Thursday, December 2, 2010

Update Dec '10: Clinical trials and patents relevant to Asherman's syndrome

Clinical trials:

There are a number of trials involving the use of misoprostol for miscarriage management (note: I am not including studies on misoprostol use for pregnancy terminations because this choice is already routinely available to women who abort. It is not routinely- let alone occasionally-available to those who miscarry). As a blog which promotes prevention, these are naturally included. Below is more information and links to the studies.

Optimal Treatment of Miscarriage OR
Which is the Optimal Treatment for Miscarriage With a Gestational ac in the Uterus and Which Factors Can Predict if the Treatment Will be Successful?Region Skane, Kvinnokliniken, University Hopsital MAS Malmo Sweden.
Study type: Open labelled randomized trial (parallel assignment).
Aim: To compare the number of women with a complete miscarriage after 10 days between expectant management versus treatment with 800 micrograms of misoprostol intravaginally in women with an an incomplete miscarriage before 14 weeks and a gestational sac retained in the uterus.
link: http://clinicaltrials.gov/ct2/show/NCT01033903?term=miscarriage&rank=5

A Randomized Trial of Two Regimens of Misoprostol for Second Trimester Termination for Intrauterine Fetal DeathAmerican University of Beirut Medical Center
Study type: Open labelled, randomized controlled crossover trial.
Aim: To compare the safety, efficacy and patient satisfaction of vaginal versus sublingual administration of misoprostol (400 mcg every 4 hours until delivery. Time frame=24 hours)
link: http://clinicaltrials.gov/ct2/show/NCT00141895?term=misoprostol&rank=7

Sublingual Misoprostol Versus Standard Surgical Care for the Treatment of Incomplete AbortionGynuity Health Projects, Egypt, Mauritania, Niger.
Study type: Open labeled randomized controlled trial.
Aim: To compare the safety and efficacy of 400 mcg sublingual misoprostol to standard surgical curretage (D&C or MVA) for incomplete abortion (ie. retained products of conception). Presumably either spontaneous or induced.
link: http://clinicaltrials.gov/ct2/show/NCT00466999?term=misoprostol&rank=50

Non Surgical Management for Uterine Residua After Pregnancy Termination, Abortion or DeliveryHaEmek Medical Center, Israel
Study type: open labelled randomized trial (parallel assignment)
Aim:To compare the outcome of misoprostol treatment (intravaginal, 800 mcg) and expectant management in the case of intrauterine residua after completion of pregnancy.
link: http://clinicaltrials.gov/ct2/show/NCT01134926?term=misoprostol&rank=56

Misoprostol for Treatment of Fetal Death at 14-28 Weeks of PregnancyGynuity, California, Illinois, Boston, New York.
Study type: Double blinded randomized trial, parallel assignment.
Aim: To establish the safety and effectiveness of two different doses of the prostaglandin E1 analogue misoprostol administered buccally as a treatment for fetal death at 14 - 28 weeks, inclusive, of pregnancy.
link: http://clinicaltrials.gov/ct2/show/NCT00671060?term=misoprostol&rank=24

Effect of Colony Stimulating Factor on Poor Endometrial Development During IVF
Official Title: G-CSF and Endometrial Growth, Embryo Implantation and Pregnancy Following FET or Donor ET
The Center for Human Reproduction (CHR) is conducting a double-blind, randomized cross over trial to investigate the effect of G-CSF on endometrial thickness in women who have failed reaching minimal endometrial thickness by standard treatments. Outcome measures will include endometrial thickness (must be >7mm for transfer), implantation and pregnancy rates compared to control patients. The study will be conducted in women undergoing transfer of previously cryopreserved embryos or transfer of embryos from donor eggs. 

There are published studies on the use of Vitamin E (tocopherol), Pentoxyfilline, and Sildenafil in women with a thin endometrium (some of whom have a history of Asherman’s syndrome (1-4)). To my knowledge this is the first trial using G-CSF for this purpose.
For more information see:
http://clinicaltrials.gov/ct2/show/NCT01202643?term=asherman+syndrome&rank=1

Safety of Leaving Cook Balloon Uterine Stent in Uterus for One Month
The Department of Obstetrics and Gynecology, Shin-Kong Wu-Ho-Su Memorial Hospital in Taiwan is conducting an open label randomized controlled trial to investigate the feasibility of leaving an intrauterine Cook balloon in the uterus for 1 month. The experimental arm of the study will be fitted with a uterine Cook stent while the control will not. Both groups will have swabs taken for culture just before hysteroscopic adhesiolysis and 30 days later, during second look hysteroscopy to evaluate the outcome of surgery.

The practice of leaving a Cook Balloon stent in the uterus for this length of time is used by some Asherman’s syndrome specialists in cases of severe and recurrent intrauterine adhesions (personal communication). In the above study there is no mention of antibiotic use, however the specialists that use the Cook balloon or Foley catheter prescribe antibiotic prophylaxy during the entire therapy to prevent the potential infection. The results of the study will also reveal the effectiveness of the Cook balloon in preventing adhesion recurrence compared to no stent. Previously there was a study comparing the IUD (3 cycles) to the Foley catheter (10 days), however the method of ‘adhesiolysis’ was blind D&C, not dissection of adhesions under direct hysteroscopic view (5). As blind D&C is the most common cause of intrauterine adhesions, it is difficult to know if the previous findings are due to the barrier method used or to fortuitous variations in the success of ‘surgery’ which is carried out blindly.

For more information see: http://clinicaltrials.gov/ct2/show/NCT01167296?term=uterine+adhesions&rank=2


SIGnificance of Routine Hysteroscopy Prior to a First 'in Vitro Fertilization'(IVF) Treatment Cycle (inSIGHT)
A multicenter single-blinded (caregiver) randomized intervention trial is being undertaken in the Netherlands to assess the cost effectiveness of screening women for intauterine abnormalities using hysteroscopy and SIS (saline infusion sonography) prior to fertility treatment (IVF/ICSI). If abnormalities are found (defined as the existence of a septum, endometrial polyp, submucous myoma, adhesions or endometritis) these will be treated on the spot, using scissors, Versapoint, grasping forceps, polypsnare or antibiotics. The primary outcome measure is cumulative ongoing pregnancy rate and live birth after randomization within 18 months of IVF/ICSI. Secondary outcome measures include cumulative implantation rates, miscarriage rates, and comparative cost calculations.

Studies have shown that minor intrauterine abnormalities can be found in 11-40% of infertile women with a normal tranvaginal sonography. Detection and treatment of these abnormalities by office hysteroscopy have led to a 9-13% increase in pregnancy rate. Therefore, it is increasingly advised to screen all infertile women on intracavitary pathology prior to the start of IVF/ICSI.

Note that women with recurrent miscarriage are excluded from the study, when it is known that women with uterine abnormalities (congenital or acquired) are at a risk of repeated pregnancy loss. This exclusion is perhaps added in order to eliminate women who have other causes of infertility that are not due to anatomical anomalies and which cannot be diagnosed and corrected via hysteroscopy. However, this possible bias could have been avoided by excluding women who tested positive for other conditions known to cause recurrent miscarriage. I also wonder how effective outcomes will be in the experimental arm if IVF/ICSI is commenced immediately after treatment, without assessing the state of the cavity (IUA often recur, and IUA are a common consequence of septum correction and myomectomy). Furthermore, would it not be possible to answer this clinical question by reviewing the prevalence of uterine abnormalities in infertile and subfertile women, the cumulative implantation, pregnancy and live birth rates following treatment of these conditions, and analyzing the costs versus benefits ratio? For example, if past studies have shown that more than 10% of infertile women have an intrauterine pathology, and 40% of these women have a live birth after treatment, is it not justified to perform a diagnostic hysteroscopy prior to IVF/ICSI?

For more information: http://clinicaltrials.gov/ct2/show/NCT01242852?term=uterine+adhesions&rank=8

Note: There appears to be an error in the table describing the intervention and control arms of the study.

Patents

Patent Applications:
WO 2010/05/054068 A2 Cyclic adenosine monophosphates (cAMPs) for reducing the formation of adhesions. This world patent application claims the use of various derivatives of cAMPs for the reduction of adhesion formation for reducing inflammation or tissue damage after abdominal or pelvic surgery.
Jackson, EK. Cyclic adenosine monophosphates for reducing the formation of adhesions. 14 May 2010.
More info http://www.ibridgenetwork.org/university-of-pittsburgh/cyclic-adenosine-monophosphates-for-reducing-the-formation-of

In contrast to adhesion barriers, the invention would not involve placing a foreign body in the surgical cavity. Present adhesion barriers can cause immunological reactions. Also, the cyclic adenosine monophosphates are naturally-occuring substances and therefore should be quite safe. The cyclic adenosine monophosphates can be quickly and easily administered with a syringe. It can be used in minimally-invasive surgery, the future of surgery, and should be effective even if blood is in the surgical field. It is likely that the invention will be more efficacious than existing adhesion barriers.

Theoretically it could also be useful for intrauterine adhesions as many of the gel barriers used for pelvic surgery are also being used/trialled post adhesiolysis in Asherman’s syndrome treatment.So far there are only limited data on the efficacy of gel barriers in the treatment of Asherman’s syndrome (6-8). One of the difficulties of using gels is that they do not stay in a fixed position which is essential for them to be effective.

Granted Patents:
2005/0084,508 A61K Topical anesthesia formulation for bodily cavities
Innovators: Vancaillie, Thierry G; Hewitt, Alan Ernest
A topical anesthetic used for in-office hysteroscopy has recently been patented. The pH is adjusted to that of the body’s to optimize the effectiveness of the anesthetic.One of the inventors is an Asherman’s syndrome specialist. He has also developed a device for administering the anesthetic.
More info: http://www.patentbuddy.com/patentdetails/2402425


References
1. 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 Human Fertility, December 2009; 12(4): 198–203.
2. Batailles N, Oliviennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Rep 2002;17(5):1249-53.
3. Sher G, Fisch D. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril. 2002 Nov;78(5):1073-6.
4. Zinger M, Liu Thomas JH, MA. Successful Use of Vaginal Sildenafil Citrate in Two Infertility Patients with Asherman’s Syndrome. JOURNAL OF WOMEN’S HEALTH 2006;15(4):,442-4.
5. Orhue AA, Aziken ME, Igbefoh JO. A comparison of two adjunctive treatments for intrauterine adhesions following lysis. Int J Gynaecol Obstet; 2003;82:49-56.
6. Abbott J, Thomson A, Vancaillie T. SprayGel following surgery for Asherman’s syndrome may improve pregnancy outcome. J Obstet Gynaecol 2004;24:710-1.
7. Acunzo G, Guida M, Pellicano M, Tommaselli GA, Di Spiezio Sardo A, Bifulco G, et al. Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Hum Reprod2003;18:1918-21.
8. Metwally M, Watson A, Lilford R, Vandekerckhove P. Fluid and pharmacological agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev2006;(2): CD001298. doi: 10.1002/14651858.CD001298.pub3.

Relevant links:
Understanding Clinical Trials

Thursday, November 18, 2010

Articles on Asherman's syndrome Etiology, Incidence, Prevention

A selection of publications about Asherman's syndrome including reviews and journal articles on its etiology, incidence and prevention is being added to the site. It can be found here or alternatively, click on the relevant tab in tab menu at the top of the page. There will be another page with articles on Diagnosis, Classification, Treatment, Reproductive Outcomes and Obstetric Complications soon.

Thursday, October 21, 2010

When infertility or recurrent miscarriage persist after treatment of Asherman's syndrome

For many women who have had Asherman's syndrome, the journey to having a baby is not over with the removal of adhesions. While many doctors will use this to support their theory that they had other underlying fertility problems to begin with, it is equally possible that in some cases, Asherman's syndrome has lasting effects on fertility. Sometimes these are obvious such as inaccessible ostia (adhesions are sometimes too risky to remove) or thin endometrium. Most doctors agree that a lining of at least 8 mm at the time of ovulation is ideal for implantation. There could be other defects that persist after surgical correction such as reduced blood flow to the uterus. There is some disagreement as to whether procedures which reduce blood flow to the uterus, such as uterine artery embolization (UAE) can reduce fertility by affecting ovarian reserve. There is another intriguing link between blood flow and egg quality: it is known that endometriosis reduces egg quality although the mechanism is unknown. This makes me wonder whether I have endometriosis (I've never had a laparoscopy). There is something incongruent about having so many eggs of such poor quality. Unfortunately there is little research and few artifical reproductive techniques which focus on the quality of the endometrium. These few studies will be the topic of a future blog. There is also little research on improving egg quality as most fertility specialists are skeptical that this is possible due to currently accepted dogma on egg development.

Many women with a history of AS end up undergoing fertility treatments. Personally, I experienced infertility for 1.5 years even after AS correction (surgery and estrogen therapy) when I had had no problems conceiving to begin with. Then I went from being infertile to now conceiving once every two months but miscarrying. I have had 5 miscarriages in one year. All of my pregnancies have been naturally conceived. The last 3 have been very early miscarriages. Of course my first thought was that I might have some recurrence adhesions from my last hysteroscopic removal of RPOC in March. An in-office diagnostic hysteroscopy ruled out this possibility. I had molecular karyotyping (MLPA) of my last miscarriage which revealed trisomy 9, 20 and triallelic markers on the X chromosome. This indicates problems with egg quality. The first pregnancy after AS occurred a few months after 2 cycles of unsuccessful IVF. I wonder whether the effect of IVF hormones had a beneficial effect on my endometrium and egg development. My plan is to now find a fertility specialist who is willing to work with me on a protocol that does not include egg retrieval and in vitro fertilization (since I conceive very easily without it), but rather one that concentrates on improving the uterine environment. My idea is to use low dose aspirin (to improve blood flow to the uterus) and low doses of FSH to stimulate about 2 follicles (to double my chances of a healthy embryo) , undergo 'in vivo' fertilization and start taking progesterone pessaries after ovulation (for luteal phase support). FSH stimulates follicles to grow which in turn secrete estrogen to thicken the endometrial lining. Some women with past AS find that their endometrium responds more favourably to this ovarian stimulation than to estrogen pills. I'm also considering the use of DHEA, a controversial hormone which is alleged to improve ovarian reserve and quality, resulting in fewer miscarriages (and presumably aneuploidies).

Unfortunately, a few of the fertility specialists I have seen in the past have been very unflexible and biased in their thinking. Many have their own 'pet' theories about what works and what doesn't without the backup of proper studies. While they are happy to point out that my suggestions have no rigorous evidence of efficacy, they seem oblivious to the fact that their own suggestions also lack robust data and in addition, are often expensive, time consuming, painful and with possible adverse effects on health. When I once pointed this out, a well respected specialist told me to stop thinking like a scientist! He also told me that if  I 'really' wanted a baby I would be willing to try risky treatments! There are still many unknowns in the area of infertility and fertility doctors don't know everything (even if some of them think they do!). For instance, this specialist convinced me that my inability to conceive was due to my low AMH levels (an indicator of poor ovarian reserve in my case due to being over 40) and in his words, I would never conceive without IVF, although he couldn't explain how IVF would improve ovarian reserve or egg quality. As an aside, I have very low FSH levels (3 when I was 42) which are meant to indicate excellent ovarian reserve. I didn't know it at the time he said this, but I was already pregnant. I went on to have 4 more pregnancies afterwards. Unfortunately my problem now is recurrent miscarriage, but his statement is still untrue. No one has been able to give me a reasonable explanation as to why I have gone from being unable to conceive for 1.5 years despite treatment for IUA, to conceiving every 2 months.

Below is a link to a chart detailing which tests and treatments are scientifically supported and which are not. Most have not been proven to be useful, although it is possible that in future there will be evidence to support them. It is up to the individual to decide, after considering risks and benefits, whether to proceed with them.

Infertility Tests and Therapies Questioned (Bupa)

More information on the validity of tests and therapies for infertility/recurrent miscarriage:

Cochrane Reviews: Immunotherapy for recurrent miscarriage (Full article: click here)
Note that this systematic review is comprised of studies where exclusion criteria included women with abnormal immune tests (eg. auto-antibody, cytotoxic antibodies, IgA deficiency etc.). Bascially, this review found that in women with recurrent miscarriage without any demonstrated abnormal immune function, there is no significant evidence that immunotherapy is useful (which one would expect). Still, many fertility specialists are eager to use these therapies on such patients.

RCOG: Implantation and Early Development - study group statement.

Miscarriage, Infertility, Antibodies and the Immune System Dr Licciardi's Infertility Blog

Wednesday, September 29, 2010

Effect of Asherman’s syndrome on infant health

Over a century after the condition was first reported, there are as of yet no analytical studies on the health of children born to women with a history of AS or even on pregnancies conceived with adhesions present. The only data available in the literature are from isolated case reports.

As mentioned elsewhere, the proportion of births after Asherman’s syndrome treatment (ie. births / total number of women treated) are around 40% across all classifications. Reproductive outcome is correlated with severity at diagnosis, with mild cases having a highest live birth ‘rates’ (‘proportion’ is actually the correct terminology) and severe cases having the lowest live birth proportion.

The risks associated with abnormally invasive placenta (accreta, percreta, increta) and low lying placenta (previa) mainly affect the mother at delivery. These can lead to significant blood loss and emergency hysterectomy. Massive hemorrhaging is a life threatening situation for the mother and requires blood transfusions. Conversely, IUGR, preterm birth and IC present a risk for the fetus.

The majority of gestations following the surgical correction of adhesions are uncomplicated and presumably healthy babies are delivered. This is partly because most women who are able to carry pregnancies have an adhesion free uterus with relatively healthy endometrium while in those with severe endometrial injury (resulting in IUA with or without fibrosis) pregnancy is less likely even after surgery, and any pregnancy achieved would generally miscarry early on.

A retrospective case control study found no difference in pregnancy outcome aside from birthweight in pregnancies with and without IUA (1). It should be noted that case-control studies and in general, retrospective studies are not the most rigorous in terms of evidence. Presumably, the extent, severity and location of uterine adhesions affect the course and outcome of the pregnancy. However, if adhesions are only mild and filmy they can stretch or even divide as the uterus grows with the pregnancy. The latter was described in a case report by Klatsky et al (2) (see cases below). As no two cases of AS are identical, it is difficult to predict the outcome and therefore close monitoring of the pregnancy by a high risk obstetrician is advised for regular screening for potential complications such as cervical incompetence, IUGR, premature labour, invasive placenta, and pre eclampsia. Regular screening will also assist in the detection of fetal abnormalities and potentially improve their management. Home births are not advisable in women with past AS even if the pregnancy appears to be progressing without problems, as invasive placenta may not be detected until the time of delivery and this could lead to serious life threatening situations.

Prematurity and neonatal complications

Most health complications in newborns delivered to women with past (or current) AS would probably be related to prematurity, as women with AS (past or current) are more likely to deliver preterm. Prematurity may be caused by other known complications associated with AS such as IUGR. Depending on the extent of prematurity, such birth defects could 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). Obviously neonatal mortality is another possible complication of premature birth and generally, the earlier the birth, the more severe the complications. Babies born during the second trimester due to cervical incompetence (as a result of previous cervical dilations associated with the index injury leading to AS and/or surgical correction of AS) are often too young to survive outside the body, and even if they do they will have severe and life long complications.

Effect of IUA during pregnancy: four case reports with different outcomes

It is very important that the uterus is assessed for adhesions after treatment of Asherman’s syndrome before conception is attempted/advised. Adhesions are known to recur in moderate and severe cases, and further surgery may be required. Complications will be increased if pregnancy occurs in the presence of thick adhesions. This is highlighted in the examples from case reports below. Note that the first example is one where the patient underwent endometrial ablation (EA) which is a procedure that mimics very severe AS. It is unclear whether the patient was counseled for the risks of a future pregnancy. Usually both IUA and extensive fibrosis are present. In fibrosis the endometrium is replaced with scar tissue to varying extents (hence it is also known as sclerotic endometrium or ‘unstuck’ Asherman’s syndrome due to the absence of adhesions). This is the most severe form of AS. Fibrosis occurs mainly as a result of thermal energy use in the uterus. Electrosurgery (e.g. resectoscope, laser etc.) also leads to IUA because of damage to the basal endometrium. EA is procedure used to treat abnormally heavy bleeding in which the endometrium is intentionally and irreversibly destroyed using thermal ablation. First reported in 1981, EA has been gaining popularity as a less invasive alternative to hysterectomy. Unfortunately damage may also occur unintentionally when these same instruments are used for other purposes such as the resectioning of uterine fibroids or polyps or the dissection of adhesions during the treatment of Asherman’s syndrome. Instead of having their fertility restored, the patient may end up with more severe adhesions and fibrosis than originally. Therefore mechanical dissection of adhesions may have better outcomes. EA should not be undertaken in women who desire future fertility and they should be informed about potential dangers of pregnancies if they fall pregnant. I have seen doctors on the internet advertizing endometrial ablation reversal in women who wish to conceive after having had the procedure. This practice is highly questionable given the high risk of severe pregnancy complications and the low chance of a live birth after EA. Pregnancy rates following EA are in the vicinity of 0.2-0.7% (3,4) with perinatal mortality reported to be 11.8% (4)

Severe AS from EA and birth defects

1. Mukul and Linn (5) reported amniotic band syndrome (ABS) in a pregnancy following endometrial ablation. The patient had three prior pregnancies and one birth. ABS , also called Amniotic Constriction Band Syndrome, is a set of congenital birth defects believed to be caused by entrapment of fetal parts (usually a limb or digits) in fibrous amniotic bands while in utero. The patient had undergone rollerball EA 7 years earlier without complications. Ultrasonography at 7 weeks revealed evidence of amniotic band syndrome: synechiae (i.e. IUA) were seen in the midquadrant of the uterus, creating amniotic sheets and bands with small compartments. The entire lower uterine segment was empty except for the right leg and a loop of umbilical cord poking through the lower uterine synechia. The fetus was of normal size but with clubbed feet, a distorted spine, and ventriculomegaly.

The patient underwent preterm labour and membranes ruptured at 26 weeks. A male infant was delivered via emergency C-section. An emergency hysterectomy was performed. The infant’s birth defects were described as follows:

“There were positional deformities in the neck, an asymmetric chest, severe scoliosis confirmed by X-ray, bilateral clubbed feet, and very limited movement of all long extremities consistent with arthrogryposis. The right lower extremity was swollen, cyanotic, denuded of skin, and without perfusion or pulses. Areas of significant necrosis on the posterior thigh of the right lower extremity were noted.”

Prognosis was poor and the parents decided to withdraw ventilation support. The infant died 6 hours after delivery.

One theory on the cause of ABS is that it occurs when the inner membrane (amnion) ruptures without injury to the outer membrane (chorion), exposing the fetus to fibrous tissue (bands) from the ruptured amnion which can entangle body parts, leading to congenital abnormalities. Another theory is that vascular disruption occurs. The latter would explain the presence of cleft lip in ABS cases. Either theory could account for its description in women with severe injury to the endometrium. Both IUA and fibrosis resulting from EA would lead to vascular disruption.

Mild to moderate IUA during pregnancy

In the three examples below, patients developed IUA from uterine curettage (i.e. D&C). One case ended in the term birth of a healthy baby while the other two resulted in congenital abnormalities. It appears that the severity of the adhesions affects outcome.

2. Klatsky et al (3) report of a pregnancy complicated by endometrial scarring which ended in a term birth of a healthy infant. The patient, a 39 year old woman, had a history of D&C for therapeutic abortion followed by three miscarriages, the last of which was completed by D&C. An ultrasound at 19 weeks identified a thick band crossing the lower uterine segment with the placenta inserting alongside it. Mullerian fusion anomalies were ruled out. Doppler flow imaging demonstrated flow along the synechia to the overlying placenta. At 25 weeks the patient passed half a cup of bright red blood. An ultrasound revealed a thinning scar with placenta still implanted on both sides and a small subchorionic hematoma. At 31 weeks ultrasound demonstrated a reduced scar with placenta visible on only one side. The patient presented at term with premature rupture of the membranes and a fetus in breech presentation. She underwent cesarean delivery. No uterine anomalies or adhesions were found, presumabley the thin uterine adhesion was evacuated with the placenta. The infant had no morphological abnormalities.

3. Deering et al (6) report a case of head entrapment of a second twin by intrauterine synechiae leading to long term health complications. The 40 year old patient had a history of two uterine curettages (ie. D&C) , one for first trimester miscarriage and a second for menorrhagia. CVS was undertaken during first trimester revealing normal male karyotypes. Diagnostic hysteroscopy and lysis of adhesions was not performed prior to IVF resulting in a twin pregnancy. She presented at 19 weeks for evaluation due to a shortened cervix and pronounced funneling (symptoms of cervical insufficiency). A McDonald cerclage was placed. Ultrasound examination also revealed a moderate sized uterine synechiae wrapped around the neck and placenta of twin B. Twin B was affected by IUGR, weighing less than the third percentile for gestational age. The development of growth restriction and discordance in twin B is thought to result from the combination of the contracted space available for twin B’s head to grow, the compression of the umbilical cord against the fetal neck by the uterine band, and the implantation of the placenta in an abnormal portion of the uterus with a potentially inadequate blood supply.

Cesarean delivery was undertaken at 26 weeks due to fetal distress of twin B and head entrapment. As seen on ultrasonography a thick uterine band was tightly constricting the neck of twin B. The location of the tissue was consistent with the uterine synechia observed on hysterosalpingogram before IVF. Twin A did well and was discharged from the NICU at 3 months. Twin B remained in the NICU until 5 months of age, at which time he was discharged to a longer-term pediatric care facility for continued care. This case demonstrates that significant uterine synechia might result in intrauterine head entrapment, as well as IUGR.

4. Baumler et al (7) report a case of premature birth of an infant with prolonged pulmonary distress syndrome and severe kyphoscoliosis (90 degrees) in a patient with IUA. The patient was 37 years of age with a history of two first trimester miscarriages and evacuation of retained products of conception (ERPC or D&C). Preterm labor occurred at 28 weeks. Midtrimester 2D, 3D and real-time 4D ultrasound revealed a horizontal miduterine separation in the form of an ‘egg-timer’. The uterine cavity was separated in two superimposed cavities. The fetus and the placenta were located in the upper part of the uterus, and the right arm of the fetus and part of the umbilical cord extended in the lower part of the uterus, through an opening in the separating horizontal membrane. The kyphoscoliosis, thought to be due to severe oligoamnios was managed conservatively.
The mother’s operative hysteroscopy carried out 6 months later confirmed both clinically and histologically the presence of a transversal muscular synechia.

The examples above illustrate the importance of diagnosing and removing IUA prior to IVF or conception. Furthermore, thick adhesions restrict the growth of the uterus, possibly increasing pressure on the cervix and leading to CI or preterm labor. The patient in the example above (6) may not even have needed IVF as her fertility problems may have been due to Asherman’s syndrome which could have been surgically corrected and allowed a better pregnancy outcome. Not only are the chances of pregnancy reduced, the health of the mother and infant are compromised as well with the presence of IUA. It is particularly irresponsible to perform IVF in patients without confirming an architecturally normal uterus. There is unfortunately a tendency for some clinicians to believe that IUA are harmless and asymptomatic (3) but this case shows that even a single thick band can have significant repercussions during pregnancy. As all cases are not treatable, in particular more severe ones where there is a tendency for scars to reform and irreversible fibrosis to occur, prevention of AS wherever possible is the best and easiest strategy available.


REFERENCES

1. Ball RH, Buchmeier SE, Longnecker M. Clinical significance of sonographically detected uterine synechiae in pregnant patients. J Ultrasound Med. 1997 Jul;16(7):465-9. Abstract

2. Klatsky PC, Tran ND, Strachowski L. A pregnancy complicated by endometrial scarring. Fertil Steril. 2009 Jun;91(6):2707-8. Epub 2008 Nov 20 Abstract

3. Cook JR, Seman E. Pregnancy following endometrial ablation: case history and literature review. Obstet Gynecol Surv 2003;58:551– 6. Abstract

4. Pugh CP, Crane JM, Hogan TG. Successful intrauterine pregnancy after endometrial ablation. J Am Assoc Gynecol Laparosc 2000;7:391– 4. Abstract

5 Mukul LV, Linn JG.  Pregnancy complicated by uterine synechiae after endometrial ablation. Obstet Gynecol. 2005 May;105(5 Pt 2):1179-82. Abstract

6 Deering SH, Heller J, Winkel C, Landy HJ. Intrauterine head entrapment of a second twin by a uterine synechia. Obstet Gynecol. 2003 Oct;102(4):693-5. Abstract

7 Bäumler M, Faure JM, Couture A, Flunker S, Boulot P. Prenatal 3D ultrasound and MRI assessment of horizontal uterine synechia. Prenat Diagn. 2008 Sep;28(9):874-5.

Tuesday, August 31, 2010

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.

Monday, July 19, 2010

Misoprostol for miscarriage management: the facts and the fiction

This is my latest Youtube video presentation. It explains the truth behind often repeated misinformation about misoprostol.

video

Misoprostol for miscarriage management is underused despite evidence of its efficacy and safety. It is an ideal alternative to D&C. It can also prevent Asherman's syndrome which mainly occurs from D&C, a blind surgery. This clip clarifies concerns about misoprostol which may be hindering its use by clinicians and patients alike.

Monday, July 12, 2010

Recent and upcoming articles on Asherman's syndrome (July 2010)

There are two articles in press about Asherman's syndrome in peer-reviewed medical journals.

One is titled: Human amnion as a temporary biologic barrier after hysteroscopic lysis of severe intrauterine adhesions: pilot study, by Amer et al. in Egypt will appear in The journal of minimally invasive gynecology. To read the abstract, please click here. It is a continuation of and follow-up on the reproductive outcome of patients from a previous study published four years earlier by the same group (Amnion graft following hysteroscopic lysis of intrauterine adhesions, Amer I and Abd-El-Maeboud J Obstet Gynecol Res Vol 32, No. 6:559-566, 2006). Although the method could be promising, there are restrictions for using amnion in Western countries due to fears of cross-contamination between donors and recipients (ie. women treated for Asherman's syndrome with the tissue). Amnion is obtained from fresh amniotic membranes shortly after birth from 'donor' patients undergoing elective cesarean section. These donor patients are screened for hepatitis B, hepatitis C, syphilis and HIV. The tissue is placed around an intrauterine balloon and inserted in the uterus following hysteroscopic lysis of intrauterine adhesions and left in place for 2 weeks. Amnion was previously used in developed countries for different gynecologic reconstructive surgeries but was abandoned after the outbreak of Creuzfeldt Jakob disease (CJD), the human variant of 'mad cow' disease. It is an incurable and fatal transmissible degenerative neurological disorder for which there is no test to screen infected tissue. I will wait until the article is published before making further comments. There is one contradiction of note in the abstract; although the patients in the study were reported to have severe intrauterine adhesions, they were described as having infertility with or without menstrual disorders such as amenorrhea or hypomenorrhea. It seems inconsistent to have severe adhesions without any changes in menstrual bleeding, and suggests that perhaps the diagnosis of severity was exaggerated. Severe adhesions are more difficult to treat and tend to recur more frequently than mild ones. Severe adhesions are also associated with poorer fertility outcomes.

The second article in press is: Separated from birth: An initial examination suggested Asherman's syndrome (Oakes and Fisseha, Am J Obstet Gynecol, 2010). This is a case study where a patient appeared to have intrauterine adhesions following a C-section (a rare cause of Asherman's syndrome), but on closer inspection turned out to have a uterine dehiscence from a hysterotomy scar. Uterine dehiscence is the incomplete separation of the myometrium at a uterine scar site.

The article Impact of previous uterine artery embolization on fertility. (Berkane N, Moutafoff-Borie C. Curr Opin Obstet Gynecol. 2010 Jun;22(3):242-7) suggests that Asherman's syndrome is a possible risk after uterine artery embolization (UAE). In another recent study (Fertility and pregnancy following pelvic arterial embolisation for postpartum haemorrhage. Sentilhes L, Gromez A, Clavier E, Resch B, Verspyck E, Marpeau L.BJOG. 2010 Jan;117(1):84-93) researchers claim that pelvic arterial embolisation for postpartum hemorrhage does not affect future fertility even though around 12% of study participants were diagnosed with Asherman's syndrome after the procedure and a further 11% exhibited symptoms of it although they declined diagnostic hysterocopy. However it is unclear from the article whether the intrauterine adhesions were pre-existing, or if they resulted from additional procedures carried out in addition to PAE to stem blood flow, such as manual removal of placenta or uterine packing. UAE and PAE are uterine-sparing alternatives to hysterectomy which employs a vascular radiological technique to treat pospartum hemorrhage and fibroids.

A new cause of Asherman's syndrome, B-lynch suture, was recently reported in Development of Asherman syndrome after conservative surgical management of intractable postpartum hemorrhage. (Goojha CA, Case A, Pierson R. Fertil Steril. 2010 Mar 25.) B-lynch suture is a 'conservative' surgical compression technique for managing postpartum hemorrhage.

I have also been told that there will be a case report on the association between pregnancy after Asherman's syndrome and an obstetric complication not previously reported, pre-eclampsia. This is consistent with the fact that pre-eclampsia is caused by ischemia and  the presence of insufficient blood flow to the placenta in Asherman's syndrome that sometimes persist even after treatment. This will be added to the list of complications in post AS pregnancies I have already written about.

There will also be a study published on reproductive outcomes following treatment where pregnancy rates were about 60%, live birth rates 40% and miscarriage rates were supposedly equivalent to those of the general population.

Friday, July 2, 2010

Tuesday, June 15, 2010

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.

Friday, June 4, 2010

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

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

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

Wednesday, May 26, 2010

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

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


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

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


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


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


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


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

Friday, May 14, 2010

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.”
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