Grand Rounds 4.27 at Monash Medical Student

Many thanks to Jeffrey Leow at Monash Medical Student for the hard work in putting together a great collection of Grand Rounds offerings. Thanks also for including a link to my recent post that reviewed Chromosomal Mosaicism Detected at the Time of Chorionic Villus Sampling.

Not only is the decision to have invasive diagnostic testing done during early pregnancy a difficult one, but sometimes the results aren't as straightforward as we would like them to be. Such is the case with chromosomal mosaicism. When counseling prior to performing the procedure is done, these subtleties are often left out of the discussion because "the patient can only digest so much at one time." Admittedly, it is a complex subject, but it does occur in 1-2% of cases, so it is a 'risk' that sooner or later will have to be confronted by any provider who performs CVS. The finding of mosaicism creates incredible uncertainty and anxiety and may lead a pregnant woman to harder decisions, more invasive procedures, and lingering doubt about the baby's outcome, even when follow-up results are reassuring, that can haunt her until after the baby is born...

Labels: chromosomal mosaicism, CVS

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Fetal Cystic Hygromas in First Trimester

Today I received another comment to a post I wrote awhile back on aneuploidy (chromosomal abnormality) from a reader who has a first trimester baby that was found to have a cystic hygroma. With the growing acceptance of first trimester screening for aneuploidy as a 'standard of care' in the U.S. (the rest of the world discovered this several years back!), we are identifying more and more fetal abnormalities early in pregnancy. Since this too is becoming a topic of widespread general interest, I thought it would be worthwhile to highlight three of the comments/questions that were addressed to me so that other readers can hear about real situations and have a point of reference to current thought on this important issue. With apologies to the readers who left the original comments, I have modified the comments as necessary to the best of my understanding so that other readers will more easily understand their concerns...


Sat Jun 09, 09:10:00 AM 2007, Laura said:
My name is Laura and I am 24 years old. Me and my husband went for our first 12 week ultrasound scan a couple of days ago and to our shock we were told that our unborn child has a cystic hygroma, which we are told is fluid underneath the skin at the back of the babies neck (the nuchal translucency) measuring 6 mm. We are devasted at this news because we are told the outlook is not good. It is our first pregnancy and it has taken us so long to get pregnant due to my polycystic ovaries, it just makes it so much harder to deal with. We decided to have a CVS (chorionic villus sampling). They took a biopsy from the placenta which they are now going to test. We should have the rapid test results for Down syndrome, Turner syndrome, and Edwards syndrome by 13th June. We are praying that they will come back clear. They are also going to do routine chromosomal studies to look for other chromosomal abnormalities that are not detected by the rapid test. They said if all the tests are normal, and if the fluid drains away by 18-20 weeks we may have a chance. Its just so hard to understand how some fluid behind the neck could indicate these sort of problems. I am only 24 years old, and so is my husband. We are young, fit and eat a very healthy diet, it just seems so unfair. Do you have any idea of our odds. What is the percentage of babies that do get over this? Have you had any success stories that could give us some hope? Thank you for your time and we hope to hear back soon. Laura

Tues Jun 12, 09:10:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD responded:
I know this is hard, especially in a first pregnancy you have had so much trouble getting to because of your polycystic ovary syndrome. Unfortunately, finding the cystic hygroma in first trimester is associated with a very high risk for a baby that has a chromosomal abnormality, most often Down syndrome (trisomy 21 = 47,+21)), Turner syndrome (45XO,missing one sex chromosome), or Edwards syndrome (trisomy 18 = 47,+18). Sometimes cystic hygromas are associated with gene defects and not chromosomal abnormalities per se. Examples of the latter include Noonan syndrome, Roberts syndrome, polysplenia syndrome, multiple pterygium syndrome, and others. At times the baby has no chromosomal abnormality or obvious genetic condition. Under these circumstances, there is an increased risk for a major heart abnormality as an underlying cause, although we do not entirely understand why babies develop cystic hygromas under these circumstances. The prognosis for the baby depends on what problems the baby has, chromosomal, genetic, and/or associated structural. If the baby has no chromosomal abnormality and does not go into heart failure (develop hydrops fetalis), it may well survive the pregnancy. If no syndromic problems, chromosomal mosaicism, or gene defects are discovered after delivery, the baby may have a reasonable chance at doing well. Your doctors will discuss this more with you after they get your test results back. At that point (if they haven't already), they will probably refer you to a genetic counselor to get more information. Good luck to both of you and thank you for reading. By the way, it is highly unlikely that anything you have any control over caused this to happen. If you will, let me know what the tests show and how the pregnancy turns out...


Sun June 24 11:50 AM 2007, Anonymous said:
Dr. Trofatter, I am 41 year old with a 14 week pregnancy. Due to AMA (advanced maternal age) I elected to have a nuchal translucency (NT) scan done and the perinatologist found a large cystic hygroma; I was told extremely large 180mm3 and the doc was not optimistic. He performed CVS that day and we just recieved news that the FISH results were normal. Because there are no genetic defects, I was told we are looking at heart abnormalities, probably severe. My husband and I are deciding whether to terminate but the normal chromosome results makes this decision difficult. I have been doing research on the web for days now and I find myself unable to take care of myself and my family. I am reading the prognosis is poor and if I wait beyond 18 weeks I cannot terminate the pregnancy in my state. My question is can or should I get repeated ultrasound hoping the hygroma goes down and how often is an ultrasound indicated for this? Will the hygroma go down all at once or little by little or how much at a time? Please help me. Thank you

Tues June 26 02:47 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD responded:
Large cystic hygromas have a very poor prognosis, even if the baby is chromosomally normal. Even if the FISH results are reassuring at this point, your baby could have a chromosomal abnormality that was not detected by FISH. Your doctors have counseled you that this baby could also have a major cardiac malformation or other major abnormality that impedes return of fluid and lymph to the heart, even in the absence of a chromosomal abnormality. If the baby develops a condition called hydrops fetalis, this would indicate heart failure for any reason and the prognosis is usually fatal at that point. If the baby is chromsomally normal, has no other genetic or syndromic problem, has no major heart abnormality, and resolves the cystic hygroma, it may well survive and do quite well in the long term. I would recommend another ultrasound before 18 weeks. In many cases, major heart and other abnormalities can be identified by that time and you will have the final results of the fetal chromosome studies back to guide your decision. I am so sorry. It is difficult to be in your situation. If you have not seen a specialist in Maternal-Fetal medicine, I suggest you consider that. Thank you for reading and best wishes to you and your family.


Tues Aug 21 01:55 PM 2007, Ed said:
Doctor, on our 1st trimester baby scan we were told that baby had a 5mm NT (nuchal translucency). We hoped that the consultant could give us some better news on a scan a few days later, but we have the terrible news that it was not simply a wide NT, but a large cystic hygroma of 7mm, extend down the back to the lumbar region. She gave us an 85% chance of choromsome problem and cardiac anomalies even if normal. Also of possible intrauterine death. We are choosing to terminate, we can't wait in hope for a CVS or amniocentesis that MAY indicate the baby is chromosomally normal because it is more likely abnormal. But we have terrible guilt in termination too, as the baby seems ok at the moment. From what I read on the internet, there is a glimmer of hope that the babies do turn out normal. Is this just crazy hope or not?Ed


Wed Aug 22, 04:55:00 PM 2007 Kenneth F. Trofatter, Jr., MD, PhD said...
Although the prognosis is poor, there is always a "glimmer of hope." With your ambivalence and guilt related to pregnancy termination, why don't you have the CVS done and wait just a couple of days. Most labs can give you an answer in as little as 72 hours if they do a "direct prep" for the more common chromosomal abnormalities found with cystic hygromas. If the baby ends up being chromosomally normal, or has a potentially viable condition such as Turner's syndrome, the "glimmer" may improve if the baby survives the first part of the pregnancy....and even if it is chromosomally normal and succumbs, you can walk away having given it the "best shot" and it sounds like that is important for you. Just a thought. Good luck to both of you.


Dr T

Labels: amniocentesis, aneuploidy, CVS, cystic hygroma, first trimester screening

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Percutaneous Umbilical Blood Sampling (PUBS)

In several previous posts, we addressed issues related to invasive diagnostic fetal testing, covering amniocentesis (early and midtrimester) and chorionic villus sampling. I got side-tracked by the ACOG Meeting in San Diego and just remembered that we had never gotten around to a discussion of the other common (though much less so than amniocentesis or CVS) invasive (and at times, therapeutic) procedure, percutaneous umbilical blood sampling (PUBS), otherwise known as cordocentesis or funipuncture.

This, quite simply (but technically tricky), involves the placement of a needle into the umbilical vein to remove fetal blood for a variety of testing purposes such as: chromosomal analysis; genetic studies; hemoglobin analysis (hemoglobinopathies); fetal anemia; platelet count; assessment of fetal acid-base status; fetal infection; coagulation system abnormalities; immune deficiencies. It is commonly used when rapid (48-72hr) and precise fetal chromosomal studies are indicated; in the definitive assessment of anemia under conditions of isoimmunization or parvovirus infection (and as a route of intrauterine transfusion if anemia is confirmed); in the evaluation of thrombocytopenia (= low platelets) resulting from either autoimmune or alloimmune (analogous to Rh-disease) conditions; in the evaluation of fetal hydrops; and, in the confirmation of fetal infections.

PUBS is performed under aseptic conditions and direct ultrasound guidance, much like amniocentesis. Without going into great detail, a slightly larger bore needle is often used than that used with amniocentesis, especially if the procedure is being done for suspected fetal anemia and a transfusion via intravenous access is warranted. When technically feasible, we prefer to access the umbilical vein within 1-2 cm of its placental insertion site. Unlike with amniocentesis, many of us actually prefer to go through the placenta to get to this site. This provides a more stable site for insertion than free cord floating around in the amniotic fluid, improves the prospects for success and probably reduces the risks of the procedure. (Fetal blood sampling can at times also be done directly from the baby, the most common sampling sites being the intrahepatic vein and the fetal heart, but special preparations and precautions must be taken under these circumstances and do not warrant discussion herein).

Although at times the fetal condition might justify earlier evaluation, most fetal blood sampling procedures are done in babies that are 23 weeks or beyond. Since we now consider almost all babies at this gestational age potentially viable, it is recommended that the procedure be performed at an institution that can handle extremely premature babies, and/or babies that may be compromised by the medical condition that led to the PUBS, and at a location in which an emergency cesarean section can readily be performed if a complication arises during or in the immediate post-procedure period.

The most common complications include fetal bradycardia (slow heart rate) during the procedure, hemorrhage or obstructing blood clot at the needle insertion site, and intrauterine infection. Fetal bradycardia is often transient and its mechanism is unclear, but it may be related to spasm in the muscles of the uterine arteries if these were inadvertently punctured during the procedure. Prolonged bradycardia is more common, and more ominous, if it occurs when a baby is severely anemic, hypoxic, acidotic, hydropic (in heart failure), or is hemorrhaging uncontrollably from either the umbilical vein or an umbilical artery. If this cannot be corrected by our typical intrauterine resuscitative measures, immediate delivery may be indicated if the baby is at a gestational age where viability is possible.

Significant fetal hemorrhage from the needle insertion site is a relatively uncommon event; however, it is more likely to occur when the baby has low platelets as may be found in autoimmune, alloimmune, or parvovirus-induced thrombocytopenia. Of these, the greatest risk is in alloimmune thromobocytopenia because the platelet counts are often dangerously low and the platelets that are present may not function normally in clot formation. Babies affected by alloimmune thrombocytopenia are also at great risk for intracranial hemorrhage remote from the labor and delivery process.

In my experience, introduction of infection at the time of the procedure, either from maternal skin bacteria or blood borne organisms such as HIV, CMV, and hepatitis viruses, is a very uncommon event. Rupturing fetal membranes also occurs infrequently, but slightly more often than with amniocentesis alone. Risks for any of these complications rises with the length and complexity of the procedure, the larger the bore of needle used, and maternal obesity.
There are theoretical risks of PUBS to the mother such as causing sensitization to fetal blood cells or platelets, causing damage to internal organs, introducing infection, or causing bleeding, but these are also very uncommon. Probably the greatest risk is that of an emergency cesarean section if this is required to manage a fetal complication.

Procedure-related fetal loss rate is difficult to ascertain but is probably in the range of 1-2% and again is related to the complexity of the procedure and the fetal problem that led to the procedure being recommended in the first place. Babies with an indication for PUBS may be critically ill and, for example, those with hydrops, especially nonimmune hydrops, may not be salvageable regardless of any interventions attempted. It is difficult to consider a loss of one of these babies to be a ‘procedure-related event’ when their morbidity is so high at the outset.

PUBS is the riskiest and most challenging of the more common invasive diagnostic procedures we perform, but it is usually reserved for the most severe fetal compromise as well. In recent years, one of the more common indications for PUBS, screening for fetal anemia, has been replaced by the noninvasive Doppler flow assessment of peak systolic velocity in the fetal middle cerebral artery. PUBS is now only done under these circumstances when a significant fetal anemia is suggested by an abnormal Doppler flow result. Also, with the recent advances in genetic and molecular technologies, many of the studies that required PUBS in the past can be performed simply on amniotic fluid and/or the cells contained within it. And, quite likely, many of these studies will be able to be performed on the small amounts of fetal cells and DNA contained in maternal blood specimens as these technologies continue to advance, further reducing the need for these invasive studies.

Labels: amniocentesis, CVS, isoimmunization, percutaneous umbilical blood sampling, PUBS

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Chorionic Villus Sampling

In the last several posts, I have discussed amniocentesis as a means of fetal diagnosis for chromosomal or genetic problems. Amniocentesis is considered to be an ‘invasive diagnostic procedure.’ We actually have to stick a needle through the fetal membranes (chorion and amnion) and into the sac surrounding the baby to obtain the fluid and cells we need to perform the diagnostic studies. Another common ‘invasive’ procedure we perform is chorionic villus sampling, or CVS. This procedure can best be thought of as a placental biopsy, sampling fetal placental tissues that lie outside the amniotic cavity. It is usually performed during the latter part of the first trimester (10-13 weeks) for reasons I will discuss later on, but actually is a procedure that can be done anytime, preferably, after 10 weeks, when technically feasible, and may be the procedure of choice when fetal chromosomal or genetic studies are indicated and there is little or no fluid surrounding the baby.

Like amniocentesis, we perform CVS under direct ultrasound visualization or ‘guidance.’ The procedure can be done transcervically or transabdominally and the route that is selected is determined by the position of the cervix and uterus and, most importantly, the placental location. When conditions are favorable for CVS to be done transcervically, the perineum, vagina, and cervix are first ‘prepped’ with an antiseptic solution such as povidone-iodine. The cervix is then grasped with an instrument such as a tenaculum that, with gentle traction, can be used to straighten the cervical canal, aligning the cervical canal and the uterine cavity. A catheter containing a semi-rigid stylet is then placed through the cervix to just inside the junction of the cervix and uterus. Then, using ultrasound to follow the path of the catheter tip, it is advanced until positioned beneath the placenta. The stylet is then removed, a syringe is attached to the catheter, and the catheter slowly withdrawn as negative pressure is applied with the syringe. Placental villi can be readily identified as feathery tissue in the tissue culture fluid. In the laboratory, the fetal chromosomal studies can be done by both direct preparations and tissue culture with results available within 3-4 days and 6-10 days, respectively. More cells are usually obtained by CVS than amniocentesis and the cells are usually more metabolically active, allowing a more rapid turn-around time for both chromosomal and biochemical analyses.

If the placenta is not in an accessible location for a transcervical CVS, the transabdominal route may be considered. In many ways, when the placental location lends itself to this approach, it is and often less uncomfortable procedure for the patient. This is also done under aseptic conditions and direct ultrasound guidance. Usually a 19 or 20 gauge spinal needle is used and, because of the large caliber needle, local anesthesia is generally injected at the needle insertion site. Once the needle is positioned under the placenta, a syringe is used to aspirate a sample of villi just as in the transcervical approach.

Although CVS can be done earlier in the pregnancy than amniocentesis, thereby providing results sooner, it is not without risks. Based on early studies, we have generally quoted patients an ‘excess loss rate (= background loss rate minus the procedure-related rate)’ related to CVS of about 1%, or twice the oft-quoted 1 in 200 risk of an amniocentesis later in pregnancy, a number also based on earlier studies. However, as is now the case with amniocentesis, more recent studies have shown that the risk of CVS has decreased with time and, especially, with the experience of the operators. Caughey and colleagues (Obstet Gynecol 2006;108:612-16) recently published a review of 20 years’ experience (1983-2003) with CVS (9,886 procedures) and amniocentesis (30,893 procedures) at a single institution. They found that while the risk of CVS was 4-fold that of amniocentesis over the entire time period, in the recent years between 1998 and 2003, the risks of the two procedures were equivalent and estimated to be about 1 in 370. The results from the FASTER trial, cited previously in our discussion of amniocentesis, also suggest the risk of CVS is only about 1 in 360, but when compared to that study’s results for amniocentesis (risk of 1 in 1600), CVS is still 4-fold riskier for losing a baby as a consequence of the procedure.

Immediate complications of CVS such as bleeding, rupture of membranes, and introduction of infection are surprisingly rare. However, as with early amniocentesis, other consequences of CVS were found during our early experience with the procedure. In 1991, Firth and colleagues reported 5 cases of limb reduction abnormalities among 289 CVS pregnancies (Lancet 1991;337:762-3), 4 of which were associated with ‘oromandibular hypogenesis (basically poor development of the lower face).’ Since the background risk of this complex of abnormalities is approximately only 1 in 175,000 live births, these findings following CVS were considered to be quite significant. Interestingly, all of these abnormalities occurred after transabdominal CVS procedures performed between gestational ages of 55 and 66 days. To make a long story short, the general consensus today is that there is not a significant risk of limb-reduction defects when CVS is performed between 10-13 weeks, but that the risk may be as high as 1-2% if done prior to this time, particularly when done in the 6 to 9 week time period (Jenkins and Wapner. Semin Perinatol 1999;23:403-13).

The only other issue that we typically discuss with women before they undergo CVS relates to the accuracy of the diagnosis. Vejerslev and Mikkelsen reported a 1% frequency of chromosomal mosaicism in CVS specimens (Prenat Diagn 1989;9:575-88). Chromosomal mosaicism indicates two (or more) populations of chromosomally divergent (different) cells, generally, those that are chromosomally normal and those that are not. A baby can have ‘generalized chromosomal mosaicism,’ thought to arise from a mutational event that occurs during the early divisions of the fertilized egg, and have all (or most) body tissues affected. While generalized mosaicism is a relatively rare event, it appears that similar mutations, occurring in the cells that are destined only to become the placental tissues, is not infrequent at all and when this occurs it is defined as “confined placental mosaicism (CPM).”

When mosaicism is found in a CVS specimen, it is recommended that another invasive diagnostic study, either amniocentesis or percutaneous umbilical blood sampling (yet, another post) be performed to rule out generalized fetal mosaicism. However, even if it appears that this is ruled out (there is still a small chance the baby could have a more limited distribution of mosaicism with fewer tissues involved), the finding of CPM still may indicate a pregnancy ‘at risk’ for complications related to placental ‘insufficiency’, including fetal loss, intrauterine growth restriction, and pregnancy-induced hypertensive disorders. Life is never as simple as it seems, is it?!?

Labels: amniocentesis, ChorionicVillusSampling, CVS

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