions and hormonally stimulate endometrial growth, even when early treatment was commenced. Other times, adhesions are not so severe and treatment after years will result in a live birth. Although treatment by an experienced AS specialist should always be sought, fertility outcome will be dependent most of all on the severity of initial injury (ie. D&C, intrauterine surgery with or without endometritis) which led to the scarring. When too many endometrial cells are removed to allow the endometrium to regenerate, this leads to recurrent adhesions and/or widespread fibrosis. In many cases even some of the underlying myometrium is removed. It is simple, without further progress in treatment strategies, there is nothing that can be done to replenish regenerative tissue that has been removed during curettage or other uterine surgery.

Early treatment does not guarantee success-just as late treatment does not guarantee failure

“Ideally corrective surgery should be performed within six months of the adhesions forming before they get too large”
This suggests that intrauterine adhesions continue to get worse over time, which is not true. Injury results in scarring anywhere in the body, and scarring is not progressive after a certain time point. Adhesions occur when scarring occurs internally and tissues are in direct contact with each other during the healing process. IUA formation is a normal physiological response to trauma-albeit trauma that is usually iatrogenic and should not have occurred in the first place. The consequences of this normal response are pathological because adhesions can lead to infertility, miscarriage and/or obstetric complications when they occur in the uterus. In actuality, IUA formation begins immediately after injury or corrective surgery and is complete by around 6-8 weeks according to Asherman’s syndrome specialists (unfortunately I am unable to find a reference for this, however studies where hysteroscopic followups are performed after D&C mention waiting 6-8 weeks at least). This is even supported in the article:

“I was devastated the scarring had come back so quickly,”

After 8 weeks, IUA do not continue to form/progress. Therefore, someone with stage I AS diagnosed 3 months after surgery will not go on to have stage IV 3 years later, because their adhesions have already fully formed by 8 weeks. There is one study which asserts that women who had early followup compared to late follow up hysteroscopy following adhesiolysis had less severe adhesions, and that early treatment would give a better outcome (4). However, early followup was 2-4 weeks after the initial surgery while late followup was 8-16 months. Thus adhesions may appear to be less ‘severe’ in the early followup group simply because they had not fully formed. The main advantage of early treatment (ie. before 6-8 weeks) is that it makes it easier for the doctor to dissect adhesions and not cause new ones inadvertently. However, in practical terms, it is highly unlikely that women will be diagnosed with AS within 6-8 weeks after a surgery (let alone treated), therefore it is usually applied as a treatment strategy after adhesiolysis instead of a uterine stent (5).

“It makes me seethe because if Asherman’s is caught early it’s totally treatable.”
“It’s treatable in the early stages, but it took two years for me to get a diagnosis.”


It is suggested that had she had surgery sooner, she would have possibly reversed the damage and regained her fertility. This is unlikely. Very severe adhesions tend to recur (3) inspite of surgery or hormone therapy. Early intervention will not make much of a difference because the extent of the initial damage is such that too many regenerative endometrial cells have been removed during the initial trauma.

It has been hypothesized (but not been proven) that the adhesive process can be progressive because adhesions limit uterine muscular activity thereby reducing perfusion of sex steroids to the endometrium which atrophy as the consequence (6). However, endometrial atrophy, which would lead to thin endometrium or fibrosis, is different to IUA. Most current classification systems only take adhesion type and extent into consideration, not fibrosis.

On the other hand, it is possible that someone with moderately severe adhesions which are treatable may develop fibrosis if treatment is not sought for years. Fibrosis would impact on fertility, not by causing IUA, but by limiting blood flow to an area of the uterus.

As one never knows whether their case is severe or not, by all means seek treatment with an AS specialist, but the best prognosis is severity.

Prevalence versus incidence“While the exact number of Asherman’s sufferers is not known, it’s estimated that 5% of D&Cs cause the condition – that’s about 3,000 new cases a year.”

The article confuses the estimated prevalence rate of Asherman’s syndrome (5%) with incidence rate after D&C. The prevalence of AS is 5%, meaning that roughly 1 in 20 women in the general population have AS. This does not however mean that the incidence rate of AS after a D&C is 5%. Incidence is the percentage of women who develop AS from a particular procedure, such as D&C. Studies have reported rates varying between 7.7 and 30% after D&C for miscarriage (7,8,9,10,11), and 25% from D&C for post partum retained placenta 2-4 weeks after delivery (2). The reason the incidence is higher than the prevalence is that not all women will have a miscarriage, and not all women who miscarry will have a missed or incomplete miscarriage or will be treated by D&C. Furthermore, there will be undiagnosed cases of AS (either because the woman does not desire more children or her infertility remains ‘unexplained’), and obviously not every woman in the population will undergo diagnosis for IUA. One should also remember that there are other causes of AS including other intrauterine surgery and genital tuberculosis (12) and these carry different incidence rates too.

It is important to report the correct incidence rate after a procedure such as D&C because this gives women a better idea of risks and helps her to make an informed decision before consenting to the procedure. There are almost always equally effective alternatives to D&C such as drugs or minimally invasive surgery like hysteroscopy which incur no or less damage.

Prevention: more information and accuracy needed

“Doctors are increasingly opting for less-invasive methods including suction or the use of tablets”

It’s unfortunate that the focus of the story was on preventing infertility through early treatment-which is misleading-rather than on promoting alternatives to D&C.
There is one sentence about prevention, and sadly it contains an inaccuracy as well as an omission. Suction D&C has never been proven to prevent AS, let alone reduce the incidence rates of AS:

Chapman and Chapman, 1990: (13)
“It is noteworthy that, of the 11 patients with isthmus stenosis, six of them were attributable to termination of pregnancy, of which all but one had been performed by suction curettage”

Dalton et al, 2006 (14)
“Intrauterine adhesions are a possible complication of office MVA (manual vacuum aspiration), even in the absence of sharp curettage, and should be considered when discussing treatment options for EPF (early pregnancy failure) with patients."

“After 262 office MVAs for first trimester pregnancy losses, we have identified 5 cases of IUAs…”


There is also no guarantee that your doctor will use only suction D&C, as many will use blunt or sharp instruments as well during the same procedure.

The mysterious ‘tablets’ mentioned allude to misoprostol, a prostaglandin E1 analogue which can evacuate the uterus after miscarriage, delivery or during termination, by causing uterine contractions. Referred to as medical management of miscarriage or retained placenta, or medical abortion depending on the situation where it is used, misoprostol is a non-invasive method which has been shown to prevent IUA compared to suction D&C in a clinical trial (7).

Here you can find out more about how misoprostol can prevent AS if you have a miscarriage. It can also prevent recurrence of AS in women who have a miscarriage after having had the condition.
REFERENCES

1. Toaff R, Ballas S (1978). "Traumatic hypomenorrhea-amenorrhea (Asherman's syndrome)". Fertil. Steril. 30 (4): 379–87.

2. Jensen, P.A. and W.B. Stromme, Amenorrhea secondary to puerperal curettage (Asherman's syndrome). Am J Obstet Gynecol, 1972. 113(2): p. 150-7.

3. Valle RF, and Sciarra JJ (1988). "Intrauterine adhesions: Hystreoscopic diagnosis, classification, treatment and reproductive outcome". . Am J Obstet 158 (6Pt1): 1459–1470.

4. Shokeir, T.A., M. Fawzy, and M. Tatongy, The nature of intrauterine adhesions following reproductive hysteroscopic surgery as determined by early and late follow-up hysteroscopy: clinical implications. Arch Gynecol Obstet, 2008. 277(5): p. 423-7.

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

6. March CM. (1995). "Intrauterine adhesions". Obstet Gynecol Clin N Am 22: 98–103.

7. Tam WH, Lau WC, Cheung LP, Yuen PM, Chung TK. (2002). "Intrauterine adhesions after conservative and surgical management of spontaneous abortion". J Am Assoc Gynecol Laparosc. 9 (2): 182–185.

8. Adoni A, Palti Z, Milwidsky A, Dolberg M. (1982). "The incidence of intrauterine adhesions following spontaneous abortion". Int J Fertil. 27 (2): 117–118.

9. Golan, A., et al., Hysteroscopic findings after missed abortion. Fertil Steril, 1992. 58(3): p. 508-10.

10. Romer, T European Journal of Obstetrics & Gynecology and Reproductive Biology
Volume 57, Issue 3, December 1994, Pages 171-173

11. Friedler S, Margalioth EJ, Kafka I, Yaffe H. (1993). "Incidence of postabortion intra-uterine adhesions evaluated by hysteroscopy: a prospective study". Hum Reprod 8 (3): 442–444.

12. Kodaman PH, Arici AA. (2007). "Intra-uterine adhesions and fertility outcome: how to optimize success?". Curr Opin Obstet Gynecol 19 (3): 207–214.

13. K Chapman and R Chapman. Asherman's syndrome: a review of the literature, and a husband and wife's 20-year world-wide experience. J R Soc Med. 1990 September; 83(9): 576–580.

14. Dalton VK, Saunders NA, Harris LH, Williams JA, Lebovic DI (2006). "Intrauterine adhesions after manual vacuum aspiration for early pregnancy failure". Fertil. Steril. 85 (6): 1823.e1–3

The DO’s and DON’T's (and maybe’s) of Managing Intrauterine Adhesions.

Based on: AAGL: Practice Report: Practice Guidelines for Management of Intrauterine Synechiae, The Journal of Minimally Invasive Gynecology Vol. 17, No.1 2010.
Practice committee members:

Malcolm Munro MD, FRCS(C), FACOG
Rafaele F.Valle,MD
Jason A. Abbott, PhD,FRANZCOG,MRCOG
Angus J.M. Thompson, MRCOG
Keith B. Isaacson, MD
Adolf Gallinat, MD
Volker R. Jacobs, MD, PhD, MBA
Fred M. Howard MD
Andrew I. Sokol, MD
Linda D. Bradley, MD

Recently, the Practice Committee of the AAGL developed guidelines for the management of intrauterine adhesions (IUA), published in the Journal of Minimally Invasive Gynecology (2010). This is a welcome initiative, and long-awaited, with over one century passing since the first description of Asherman’s syndrome in the literature (1). Although these guidelines were based on studies published in peer-reviewed medical journals, there are limitations and room for more specific guidelines, as the authors themselves acknowledge, due to a lack of comparative studies and rigorous medical evidence from randomized controlled trials (RCTs). For example, studies were conducted using different surgical modalities, surgical tools, adjunctive therapies, and hormone therapy protocols. Many studies are also old and/or conducted retrospectively. One of the difficulties of studying IUA is that it is under diagnosed so that many women may not realize they have it. This results in a small sample size for studies, especially when patient treatment is spread between different centers. Additionally, the skills of the surgeon are important in influencing outcome which makes comparisons between different studies difficult. Consequently, drawing meaningful conclusions on treatment is problematic. To circumvent these shortcomings, the authors classified data based on the highest level of evidence found in the data and graded them according to a system outlined by the US Preventive Services Task Force. In most cases the evidence is based primarily on consensus and expert opinion (Level C). Hopefully trials will be forthcoming which meet today’s strict standards of clinical research, and recommendations which are stronger and more specific will result from them.

The goal of IUA management is to restore the volume and architecture of the uterine cavity and its communication with the fallopian tubes and cervical canal by removing IUA, preventing their recurrence and regenerating deficient endometrial growth.

Below is a summary of the recommendations of the article. My additional comments are in blue font.DIAGNOSISHysteroscopy is the most accurate method for diagnosis of IUA and should be chosen over HSG and SHG (although the latter are reasonable alternatives if hysteroscopy is not available).
(Grade B)

CLASSIFICATION
Although there are several classification systems, none is considered superior over the other, probably reflecting inadequacies in all current systems. (Grade C)

An accurate and universal classification system for IUA is important for enabling the comparison of studies and providing prognostic indicators of fertility outcome. (Grade B)


TREATMENT
DO's:

Only expert hysteroscopists familiar with IUA treatment should attempt to treat extensive or dense adhesions. (Level C)(Surgeons who are inexperienced may inadvertantly cause further irreparable damage).
Direct visualization of the uterus during hysteroscopic lysis of adhesions using a tool for dissection is the treatment of choice for IUA which underlies infertility, recurrent pregnancy loss, pain or other related symptoms. (Level C).

In some women expectant management may be acceptable. (Level C)
(ie. if adhesions are thin and filmy and/or cover a small surface area treatment benefits may not outweigh treatment risks).

Estrogen therapy with or without progestin may reduce reformation of IUAs. (Level B)(Estrogen therapy dose and length will depend on severity. See also Recommendations for Future Research).
MAYBE's:

Gel barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel may reduce IUA recurrence follow surgical correction, however there is not enough data on pregnancy outcomes following their use, so should not be used without more rigorous trials. (Level A)
(Potential problems with gel barriers are that they are difficult to keep in place, become less viscous at body temperature, draining out of the uterus. See also Recommendations for Future Research).

Foley catheter or IUD should not be used routinely after corrective surgery without further data from trials supporting their benefit. This is because they may increase the risk for infection. (Level C)
(There have been reports of IUDs puncturing the uterus. Also, some doctors also believe that intrauterine pressure from balloons can hinder endometrial regeneration. However, both the Foley catheter and the Cook stent-which curiously was not mentioned in the article-have been used successfully (2)).

Supporting or refuting the use of prophylactic antibiotics before, during or after surgical adhesiolysis. (Level C)
(However, antibiotic prophylaxis should be used in the case of barriers, as a foreign object inside the uterus increases the risk of infection. See also Recommendations for Future Research).

Medications to improve blood flow to the endometrium should be used only after being supported by rigorous research. (Level C)(These include low-dose aspirin, Coenzyme Q-10, vitamin E, and Sildenafil citrate.ie. Viagra, and even herbal remedies such as raspberry leaf tea).
Prevention of complications (eg. perforation) or improved outcomes with the use of external imaging techniques or laparoscopy, however these techniques may have advantages in case perforation does occur. (Level B)(Another advantage is that laparoscopy allows the surgeon to view the pelvic cavity where there may be endometriosis (3), especially in the more severe cases where laparoscopy is often used).
DON’T's:

There is no evidence to support blind D&C or blind cervical probing in the treatment of IUA (Level C)(The authors state that D&C should not be used because it does not permit accurate diagnosis and classification. The bigger concern should be that blind curettage may cause further and irreversible damage and is the underlying cause of most IUA (4)).
Copper (inflammatory), progestin-releasing (suppress endometrium) and T-shaped IUDs (small surface area) should not be used after adhesiolysis. (Level C)

Laparotomy should be considered as a last resort (eg. when hysteroscopic surgery fails) (Level C)
Electrosurgery/laser: There is some disagreement over which tools are best suited for adhesiolysis. Some surgeons prefer to use microscissors and stress that thermal energy tools offer no advantage over scissor dissection with regards to either speed or hemostasis (2). Furthermore, these modalities (including resectoscope, Nd:YAG laser, monopolar/bipolar electrode) deliver energy that can cause injury to surrounding tissues and therefore some believe it is prudent to avoid them for the treatment of IUA (2). Indeed, electrosurgical tools are normally used for endometrial ablation which burns away endometrium and intentionally induces Asherman’s syndrome in women with excessive bleeding. However, other doctors claim that in experienced hands these tools are safe. Which ever the case, this is an issue which probably needs to be further examined to refute any safety concerns.POSTOPERATIVE ASSESSMENT:Follow-up evaluation of the uterine cavity is recommended after treatment of IUA. (Level B).(This is an important factor in determining outcome as adhesions may reform and further surgery may be needed. If a pregnancy occurs in a uterus with IUA, there is a higher likelihood of infertility, miscarriage and pregnancy complications (5). Patients should undergo either HSG, SHG, or in-office hysteroscopy (with as narrow cervical dilation as possible) in order to verify the uterine cavity is free of adhesions. A mid-cycle scan should also be used to measure the endometrial thickness at ovulation. Ideally this should measure 7-8 mm for implantation to be successful. Some women with corrected IUA have thin endometrium which may require hormone treatment to thicken. If adhesions blocking the ostium are present, natural conception is not possible and IVF will be recommended).
RECOMMENDATIONS FOR FUTURE RESEARCH:

1. Prospective trials on the effect of intraoperative and postoperative antibiotic prophylaxis on surgical and fertility outcome.(I don’t know of doctors who do not use antibiotics during or after operative hysteroscopy. Also, the article states: “…it has been proposed that infection may be a primary cause of IUAs…” Antibiotic prophylaxis is wise for preventing infections whether or not they lead to IUA. However, at this stage, there is actually no evidence to support that most IUAs result from infection, whether frank or subclinical. In fact, there is limited evidence to the contrary (6,7). Also see The subclinical infection myth).2. Prospective trials of adjunctive hormone therapy efficacy with respect to surgical and fertility outcome.(The optimum dosage of estrogen (E2 with or without progestin, P4) and length of treatment have not been studied. Progynova (Estradiol valerate) a synthetic version of a naturally occurring estrogen or Premarin, a combination of around 11 conjugated equine estrogens extracted from pregnant mare urine, are usually used. These compounds have not been compared to each other in trials).
3. Prospective trials of barrier method (IUD, Foley catheter and gel adhesion barriers) efficacy with respect to surgical and fertility outcome.
(Presumably the Cook stent, which is used by some doctors (2), should also be included in trials. Regarding the use of gel adhesion barriers which are potentially the least invasive and risky type of barrier, one questions why there is not more research on their use to prevent IUA from occurring in the first place. If gel barriers are therapeutic for reducing IUA reformation after hysteroscopic adhesiolysis perhaps their use after D&C and other primary intrauterine surgery would reduce the incidence of IUA. There is so far only one study and results show only 10% of women who received Seprafilm after curettage for miscarriage developed IUA vs 50% amongst controls (8)).
4. Stem cells for future treatment: As discussed in a previous blog, some cases are currently not treatable because the extent of damage to the basal endometrium (sometimes curettage even removes part of the underlying myometrium) from which the functional layer regenerates. This leads to persistently thin endometrium or reformation of IUA after corrective surgery and excludes the possibility of carrying a pregnancy. Surrogacy is the only option in such cases. However Dr Chaitanya Nagori and Dr Sonal Panchal of Nagori Institute of Infertility in India claim to have used stem cell technology to thicken the endometrium in women who underwent excessive ‘cleaning’ up of the uterus (ie. a euphemism for D&C), although they do not mention the presence of IUA. The process involved isolating adult stem cells from the bone marrow of the patient, transplanting the purified stem cells into the patient’s uterine cavity under transvaginal sonographic guidance, and stimulating the production of endometrial angiogenic stem cells by administering estrogen before IVF treatment. Using this technique they reportedly were able to increase ‘negligible’ endometrial growth to 6mm three months after the transfer and estrogen therapy. Although they assert that IVF drugs alone did not increase the patient’s endometrial measurement, it remains to be proven whether this effect is due to the post-transplant estrogen treatment or from the stem cell therapy. Nonetheless, the concept of using stem cells for tissue repair in the uterus is intriguing, and possibly the best hope in future for very severe cases of IUA (uterine transplant is another future possibility). This could be more convincing if recurrent IUA was prevented with stem cells following hysteroscopic adhesiolysis. Definitive proof would be obtained if the stem cells and their progeny were biochemically labeled so as to be identifiable from the original tissue. This could be done in animal studies, for example. The great advantage of stem cells is that they have the capacity to differentiate into a range of cells that are necessary to rebuild a normal uterus, from myometrium and endometrium to the blood vessels which supply them with blood and hormones. Furthermore, as the stem cells are derived from the patient’s own bone marrow ie. autologous adult stem cells, there is no risk of either rejection or ethical controversy (as with embryonic stem cells). Unfortunately at this stage there are no published studies on this treatment.
REFERENCES

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

2. March, CM; Miller, CE. Hysteroscopic lysis of intrauterine adhesions. Ob.Gyn. News 2006; 41(23):36-37. Abstract

3. Palter. SF, High Rates of Endometriosis in Patients With Intrauterine Synechiae (Asherman's Syndrome). Fertility and Sterility 2005; 86 (null):S471-S471. Link

4. Palter S, Spyrou P. Asherman’s syndrome: Etiologic factors, patterns of pregnancy loss, and treatment results. Results from an international registry. Fertility and Sterility 2003; 80(3):36-7. Link

5. March CM. Intrauterine adhesions. Obstet Gynecol Clin N Am 1995;22(3):491-505. Abstract

6. Jensen, P.A. and Stromme, W.B. Amenorrhea secondary to puerperal curettage (Asherman's syndrome). Am J Obstet Gynecol 1972; 113: 150–4.

7. Polishuk, SO Anteby and D Weinstein, Puerperal endometritis and intrauterine adhesions, Int Surg 1975;60:418–420. Abstract

8. Tsapanos VS, Stathopoulou LP, Papathanassopoulou VS, Tzingounis VA. The role of Seprafilm bioresorbable membrane in the prevention and therapy of endometrial synechiae. Biomed Material Res. 2002;63:10-14. Abstract

Related Links:Good news: Grow endometrium by stem cells. (Times of India)

Recommendation Grading:
Level A: Recommendations are based on good and consistent scientific evidence.
Level B: Recommendations are based on limited or incomsistent scientific evidence.
Level C: Recommendations are based primarily on consensus and expert opinion.

Complications in post Ashermans syndrome Pregnancies (Part II)

Continued from Part I
Click here for pregnancies in the presence of intrauterine adhesions (synechiae).

Cervical incompetence/insufficiency
Cervical incompetence or insufficiency is when the involuntary muscle of the cervix is structurally weak and unable to sustain the weight of the growing fetus. Effacement (shortening and thinning of the cervical walls) occurs prematurely and in the absence of contractions, resulting in bulging of the amniotic membranes, leading to rupture and premature birth. This often occurs during the second trimester before the fetus is able to survive outside the uterus. Cervical incompetence is associated with AS although it is thought to result not from having had scarring but rather as a consequence of frequent dilations of the cervix during procedures such as D&C and hysteroscopy- which itself is used to correct AS. The less widely and less often the cervix is dilated, the better, as frequent dilations of over 8mm put women at an increased risk of cervical incompetence in subsequent pregnancies. In order to monitor for CI, transvaginal ultrasound measurements of the cervix should be undertaken beginning during second trimester at around 16 weeks. Women cannot sense or predict its occurrence and it is also difficult for Obgyns to predict and prevent even with close monitoring as it may have a very sudden onset. It is thought that the increased rate of second trimester pregnancy loss in women with past AS is due to CI. In one study, 3 of 15 pregnancies (20%) were complicated with second trimester fetal loss (9) probably caused by CI. Cervical incompetence may be managed with bed rest and cervical cerclage (9). Cerclage is a cervical stitch sewn to prevent the cervix from opening and it may be placed vaginally or abdominally. Cerclage is a controversial obstetric procedure and studies are continuing to investigate how effective it is. Therapeutic cerclage is used when the cervix is showing signs that it is dangerously shortened ( under 2cm) or funneling, however it is not always effective at this stage and pregnancy loss may still occur. ‘Prophylactic’ cerclages are usually indicated in women with a past history of CI ie. whom have already experienced CI in a previous pregnancy. Because cerclage itself carries the risk of infection, inflammation, and rupture of membranes, it is not routinely recommended in women with past AS. Instead, monitoring of cervical length and therapeutic cerclage if needed is recommended. Interestingly, a study on women with short cervix during pregnancy (under 1.5 cm measured around 22 weeks of gestation) found that progesterone supplementation reduced spontaneous delivery before 34 weeks compared to placebo (25).

Possibilities for prevention of CI include the reduction/replacement of D&C with drugs or expectant management, the use of smaller instruments necessitating less dilation during hysteroscopic surgery (11), and the use of misoprostol for cervical priming (instead of mechanical force for dilation).

IUGR
IUGR (intrauterine growth restriction, or fetal growth restriction) refers to a condition where the fetus is smaller than expected for its gestational age (less than the 10th percentile). Newborns with IUGR are termed small for gestational age (SGA). IUGR is caused by a reduction in oxygen and nutrients delivered to the growing fetus due to a lack of adequate blood flow to the placenta. As the endometrium of women with past AS may be damaged, blood flow to the uterus and placenta may be suboptimal, leading to poor placenta perfusion. There are also other causes of IUGR including high blood pressure, diabetes, cigarette smoking, substance abuse, malnutrition, and kidney disease. A lack of oxygen reduces the fetal heart rate and puts the life of the fetus at great risk. IUGR may be early or late-onset, however the earlier the onset, the greater the risks. Risks include premature delivery, stillbirth, and long-term growth problems in children. Diagnosis is made by ultrasound measurements of the fetal size and fetal weight estimation. Doppler flow studies can be used in conjunction with ultrasound to measure the quantity and velocity of blood flow in the fetal brain and umbilical cord. IUGR cannot be predicted or reversed, however its possible presence should be closely monitored in women with a past history of AS. Placenta previa, another potential complication of AS, is also associated with IUGR. Bed rest and increased maternal nutrition may help, as may aspirin therapy to improve blood flow. If IUGR is threatening the well being of the fetus, early delivery may be necessary ie. via C-section. Yasmin and Adeghe (26) report a case of early-onset symmetrical fetal growth restriction in a patient with treated AS. At 20 weeks the fetal measurements corresponded with 18 weeks. A detailed scan at 29 weeks revealed measurements under the 3rd centile with oligohydroamnios and uterine artery flow suggested poor placental perfusion. The baby was delivered via C-section at 29 weeks. The placenta was calcified and partially adherent to the uterine wall. Interestingly, there are no other published studies mentioning IUGR as a complication of AS, although one would not expect it to be a rare consequence. It is possible that some cases of IUGR in women with a history of AS have been attributed to other causes, as there are potentially many confounding risk factors.

Premature Birth
Premature or preterm birth is defined as spontaneous labour followed by birth before 37 weeks of gestation. The duration of most pregnancies is around 40 weeks, with babies born between 37 and 42 weeks considered full term. There are several factors which are linked to prematurity which makes it difficult to always know the exact cause. Certain life style factors (smoking, drinking/drugs, stress etc.), and medical conditions (diabetes, hypertension, infections, underweight or obesity etc.) are associated with prematurity. Certain women are also predisposed to premature delivery: those with twin/triplet ie. multiple pregnancies, women with previous premature birth, and women with uterine or cervical abnormalities (congenital or acquired). The overall rate of premature birth in the US is 12.8% (27). However, in women with a past history of AS rates of premature delivery from 17.912-50% have been reported (9, 10, 28, 29, 30) In some cases, but not all, prematurity occurred in conjunction with abnormal placentation (eg. adherant placenta, placenta accrete and/or previa etc). Other studies have linked prematurity to induced surgical (ie. D&C) abortion but not to medical abortion, which supports a correlation between endometrial trauma and premature delivery. Note that most terminations are now carried out medically (however, unfortunately, standard management of missed or incomplete miscarriage continues to be D&C in many countries, more for cultural reasons rather than medical ones).

Premature birth is the leading cause of neonatal mortality and morbidity. Infants born prematurely are at an increased risk for both short and long-term health complications. The earlier the birth, the higher the risk for health complications. Complications are more likely to occur and with more severity in infants born before 32 weeks than after. As medical care continues to improve, infants are surviving at earlier gestational ages, however the current limit for viability is generally around 24 weeks. Potential health complications of ‘premies’ include:

-neurological problems (eg. cerebral palsy, apnea of prematurity, retinopathy of prematurity),
-respiratory problems (eg. respiratory distress syndrome),

-cardiovascular problems (eg. patent ductus arteriosus),

-gastrointestinal/metabolic disorders (eg. rickets, inguinal hernia),

-hematological conditions (eg. jaundice, anemia) and

-infections (eg. sepsis, UTI).

Pregnancy loss due to cervical insufficiency (CI), which occurs without labour and has a different etiology, is not considered premature birth. However, cervical cerclage and progesterone supplementation may be used to prevent/manage both conditions. Progesterone derivatives have been shown to reduce the frequency of premature delivery both in women with previous premature delivery (31) and women with short cervix (25).


Uterine rupture

The most common factor predisposing to uterine rupture is a uterine scar. This may be caused by D&C, C-section or hysteroscopic surgery (eg. myomectomy, reparation of congenital uterine malformations etc.). Not surprisingly, there have been several reports of uterine rupture among women with a past history of AS (7, 32, 33, 34, 35). In most of these cases, prior uterine perforation occurred during hysteroscopic adhesiolysis , however in rupture has also been reported in women without prior perforation (33). The thinning, weakened and increased fibrosis of the myometrium undoubtedly predispose to rupture of the uterus (2, 36).

This long list of potentially serious complications supports the recommendation that women who have had AS, even after correction, should be carefully monitored by a high risk Obstetrician, and preferably one who is aware of the reported complications in order to optimize the well-being of the pregnancy and the patient. These serious complications also add to a growing list of reasons why prevention of AS from occurring is more compelling than relying solely on treatment of the condition. In all of these complications endometrial damage is the common denominator which has the potential to affect placental attachment, uterine/cervical strength and/or placental perfusion. Finally, it is interesting to note that while complications and sequelae readily attributed to C-sections are being closely monitored and the number of C-sections is being audited by hospitals and organizations such as the WHO with a view to reducing their frequency (37), the same is not being done for D&C. Why not? A reduction in D&C rates would lead to fewer obstetric complications necessitating C-sections. Furthermore, the public health costs of diagnosis, surgical correction, treatment for infertility and obstetric complications resulting from D&C should be reason enough to reduce the reliance on this procedure-not to mention the impact on women's health and well-being.

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