The Miscarriage Study: 400 vs 800 mcg misoprostol

Mater Mother’s Hospital in Queensland has been conducting a randomized controlled trial comparing two doses of misoprostol (800 mcg versus 400 mcg) for the medical management of miscarriage. More information can be found in the brochure for The Miscarriage Study on their website:

http://brochures.mater.org.au/Home/Brochures/Mater-Mothers--Hospitals/Miscarriage

Medical management is only available to women participating in the Miscarriage Study. Surgery or expectant management is offered as standard care options to women who choose not to participate.

The web brochure explains that the study is being carried out because currently there is no agreement on the most effective dose for misoprostol use in miscarriage. However it points out that 800mcg is the most common dose used in studies. While it is true that researchers have not determined a dosage/regimen which is as effective as D&C i.e. the ‘optimum’ protocol for medical management using misoprostol, preliminary guidelines based on hundreds of studies have been produced by the expert group convened by WHO in Bellagio in February 2007. They are published in a supplement to the International Journal of Gynecology and Obstetrics (2007, vol. 99) and can be read here. According to these guidelines, 600-800 mcg misoprostol is the recommended dose for first trimester miscarriage. The guidelines for misoprostol use according to indication and gestational age are also available at: http://www.misoprostol.org/ This website also provides excellent resources to clinicians interested in information about misoprostol use and the misoprostol debate.

The researchers have chosen to study quite a low dosage of misoprostol to reduce side effects. However, it has already been established that even 600-800 mcg is not as effective for first trimester miscarriage as the standard care D&C (it remains questionable as to why it is imperative for medical management to be equally as effective as D&C for it to be used when medical management offers the advantages of being non-invasive, cheap, free of anesthetics and safer for future fertility than D&C).The drug is inexpensive, so cost is evidently not an issue. Furthermore, the optimum dose for use in termination up to 7 weeks is 800 mcg (in combination with mifepristone). A recent study found that this dose should not be lowered (link). Apparently misoprostol side effects for termination are not a concern for women. One would imagine the same for women who miscarry.


Misoprostol is listed in the Standard Drug List of Queensland Hospitals for use in miscarriage and is currently used in this hospital for the treatment of other pregnancy complications. The Therapeutic Goods Administration (TGA), which is the Australian equivalent of the FDA in the US, has not approved of its use in pregnancy in Australia.

However, the Queensland Health and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists support its use in the treatment of miscarriage. Despite this, misoprostol use for first trimester miscarriage remains uncommon in Australia. The drug is quite commonly used for miscarriage management in European countries. In contrast, a combined misoprostol/mifepristone regimen is offered by most if not all services in Australia specializing in pregnancy termination. It has also become common practice for labour induction despite the fact that there is not more evidence to support its use for this indication than for miscarriage. Interestingly, expectant management is considered acceptable although it is not more effective than for miscarriage management in clinical trials. Health professionals excuse the restricted access to misoprostol for miscarriage management with the pretext that misoprostol is not TGA approved, yet misoprostol use in ALL obstetric/gynecologic indications is not approved (misoprostol was developed for the treatment and prevention of ulcers). The unlicensed use of misoprostol for terminations is cunningly circumvented by a legal loophole which allows its use in combination with mifepristone which is only TGA approved for use in pregnancy termination. Unlicensed use of misoprostol in labour induction, curiously, does not seem to hinder clinicians from using it for labour induction even though substantially less is known about the short and long term effects it may have on infants exposed to it. Misoprostol is also used in the treatment of osteoarthritis and marketed under the name Arthrotec. Curiously, there is no debate over the unlicensed use of misoprostol for arthritis. Yet none of the above has lead to questioning the objective validity behind the selective use of misoprostol for some unlicensed obstetric (or other) indications but not for miscarriage management. Why is it that the only people who seem to be prevented from using misoprostol are women who miscarry?

Most women who miscarry have no choice but to undergo a costly D&C, potentially leading to long term adverse effects on fertility (Asherman’s syndrome) and a host of possible future obstetric complications (placenta accreta, percreta, previa, IUGR, pre eclampsia, preterm birth, cervical insufficiency leading to second trimester loss, and uterine rupture). It is ironic that the very women who desire a pregnancy most are also those who are exposed to iatrogenic infertility and/or pregnancy complications arising from surgical management. Disappointing overall reproductive outcomes (40%) and associated healthcare costs (not to mention patient discontent) do not make the approach of relying on treatment of Asherman’s syndrome a paradigm. The restriction of a safe, inexpensive and non-invasive alternative such as misoprostol for miscarriage management can be considered unethical and perhaps even discriminatory as it is available to other populations of women for unlicensed obstetric/gynecological indications.


The Mater Mother’s Hospital webpage mentions potential complications from surgical management (D&C) without specifically naming Asherman’s syndrome (intrauterine adhesions and/or fibrosis) or cervical insufficiency (from cervical dilation). It also quotes the risk of complications from D&C as 1:200-500 surgeries, a greatly underestimated frequency (see Frequency of intrauterine adhesions after curettage).

It is encouraging to see local studies on misoprostol for miscarriage management. Even if 400 ug will turn out to have a significantly lower success rate than 800 ug, exposure to women and clinicians could help promote awareness about it and increase its demand/use. Perhaps it is a sign that Australia is finally ready to implement medical management as a routine care option.

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.

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.

How AS causes infertility or miscarriages

Asherman’s syndrome (AS) can lead infertility in a number of ways. No two cases are identical and it can manifest as infertility according to how and which parts of the reproductive anatomy is affected. AS is characterized by intrauterine adhesions (IUA) and/or fibrosis (non-functional scar tissue).

Infertility may be caused by adhesions occluding the tubal ostia, uterine cavity, or the cervix, thereby interfering with the migration of sperm or implantation of the embryo (1). The presence of defective endometrium in the fundus and ostia which are partially obliterated by the adhesions may also predispose women to tubal and cervical pregnancies (2,3). Partial obstruction of tubes can lead to pregnancy complications such as ectopic pregnancy because the fertilized egg may be physically impeded from migrating to the uterus for implantation. If ostial obstruction is so extensive that it cannot be corrected through hysteroscopic adhesiolysis, in vitro fertilization is the only possibility for a biological offspring (providing that the rest of the uterus is functional and adhesion free). Cervical pregnancy (another form of ectopic pregnancy) may occur if the embryo implants in the cervix. Adhesions involving the cervix may result in the cervix being closed (outlet obstruction). This obviously prevents the sperm from encountering the egg. It has also been noted that in women with outlet obstruction due to adhesions blocking the lower uterus or cervix, endometrial measures are thinner than in women where adhesions are limited to the upper uterus (4). It is thought that the underlying cause of this is a feedback loop to prevent haematometra from occurring. Haematometra is the formation of a large clot of blood from trapped menstrual debris and it very rarely occurs in the former subgroup of women.

Another possible way Asherman’s syndrome can result in infertility is by causing endometriosis. Some authors have noted that women with extensive adhesions either in the uterus or cervix, blocking menstrual flow, later develop endometriosis (5). This was discovered because laparoscopic (keyhole) surgery is sometimes carried out at the same time as hysteroscopy when performing adhesiolysis of IUA. Laparoscopy helps to prevent uterine perforation in severe cases where it may be difficult to judge the limits of the uterine cavity. Endometriosis is the growth of endometrial lining outside of the uterus. It can occur anywhere in the body, though most commonly occurs in the abdomen. Although the cause(s) of endometriosis remain unknown, one of the theories put forth by John A. Sampson is known as the theory of retrograde menstruation. It speculates that a back flow of blood and debris through the fallopian tubes and into the abdomen enables its implantation to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as endometriosis. (As an aside to those who practice yoga, this is why inverted positions such as headstands are avoided during menstruation). Endometriosis itself can lead to infertility by causing pelvic adhesions (Note: not to be confused with intrauterine adhesions which occur INSIDE the uterus). Pelvic adhesions (or extrauterine adhesions) can twist and distort the fallopian tubes and prevent fertilization or implantation.

Many women who have had Asherman’s syndrome develop a thin endometrium even after surgical correction and hormonal therapy to stimulate endometrial regeneration. An optimal thickness of the endometrium (>8mm) is considered to be one of the prerequisites for successful implantation of the embryo. Thin endometrium can be caused by either too much of the endometrium having been removed during D&C (or other uterine surgery) or cervical obstruction (as described above). A thin endometrium may be unresponsive to hormones (6) and may lead to infertility in the form of implantation failure or early miscarriages known as ‘chemical pregnancies’ due to a lack of blood supply and poor placental perfusion. Thin endometrium can also occur in women who have had D&Cs, even if they did not develop Asherman’s syndrome. In fact, a recent study found that the endometrium of women is thinner for about 6 months after a D&C (7). A recent study suggests that treatment with tocopherol (ie. vitamin E) and pentoxifylline may help to thicken the endometrium (8), improving implantation. Of course IUA must be removed before pregnancy can be attempted.

The exact mechanisms by which IUA predispose to miscarriages are unknown, however, it is suspected that constrictions of the uterine cavity by adhesions, lack of adequate functional endometrium to support implantation and defective vascularisation of the residual endometrial tissue due to fibrosis may account for repeated pregnancy loss (9). If an embryo implants in an adhesion or a fibrotic region, it will not grow successfully because it will not have an adequate blood supply, essential for providing the growing embryo with oxygen and nutrients. This can lead to miscarriage. Interestingly, this is analogous to the situation where women with Mullerian malformations such as septate uterus often undergo miscarriage when the embryo implants in the septum (10). If IUAs obstruct the openings of one or both of the fallopian tubes (known as ostia) this prevents the sperm from fertilizing the egg (which normally happens in the fallopian tubes after ovulation).

There is another potential cause of second trimester miscarriage which has been often reported in women with a past history of Asherman’s syndrome: cervical incompetence, also known and cervical insufficiency, however, I will write about this under a future blog topic, post-Asherman’s syndrome obstetric complications, since these miscarriages are not due to adhesions or fibrosis per se but to previous dilations of the cervix during surgeries.


As a consequence of the above, many women who have untreated Asherman’s syndrome are either unable to conceive, or suffer from repeated miscarriages. However, depending on the location, extent and severity of IUA/fibrosis, patients may conceive and carry a pregnancy without treatment. This is not recommended and is usually a chance finding on ultrasound when an adhesion or synechia is detected. There have been isolated case reports of successful and uncomplicated pregnancies in the presence of IUA (11). In the best case scenario, the adhesions are minimal and thin, stretching with the pregnancy such that it does not impinge on the growth of the fetus or uterus. However, women are strongly advised to use contraception to avoid pregnancy until surgical correction of adhesions to avoid pregnancy complications. In women who conceive without removal of adhesions, the reproductive outcome is usually poor: in one well known study, it was reported that of the 46% of patients with untreated IUA who conceived, 40% of the pregnancies ended in spontaneous miscarriage, 12% of which were ectopic. Of the viable pregnancies, 23% delivered prematurely and 13% had placenta accreta with only 53% delivering viable infants (12). Obviously, the more severe the classification of AS, the more likely complications are to occur if a pregnancy occurs. On the other hand, pregnancy itself is probably less likely to occur in more severe cases. Note that these complications may also occur in women after treatment of Asherman’s syndrome, however not as frequently. This will be covered in a future blog.

The moral of the story is: get treated by a trusted Asherman’s specialist if you have Asherman’s syndrome and make sure the uterine cavity is clear (via a follow up hysteroscopy or HSG) and that adhesions have not recurred before trying to conceive. Even better, avoid getting Asherman’s syndrome by using alternatives to D&C.


References


1.Yu, D, Wong, YM, Cheong, Y, Xia, E, and Li, TC. Asherman syndrome--one century later. Fertil Steril 2008;89(4):759-79.

2. Dicker, D, Feldberg, D, Samuel, N, and Goldman, JA. Etiology of cervical pregnancy. Association with abortion, pelvic pathology, IUDs and Asherman's syndrome. J Reprod Med 1985;30(1):25-7.

3. Forssman, L. Posttraumatic intrauterine synechiae and pregnancy. Obstet Gynecol 1965;26(5):710-3.

4. Lo ST, Ramsay P, Pierson R, Manconi F, Munro MG, Fraser IS. Endometrial thickness measured by ultrasound scan in women with uterine outlet obstruction due to intrauterine or upper cervical adhesions.Hum Reprod. 2008 ;23(2):306-9. Link

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

6. Shufaro, Y, Simon, A, Laufer, N, and Fatum, M. Thin unresponsive endometrium--a possible complication of surgical curettage compromising ART outcome. J Assist Reprod Genet 2008;25(8):421-5.

7. Moon KS, Richter KS, Levy MJ, Widra EA. Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development? Fertil Steril. 2009;92(5):1776-9. PMID 19560759

8. Acharya S, Yasmin E, Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies--a report of 20 cases. Hum Fertil (Camb). 2009;12(4):198-203. Link

9. Polishuk, WZ and Sadovsky, E. A syndrome of recurrent intrauterine adhesions. Am J Obstet Gynecol 1975;123(2):151-8.

10. Golan, A, Schneider, D, Avrech, O, Raziel, A, Bukovsky, I, and Caspi, E.
Hysteroscopic findings after missed abortion. Fertil Steril 1992;58(3):508-10.

11. Klatsky PC, Tran ND, Strachowski L. A pregnancy complicated by endometrial scarring. Fertil Steril. 2009;91(6):2707-8.

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

A hidden cause of ‘unexplained’ infertility and miscarriages: ignorance about AS

Asherman’s syndrome remains a cause of infertility –ie. the inability to conceive or carry a pregnancy- the latter sometimes resulting in repeat miscarriages- which is often overlooked. This is because both doctors and women alike are often unaware of this ‘syndrome’ which rarely gets a mention outside of infrequent gynecological journal articles or anti-abortion propaganda (which ignores the fact that a D&C for any reason or intrauterine surgery can cause the condition). Furthermore, it may be difficult to make a link between a surgery and problems or complications which may occur years later. Another reason is that it is incorrectly thought of as being a rare condition, despite reports of up to 30% of women developing intrauterine adhesions (IUA) after D&C for missed miscarriage and 25% if D&C is performed following delivery (1,2).

Ironically, perhaps another reason it remains so hidden is due to its very symptoms: infertility and miscarriages. Unfortunately, even among highly educated medical professionals, there remains a tendency to consider women who exhibit these as having other fertility flaws rather than to contemplate that problems could be the result of a routine procedure they or a colleague carried out. I was dismayed to have read so many peer-reviewed medical articles where this view is expressed. In fact, Dr. Joseph Asherman, the doctor who described the condition in detail in 1948 and whose name the condition was coined after, quite strangely believed that "adhesions are certainly not to blame for the incapacity to conceive" (3). Of course, this view is certainly refuted today. I will write about this and other errors Dr Asherman (and others) made in a future blog. With all due respect, one should keep in mind that his speculations were based on what he could extrapolate from the imaging techniques and medical and scientific knowledge available in the 1940s and 1950s. Today we are in a much better position to analyze medical conditions. However many study authors continue to suggest that any failure to achieve pregnancy or live birth after 'successful' treatment of IUA as ‘evidence’ of other additional underlying fertility issues even though there could be endometrial dysfunction due to fibrosis for which there are currently no accurate tests. Current live birth outcomes are around 40% at best. This means that they attribute at least 60% of post AS infertility to hypothetical additional infertility factors. Therefore, secondary infertility is often incorrectly labeled as primary infertility.

It is of no surprise that Asherman's syndrome was first noted in a woman who developed amenorrhea after a postpartum curettage (6). If she had not 'proven' her fertility by giving birth her infertility would surely be ascribed to some other undefined cause. Thus, if a childless woman who has a D&C to treat a miscarriage and develops AS, many doctors are less likely to investigate it and put down her future infertility (and prior miscarriage) to other 'unknown' fertility problems. It does not help that the older a woman, the more likely she is to have a miscarriage and therefore undergo a D&C- and develop AS. Age-related infertility can then be the excuse, and if you are a woman aged 40 or over and have ever been to see a fertility specialist as I have, you will have this drummed into you like a mantra. (On a personal note, this is why it especially sucks to get AS after the miscarriage of a first pregnancy when you are an older woman!!!). Most D&Cs are carried out for miscarriage, and proportionally more miscarriages occur in older women at the same time as their natural fertility is declining.


Also unfortunate is that the indirect association between women who do have other fertility problems and AS is often thought to be a direct association. The correlation is due to the fact that women with fertility problems are more likely to miscarry, and therefore have D&Cs-the cause of AS- however unfortunately some doctors will only look at the simplest assocation. There is a review article (4) which misleadingly describes Mullerian defects (eg. septate uterus) as a cause of AS due to 'stagnation of menstrual debris or old blood inside the uterine cavity'. This assertion has no basis whatsoever, nor have I read any similar claim in any other peer-reviewed medical article. (Note: incidentally, that article which is ironically titled 'Ashermans syndrome (IUA): Has there been any progress over the last 20 years?' is undoubtedly the most unconventional review on Asherman's syndrome I have ever come across. Perhaps I can go into the details of this in a blog of its own). In fact it has already been noted that women with Mullerian defects often have had several miscarriages and D&Cs, and it is the latter which increases their risk of developing AS (5). Furthermore, it doesn't take a rocket scientist to realize that blindly scraping in any uterus, let alone an unusually shaped uterus with a wall in the middle, is likely to result in injury leading to IUA. In reality, the only female population that is ‘predisposed’ to AS is anyone who is likely to undergo D&C or intrauterine surgery more frequently than the 'normal' population, whatever the reason might be. No wonder there is so little sympathy or admission of responsibility by the medical community when it is in their interest to blame the patient’s age or other undefined fertility issues for infertility instead of standard medical care.

Even when menstrual disturbances -which are hallmarks of AS- are reported by patients they are either brushed aside as imaginary, explained as normal for one’s age or following miscarriage, or put down to other ‘proof’ of other fertility problems.


The sayings:

“Science progresses best when observations force us to alter our preconceptions.” (Vera Rubin)

“Those who have excess faith in their theories or in their ideas are not only poorly disposed to make discoveries, but they also make very poor observations.” (Claude Bernard)

come to mind.

The bad news is that if Gyns/ObGyns are missing (intentionally or not) the link between cause and effect (ie. D&C and infertility/miscarriages) and making biased and incorrect assumptions about other causes of infertility to ‘explain’ reproductive outcome failure, this gives less incentive for doctors to replace the current standard of care for miscarriage with drugs such as misoprostol or hysteroscopic removal of retained tissue instead. Instead, these attitudes help to maintain the status quo and enables D&Cs to continue to be used widely and indiscrimminately, ignoring the risks.

The most accurate method for diagnosis of IUA is hysteroscopy because it allows a direct view of the inside of the uterus however it is not routinely carried out during infertility workups. Couples considering artificial reproductive technology (ART) are referred for other diagnostic procedures such as ultrasound and HSG however these may not accurately detect the presence of IUA. Also, there is currently no test available for endometrial function which is essential to proper embryo implantation and successful pregnancy. Unfortunately there are few gynecologists who are trained to perform hysteroscopy. Only 15% of US doctors perform office hysteroscopy (7). In comparison, 100% of urologists use office cytoscopy to evaluate bladder pathology. I find it disconcerting that hysteroscopy is such an underutilized technique and question if this would be the case if those likely to benefit from it were men (similarly, would D&C continue to be used if it caused male infertility?). Perhaps our own inaction and passivity as women are in part to blame. Undergoing IVF in the presence of AS is a very expensive waste of time and once again, it is the patient (and broader community if fertility treatment is government subsidized, as in some countries) who suffers most from it, not the fertility specialists! (on the contrary...) IVF is bound to fail if the cavity is not suited for embryo implantation/growth. Even if a patient has other fertility problems such as blocked tubes or her husband has poor sperm quality, the patient must first correct IUA, if present, to enable her to conceive and carry a pregnancy through IVF.

Prospective studies in women with infertility and/or recurrent miscarriages who underwent diagnostic hysteroscopy revealed AS rates of 19-23.6% (8)(9)(10)(11). In other words, 1 in 4 to 1 in 5 women who are infertile or suffer repeat miscarriages have been shown to have IUA. For this reason, diagnostic hysteroscopy should be considered by any woman with unexplained infertility especially if she has ever had a D&C or intrauterine surgery for ANY reason. It especially makes sense to investigate the cavity further if she is either considering IVF or has had unsuccessful IVF treatments. The recommendation to use hysteroscopy in infertility workups appears to be controversial. Interestingly, diagnostic D&Cs are far more commonly used in gynecology even though they carry more risks and provide zero information about the presence of IUA. In the following

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

Quoting from the presentation:

“It is no more acceptable for a gynecologist to insert a sharp curette into a uterine cavity blindly to discover and remove suspected pathology than it is for an orthopedist to insert a curette into a knee joint blindly.”


REFERENCES

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

2. Eriksen, J and Kaestel, C. The incidence of uterine atresia after post-partum
curettage. A follow-up examination of 141 patients. Dan Med Bull 1960;7:50-1.

3. Asherman J. Traumatic intrauterine adhesions and their effect on fertility. Int J Fertil 2:49, 1957.

4. Panayotidis C, Weyers S, Bosteels J, van Herendael B.5. Intrauterine adhesions (IUA): has there been progress in understanding and treatment over the last 20 years? (2009) Gynecol Surg 6(3):197-211.

5. Golan, A, Schneider, D, Avrech, O, Raziel, A, Bukovsky, I, and Caspi, E.
Hysteroscopic findings after missed abortion. Fertil Steril 1992;58(3):508-10.

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

7. Isaacson, K. Office hysteroscopy: a valuable but under-utilized technique. Curr
Opin Obstet Gynecol 2002;14(4):381-5.

8. Raziel, A, Arieli, S, Bukovsky, I, Caspi, E, and Golan, A. Investigation of the
uterine cavity in recurrent aborters. Fertil Steril 1994;62(5):1080-2.

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

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

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

Miscarriage management after Asherman’s syndrome

Unfortunately, I can now talk from experience about how miscarriages can be dealt with post Asherman’s syndrome (AS), and what to expect. I lost my pregnancy at 14 weeks due to a trisomy 21 detected by karyotype analysis and QF-PCR of chorionic villi sampling. The first inkling that something was wrong was at the 12 week scan. Actually, the blood serum levels of PAPP-A and bHCG I’d had during the 11th week already showed a problem, but it wasn’t until my ultrasound that I learned of this. The ultrasound only confirmed that things were not right. Only two weeks earlier I’d had another ultrasound and all seemed fine- the heart beat, the CRL, etc. Now the nuchal fold measured 7mm and there was hydrops- an accumulation of fluid around the fetus. I was told there was a high probability that the pregnancy would end spontaneously.

Fast forward to week 14 and there was no longer a heartbeat.

I’d always talked about misoprostol and ironically now I would have to use it myself. There was no way on earth I’d undergo another D&C (suction curettage or whatever you want to called this blind invasive procedure)- the procedure which caused Asherman’s syndrome when I had it 3 years earlier for a blighted ovum. I could not risk exacerbating the condition. If only my initial ObGyn had agreed to treat me with misoprostol I could have avoided all the surgery and heart ache that followed. I’m quite sure I’d have a child by now.

Since I was relatively far into the pregnancy and the fetus had developed to 14 weeks before dying spontaneously, I booked in the hospital for the misoprostol induction. I don’t know which hospitals/ObGyns use misoprostol regularly, however, in the interest of informing women, my procedure was performed at the Royal Hospital for Women in Randwick (Sydney). I’m sure there are other hospitals (and doctors) that are familiar with misoprostol use, and yes, it is completely legal even if it has not been approved by the TGA (Australia's equivalent of the FDA) for gynecological indications for dubious reasons. By the way, the doctor who refused to give me misoprostol works at St George Hospital. I’d be interested to know if that hospital carries out medical management of miscarriage- please drop me a line or comment below if you know.

In total, I was given a dose of 1 mg (milligram) of misoprostol over the course of a day. Initially, one pill ie. 200 mcg (vaginal) was given to test for any adverse reactions, allergies etc. I began cramping but there was no bleeding. About 5 hours later cervical dilation was checked (closed) and I was given 400 mcg (2 pills). The cramping intensified, but again, there was no bleeding. Shortly after my third and final dose, about 5 hours after the last dose, I began having strong contractions. It was quite painful so I’d definitely recommend panadeine forte. Strangely, there was still no bleeding unlike with my first miscarriage which began like a period. About 40 minutes after my final dose, the waters broke and amniotic fluid spilled out soaking the bed. After this point the pain stopped although I was still feeling crampy for at least a week afterwards. Roughly half an hour after the waters broke, I delivered the tiny baby. The umbilical cord was thin and weak and broke off from the placenta. It is at this point that I began bleeding. I continued bleeding heavily throughout the night and the next day. I also bled strongly for about a week afterwards and on and off during the following week. The placenta should have come out soon afterwards but it was not until 3.5 hours passed that it did. Luckily I’d discussed the possibility of retained placenta previously with my ObGyn and we agreed to wait it out (normally most doctors would jump at the opportunity to do a D&C in this situation) while the nurses and midwives monitored me closely for signs of infection and hemorrhage. As it’s difficult to know if the placenta is complete on visual inspection, and women with a history of Asherman’s syndrome- even after surgical correction- are at an increased risk of placental conditions such as placenta accreta, percreta, increta, and previa, I knew retained placenta was a possibility.

Before the placenta delivered my temperature reached 40 C and the midwife was somewhat concerned, however misoprostol itself can cause fever. The morning after, my blood pressure was 90 on 60 (normally it is around 110-115/65-70) and I was told this could be due to blood loss.

The next morning I underwent an ultrasound to check for retained placental fragments. Around 32 mls of material was found in the uterus but it was impossible to tell whether this was simply blood and blood clots, or if there were retained products of conception (RPOC). Doppler flow analysis suggested that there were retained placental fragments in the posterior of the uterus- the same area where the placenta had implanted in this pregnancy. I had another ultrasound a week after the first. The second ultrasound showed that the fluid in the uterus had roughly halved, but it was still not possible to tell for sure via ultrasound whether there were retained products.

In the following week I bled little despite having around 18 mls of content in my uterus so I became concerned that perhaps there were retained fragments. This would not be a surprise given my pregnancy reached second trimester and my previous history of Asherman’s syndrome. I contacted my trusted Asherman’s syndrome specialist for a hysteroscopic procedure to remove any retained fragments of placenta. This procedure was done 3 weeks after the misoprostol treatment. It turns out I did have many retained fragments which were gently scraped off using the hysteroscope itself. Luckily I did not have any clinical infection from the retained tissue (perhaps just 'subclinical' ;) ?). There were no adhesions. I was given prophylactic antibiotics to prevent infection after the surgery.

I should also mention that to prevent any possible adhesions, I was prescribed 2mg/day progynova (a synthetic estrogen) for 28 days by an Asherman’s syndrome specialist. The other option was Premarin (0.625 mg). These help the endometrium grow and thereby prevent uterine walls from adhering in the case of scarring.

I’m now awaiting my next period after which I’ll have a mid cycle scan to measure endometrial thickness at ovulation, and either an in--office hysteroscopy or an HSG to check for adhesions. Hopefully the removal of RPOCs did not cause any scarring.
Note that the dose of misoprostol I was given was decided according to my pregnancy stage (14 weeks) and status (fetal demise). Doses vary and guidelines should be adhered to.


Here is a summary of my suggestions (as a non MD) if you find yourself in this situation:

1. Don’t have a D&C for a miscarriage as it can cause further damage especially if you have had AS previously. Also, your endometrium may get thinner each time you have a D&C.


2. Misoprostol helps clear out most of the uterine contents. It is more painful than a D&C but worth it in the long run- unless you are not interested in preserving your fertility. NOTE: If you have had a previous Cesarean section or uterine perforation or severe AS, discuss with your ObGyn to see if misoprostol is safe for you (or you may need to take a lower dose than what I was given).

3. You should have estrogen therapy to prevent adhesions from forming. I'm not sure if this is 100% necessary but Asherman's specialists recommend it. Some women didn't use it because of adverse reactions to estrogen (blood clots etc.) and they did not develop adhesions.
4. You will probably have retained tissue and require a hysteroscopy (not a blind D&C!!) to remove it. In most cases if you have had a missed miscarriage you will need to either use misoprostol or, alternatively, wait to miscarry before hysteroscopy can be effective, otherwise there is just too much tissue and blood to work with.

5. Have a mid cycle scan to measure endometrial thickness after your first post-treatment period and always check that your uterine cavity is free of adhesions before you attempt to conceive again just in case. An in-office hysteroscopy is best but failing that, an HSG can be done.

There are also some implications that can be speculated:

1. It may take a few hours for the placenta to deliver when using misoprostol post AS if you are beyond the first trimester.

2. It is likely that if you have had AS, you will have retained products after every future miscarriage. Hysteroscopic removal of tissue allows the doctor to view your uterus as he/she clears it. Note: Hysteroscopy itself can cause complications if undertaken by an unexperienced or unskilled doctor. Please see only a highly experienced specialist.

3. You should anticipate that you may have placenta accreta in a future pregnancy particularly if the placenta does not deliver when expected or you have had confirmed RPOC. Obviously, any woman with past AS should be monitored throughout their pregnancy by a high-risk Obstetrician.

I will try to write about the known pregnancy complications in women with a history of AS in the near future.

There are two more interesting points: Initially I believed that I may not get RPOC because the placenta had implanted in a region which was never affected by intrauterine adhesions. The fact that it is possible to get RPOC in a new, previously unaffected area suggests that perhaps the placenta implants deeply because the endometrium is slightly thinner than it should be ideally. Or maybe blood flow to the uterus is somehow affected and in order for the pregnancy to establish the placenta needs to invade the endometrium more deeply.

Secondly, I have to question once again whether there is any truth at all to the unfounded claim by certain doctors that Asherman’s syndrome can occur ‘spontaneously’ after miscarriage. I would have to have actual evidence to believe this. In my own case I had no adhesions 2 weeks after miscarrying using misoprostol-and this is even after having had intrauterine adhesions in the past (from a D&C). In other words they did not reoccur, nor did any new ones develop. I suspect that if I was treated with blind D&C rather than misoprostol, lo and behold I would develop ‘spontaneous’ adhesions in a new region: the posterior region of my uterus (where the RPOC were). It doesn't make sense for such an evolutionarily destructive mechanism to occur in nature (unless extremely rarely).

In retrospect, I have to wonder why my first Obgyn (ie the one who caused me to have AS) so steadfastly rejected my request to use misoprostol instead of a D&C when it can be used even until the third trimester. He made me believe that it could only be used until 8 or 10 weeks. I also wonder why, as a doctor who was aware about Asherman’s syndrome, my strong concern about acquiring it, and knew of the Asherman’s syndrome support group, he did not refer me for a hysteroscopic removal the supposed RPOC I had? What, may I ask, is the purpose of informing gynecologists about Asherman’s syndrome if they will continue to perform damaging D&Cs while refusing to offer other options? ‘Consent’ for D&Cs is hardly possible when other options are not made available. Please, let us not make Obstetricians/gynecolgists believe that treatment is so simple and effective that causing Asherman’s syndrome is just a little glitch with few consequences for the patient.

Finally, my experience has shown once again that prevention of Asherman’s syndrome is best: the condition leads to a cycle of costly and lengthy complications with retained products (not to mention possible obstetric complications in future pregnancies) which could be avoided if medical management (ie. misoprostol) was used in the first instance.

Asherman's syndrome after curettage is not rare

Asherman's syndrome is ‘uncommon’. How many times have I come across that sentence or a variation of it (Asherman’s syndrome is ‘rare’ or even ‘extremely rare’ etc.). They were my ObGyn’s famous last words too. Oh, how I wish they were true. A simple google search of Asherman’s syndrome will show that many links contain this inaccuracy. Even the reputable ncbi/nih writes:

"Asherman syndrome is a rare condition. In most cases, it occurs in women who have had several dilatation and curettage (D&C) procedures."

No true!!! It often happens after a single D&C procedure. How often? Well, according to various studies published in peer-reviewed medical journals, the actual incidence of intrauterine adhesions (IUA) after D&C for miscarriage ranges between 7.7% and 30%, and after a repeat procecure, up to 40%. To be clear, some of these studies are not new. However, there is no reason to suspect that incidence rates would change as the techniques used are for the most part the same. The main cause of IUA is blind instrumentation in a uterus softened by the presence of hormones (as in pregnancy). Even the more recent manual vacuum aspiration has been associated with IUA (Dalton et al, 2006). Furthermore, sharp/blunt/suction D&C are often all used in the same procedure. Anyone who is familiar with the literature on Asherman’s syndrome will know that the references below are cited as references in recent review papers (see Yu et al,2008; Kodaman and Arici, 2007). [Obviously an institutional (or personal) subscription is needed to view the entire article]. Another potential criticism about these studies is that they are not RCTs. (One is an RCT but it does not meet the criteria for inclusion in the Cochrane Collaboration 's library (click here for more details). For non-scientists/doctors, I will describe what RCTs and the Cochrane library are in further detail in a later blog. For now, suffice to say that RCTs meet the most rigorous standards of scientific methodology.) Unfortunately, to date there are NO RCTs on Asherman’s syndrome (including etiology and treatment) in the Cochrane database.

Nevertheless, according to the available studies on the topic, the following incidence rates have been reported:

1. Adoni et al (1982) found the incidence of IUA to be 30.9% after D&C for a ‘late’ miscarriage. This is taken to mean a missed miscarriage where the products of conception have not been expelled despite the pregnancy’s failure. IUA were detected via hysterography.

2. Golan et al.(1992) did a prospective analysis of 60 women and found that 16.7% of women undergoing D&C for missed miscarriage had IUA detected by hysteroscopy (gold standard method of diagnosis).

3. Friedler et al (1993) also did a prospective study on women with missed miscarriages who underwent D&C and found that 16 of the 98 patients, or 16.3%, had IUA detected by hysteroscopy.

4. Romer et al’s (1994) prospective study diagnosed IUA in 30.2% of women who had D&C for either missed or incomplete miscarriage. This was diagnosed hysteroscopically.

5. Westendorp et al (1998) prospectively examined wome who had repeat D&C for incomplete miscarriage or retained POC (after either miscarriage or delivery) and found that on hysteroscopy, a whopping 40% of them had IUA. 30% were severe.

6. Tam et al (2002) performed a prospective study on IUA incidence after D&C for missed or incomplete miscarriage and compared it to women treated expectantly or using misoprostol. They found that 7.7% of women in the D&C group developed IUA while none developed it in the misoprostol group or expectant group. Again, hysteroscopy, was used for detection.

7. Eriksen and Kaestel (1960) reported in their retrospective analysis that approximately 25% of women undergoing post partum curettage developed IUA.

I don’t know about you, but I find all this unsettling. Why didn’t anyone tell me this before I had a D&C?!

Asherman’s syndrome is thought to affect 5% of the population. I don’t recall if there is a particular reference for this, but I know I’ve heard a few Asherman’s syndrome specialists say it. Of course it is difficult to know the exact prevalence as many cases are not diagnosed. Also, some women may have it but not desire a further pregnancy so they never find out if they are infertile or have pregnancy complications associated with Asherman’s syndrome.

What is striking is that this incidence (5%), is not very different from the rate of conditions such as PCOS, another cause of infertility (which, by the way, is not iatrogenic...) Yet, when do you ever hear people say: PCOS is a rare condition?! You will read everywhere that PCOS is ‘common’ or ‘exceedingly common’. There are entire sections of gynecology journals devoted to this condition and hundreds of studies. Asherman’s syndrome, in contrast, is largely ignored by the medical community. Are doctors repeating the supposed ‘rarity’ of Asherman’ syndrome to make women feel that D&Cs are safer than they really are?

Perhaps this misconception once served a purpose- to prevent doctors from hesitating to perform D&Cs in situations where uterine evacuation was necessary and in a time when there was no other option, and to prevent patients from fearing a necessary treatment. Today this myth no longer serves a purpose. D&C is no longer a ‘necessary evil’ as there are other methods such as hysteroscopic guidance or uterus-evacuating drugs to obtain the same result- minus the serious complications.
The first step towards change would be to accept that Asherman’s syndrome is NOT rare.


References (in order of appearance in text)
Dalton VK, Saunders NA,Harris LH, Williams JA, Lebovic DI. Intrauterine adhesions after manual vacuum aspiration for early pregnancy failure. Fertil Steril 2006;85(6):1823 e1-3.
Kodaman, PH and Arici, A. Intra-uterine adhesions and fertility outcome: how to optimize success? Curr Opin Obstet Gynecol 2007;19(3):207-14.

Yu, D, Wong, YM, Cheong, Y, Xia, E, and Li, TC. Asherman syndrome--one century later. Fertil Steril 2008;89(4):759-79.

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

Golan, A, Schneider, D, Avrech, O, Raziel, A, Bukovsky, I, and Caspi, E. Hysteroscopic findings after missed abortion. Fertil Steril 1992;58(3):508-10.

Friedler, S, Margalioth, EJ, Kafka, I, and Yaffe, H. Incidence of post-abortion intra-uterine adhesions evaluated by hysteroscopy--a prospective study. Hum Reprod 1993;8(3):442-4.

Romer, T. Post-abortion-hysteroscopy--a method for early diagnosis of congenital and acquired intrauterine causes of abortions. Eur J Obstet Gynecol Reprod Biol 1994;57(3):171-3.

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

Westendorp, IC, Ankum, WM, Mol, BW, and Vonk, J. Prevalence of Asherman's syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion. Hum Reprod 1998;13(12):3347-50.

Eriksen J, Kaestel C. The incidence of uterine atresia after post-partum curettage. A follow-up examination of 141 patients. Dan Med Bull 1960; 7:50-1.