First Trimester Screening for Aneuploidy
Wednesday, December 13, 2006
Kenneth F. Trofatter, Jr., MD, PhD
First trimester screening for aneuploidy, or as it is commonly referred to as ‘combined first trimester risk assessment,’ has gained widespread acceptance in other developed nations over the past decade, and is slowly coming into its own here in the U.S over the past couple of years as well. This screening test uses a combination of fetal measurements, maternal blood pregnancy ‘markers,’ maternal characteristics (age, weight, race, family/pregnancy history, and certain medical problems, such as diabetes) and a large, and continuously expanding, data repository to generate risk numbers for trisomy 21 (Down syndrome) and trisomies 13 and 18. The primary measurements of the baby include the ‘crown-rump length (CRL)’ (top of head to bottom of butt) and the ‘nuchal translucency (NT)’ (clear space between the skin and underlying soft tissues of the back of the neck, head, or upper trunk). The wider the nuchal translucency, the greater is the likelihood that the baby has aneuploidy. A special certification process has been developed for performing NT measurements and completion of this in an acceptable fashion is required before access to the database for combined risk assessment can be obtained. The presence or absence of a fetal nasal bone can also be factored into the risk assessment, since the absence of the same (or the presence of one that is smaller than usual) has also been associated with aneuploidy, especially trisomy 21. Separate certification is required for this to be used in the risk assessment process.
The maternal blood samples assess levels of free β-hCG (the ‘pregnancy hormone’ secreted by placental tissues, the trophoblasts) and pregnancy-associated plasma protein A (PAPP-A) (associated with differentiation of the placental trophoblasts). Free β-hCG levels usually decrease after 10 weeks’ gestation in normal pregnancies, whereas they often remain elevated or increase in cases of trisomy 21. Indeed, the difference between these and normal pregnancies increases with gestational age. In contrast, babies with trisomy 21 tend to have lower levels of PAPP-A than normals, but the difference between these and normal babies tends to decrease with gestational age.
For combined risk assessment, the fetal crown-rump length must be between 45 and 84 mm, roughly corresponding to 11-14 weeks’ gestation. The maternal blood screening can be done at the same time the fetal measurements are obtained, or as early as 8-9 weeks,’ and then combined with the fetal measurements when these are performed. The advantage of this latter approach is that a ‘final result’ can be obtained the same day, whereas about a week is required for the former because that is the time required for processing of the maternal blood samples. The test is most reliable (has the greatest combined sensitivity of the NT and blood screens) at the gestational ages between 11 and 12 weeks and this is also the time when it is easiest to obtain the most accurate NT and CRL measurements.
The ‘sensitivity’ of the test relates to the probability if the disease (in this case aneuploidy) is present, the test will be positive. Neither the NT measurement nor the blood tests by themselves have sufficient sensitivity to stand alone as a good ‘screening test’ that would be widely acceptable. At the risk of great over-simplification, combined risk assessment has been shown to have the capability of detecting trisomies 21, 13, and 18 in 85-95% of cases with false positive rates (probability that the test is abnormal, but the baby is not aneuploid) in the range of 5% or less. In our own experience over the past two years, we have not missed a case of one of these trisomies in ‘at risk’ women (women expected to be 35 years or older at delivery), younger women at increased risk for aneuploidy, or who simply wanted reassurance and had this screening performed.
There are distinct advantages to combined first trimester screening. In most instances, it provides early reassurance to ‘at risk’ and even low risk women who undergo the screening process. It also offers the opportunity for early detection of babies with the chromosomal abnormalities noted above, and for detection of other chromosomal abnormalities (and congenital heart defects as a side benefit in babies that may or may not have a chromosomal abnormality) that might also be accompanied by abnormalities of the NT. This allows patients more time to consider their diagnostic and therapeutic options at a time in the pregnancy where privacy and confidentiality are much easier to preserve. At the same time, the cost, sensitivity, and false positive rates are comparable to, if not better than, that of midtrimester screening.
There are also some limitations of first trimester screening that must be conveyed to all women considering this procedure. The test is still just a ‘screening’ test and therefore cannot replace an invasive diagnostic test such as chorionic villus sampling, amniocentesis, or umbilical cord blood sampling for the definitive diagnosis (or not) of aneuploidy. Although ‘false positive rates’ are low, a “positive result” does not mean that a baby definitely has a genetic abnormality. Indeed, many will not. By the same token, a “negative result” does not guarantee the absence of a chromosomal abnormality, other heritable or syndromic problems, or fetal birth defects that are not clearly related to a specific genetic cause. For that reason, even to women who have had ‘reassuring first trimester screening, we offer both maternal serum alpha-fetoprotein (MSAFP) screening at 16 weeks’ and a ‘targeted’ genetic sonogram at 18-20 weeks’ gestation.
In the next (or some time in the near future) post, we will discuss what it means to have an “abnormal” first trimester screen as well as the options for follow-up of the same…
25 Comments:
At Sun Oct 07, 10:02:00 PM 2007,
Anonymous said…
Thanks for putting so much effort into a fascinating and endlessly informative blog!
How reliable is the screening for multiple gestations? Isn't beta-HCG elevated in that case? Or is there sufficient info in the database on twins, triplets, etc. that the differences can be taken into account and reliable estimates of risk can still be made?
At Thu Oct 11, 05:39:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Oct 7: Great question. I will probably use this query in a full post at some point if you don't mind. There is excellent and constantly expanding data in the database for multiples. I do not know the adequacy of this for triplets, but the detection rate in twins ranges between 75-85% at a false-positive rate of 5%. It is actually quite good. I encourage women with twins to have first trimester screening done also because of the possible deection of early evidence of twin-to-twin transfusion sequence in monochorionic twins and congenital birth defects for which all twin pregnancies are at greater risk. Thank you so much for reading and for your question! Dr T
At Fri Oct 19, 02:05:00 PM 2007,
Anonymous said…
I am 10 weeks pregnant and scheduled for what my OB calls an "Ultrascreen" in November. It sounds very much like what you are describing but is performed between 11-13 weeks gestation. I will be having it during the beginning of my 13th week due to travel. I requested the earliest screen available due to AMA (I'm 34), and was told this is the the screen I want. Are you familiar with this screen and is the accuracy less effective due to it not being completed within the 1st trimester?
Thank you so much for this wonderful site.
Melissa
At Fri Oct 19, 08:18:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Melissa Oct 19: You will still be in first trimester when you have the test done. I think the screen is probably a little more reliable at 11-12 weeks, but there is not enough of a difference to worry about that. Remember, it is still just a screening test that does not detect all chromosomal abnormalities or other problems the baby could have. But, the odds are in your favor for a good outcome, so best of luck to you. Dr T
At Mon Jan 21, 11:47:00 AM 2008,
Anonymous said…
Thank you for this informative article! Can you tell me if the ultrasound is typically tranabdominal or transvaginal. I would like to mentally prepare myself if it is the former. :) Thank you!
At Fri Jan 25, 10:58:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Jan 21: In most cases we can do the nuchal translucency measurements transabdominally. Of course, a lot depends on how cooperative the baby is! Don't sweat either, you WILL survive the procedure! Dr T
At Sat Mar 08, 11:38:00 AM 2008,
Anonymous said…
Dear dr T,
first I want to thank you for this blog.
I did my first trimester screening and these are results:
age at term : 29.5
diabetes : no
Caucasian
weight: 87kg
smoking: no
____________________
free bhcg 105 ng/ml - 2.59 MoM
PAPP-a 1.81 mlU/ml 1.29 MoM
CRL 50mm
NT 1.7mm - 1.26 MoM
____________________
Biochem. risk + NT 1:1723
Double test 1:1029
Age risk: 1:1015
Trisomy 18 risk <1:10 000
____________________
I see that all numbers are ok, except free beta hcg levels, which are very high.
What do you think, what that means?
What can cause beta hcg to be so high?
I know that my ovulation and implantation were late, and I feel when hormones are fluctuating, could it be just momentary...?
Please answer me, I'm very anxious.
At Tue Mar 11, 05:57:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Mar 8: The placental cells (trophoblasts) make the hCG and PAPP-A. Since you have 'healthy levels' of BOTH, perhaps you just have a very healthy developing placenta! The 'risk assessment' is based on the combination of findings, so relax and enjoy your pregnancy. There is no reason to even suggest anything to worry about at this point. Best of luck to you and please let us know how things turn out. Dr T
At Fri Mar 14, 11:28:00 AM 2008,
Anonymous said…
I just had my results from the Ultrascreen.
My report shows:
NT(mm):2.7
CRL (mm): 65.7
Free Beta hcg (MOM): 0.98
Percentiles: 50
Papp-A MOM: 0.47
Delta NT: +1.06
Nasal Bone***Present nasal bone is not considered when Down Syndrom risk results are greater than or equal to 1 in 100.
RESULT: Down syndrome after screening 1 in 44--Increased risk
Trisomy 18/13: 1 in 3,402--within range.
AGE: 34 yrs.old
I am saddened by the results and confused by these numbers. What is considered a normal range for each category? What was even more confusing is that when the technician did the sonogram, she said everything looked great, she pointed out three facial bones, including the nose and said that babies with Down Syndrome would not show these bones even at 12weeks 5 days gestation. She seemed very reassuring, said everything seems fine, and knowledgable. She said the pictures were great and the doctor would discuss the results. I don't understand.
At Fri Mar 21, 06:36:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Mar 14: The increased risk in your case is probably being driven by the NT measurement and the relatively low PAPP-A when compared to the 'normal' hCG. At this point you still only have about a 2% chance the baby has Down syndrome. With regard to the ultrasound, sometimes baby's that have Down syndrome will look remarkably "normal" until later in the pregnancy. Even the more characteristic abnormalities associated with Down syndrome (A-V canal defects in the heart and duodenal atresia, for example) are not present in all babies and will not be evident at this early gestational age. Keep your hopes up and we will all be pulling for you. Please let us know what you find out. Dr T
At Fri Mar 28, 12:01:00 PM 2008,
Anonymous said…
Hi Dr. Trofatter,
This is a great blog, thank you! I've been searching for clues as to what else causes elevated free beta hCG levels (besides trisomy 21) and have gotten only research papers and your blog. I would really appreciate it if you had a moment to look at my case.
My combined screenings came out as follows:
singleton
CRL 63.6mm, GA 12w6d
Overall risk asessment:
Trisomy 21 risk - 1 in 743
Trisomy 13/18 risk - 1 in 14,901
_______________________________
Free beta hCG % 97.5/2.88 MOM
PAPP-A % 40/MOM 0.84
_______________________________
NT 1.2mm (Trisonmy 21 risk 1 in 4764 on this basis alone)
_______________________________
My stats are 33 yo at term, caucasian, 115 lbs maternal weight.
I know one poster already presented with a free beta of 2.59 MOM, but she also had a high level of PAPP-A, where as I do not. You also mention in the main article that hCG levels tend to diverge and PAPP-A levels converge... A midwife at my hospital called me back and assured me you're not allowed to pick one marker out of the screening to be alarmed, but she also couldn't tell me what else could cause such an elevated level of the beta hCG.
Since you mentioned these markers are produced by placental cells, perhaps it's of some interest that the u/s results also indicate a low anterior placenta, and they weren't sure if the umbilical cord had 2 or 3 blood vessels.
Thanks and have a good weekend!
At Fri Mar 28, 12:14:00 PM 2008,
Anonymous said…
Hi,
I hadn't seen your article from yesterday when I posted a moment ago. I'm the "33 yo at term caucasian, 115 lbs with free beta hCG MOM of 2.88."
Perhaps it is also of interest that I miscarried and had a D&C a couple months before this pregnancy? (I also had an elective abortion at 19 yo.)
I was 9.5 weeks pregnant when I got into a car accident on 11 Nov. 2007. The next day the abortion was confirmed (CRL correlated with fetal death at 9.5 weeks) and dilation commenced that day with the curretage the next morning. They told me to wait one cycle before trying again, and bingo presto, my LMP was 17-December-2007.
This perhaps explains my weird implantation site (low anterior), but I have no idea if it explains anything else :(
Thanks *so* much for reading.
At Sun Mar 30, 04:38:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Mar 28: Sometimes folks just have very 'healthy' placentas and seem to make more hCG! This is commonly seen in some diabetics and in multiple gestations. In your case, however, there is a possibility that because of the short interval between the D&C and the conception of this pregnancy this baby implanted on a denuded (still healing) portion of the endometrium and had growth of the trophoblasts (placental cells) into the myometrium ( muscle of the uterus) rather than just the endometrium alone. Under normal circumstances, there is a balance between proliferation and invasion of the trophoblasts and your body's immune system limiting that growth and invasion. The myometrium is not able to control the growth of the trophoblasts as well as could have been done in the endometrium. (We see this, routinely, with tubal ectopic pregnancies). If this has occurred, it may increase your risk for a placenta accreta wherein the portion of the placenta that has invaded the myometrium does not detach normally following delivery. I don't know for sure in your case, but this is certainly a possibility and one of the reasons I recommend women wait at least 2-3 months after a D&C to get pregnant again. Sometimes we can actually visualize a placenta accreta by ultrasound later in the pregnancy. Good luck to you, thanks for reading, and let us know how things turn out. Dr T
At Thu Apr 10, 12:35:00 PM 2008,
Anonymous said…
thanks for the blog! i just found it as i was researching high hcg levels. i'm 29, asian, 5'6"/135lb, and 15w with our first child.
anyhow, i had the nt test done and received the following assessment: nt = 2.7, free beta hcg = 2.77, papp-a = 1.18, T21 risk of 1:46 and T13/18 risk of 1/10,000+. i read in an nih study that chinese women tend to have much higher MoM on the serum markers. have you found that to be true in your experience? could it be possible that i have a "healthy" placenta that's generating so much hcg? i did have a d&c in september and a septate resection at the end of november prior to getting pregnant the cycle following the resection surgery if it helps. also, i am not diabetic (have not been tested for gestational diabetes). i'm very anxious as this is our first child and the my risk for T21 is causing more than just my eyebrows to rise. thank you for your help!
At Sat Apr 12, 12:52:00 PM 2008,
Anonymous said…
Dear dr T,
I am an italian pregnant woman and your blog is very interesting. Excuse me for my english mistakes.
I expect my third baby and these are the result of ultra screen:
age: 36
diabetes : no
Caucasian
weight: 66kg
smoking: no
weeks gestation test:12+4
____________________
free bhcg 49.4 ng/ml - 1.82 MoM
PAPP-a 1.1 mlU/ml 0.34 MoM
CRL 71mm
NT 2 mm - 1.13 MoM
____________________
Combination risk Trisomy 21 1:69
Combination risk Trisomy 18 1:10000
Age risk: 1:207
Please answer me, I'm very anxious.
Stefania
At Tue Apr 15, 06:12:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Apr 10: Your ethnicity may be playing a role here, but many laboratories already 'correct' for that. You also could just have a 'healthy placenta' or a placenta that has grown into the muscle layer of the uterus as a consequence of your septum resection. When this occurs it is called a placenta accreta. I am reassurred that the PAPP-A level is very 'normal', so hopefully, on of these other factors is the cause of your abnormal screening results. Let us know how things turn out and thanks for writing! Dr T
At Tue Apr 15, 07:07:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Stefania Apr 12: The test results indicate that you are at increased risk for having a baby with Down syndrome (trisomy 21). The high hCG level combined wih the low PAPP-A level is often found with Down syndrome. Remember, however, the test is just a SCREENING test. It does not sa for sure that your baby has Down syndrome. If you want to find out, you will have to have some form of DIAGNOSTIC test performed, either chorionic villus sampling or an amniocentesis. Good luck to you my friend, let us know what you find out, and thank you for writing all the way from Italy! Dr T
At Fri Apr 18, 05:54:00 AM 2008,
Anonymous said…
I was so pleased to find your blog! There is not much information available to those of us who want/need details and technical answers! I have a question about the reliablility of my screening due to the lab dating my blood draw incorrectly. My paperwork states that I was 10w4d for the blood draw, but I was actually 10w0d. I know it's not much difference, but could it change my odds at all? Overall, my final odds were great, but I am a bit concerned about my low Papp-A level (if it rises daily, though, maybe it would've been better if dated correctly???). I am also quite concerned that my results just aren't accurate. What do you think? Here's my information:
Age:37
Caucasion
178 lbs.
non-smoker
letrozole and IUI to conceive
GA@u/s: 12w1d
NT(mm):1.37
free beta hCG MOM:.64
PAPP-A MOM: .44
DS odds: 1/1792
trisomy 18/13 odds: 1/4476
Thank you so much for your time! I am SO ready to let go of my worries and enjoy this pregnancy (as is my poor husband!!!).
At Sun Apr 20, 06:38:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Apr 18: The results are so good, that 4 days should not make a difference. Congratulations and best wishes fo the rest of the pregnancy. Let us know how things turn out! Dr T
At Wed Apr 23, 04:16:00 PM 2008,
Anonymous said…
Thank you for all this information. I do have a question. At 11.5 weeks our baby's NT scan result was 5.5 mm. I do not have blood test results and I am not sure if they were done. The same day I was sent for a CVS test. Both the fast result and the cultured result showed a normal karyotype. Our doctor is suggesting we also do an amniocentesis next week (at 15w5d). What are the chances of a normal CVS test result and an abnormal amnio result? An ultrasound at 14w2d showed an NT of 2.4 mm, a good length and nothing out of the ordinary. We are aware that we will have an ultrasound around 20w to examine in depth the baby's heart and look for any structural defects. Is an amnio worth the risk after a CVS? I am 35.
Thank you,
Cathy
At Thu Apr 24, 04:35:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Cathy: It is unlikely that you will learn anything new from an amniocentesis at this point. It is true that sometimes a baby can have a chromosomal mosaicism (two genetically different populations of cells - usually one normal and one abnormal) but that is often picked up by CVS. It is also possble that the CVS grew only your cells, but in mots laboratories today, that is also unlikely and if the chromosome studies came back a normal BOY, then that would be almost impossible! Personally, I would suggest having you wait until you have the targeted ultrasound done at 18-20 weeks before considereing any more invasive studies unless aa physical abnormality of the baby is seen before then. Remember, though, babies can be chromosomally NORMAL and still have major malformations, particularly of the heart. I certainly wish you the best and please let us know how things turn out. Dr T
At Sun Apr 27, 11:02:00 AM 2008,
Neil said…
This seems such a helpful blog, and I'd really appreciate some advice. My girlfriend (age 36 next week) has just been for First Trimester Ultrasound and some of the results are below
gestational age = 12wks+1
----------------
Biochemistry
free bhcg 32.000 IU/I (0.6536 MoM)
PAPP-a 3.591 IU/I (1.1845 MoM)
----------------
CrownRump Length 58.6mm
Nuchal T 1.7mm
Adjusted Trisomy 13/18 risk = 1:559
Adjusted Trisomy 21 risk = 1:350
The doctor didn't comment on any of the numbers above, but did mention Ductus Venosus (a-wave) reverse flow and said this increased the Trisomy risks.
He didn't seem overly worried though.
From reading the internet (which maybe we should never have started) we are both now worried that this reverse flow problem seems very very serious, not just for chromosome disorders but generally for the health and development of the fetus.
Are we panicking without reason? Or should we be getting much more advice from the doctors?
There is also high chance of pre-eclampsia (both mother and sister) in my girlfriends family, and we're beside ourselves with worry at the moment. First succesful pregnancy after 2 years trying and things don't sound good.
Any advice would be greatly appreciated.
thanks
At Wed Apr 30, 05:39:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Neil: Oh. I don't know - things sound pretty good to me! The aneuploidy risk are about half your partner's 'age alone' risks and it is sometimes easy to get abnormal ductus venosus waveforms that don't mean anything at this point. Could they if they were real? Sure, but babies can have cardiovascular malformations that are not related at all to fetal chromsomal abnormalities and my suggestion at this point is that you bask in the relief of the reassuring first trimester screen and get a couple of more good ultrasounds along the way to carefully evaluate the baby's anatomy. The family history does put her at increased risk for preeclampsia, but unless there is some predisposing heritable cause, such as a genetic thrombophilia, there is not much you can do about that at this point and it is aproblem we deal with on a daily basis. Uterine and umbilical artery Doppler flow studies can give you a better idea about the 'normality' of the placentation and your doctors can explain why when you ask! Take a few deep breaths and relax. Thanks for reading and let us know how things turn out. Dr T
At Wed May 07, 05:19:00 AM 2008,
Anonymous said…
Hi. I am 40 yrs. Had my first trimester screening at 11 weeks. I'm afraid I dont have the blood test results or the NT measurement. However, the doctor said that my age risk for T21 is 1:65. After the screening my risk decreased to 1:98. What would account for that small change in risk? I am still in a high risk group and am contemplating an amnio.
At Fri May 09, 07:19:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous May 7: Without the other information I cannot tell you what is driving your risk, but I bet your age is a primary factor. I often tell my patients with a 1 in 100 risk that they can proceed with amniocentesis or await the results of further ultrasound studies. A completely normal genetic sonogram at 18-20 weeks can reduce your risk as much as 90%. In the end, the choice is yours! Let us know what you decide to do and what you find out. Dr T
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