Asherman's Syndrome: Diagnosis, Treatment, and Prevention

In our last post, we described the condition called “Asherman’s syndrome” wherein scarring of the intrauterine cavity can cause aberrations of menstrual bleeding (in the most extreme cases very light or absent periods), infertility, recurrent pregnancy loss, and other pregnancy complications. The extent of the scarring is correlated with the risks for these problems; however, some women will have minimal scarring and little if any aberration of menses and still be at risk for one or more of these complications. In today’s post we will briefly address the diagnosis, treatment, and prevention of Asherman’s syndrome…

The first step to establishing the diagnosis is maintaining a high index of suspicion. It is surprising to me, for example, how often a woman will present with recurrent pregnancy loss, where she has never been asked about specific events surrounding her management and complications related to previous pregnancies and/or these previous losses (i.e., postpartum hemorrhage, D&C for retained products of conception and the timing of the same with regard to the length of time from the delivery, D&C’s for missed or incomplete miscarriages and elective abortions, prolonged bleeding, fever, infection or evidence of infection on the pathology report, length of time between the death of the baby and the actual miscarriage or medical/surgical evacuation of the uterus, complications related to the D&C’s themselves, such as hemorrhage or uterine perforation). Yet, we know that the risk of intrauterine scarring (synechiae) increases with the number of D&C’s, the duration between fetal loss and the procedure itself, and any of the other complications noted above.

Clearly, if a patient has complete absence of menstrual bleeding, a history of an intrauterine procedure and/or infection, and documented ovulation, the diagnosis is readily apparent. However, since not all Asherman’s patients will have the most extreme presentation of the condition, and since ultrasound alone is unlikely to help establish the diagnosis under these circumstances, it is probably under-diagnosed, or at best the diagnosis is delayed in many instances. Occasionally, the diagnosis can be made using sonohysterography in which fluid is used to distend the uterine cavity while performing an ultrasound, or by hysterosalpingogram in which a radio-opaque dye is instilled into the uterus to outline its contour, but by far the most efficient and reliable approach is to perform hysteroscopy in which the uterine cavity is directly visualized with the aid of a special instrument that provides light and magnification.

Interestingly, in one prospective study in which hysteroscopy was performed routinely following D&C’s for uterine evacuation of early pregnancy, intrauterine adhesions were found in 16% of women after one procedure and 32% after three or more (Friedler, et al., Hum Reprod 1993;8:442-44)! Similarly, Westendorp and colleagues (Hum Reprod 1998;13:3347-50) found that 40% of women who underwent a D&C for retained placenta longer than 24 hours after delivery, or who required a repeat D&C for incomplete abortions, had intrauterine adhesions present by hysteroscopy three months after the intervention and almost half of these had moderate to severe disease (Grade III and IV).

Although treatment for Asherman’s syndrome has had various approaches, successful treatment relies on the lysis (breakdown) of the adhesions and restoration of some degree (the more the better) of normal-appearing and functioning endometrium (the inner lining of the uterus). The gold standard at present involves surgical removal of adhesions under direct visualization using operative hysteroscopy. The success depends on the experience and skill of the surgeon and in the most severe cases (complete obliteration of the uterine cavity by scar tissue), the procedure can be quite difficult. Even in skilled hands, the risk of recurrence of scar tissue following the initial operation is very high and many surgeons try to minimize this risk by avoiding surgical techniques (such as electrocautery) that will further promote scarring. Following the procedure itself, patients are often placed on high doses of estrogen to stimulate the endometrium and in some cases, balloons, catheters, or other forms of stents are placed into the uterine cavity to help prevent adherence of the walls. Another option is to have repeated in-office hysteroscopic lysis of adhesions once the primary procedure has been performed.

Even with all these precautions, recurrence of adhesions is extremely common and success, measured in terms of restoration of fertility, is relatively low. In moderate to severe Asherman’s syndrome, recurrence rates range between 20-40% and 40-50%, respectively (Valle, et al., Am J Obstet Gynecol 1988;158:1459-70; Yu, et al., Fertil Steril 2008;89:715-22). Conception and pregnancy success depends on the success of the lysis of adhesions, the degree to which a normal endometrium can be restored, damage done to the uterus by the procedure itself and, eventually, the site of implantation of a subsequent pregnancy. As also reported in the article by Yu and colleagues noted above, “…the chances of conception in women who remained amenorrheic (2 out of 11); 18.2%) were significantly lower than in those who continued to have menses (37 out of74; 50%)…the conception rate in women who had reformation of intrauterine adhesions (2 out of 17; 11.8%) was significantly lower than that of women who had a normal cavity (26 out of 44; 59.1%)."

And, as we pointed out in our previous post, even if conception occurs, a good outcome is not guaranteed. Probably no more than one-third of women with moderate to severe adhesions will successfully carry a pregnancy and of those, there is increased risk for cervical incompetence, intrauterine growth restriction, fetal loss (early and late), placenta accreta or placenta previa, premature delivery, preeclampsia, cesarean delivery, uterine rupture, peripartum hemorrhage and hysterectomy.

In closing, let us just mention a few thoughts on prevention of Asherman’s syndrome. Based on several reports, the risk of Asherman’s could be reduced significantly if pregnancy-related D&C procedures could be minimized or done less traumatically. To that end, in recent years, the prostaglandin drug, misoprostol, has been used effectively even in first trimester uterine evacuations and compared to D&C is clearly associated with a reduction in risk for adhesions (Tam, et al., J Am Assoc Gynecol Laparoscop 2002;9:182-5). When given the option of instruments to use for D&C, a plastic suction curette is probably (but not completely) less traumatic than a sharp metal curette and efforts should be made to reduce the degree to which the endometrium is denuded by either. Prophylactic antibiotics, although rarely used when a D&C is performed, unless there is frank evidence of infection, might be considered in patients who opt to defer uterine evacuation following fetal loss in preference to awaiting spontaneous abortion. I think if I learned nothing else from this review myself, it was the fact that the risk of Asherman’s appears to go up dramatically with the length of time from fetal death to uterine evacuation although the factors that contribute to this risk are not entirely clear.

Labels: Asherman's syndrome, cervical incompetence, IUGR, placenta accreta, placenta previa, recurrent pregnancy loss

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Indications for Doppler Flow Velocimetry During Pregnancy

Recently, I received a phone call from our billing office reporting that an insurance company had declined to reimburse us for a claim that included charges for Doppler flow velocimetry for the indication of intrauterine growth restriction (IUGR). My response to the office personnel was simply that that is the most widely accepted indication we have for these procedures and that I would compose a letter of explanation to the insurance company, the contents of which are detailed below...

Doppler flow velocimetry (DFV) is a noninvasive method to assess resistance to, and velocity of, blood flow using ultrasound technology. In pregnancy, it has been proven to be a valuable adjunct to fetal assessment because often DFV abnormalities will precede detectable fetal abnormalities of growth, amniotic fluid, and placental insufficiency and can help assess the severity of fetal compromise when these abnormalities are suspected.

The principles underlying the most common indications for DFV are as follows:

Under normal conditions, the placenta offers little resistance to fetal and maternal blood flow, even during diastole (i.e., between heart beats); and, there is no preferential blood flow to the brain as reflected in normally high resistance, especially from late midtrimester on, at the expense of perfusion of other organs...

Under abnormal conditions, blood flow to the placenta may be reduced and accompanied by increased resistance to perfusion (fetal and/or maternal) and/or there is preferential blood flow to preserve ‘essential’ organs such as the brain (‘brain-sparing effect’) as manifested by low resistance Doppler patterns to these organs and eventually reduced perfusion (fetal blood flow redistribution) of ‘nonessential’ organs such as the kidneys.

Some factors that lead to aberrations in DFV patterns include:

• Abnormalities in placentation or of the umbilical cord
• ‘Placental insufficiency’ regardless of fetal size
• Fetal anemia resulting from maternal isoimmunization, viral infection (e.g., parvovirus B19 and CMV), twin-twin transfusion syndrome, fetal-maternal hemorrhage…
• Chromosomal abnormalities
• Cardiac and intracranial malformations

When indicated, DFV evaluation of the following may contribute valuable information with regard evaluation of the pregnancy, but should be performed by individuals trained and experienced in the performance and interpretation of the results:

Maternal:
Uterine arteries

Fetal:
Umbilical arteries
Middle cerebral arteries
Ductus venosus
Umbilical vein

Common indications for Doppler flow velocimetry studies include:

• Abnormalities of growth (both intrauterine growth restriction(IUGR) and excessive fetal growth (macrosomia)
• Fetal anomalies (e.g., cystic hygromas, cardiac, thoracic, diaphragmatic, neural tube, renal, and abdominal wall)
• Fetal hydrops
• Oligohydramnios (decreased fluid) and polyhydramnios (increased fluid)
• Poor OB history (e.g., preeclampsia, IUGR, previous stillborn…)
• Known maternal risk factors: hypertension, preeclampsia, diabetes, autoimmune disorders (overt and subclinical), thrombophilias (acquired and genetic)
• Abnormal maternal serum screening (e.g. elevated MSAFP and/or increased risk for fetal chromosomal abnormality)
• Multiple gestation
• Maternal trauma (fetal-maternal hemorrhage)
• Suspected placental abruption
• Known maternal isoimmunization
• Exposure to parvovirus B19

In recent years, DFV has become the primary means of screening related to fetal anemia. This is done by evaluating the peak systolic velocity (PSV) in the fetal middle cerebral artery. Its negative predictive value is so high that it has obviated the need for, and the expense of, repetitive invasive procedures when there is known maternal isoimmunization, Parvovirus B19 exposure, or other potential causes of severe fetal anemia such as trauma or placental abruption or placenta previa that might lead to fetal-maternal hemorrhage or fetal blood loss.

It is also the primary means of ruling out fetal anemia as a cause of hydrops fetalis and it is the mainstay in the assessment of multiple gestations as a means of screening and staging possible twin-to-twin transfusion syndrome. DFV of the fetal ductus venosus in early pregnancy has also proven useful in the identification of fetuses at risk for chromosomal abnormalities and major congenital heart defects. DFV of the branch pulmonary arteries can help predict the risk of fetal pulmonary hypoplasia in cases of premature and prolonged rupture of membranes.

DFV is no longer considered ‘experimental’ and it has become a ‘standard of care’ in the hands of specialist in Maternal-Fetal Medicine for the evaluation and management of complicated pregnancies.

Labels: Doppler flow velocimetry, fetal hydrops, isoimmunization, IUGR, oligohydramnios, polyhydramnios

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Amniotic Fluid - 3 - Oligohydramnios: Causes of Too Little Amniotic Fluid

Having discussed where amniotic fluid comes from and how we assess amniotic fluid volume, let’s address the most common amniotic fluid abnormality – too little fluid or oligohydramnios. There are 3 primary reasons why there is too little amniotic fluid: 1) rupture of membranes; 2) fetal abnormalities; 3) placental abnormalities.

Spontaneous rupture of membranes (SROM) can occur at any time in pregnancy. Most of the time, the membranes remain intact until the onset of labor, or just before labor, after the cervix has begun to change (efface and dilate). If membranes rupture prior to the onset of uterine contractions, it is called premature rupture of membranes or PROM, and if they are ruptured for more than 24 hours, prolonged premature rupture of membranes or PPROM. There are lots of things that can lead to rupture of membranes, but the ones we worry about most are infection, fetal anomalies that result in too much fluid (polyhydramnios or hydrammnios) and uterine overdistention, and cervical incompetence. The earlier in pregnancy that the membranes rupture, the greater the likelihood that it is associated with infection (with or without cervical incompetence) and this is usually infection with organisms that the mother carries in her body that get inside the uterus by ascending vaginal, blood-borne, or lymphatic transmission. However, the focus of this discussion is not to discuss SROM, but to remind readers that it is a very common cause of decreased amniotic fluid and when it occurs, the baby and the mother need to be evaluated carefully to look for causes. Since infection is often associated with PROM, that is usually what constitutes the greatest risk to the baby.

The least common, but often most serious, causes of decreased amniotic fluid are fetal abnormalities. If you recall in our first post on this subject, most of the amniotic fluid from early midtrimester on is fetal urine. Abnormalities of the fetal kidneys and urinary tract can lead to decreased urine output or the complete absence of amniotic fluid (anhydramnios) in the most severe cases. Babies can have the complete absence of both kidneys (bilateral renal agenesis), nonfunctioning kidneys associated with polycystic or multicystic renal dysplasia, or obstructive uropathies where there is blockage of urine at the urethra (usually the result of ‘posterior urethral valves’ in male children), or blockage of the ureters at various levels between the kidneys and the bladder (e.g., ureteropelvic junction (UPJ) or ureterovesical junction (UVJ)obstructions). An important point to note here is that if the baby only has ONE nonfunctioning kidney, or a blockage that affects only ONE side, the amniotic fluid is usually normal and the consequences of too little fluid for too long do not develop. However, if both kidneys are affected, this can lead to the complete absence of amniotic fluid and a condition that has been named “Potter’s sequence” which will be detailed in our next post on this subject.

Other causes of decreased fluid that may be transient (and therefore less serious) and/or reversible are congenital viral infections, such as cytomegalovirus (CMV) which has a predilection for the fetal kidneys, or conditions that affect maternal hydration. With regard to the latter, as we pointed out previously, if the mother becomes very dehydrated, or if she has a condition that severely decreases her plasma volume, the fluid around the baby, which depends so much on passive distribution from the mother across the placenta, can acutely decrease. Common conditions in which this is seen include: hyperemesis (too much vomiting), diarrhea, maternal sepsis, hemorrhage, placental abruption or previa, diabetic ketoacidosis, excessive fluid loss during fever or heat exposure, and severe preeclampsia. Oligohydramnios resulting from many of these conditions can be reversed or improved with expansion of the maternal plasma volume.

The last conditions I would like to discuss that lead to decreased amniotic fluid are those that result in decreased perfusion (blood flow) to the fetal kidneys. When it comes right down to it, the kidneys are ‘nonessential organs’ with regard to survival of the baby while it is inside its mother. For example, babies that have bilateral renal agenesis (no kidneys at all) can go all the way to term because the placenta and the mother serve as the means of removing ‘waste products’ from the baby. (They cannot survive after delivery for the reasons I will detail in my next post). Production of urine by the baby requires blood flow through the kidneys. When babies become dehydrated, or when they have to, preferentially, send blood to ‘essential organs’ such as the brain and the heart because they are not receiving enough oxygen and nutrients to support their whole bodies’ needs, their regulatory mechanisms of survival shut down blood flow to the kidneys, thereby, curtailing the production of urine.

This can occur as the result of primary fetal problems such as severe anemia associated with isoimmunization or parvovirus infections, or cardiac malformations or dysfunction from a variety of different causes. More commonly, however, this occurs as the result of abnormalities of placentation (small placentas and/or placentas that have not had normal invasion of the maternal spiral arterioles in the placental bed), wherein the babies have outgrown the capacity of the placenta to provide sufficient oxygen and/or nutrients. When ‘placental insufficiency’ occurs it is usually accompanied by intrauterine fetal growth restriction (IUGR). This usually means the baby is small for its gestational age, but there are occasions when this can occur in large babies, such as those seen in uncontrolled diabetic mothers, whose size also exceeds the capacity of the placenta to maintain their metabolic demands. When the amniotic fluid starts to go down in circumstances of placental insufficiency, this is also usually the result of ‘fetal blood flow redistribution’ away from the kidneys and to the essential organs necessary for survival.

Having discussed some of the more common causes of oligohydramnios, in our next installment of this series, we will address the evaluation, management, and consequences decreased amniotic fluid in pregnancy ….

Labels: amniotic fluid; AFV, IUGR, oligohydramnios, premature rupture of membranes

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 2 - Late Pregnancy Complications

In our last post, we discussed the role of plasminogen activator inhibitor-1 (PAI-1) in helping to maintain the balance between the clotting and fibrinolytic (clot-dissolving) sides of the coagulation system. The primary function of PAI-1 is to inhibit plasminogen activators (t-PA and u-PA) from converting plasminogen to plasmin which is responsible for initiating fibrinolysis. The premise is that if there is too much PAI-1 activity, clots will tend to hang around longer and if there is too little, the individual would be at increased risk for bleeding problems. Before we can address possible roles of abnormalities of PAI-1 production and activity in adverse pregnancy outcome and recurrent pregnancy loss (RPL), it would be helpful to understand changes that might occur in these parameters during normal pregnancy.

Kruithof and colleagues (Blood 1987;69:460-6) reported that both plasminogen activators (t-PA and u-PA) and plasminogen activator inhibitors increased during pregnancy. t-PA and u-PA increased 50% and 200%, respectively, throughout normal pregnancy. They also found that PAI-1, produced predominantly by endothelial cells lining blood vessels, increased nearly 10-fold by term over that found in nonpregnant women and a second plasminogen activator inhibitor, PAI-2, not found in nonpregnant women, but produced by the placenta, was present in very high concentrations by term. The increase in both activators and inhibitors appeared to maintain the balance between the clotting and fibrinolytic systems during normal pregnancy because no changes in plasminogen or the overall fibrinolytic activity were found. Within “three to five days after delivery most parameters of the fibrinolytic system were normal again.”

In 1989, Estelles and colleagues (Blood 1989;74:1332-8) reported that women with severe preeclampsia in third trimester had significantly higher levels of PAI-1 than nonhypertensive women. Interestingly, PAI-2 levels were significantly lower in the preeclamptic women and a positive correlation between birth weight and PAI-2 levels was found (in other words, the higher the PAI-2, the greater the birth weight); and birth weight was inversely correlated with PAI-1 levels (higher the PAI-1 activity, the lower the birth weight). The presumption is that the lower PAI-2 levels correlated with a decreased placental mass or function in preeclamptic women. Regardless, the high levels of PAI activity in severe preeclampsia appear to be solely related to the increased activity of PAI-1. And, as many of our readers are aware, this might account in part for the coagulation abnormalities frequently accompanying the more severe forms of preeclampsia.

Unfortunately, these observations late in pregnancy don’t really tell us whether elevated levels of PAI-1 in preeclampsia are a cause, an effect, a response, or a contributor to the disease process itself. Based on several observations by other investigators, and the putative role of PAI-1 in placentation early in pregnancy (which we will eventually get to here), perhaps it is all the above. There does appear to be a genetic predisposition/association with abnormalities in PAI-1 production and later pregnancy complications. Yamada and colleagues (J Hum Genet 2000;45:138-41) evaluated the association between preeclampsia and deletion/insertion polymorphisms (4G or 5G) in the promoter of the PAI-1 gene. The 4G/5G polymorphism was assessed in 115 women with preeclampsia, 210 normotensive pregnant women and 298 nonpregnant controls. The frequency of the 4G allele (which results in increased production of PAI-1) and of 4G/4G homozygosity was significantly higher in the preeclamptic women than either the normal pregnant or nonpregnant controls, suggesting that the presence of 4G is one risk factor for preeclampsia and perhaps more severe manifestations of the disease.

Along the same lines, Glueck, et al. (Metabolism 2000;49:845-52) evaluated complications in 133 women with at least one pregnancy, and found a significant association of the 4G/4G PAI-1 polymorphism with prematurity, intrauterine growth restriction (IUGR), and “total complications of pregnancy” that was independent of the presence of other genetic thrombophilias (factor V Leiden, MTHFR C677T, and prothrombin G20210A mutations). In a subsequent study (Glueck, et al., Obstet Gynecol 2001;97:44-8), they reaffirmed the presence of the 4G/4G genotype as a risk factor for IUGR and extended their findings to include associations with severe preeclampsia, placental abruption, and stillbirth. They also reported that “the hypofibrinolytic 4G/4G mutation of the PAI-1 gene…is frequently associated with the thrombophilic factor V Leiden mutation” which would further increase the risk of problems related to clotting.

Over the years, PAI-1 made by vascular endothelial cells was found to be induced by angiotensin II which is produced by the action of the angiotensin I-converting enzyme (ACE). In a fascinating paper published in 2003, Xia and colleagues (J Soc Gynecol Invest 2003;10:82-93) reported that 18 of 20 women with severe preeclampsia were found to have IgG antibodies to the angiotensin II type 1 (AT1) receptor. None of 18 normotensive pregnant women had these autoantibodies. They also found that the serum from the same 18 of 20 women with these AT1 receptor autoantibodies stimulated PAI-1 secretion by trophoblasts (placental cells) in culture. Activation of the trophoblast AT1 receptors was also correlated with decreased trophoblast migration and invasion in tissue culture models and this, too, was directly correlated with PAI-1 production. We will return to this point in our subsequent discussion of the role of PAI-1 in recurrent early pregnancy loss. Bobst and colleagues (Am J Hypertens 2005;18:330-6) further reported that AT1 receptor autoantibodies found in preeclamptic patients stimulated PAI-1 (and the cytokine IL-6) production by human kidney (mesangial) cells in culture. Reversible ‘damage’ to the kidney is one of the events which characterize preeclampsia and the more severe the kidney impairment, generally, the more severe the preeclampsia with regard to hypertension and decreased urine production...(more to follow!)...

Labels: IUGR, PAI-1, preeclampsia, thrombophilias

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