Grand Rounds 4.45 by Edwin Leap, MD

Many thanks to Edwin Leap, MD for putting the huge effort into compiling this week's Grand Rounds! I submitted a more obscure offering that was written in response to readers' questions related to FSH and Aneuploidy and am grateful he included it as well.

As women approach menopause their FSH (follicle stimulating hormone) levels rise as the varian hormonal production begines to decline. Since their risk for babies with chromosomal abnormalities rises at the same time, it is only logical to ask if one might cause the other. At this point, it appears that this is not the case - they are coincidental, but unrelated events.

Labels: aneuploidy, chromosomal abnormalities, FSH

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Assessing Fetal Lung Maturity - 2

The fetal lungs are the last organ system to “mature” so that survival outside the womb is possible. Maturity involves several components. First, there must be sufficient surface area within the lung to allow sufficient exchange of gases (oxygen in and carbon dioxide out) to support metabolic functions. This is accomplished by millions of small sacs called alveoli that give the lungs a sponge-like appearance. Second, the alveoli must develop to the point that the inner lining of cells (epithelial cells) that come in contact with inspired air are very thin – gas exchange can only occur over a short distance between the blood vessels in the alveoli and the air that fills the alveoli. Third, the alveoli must be able to remain open so that the air can get into them and gas exchange can take place. The first two events are generally quite complete by about 32-34 weeks, however, the third is the most essential component from that point on and it is the focus of our fetal lung maturity testing as we shall explain.

Alveoli are like little bubbles. The laws of physics predict that because of the high ratio of surface tension to volume of little bubbles, their tendency is to collapse. To prevent this from happening, certain cells in the lungs – the type II alveolar cells – begin to excrete chemicals that can reduce the surface tension in the alveoli. These chemicals are called ‘surfactants’ and they are a complex combination of phospholipids and apoproteins. When sufficient surfactants are produced that the alveoli can remain open to function, the fetal lungs are considered ‘mature’. Prior to this time, the baby is at risk for developing respiratory distress syndrome (RDS). RDS occurs in about 1% of all pregnancies and it can have serious short- and long-term consequences, involving both the lungs and other organs, that can extend beyond the neonatal period in its most severe forms.

When babies are very premature, RDS is the result of a combination of both alveolar epithelial cell immaturity (the lining cells have not yet thinned out) and a deficiency of surfactants. Later in pregnancy (“near term”), severe RDS can sometimes also occur but at this point it is usually the result of insufficient surfactants alone – but the end result can be just as devastating. Certain medical conditions can delay surfactant production in babies, the most common being maternal diabetes with poor blood sugar control and isoimmunization (such as Rh-disease). Large babies (macrosomic) are also at greater risk for RDS even if maternal diabetes is not contributing to the fetal size. Babies who have developed heart failure (hydrops fetalis) for any number of reasons can also have a relative deficiency of surfactants (as well as pulmonary edema). For reasons that are not entirely clear, babies delivered by cesarean section, particularly, when this is done prior to the onset of labor, are also at increased risk for respiratory difficulties.

The amniotic fluid is mostly fetal urine, but it is mixed with effluent from the fetal lungs as well. The fluid from the fetal lungs contains surfactants and other indicators of type II alveolar cell activity. When we perform an amniocentesis to assess fetal lung maturity, we are looking for direct and/or indirect evidence to support the presumption that there is adequate surfactant present to minimize the risk for RDS. One should realize that all of the tests we will discuss have some degree of “false positivity” – an indicator suggesting lung maturity, but the baby still develops respiratory problems – however, there is enough experience with their use that a “mature” value with a test result generally means the baby has at least a 95% chance of not developing RDS.

Having provided this information as background, the actual tests commonly used to evaluate fetal lung maturity will be discussed in our next post….

Labels: amniocentesis, diabetes, fetal lung maturity, fetal macrosomia, Rh-isoimmunization, surfactants

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Assessment of Fetal Lung Maturity - 1

On this site we have been firm advocates of preventing complications related to iatrogenic prematurity and, particularly, “late preterm births.” Indeed, in our own medical community, it appears the message has had a clear impact, particularly, over the past year or so since the American College of Obstetricians and Gynecologists has also come out in support of delaying elective deliveries (cesarean sections and inductions) until at least 39 weeks unless pulmonary lung maturity is first documented. Whereas in the past, I used to field phone calls on a daily basis from physicians requesting support to “induce Mrs. Jones at 37 weeks because her baby is huge and she is just miserable” or “her blood pressure may be creeping up and I am out of town next week, so I just thought I would do her repeat c/section tomorrow, what do you think?,” I now get phone calls for those sorts of indications, but accompanied by a request to perform an amniocentesis to assess fetal lung maturity.

However, some of the patients show up on our doorsteps either unclear about what “assessing fetal lung maturity” entails, or in denial of the same, or hoping, if they play dumb, I won’t figure out why they’re there. Unfortunately for them, I always ask, “What is your understanding of what your doctor would like us to do for you today?” Even if some of them have difficulty telling me that they are there to have an amniocentesis done, usually I will drag out of them that their doctor would like to “get me delivered.” That usually breaks down the barriers to discussing what an amniocentesis entails and the importance of assessing fetal lung maturity.

Some, honestly do not realize that “figuring out if the baby’s lungs have a reasonable chance of working well when they’re born” involves an invasive diagnostic study with a very long (but thin) needle. In fact there isn’t a day that goes by when we don’t have a patient ask, after we have done the preliminary ultrasound evaluation to determine fetal position, amniotic fluid volume, and placental location in preparation for the amniocentesis, “Well do the lungs look mature?” as they are sitting up and starting to clean off the ultrasound gel in premature preparation for leaving. When I then tell them that “we cannot determine that simply by looking” and start explaining what an amniocentesis is all about, and their eyes get as large as saucers and they start hyperventilating, it is clear they weren’t completely informed by their provider as to the nature of the evaluation. However, once they understand that their doctor does not plan to deliver them without that information, the discussion, again, becomes much more straightforward.

We have already discussed amniocentesis in other contexts and there is no reason to rehash the procedure or the risks associated with it, which are generally, quite small late in pregnancy. Instead, in our next post, I will discuss what it is we are looking for when we do fetal lung maturity testing and then we will describe some of the diagnostic tests currently available for that purpose…

Labels: amniocentesis, fetal lung maturity

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Grand Rounds 4.44 at GruntDoc!

Thanks to GruntDoc for the effort put into hosting this week's Grand Rounds 4.44. I am grateful that he included my recent post on Amniocentesis is Not Without Risk.

Admittedly, it is a long post, but it tells a story. I may be wrong, but I get the sense that the decisions being made by a couple of the featured readers are based on incomplete information and/or biased presentation of the same. (And, for our physician readers, I am not ruling out the possibility that certain patients hear what they want to hear!). That frustrates me because there is no one more vulnerable to that than pregnant women and their families.

It is sometimes hard to present the advantages/disadvantages and risks/benefits of the screening tests that are available during pregnancy without keeping our own feelings out of the equation, but an honest effort must be made to do so. That is especially true when the outcome of such a screening test might lead to an invasive diagnostic study such as an amniocentesis that could put the pregnancy at risk, albeit the risk is small. I am careful to tell patients that, they alone can make a decision with which they are most comfortable - a decision I cannot and will not make for them. In fact, I go so far as to tell them that I don't care what decision they make and that I don't care what they do with the information they may get from the procedure! But, to make that decision, they deserve to have balanced information with some responsibility on the part of the provider that they actually understand the information they are given. In the end, all we can promise is that if their choice is to proceed with an amniocentesis, we will do the best we can to make it, technically, the safest procedure possible.

Labels: amniocentesis, first trimester screening

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Amniocentesis is Not Without Risk

Occasionally, a series of comments are left that leave me feeling quite disturbed. Included below is such a series received over the past few weeks, and to which I responded, that tell a story all by themselves. Please read all the way to the end and you will understand why they have been linked together…

• At Wed Jul 16, 04:42:00 PM 2008, anonymous said…

Dear Dr T
Just found this site and took a lot of encouragement from it. I an agonizing over the amniocentesis and have been for the past 4 weeks. I am now week 20 and this is my last chance to have it. My age is 42. I got pregnant very quickly and my (first trimester screening) test results were… overall risk 1/1250 for Down syndrome. I decided not to have amnio based on this and am now so anxious about the prospect of Downs I feel quite ill with the worry. My local hospital claims their amnio miscarriage rate is between 0.5 and 1.0 per cent. I am torn between not getting pregnant again given my age and driving myself ill with stress of not knowing for sure.

Many thanks.

• At Fri Jul 18, 05:23:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous July 16:
I cannot make the decision for you, but I will tell you four things: 1) You got a GREAT test result for your age; 2) The quoted risk of the amnio at your hospital is 5 to 10 times greater than the chance that this baby has Down syndrome; 3) If you lose the baby as the result of the amnio, odds are you will be losing a NORMAL baby; and 4) If you get pregnant again, the odds are about 20-25 times greater than your current risk that you will have a chromosomally abnormal baby! But, the final choice is yours and you have to live with whatever decision you make, so best wishes!
Dr T

• At Thu Jul 17, 11:24:00 AM 2008, agoura said…

Hi Dr.
I am 30 yrs old and this is my 1st pregnancy- I am 20 weeks along. I have had an ultrasound at 18 weeks and was called in for genetic counseling because they saw a variation - an echogenic focus was found in the left side of the heart. Although they note it's a "soft marker" for Downs Syndrome my Dr. recommended I have an amnio. They said my rate of having a baby with Down Syndrome (from my APF testing) was 1 in 2600 - but now because of these new findings my ratio has gone up to 1 in 1445. I know it seems very unlikely - I guess my question to you is- how many children in your experience have you seen this echogenic focus and they actully turn out to be healthy babies versus babies being born with a birth defect. The baby (i was told) was very healthy and growing as it should, and all my testing came back with great results - this has been the only bump in the road. I am going ahead with the amnio- do you think I should really be worried about miscarrying OR having a baby with D.S?
Thanks for your advice!

• At Fri Jul 18, 05:02:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To agoura:
Almost ALL babies with echogenic intracardiac foci (EIFs) are NORMAL. In fact EIFs are very common and are present in about one-third of all Asian women. An EIF alone is a terrible reason to do an amniocentesis and I never recommend that to my patients - especially if they have a risk assessment as good as yours. The risk of the amnio is still three to five times greater than the chance of having a chromosomally abnormal baby in your case. And, think about this - if you lose the baby as the result of the amnio, the overwhelming odds are that the baby you lose would be chromosomally normal. Even factoring in the EIF (which I am truly loathe to do), the chance of having a baby with Down syndrome is still much less than your age alone risk which happens to be about 1 in 840! And, when you get pregnant again, the risk will be even higher. But, the final choice is yours. Good luck!
Dr T

• At Thu Jul 17, 04:45:00 AM 2008, Anonymous said…
Hi Dr, I am writing from Australia and am 18 weeks pregnant. My 12 week scan gave me a score of 1:1010 for Down Syndrome... I will be 38 when the baby is delivered and am constantly filled with anxiety about not having an amnio. I booked in for one but then cancelled as no one had advised it. What sort of reassurance can I get from the 19 week scan and can I still have an amnio? What should I be asking them to look for? I understand I should have faith in the score, but I could be the 'one'. Is there less chance of a miscarriage having an amnio at 19 weeks? Thanks so much for your time.

• At Fri Jul 18, 04:56:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous from Australia:
The test result is what it is and in your case it is a very good result. Your ‘age alone’ risk for Down syndrome in first trimester is 1 in 100 – ten times more than your calculated risk assessment – and that is information based on your pregnancy and not just a whole population of 38 year old women. It is much more reliable than counseling you based on age alone. The 18-20 weeks scan, if all is normal, will further reduce your risk more than 50% (range 50-90%). You can certainly wait until then to do the amnio and most good genetic labs can give you a result by fluorescent in situ hybridization (FISH) regarding many common chromosomal abnormalities (including Down syndrome) in 72 hours or less. The final choice regarding the amnio is yours, but remember this, if you are the 1 in 200 to 1 in 500 person who LOSES their baby from the amnio, odds are you will lose a perfectly NORMAL baby! Good luck.
Dr T

• At Fri Jul 11, 02:42:00 AM 2008, katja said…

Hi Dr T,
I had an amnio done 3 days ago, the procedure went fine and I'm ok, just some mild cramping. When are you considered to be 'safe' from miscarriage due to the amnio? My doctor said the first 48 hrs are crucial, and then some can have an infection up to a month after the procedure. Does that seem right to you? I read some stories about women losing fluid and having infections even a month later. What are the reasons for that infection? Do the membranes close up themselves or is it possible the hole doesn't close up at all?

Thank you, Kat

• At Sat Jul 12, 08:53:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Kat:
The first 48-72 hours are critical from the standpoint of rupturing membranes following an amnio based on the needle entry alone. We use very thin needles and the hole generally closes up completely within that period of time. But the risk of infection does extend out about a month and that is the most common cause of delayed rupture of membranes. Early delivery is almost inevitable if you do develop an intrauterine infection under those circumstances – no antibiotic regimen will help. Fortunately, infection is remarkably rare following amniocentesis.
Dr T

• At Fri Jul 18, 12:04:00 PM 2008, Chris said…
I had an amniocentesis at 16 weeks. I did not have any real cramping, fever, spotting, leaking of fluid after the amnio. At my 20 weeks ultrasound, I was told the baby had died in utero. The doctors blamed it on the amnio. The amnio showed that there were no chromosomal defects. If I lost the baby due to an infection, wouldn't I have had symptoms.

Also, if the baby hits the side of the needle, could this cause fetal demise and if it could, how long would it take for the fetus to die?

• At Fri Jul 18, 06:48:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Chris July 18:
I am so sorry for your loss. But others should know that an amniocentesis is a procedure that does carry some risk, and so I hope you don’t mind if I include your comment in a post that addresses this subject.

It is unusual for a baby to die from a needle stick alone. Inadvertent laceration of the umbilical cord would be a more common cause of fetal death. When babies are lost as the result of an infection, I have been truly amazed by how much infection can be 'hidden' inside the uterus without the mother having a fever, pain, or even an abnormal white blood count. Sometimes the only sign is rupture of membranes and uterine cramping. Again, I am so sorry for your loss, but please let us know what you find out. I know it is hard, but thank you for sharing your story. Amniocentesis does carry some risks.
Dr T

Labels: amniocentesis, echogenic intracardiac foci, first trimester screening

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Groundrules for Comments and Communication

As some of our regular readers already know, about 6 months ago I took on the role of interim Chair in our Department of OB/GYN. The added responsibilities have drastically cut into the time and energy I have had to devote to this site, although the readership has continued to increase from all over the world. While the members of the search committee have worked hard to find a Chair, they are just now narrowing the candidates down to the serious contenders and the process may take another six months. I think I can hold on that long!

Anyway, when I first began writing for Fruit of the Womb, I took the somewhat unique approach of offering to begin a dialog with any of you who were interested, despite the fact that this site is not set up in a way that that can be easily done. However, be that as it may, as many of you who have been the recipients of my responses are aware, I have tried to respond to virtually every comment that arrives in my mailbox. At times that can be almost overwhelming and sometimes limits the time I have to address new topics. For example, over the weekend, I had a few minutes to myself and sat down to write a new post, but when I opened up the mail, there were approximately 90 new comments from our readers. Six hours into composing my responses, I knew there would be no new posts that day for the general readership!

While responding to your many questions this weekend, I realized that I need to clarify once again the 'comments process' and also tell you what I will and will not do for you as my readers. Please respect my groundrules! Several readers left the same questions under different posts. As the process below details, I understand why that is a temptation, but please do not do that! It only slows me down. Several other readers asked that I communicate directly with them via their personal email addresses – sorry but I cannot do that either. Recently, a couple of you have tracked me down to my workplace, called, and requested to talk with me directly – that is an absolute no-no! Not fair to my staff, my patients, or to me! Occasionally, I need a few minutes during the day to run to the bathroom. Anyway, here is the way things work when you write a comment:

1) You write and submit a comment.

2) Someone (not me) at Healthline reviews the comment and decides if it 'acceptable' to be posted on the site. Mind you, it does not have to be well-written, have good spelling, or even be flattering; it probably does need to be relatively devoid of overt obscenities!

3) After the comment passes initial screening, it gets posted in the 'Comments' section under the post to which it was originally submitted. Therefore, expect a delay from the time you write the comment until the time it actually appears. If this is over a weekend or a holiday, it could be several days. It is your responsibility to remember to which post you submitted the original comment so that you can check to find my response.

4) Only after your comment is screened, and simultaneous to its being posted, the comment gets sent to my email box.

5) Only then do I have the opportunity to respond to your comment. I will usually do so somewhere beneath where your comment appears in the post, but sometimes will incorporate it into an entirely new post if I think it may be of interest and provide worthwhile information for a good number of other readers. If I do the latter, I will usually leave a note under your comment to let you know where to look for the detailed responses to your questions. It may take me a week or longer to respond, so if you have an ‘urgent’ situation, this is not the way to get a quick solution to your questions.

6) I try to respond to as many comments as possible, but there are some for which I have no response.

7) The drawbacks to this system are the built-in delays, the occasional 'missed' comments, either posted to the site without my knowledge, or sent to me without having been posted to the site, and most importantly, I never know (unless you write back) whether or not you have actually found your way back to the initial post and seen my response!

When I do respond, please be aware of the limitations of my answers. I will make an honest attempt to provide unbiased information, presenting the various opinions on “both sides of the fence,” reserving the right in the end to tell you where I stand on the issue and why, but understand, this is not a peer review journal! I can provide some thoughts, some information, some clarification of something you do not understand, some questions you might ask your providers, and maybe even a correct solution (given enough information) to your particular problem, but I cannot possibly understand your entire situation and I certainly CANNOT replace your own doctors in providing all the answers for your care. As wonderful as the internet is, it does not take the place of the face-to-face and hands-on attention of a physician who knows you well. So, don’t be afraid to ask them your questions, the same ones you are asking me! If they tell you something and you do not understand, then ask them to explain it a way that you do. Don’t ever leave your doctor’s office with big questions lingering in your heads, unless of course your doctor tells you up front that “I don’t know myself at this time.”

To all of you, thanks for being such loyal readers and for sticking by me during these tumultuous times!
Dr T

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Ethnic Differences in Components of First Trimester Screening for Aneupolidy

In our last post, we briefly discussed the use of fetal nasal bone (NB) assessment in first trimester screening for aneuploidy and mentioned in passing that ethnic differences have been described. The reader below was curious to find out if ethnicity plays a role in the interpretation of the various components of the screening...

• At Wed Jul 02, 11:35:00 PM 2008, Anonymous said…

Out of curiosity, when you mention race being one of the factors taken into consideration, how does that play out? Are you (when combined with the other factors) at a higher risk for an abnormality if you are African American or Asian than you are if you're Caucasian, etc? Thanks.

• At Thu Jul 03, 02:46:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous July 2: Ethnicity alone does not necessarily increase risk for certain fetal abnormalities or chromosomal abnormalities, but it does factor in to what is considered 'normal' ranges for the maternal serum markers (β-hCG and PAPP-A) in first trimester. Below is an abstract from an article that makes this point. Furthermore, there are differences in the rate of visualization of fetal nasal bones in first trimester in mothers of different ethnic origins. Yeung Leung and colleagues (Am J Obstet Gynecol 2008;epub ahead of print) found a higher incidence of absent nasal bones in women of Asian origin than in Caucasians and, similarly, Prefumo and colleagues (BJOG 2004;111:109-112) found a lower rate of visualization in women of African origin. Thus, when nasal bone detection is included in first trimester risk assessment, its absence may result in greater false positive screening rates in women of these ethnic backgrounds unless that factor is corrected for statistically or by a sufficient ethnic-specific population database.

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Maternal weight and ethnic adjustment within a first-trimester Down syndrome and trisomy 18 screening program. Krantz, et al., Prenat Diagn 2005;25:635-40.


OBJECTIVE(S): To estimate weight and ethnic group correction factors for first-trimester screening markers. METHODS: Ethnic-specific median MoM free beta hCG and pregnancy associated plasma protein A (PAPP-A) and delta nuchal translucency values were calculated for cohorts of maternal weight (20 lb each) using data from 51,206 patients undergoing first-trimester screening. False-positive rates for Down syndrome and trisomy 18 were evaluated both prior to and after weight and ethnicity adjustment. RESULTS: Free beta hCG and PAPP-A significantly decreased with increasing maternal weight while nuchal translucency increased by a clinically insignificant amount. For free beta hCG the regression formula indicated that after accounting for maternal weight MoM values were 16% higher for African Americans, 6% higher for Asians and 9% lower for Hispanics compared to Caucasians (p < 0.001, p = 0.001, p < 0.001, respectively) but there was no significant difference for Asian Indians. For PAPP-A, MoM values were 35% higher for African Americans (p < 0.001) but were not significantly different for the other ethnic groups compared to Caucasians. Down syndrome false-positive rates did not vary with maternal weight prior to (p = 0.291) or after weight adjustment of biochemistry (p = 0.054). Trisomy 18 false-positive rates varied significantly with weight both before (OR = 1.455 per 20-pound increase, p < 0.001) and after (OR = 1.066 per 20-pound increase, p = 0.01) weight adjustment of biochemistry; however, the odds ratio was greatly reduced after weight adjustment. CONCLUSION(S): The first-trimester screening markers, free beta hCG, PAPP-A and nuchal translucency vary with maternal weight and ethnicity. Adjustment of free beta hCG and PAPP-A is indicated but adjustment of nuchal translucency results may not be necessary. Copyright 2005 John Wiley & Sons, Ltd.

Labels: first trimester screening, hCG, nasal bone assessment, PAPP-A

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Fetal Nasal Bone Assessment in First Trimester Screening for Aneuploidy

The reader below underwent combined first trimester screening for aneuploidy and during the process, the baby was found to have an absent nasal bone. Due to the difficulty in routinely obtaining a definitive assessment of the nasal bone, and its current limited usefulness in screening women of all ages and ethnicities, many providers have elected not to include that in their certification for routine first trimester screening...

• At Fri Jun 27, 12:34:00 PM 2008, Anonymous said…

Hello,
I'm 12 weeks and 6 days and had first trimester screening done two days ago… I'll be 38 years old when this baby is born. The results were very bad due to the lack of nasal bone... my risk factor is 1/20 for Down syndrome. I have read all through your blogs and don't see anyone else with this problem... I'm very scared now and wish I would have not had the test. How common is it for a nasal bone to develop slowly? I have two other healthy children. The neck fluid (nuchal translucency) was fine though. Any information you can provide would be very much appreciated... I'm very panicked. Thank you.

• At Thu Jul 03, 07:59:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous June 27: Sorry, I missed your comment before today. Not everyone who does first trimester screening (FTS) is "certified" to perform nasal bone (NB) assessment and even among those who are, it has been found to be difficult to perform consistently (Rosen, et al., Obstet Gynecol 2007;110:399-404). At this point, the greatest value appears to be not necessarily in including it in the screening of all women for aneuploidy in first trimester, because of the low positive predictive value in unselected populations, but as an adjunct to screening “high risk” populations such as women who will be 35 years or older at delivery and those who carry balanced translocations involving chromosome 21 (Prefumo, et al., Am J Obstet Gynecol 2006;194:828-33).

Publications by Cicero and colleagues in 2001 (Lancet 2001;358:1665-7) and 2003 (Prenat Diagn 2003;23:306-10) reported finding the absence of nasal bones in about 2/3 of first trimester screenings of babies with Down syndrome (trisomy 21) compared to 1% or less of chromosomally normal babies. By including nasal bone screening in their FTS, they were able to detect more than 90% of babies with a false positive rate of only 0.5% (and 97% at a false positive rate of 5%). As confirmed in the recent study whose abstract is below. including the nasal bone in the first trimester screen may not increase the detection rate of Down syndrome, but it does help reduce the "false positive rate" as had previously been demonstrated by Cicero and others. In other words, if the nasal bone is present, the baby is less likely to have a "positive screen" under circumstances in which the baby really does not have Down syndrome.

By the way, you stated your results “were very bad due to the lack of nasal bone." But I am curious to know what were the results of the other components of your first trimester screen. Best regards and please let us know what you find out.
Dr T

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Has, et al., Fetal Nasal Bone Assessment in First Trimester Down Syndrome Screening. Fetal Diagn Ther 2008;24:61-66.
Objective: To evaluate the contribution of nasal bone assessment in the first trimester Down syndrome screening. Methods: The fetuses which underwent first trimester screening with nuchal translucency (NT) measurement were evaluated for the absence or presence of nasal bone according to the instructions described by the Fetal Medicine Foundation, London. Results: Among the 1,807 fetuses included in the study, 9 had trisomy 21. The detection rate of Down syndrome with NT measurement was 77.8% (7/9) with a false-positive rate of 4.5%. Incorporation of biochemical tests (PAPP-A, and free beta-hCG measurement) into the screening increased the detection rate to 88.9% (8/9) and decreased the false-positive rate to 3.6%. The prevalence of absent nasal bone was 7/1,798 (0.39%) in chromosomally normal fetuses, and 3/9 (33.3%) in Down syndrome fetuses. Sensitivity, specificity, positive predictive and negative predictive values of absence of nasal bone for trisomy 21 are 33.3% (CI: 0.12-0.64), 99.6% (CI: 0.99-0.99), 30% (95% CI: 0.11-0.53) and 99.7% (95% CI: 0.99-0.99), respectively. The positive likelihood ratio of absent nasal bone was 85.6 (95% CI: 26.2-279.5), and the negative likelihood was 0.67 (95% CI: 0.42-1.06). When nasal bone assessment was incorporated into the NT risk assessment or combined test, the detection rate of trisomy 21 was not changed, however, the false-positive rate decreased to 3.4 and 3%, respectively. Conclusion: The absence of fetal nasal bone has a high positive likelihood ratio for Down syndrome in the first trimester screening, and the presence of nasal bone may potentially lower the need for invasive testing. Copyright © 2008 S. Karger AG, Basel.

Labels: first trimester screening, nasal bone assessment

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First Trimester Screening and Twins

Below is a series of excellent questions and my responses related to first trimester screening from a woman who has an IVF pregnany and twins...

• At Fri Jun 27, 06:53:00 AM 2008, Anonymous said…

Hi: How reliable is first trimester screening (FTS) in twins pregnancy? I was told it is not and some said it is. We are trying to make a decision if we will pursue chorionic villus sampling (CVS). I am 36 and I would be 1 month away from 37 when it is my due date. I am now 11 weeks almost 12. I did the FTS and the ultrasound looks good. The genetic counselor said the blood test will not be as accurate as in singleton pregnancy. The spaces on the necks (nuchal translucencies) on both babies are normal and look good. We conceived using IVF (1st cycle). It is unexplained infertility. I had natural pregnancy once but miscarried during 7-8 weeks (no heart beat detected). No family history of birth defect on either side. I am Asian if this matters and my husband is white (British/ French). I really appreciate your opinion. Thank you.

• Tue Jul 01, 01:05:00 PM 2008, Anonymous said…
Dr. T.
I left comment earlier on 6/27 about reliable in FTS in twin. I just got the test results for FTS:

IVF/ICSI cycle
36 yrs (asian) weight 165 lbs
Gest Age: 11.3 wks
IDDM: no DS HX: NO
NT: 1.3 mm and 1.5 mm
CRL: 49.3mm and 48.3 mm
Nuchal Translucency: 1.08 MoM/ 1.25 Mom
PAPP-A: 3.00 MoM
hCG - 1.36 Mom

Down Syndrome: Screening Risk 1:660 Age Risk 1:130
Risk Cutoff: 1:50
Trisomy 18: Screening Risk - can't accurately estimated in twin
Age Risk 1:470
Risk Cutoff: 1:100

We were told by the genetic counselor and another doctor who does CVS that our position is good base on the FTS result. We would do amniocentesis at 16 weeks, but if there would be an unfortunate result, would that be too late to do selective reduction which it could be 18 weeks by the time we get the result?

I would appreciate any comment based on your expertise. These tests are very confusing and driving us crazy. Thank you so much for having such an informative blog for all Moms-to-be.
W.

• At Tue Jul 01, 05:51:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To W: Those are very good first trimester results. Personally, I have found combined first trimester screening (NT measurements plus maternal serum markers) to be very helpful in twins. Below is an abstract from a recent article that gives you some idea of its value. I would suggest an MSAFP only (and perhaps another ultrasound) at 16 weeks and then a good genetic sonogram at 18-20 weeks. If all that checks out fine, you probably do not need to have any invasive procedure done and with those first screening results, we would not ordinarily recommend a CVS at all. Of course, regardless of what we suggest, the final choice is yours!

It is not too late to do selective reduction at 18 weeeks or even later, but the risks do go up with gestational age. If you have an amnio done and you are seriously considering selective reduction if one of the babies is chromosomally abnormal, consider having a FISH study done from which you can get a result back in about 72 hours. I am NOT recommending it in your case at this time, but if you elect to proceed with the amnio,that is an option to consider.

Best of luck and please let us know how things turn out. By the way, at the time of the genetic sonogram, ask your doctors to evaluate your cervical length as well! Infertility patients are notorious for having unsuspected cervical incompetence, especially with multiple gestations!

Thanks for reading and good luck to you for the rest of the pregnancy!
Dr T

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Chasen, et al., First-trimester risk assessment for trisomies 21 and 18 in twin pregnancy. Am J Obstet Gynecol 2007;197:374.e1-3.

OBJECTIVE: Our objective was to describe performance of first-trimester combined risk assessment in twin pregnancies. STUDY DESIGN: Twin pregnancies that underwent risk assessment in our ultrasound unit from 2003-2006 were included. Adjusted risks for trisomies 21 and 18 that were based on age, nuchal translucency (NT), and biochemistry were provided for each twin. Detection rates for Down syndrome and trisomy 18 were calculated for age/NT, and age/NT/biochemistry at a screen-positive rate of 5% of pregnancies. RESULTS: Five hundred thirty-five pregnancies were included. Median maternal age was 34 years, with 47% of women > or = 35 years old. There were 7 fetuses in 6 dichorionic pregnancies with Down syndrome and 3 fetuses in 3 pregnancies with trisomy 18. For a 5% false-positive rate, age/NT identified 83.3% of Down syndrome and 66.7% of Trisomy 18 pregnancies. Adding biochemistry resulted in 100% detection rates for both conditions. CONCLUSION: The addition of biochemistry may enhance first-trimester risk assessment in twin pregnancies. Further studies with larger numbers of affected pregnancies are needed.

Labels: amniocentesis, chorionic villus sampling, first trimester screening, FISH

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Elevated FSH and Aneuploidy?

The reader whose comments are featured below has had two miscarriages associated with chromosomally abnormal babies. She also has several medical problems that may or may not decrease her chances for a successful pregnancy. I thought her questions were excellent and I tried to provide answers for those while expanding on several other issues about which she did not have questions. I have paraphrased or expanded some of her comments to improve clarity for other readers...

• At Sat Jun 14, 11:29:00 PM 2008, Polly Gamwich said…(and my responses follow her questions in italics):

Hi Doctor,

I am 31 years old. At age 29 I had two miscarriages, the first at 10 weeks due to Turner’s syndrome (45XO) and the second at 8 weeks due to XXYY. When I was 30 I had two chemical pregnancies. I have yet to have a live birth.

I have elevated FSH (12.3), am a compound heterozygote carrier for MTHFR polymorphisms and am currently being treated (with folic acid), and have Hashimoto's thyroiditis, currently being treated for hypothyroidism. I have four questions for you:

1. Am I more at risk of having a chromosomally abnormal baby, as a woman in her 40's might be because of my elevated FSH?

Increased FSH (follicle stimulating hormone) is associated with decreased ovarian reserve and that is associated with aging, as is the risk for producing an egg with an unbalanced chromosomal complement (aneuploidy), BUT the two do NOT appear to be related. Indeed two recent publications clearly show no direct relationship between the FSH level and aneuploidy risk (Massie, et al., Fertil Steril 2007;87;S7 and Thum, et al., Fertil Steril 2007;Oct 20 – epub ahead of print) (Note: FSH is made by the pituitary gland. Its production is regulated by a negative feedback loop secondary to estrogen produced by the ovaries. When estrogen levels are high, FSH levels decrease (are suppressed) and when estrogen levels are low, as occurs during the luteal phase (after ovulation) of the menstrual cycle, menopause, or premature ovarian failure, then FSH levels are elevated).

2. Why does your body allow you to even GET pregnant with chromsomally abnormal babies ... why doesn't it just pass the baby without implantation??

Most chromosomally abnormal babies do NOT make it successfully through the implantation process and of those that do, very few will survive the first trimester.

3. I've had all the testing there is (and more) and we're treating all the problems ... why would my risk of miscarriage go up after the 2nd miscarriage? (I've heard that if you've had two losses you have a better chance of having a healthy pregnancy, however if you have more than 2 miscarriagess you have a worse chance of having a healthy pregnancy ... I would assume this is assuming an untreated issue??)

That is only true if there is NO IDENTIFIABLE CAUSE for the losses. You DO have an identifiable cause - babies that had chromosomal abnormalities. So, that may just be a string of bad luck or there is a very small possibility you are at risk for recurrent aneuploidy for reasons we do not yet understand. I guess I would have several other concerns and these are related to your Hashimoto’s thyroiditis. Hashimoto’s disease is an autoimmune condition characterized by the presence of antibodies against your thyroid gland. Recent studies have confirmed that autoimmune thyroid disease is associated with unexplained infertility and recurrent implantation failure (Belver, et al., Hum Reprod. 2008 23:278-84).

Furthermore, sometimes the presence of one autoimmune condition can be an indicator of others since these result from imbalances in your immune response that cause you to attack your own tissues as if they are ‘foreign’ to your body. Some individuals will develop polyglandular autoimmune syndromes characterized not only by Hashimoto’s disease, but also by premature ovarian failure, type 1 diabetes, and autoimmune adrenal deficiency (Addison’s disease – 90% of which is the result of autoimmune adrenalitis). Other conditions thought to have an autoimmune basis, such as pernicious anemia and myasthenia gravis, may also be found under these circumstances. My question to you, in view of your Hashimoto’s disease and elevated FSH) is have you been screened for any other autoimmune conditions that could have a deleterious affect on your fertility?

4. I get pregnant on every cycle I attempt (4 months we've tried - we've had 4 pregnancies and 4 miscarriages) ... will I have more miscarriages than the average women because my babies seem to implant whether they are healthy or not?

No. I do not think you are unique in that regard. You have just had a rough time with the conception side of things at least as reflected in those babies that were shown to be chromosomally abnormal. In that regard, if it has not been done already, your husband should have a careful semenanalysis performed because there is a possibility he is contributing to the situation as well. I wrote a post on the contribution of the male partners to pregnancy loss and infertility earlier in the year. Also, you might be a good candidate for either IVF and/or prenatal genetic diagnosis (PGD) to help improve your chances of having an implantation of a chromosomally NORMAL embryo!
Thank you,
Polly
Great questions and thanks for writing. Best of luck to you.
Dr T

• At Tue Jun 17, 10:33:00 AM 2008, Polly Gamwich said…

Dr. Trofatter,

Thank you so much for your response. Your articles are excellent and your compassion and respect for women is overwhelming - thank you.

And in my case, of the things that you suggested, I wanted you to know that you're right on. I wanted to follow up to your June 14th response with this:

We are actually testing my eggs (not our embryos - unfortunately, we can't/won't do PGD on embryos for moral/religious reasons) because we were so worried about chromosomal abnormalities being caused by the eggs. We have done one IVF retrieval and we retrieved 6 eggs, 5 were mature: Based on CGH polar body testing of the eggs: 3 were abnormal, 1 was normal and 1 was inconclusive - the good news is - I DO HAVE NORMAL EGGS IN THERE SOMEWHERE! (and note: we did do oocyte vitrification ... I'm curious if you have any articles on that - we know it's not proven, but without being able to do PGD on embryos, it was the best option for us.)

We've been suffering through miscarriages for two years and our Reproductive Endocrinologists still have yet to do a traditional semenanalysis. We're having one done in a few weeks. But we have had the Sperm DNA Defragmentation (SDFA) test done on my husband and it came back 50% abnormal - I guess that means that either the DNA is bad or the ability for the DNA to appropriately work with the egg's DNA is affected - is this what the post you refer to is about? Anyhow, my husband has been taking antioxidant supplements for three months and we will retest his semen soon. If this turns out to be a problem, we'll move to in vitro fertilization with intracytoplasmic sperm injection.

I just thought I'd close the loop on some of your statements/comments/questions.

Again, Doctor, I really appreciate your dedication to your field and the support you provide to so many women.

Take care,
Polly

Note: Oocyte vitrification is a relatively new cryopreservation technique in which the ice formation is totally avoided (Bagchi, et al., Expert Rev Med Devices 2008;5:359-70). Using this technique, mature or immature oocytes are retrieved following ovarian stimulation and then cryopreserved for further attempts at in vitro fertilization. Recent studies have demonstrated that not only is the technique successful in achieving pregnancy, “the results indicate that the mean birth weight and the incidence of congenital anomalies are comparable to that of spontaneous conceptions in fertile women or infertile women undergoing in-vitro fertilization treatment…” (Chian, et al., Reprod Biomed Online. 2008;16:608-10).
Dr T

Labels: autoimmune thyroiditis, FSH, oocyte vitrification, recurrent aneuploidy, recurrent pregnancy loss

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