Wednesday, April 21, 2010

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
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)

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)


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).

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 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).

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).

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.

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.

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

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.

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

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.

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.

Thursday, April 8, 2010

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 (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.


(numbering continued from Part I)

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

9. Capella-Allouc S, Morsad F, Rongieres-Bertrand C, et al. (1999). "Hysteroscopic treatment of severe Asherman's syndrome and subsequent fertility". Hum Reprod 14 (5): 1230–1233. Abstract
11. Fernandez H, Al Najjar F, Chauvenaud-Lambling et al. (2006). "Fertility after treatment of Asherman's syndrome stage 3 and 4". J Minim Invasive Gynecol 13 (5): 398–402. Link to complete article

25. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the Risk of Preterm Birth Among Women with a Short Cervix. New England Journal of Medicine, 2007;375:(5)2, 2007; 462-469. Link to pdf
26. Yasmin H, Adeghe JH. Severe early-onset intrauterine growth restriction (IUGR) in a woman with Asherman's syndrome. J Obstet Gynaecol. 2004 ;24(3):312-4. Abstract

27. Martin, J.A., et al. Births: Final Data for 2006. National Vital Statistics Reports, volume 57, number 7, January 7, 2008.

28. Yu D, Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman’s syndrome. Fertil Steril 2007; 89(3):715-22. Abstract.

29. P.McComb, B.Wagner. Simplified therapy for Asherman"s syndrome. Fertility and Sterility; 68(6):1047-1050. Abstract
30. Protopapas A, Shushan A, Magos A. Myometrial scoring: a new technique for the management of severe Asherman's syndrome. 1998;69(5):860-4.Abstract

31. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate. New England Journal of Medicine, 2003;348(24):2379-85. Link to pdf
32. Deaton JL, Maier D, Andreoli J Jr. Spontaneous uterine rupture during pregnancy after treatment of Asherman's syndrome. Am J Obstet Gynecol. 1989;160(5 Pt 1):1053-4. Abstract

33. Shiau CS, Hsieh CC, Chiang CH, Hsieh TT, Chang MY, Chang Gung. Intrapartum spontaneous uterine rupture following uncomplicated resectoscopic treatment of Asherman's syndrome. Med J. 2005 Feb;28(2):123-7. Abstract with link to free article

34. Gürgan T, Yarali H, Urman B, Dagli V, Dogan L. Uterine rupture following hysteroscopic lysis of synechiae due to tuberculosis and uterine perforation. Hum Reprod. 1996;11(2):291-3. Abstract35. Hulka JF.Uterine rupture after treatment of Asherman's syndrome. Am J Obstet Gynecol. 1990 May;162(5):1352-3.
36. Felmus LB, Pedowitz P, Nassberg S. Spontaneous rupture of the apparently normal uterus during pregnancy. A review. Obstet Gynecol Surv 1953;8(2):155-172.

37. Nils Chaillet, Eric Dubé, Marylène Dugas, Diane Francoeur, Johanne Dubé, Sonia Gagnon, Lucie Poitras, Alexandre Dumont. Identifying barriers and facilitators towards implementing guidelines to reduce caesarean section rates in Quebec. Bulletin of the World Health Organisation 2007;85(10):733-820. Complete article