Composite Results are the Strength of First Trimester Screening for Aneuploidy

The reader below faces what appears to be a growing dilemma for patients (and their providers) in the laboratory reporting of results from first trimester screening for aneuploidy. The data that supports this screening modality has always emphasized that the power of the screening test is in the COMPOSITE test results and NOT the individual ‘analytes’ which include the actual nuchal translucency measurement along with the hCG, PAPP-A, and other factors.

As can be seen from the ‘results’, she is being given risk results for trisomy 21 (Down syndrome) that range between 1 in 47 ( based on the biochemical screening alone) to 1 in 612 (based on the ultrasound evaluation of the baby). The COMPOSITE (and in my mind the KEY information) is the 1 in 292 “adjusted risk” but as a patient (and even as a doctor), how are you going to sit with reconciling the great disparity in risks in a way that will help you make the most unbiased decisions possible regarding further evaluation of the baby and, particularly, the invasive diagnostic studies which carry their own inherent risks…?

Singapore Mother has left a new comment on your post "Understanding Interpretation of First Trimester Sc...":

Dear Dr. T,

I am 39 years old. The results of my test are as follow:

@ 12 weeks + 0 days

Crown-rump length (CRL) 56.1mm
Nuchal translucency (NT) 1.4mm

Maternal Serum Biochemistry
Free B-hcg 129.4 IU/I = 1.993 MoM
PAPP-A 0.557 IU/I = 0.578 MoM

Trisomy 21
1:122 (Background risk)
1:612 Adjusted risk (US)
1:47 Adjusted risk (BC)
1:292 (Adjusted risk)

Kindly please shed some light... Thank you so much!


To Singapore Mother July 7: Personally, I think it is VERY confusing and unfair to present the data to patients in this way. The strength of the first trimester screening is in the COMPOSITE results and NOT the individual tests - and yet you were given the risk assessment based on those individual tests. All that can do is make you worry about the greates ‘risk’ estimate and any laboratory that does this should be banned from first trimester screening because they are presenting 'data' out of both sides of their mouths without providing adequate counseling to the patients or realistic expectations as to what balanced information most providers can offer! Albeit, this is just my opinion.

The long and short of your results are that you have a 1 in 292 risk of Down syndrome which is less than half your age alone risk. Some laboratories will still report this as "screen positive" because it falls below there cut off, but that also means your baby has a 291 out of 292 chance of being chromosomally normal. If the odds still worry you, then you can have either a genetic amniocentesis done or simply have an expert sonogram done at 18-20 weeks. If the latter is 'normal' your a priori risk is reduced by at least another 50%. Best wishes and let us know how things turn out.
Dr T

Labels: first trimester screening, hCG, PAPP-A

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Low hCG and PAPP-A in a Patient with an Autoimmune Disorder

The following comment was left on an old post "Affect of Smoking on PAPP-A Levels in First Trimester." The case is interesting because it reminds us that abnormal maternal serum markers in first trimester might be the result of factors unrelated to fetal chromosomal abnormalities....

Hi! I just got my 1st trimester screening test results today, and would love you thoughts.

I will be 40 years old when I deliver. I was 12 weeks when I did the testing.

NT: 1.5
Nasal Bone present
Free b - HCG: 0.29 MoM
Papp A - 0.34 MoM

Down syndrome risk: 1:1600
Trisomy 18 & 13: 1:50 (normal for my age 1:150)

I have an autoimmune condition, polymyositis that is under control. I am taking 12.5mg prednisone 1xday. I am ANA and Jo-1 positive.

Can you please help me understand these results? I am trying to look at the fact that it is only a 2% chance of the trisomy abnormalities, but it is difficult.

Are there any other reasons that my blood levels would be so low for both? Is there anything I should be precautionary about through the rest of my pregnancy because of this?

Thanks,
WJD

The combination of the low hCG and the low PAPP-A is typically a pattern seen in pregnancies complicated by trisomies 18 and 13 (in contrast to an elevated hCG coupled with a low PAPP-A in Down syndrome – trisomy 21). Both hCG and PAPP-A are produced by the trophoblasts of the placenta and low values could be the result of either a small placental mass or decreased production because of metabolic dysfunction. Both of these factors might be at work in trisomies 18 and 13.

However, in your case, there is also the possibility that your baby is chromosomally normal but has an abnormality of placentation that resulted from your autoimmune disorder. The immune system probably plays a very important role in normal placentation and the presence of certain autoantibodies (e.g., antiphospholipid antibodies, lupus anticoagulants, and anti-beta-2-glycoprotein-1) are thought to be associated with increased risk for abnormalities of placentation resulting from abnormal trophoblast migration and invasion of the maternal spiral arterioles. Indeed, if you have not been screened for these specific autoantibodies, I would recommend that you have that done. Such pregnancies are at increased risk for poor fetal growth (intrauterine growth restriction), fetal loss, pregnancy-induced hypertensive disorders, and early delivery. If you have any of these other autoantibodies, you might also be at increased risk for thromboembolic complications as well.

Whenever we find a pregnancy that has low hCG and PAPP-A levels and a chromosomally normal baby, it is recommended that fetal growth be followed at serial intervals, Doppler flow studies (e.g., umbilical, uterine , and fetal middle cerebral arteries) be done to evaluate impaired placental perfusion from either the fetal or maternal side and evidence of fetal blood flow redistribution (preservation of the brain at the expense of perfusion of ‘nonessential’ organs because of reduced placental transfer), and both mother and baby be monitored carefully for evidence of compromise. Your doctors can give you specific details of what should be done with regard to the latter.

Best of luck to you and please let us know how things turn out.
Dr T

Labels: first trimester screening, hCG, PAPP-A

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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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Elevated hCG Detected at the Time of First Trimester Screening for Aneuploidy

Below are comments and questions from a reader who underwent combined first trimester screening for aneuploidy. Although the composite screening results did not place her at increased risk for having a baby with trisomy 21 (Down syndrome) or trisomies 18 and 13, she expressed some concern about the significance of the high free-β-hCG result. High free-β-hCG accompanied by low PAPP-A levels (which she did not have) are major determinants of risk for Down syndrome, regardless of the nuchal translucency result. Since I have gotten several queries about this, I thought it might be a good idea to post my thoughts, both in general and with specific attention to our reader’s medical history detailed as follows:

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-β-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 assessment:
Trisomy 21 risk - 1 in 743
Trisomy 13/18 risk - 1 in 14,901
_______________________________

Free-β-hCG % 97.5/2.88 MOM
PAPP-A % 40/MOM 0.84
_______________________________

NT 1.2mm (Trisomy 21 risk 1 in 4764 on this basis alone)
_______________________________
My stats are that I am a 33 year old (at term), Caucasian, 115 lbs maternal weight.

I know one poster already presented with a free-β-hCG 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 hCG.

Since you mentioned these markers are produced by placental cells, perhaps it's of some interest that the ultrasound results also indicate a low anterior placenta, and they weren't sure if the umbilical cord had 2 or 3 blood vessels. 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 age 19.) I was 9.5 weeks pregnant when I got into a car accident on 11 Nov. 2007. The next day the loss of the baby was confirmed (CRL correlated with fetal death at 9.5 weeks) and dilation commenced that day with the curettage 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 and have a good weekend!

Sun Mar 30, 04:38:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Mar 28: In addition to high hCG levels in Down syndrome (and some other chromosomal abnormalities), sometimes folks just have bigger placentas that make more hCG! This is commonly seen in some diabetics and in multiple gestations. Elevated levels of hCG are also found with molar (or partial molar as would be the case with a baby present) pregnancies and choriocarcinoma. These latter conditions are called ‘gestational trophoblastic diseases’ and they are accompanied by uncontrolled proliferation of the placental trophoblasts and excretion of very high levels of hCG (much higher than yours). Also, in your situation, the hCG may be somewhat ‘artificially elevated’ because of your slight build (although the results are generally ‘corrected’ for maternal weight, there are some difficulties in interpretation at the high and low extremes). However, let me postulate another possible cause in your case (and bear in mind this is JUST a hypothesis)…

There is a possibility that because of the short interval between the previous pregnancy loss with the D&C and the conception of your current pregnancy that 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 which limits that growth and invasion. The myometrium is not able to control the growth of the trophoblasts as well as can be done in the endometrium. (We see this, routinely, with ectopic pregnancies that grow into and sometimes through the muscular wall of the fallopian tube).

My concern is that 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 to women that they 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 and you might ask your doctors to consider this option.

Anyway, despite my positing, the overwhelming odds are that both you and the baby are going to do just fine this pregnancy. So, good luck to you, thanks for reading, and let us know how things turn out.
Dr T

Labels: first trimester screening, hCG, PAPP-A

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Low Early Pregnancy 'Hormone' Levels: hCG and Progesterone

The two recent readers shared their stories with us regarding early pregnancies complicated by “low hormone levels” and subsequently loss of their babies. Many questions arise regarding what it means to have low human chorionic gonadotrophin (hCG – the ‘pregnancy test’ hormone) or progesterone levels and what can be done about it, if anything? Do low levels mean you will lose a pregnancy? Can low levels indicate other potential problems with a pregnancy? All of these are frequently asked questions relevant to many of our readers and I will try to address them after responding to our readers’ questions below…

• At Thu Dec 20, 03:24:00 PM 2007, siniamejia said…

I am approximately 5 weeks pregnant, and had my levels of hCG checked (because I was bleeding). My doctor said my levels were really low and also my progesterone levels were low and that it looks as if this pregnancy will not turn out to be healthy. My levels were 114 Saturday and only 145 today (5 days later). He says that I should have a D&C but I refused, so he told me that I will miscarry or should. I am so upset right now because I do not want to be the one to make the decision to have that done. I feel like maybe there still is hope and maybe a couple of days from now the bleeding will stop and the numbers will increase. I am still praying and I still have hope that my baby could still make it, but my doctor really doesn’t think so. I am so hurt, I never even imagined this. I have a 8 year old son and a 5 year old daughter, which were both high risk pregnancies. My son was born at 24 weeks and weighed 1 pound at birth. He is completely healthy and normal. With my daughter, I had early contractions the whole pregnancy, not to mention that I couldn’t hold food down and needed an IV everyday in the hospital. Could this mean that my husband and I can’t have anymore children. I am still young and I lost a lot of weight. I exercise and maintain a healthy life, why could this be happening to me? It’s so painful, emotionally. Please help. Thanks.


• At Fri Dec 21, 05:54:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To siniamejia Dec 20: There is always hope, but I am afraid your doctor is correct in telling you this pregnancy will not make it. Your hormone levels are not only low, they have not risen appropriately. You have had two other children, and even if those pregnancies were complicated, that probably has nothing to do with what is going on with this pregnancy. The most common cause of an isolated miscarriage in a woman who has previously had successful pregnancies is a chromosomally abnormal baby. Fifteen to 20% of all pregnancies miscarry and MOST of those are babies that are not chromosomally normal. It is still your baby, and I know you will be sad and you will go through wondering about what "could I have done to prevent this and what could have been", but this is certainly no reason to think that you cannot ever have another baby.

With regard to a D&C, as long as you are not bleeding heavily or have any evidence of infection, you are not in any danger and don't need to do anything else at this time. Waiting is just fine under these circumstances. My only other concern is with your history of weight loss and hyperemesis with your last pregnancy. Some women who lose an excess amount of weight (and I do not know if that is true in your case) will become nutritionally depleted and/or hormonally ‘imbalanced’ and not ovulate regularly. This could also deleteriously impact your pregnancy success but if you are having regular cyclic periods, then this is not likely to be the issue in your case. My best wishes to you and thanks for reading.
Dr T

• At Thu Dec 20, 10:58:00 AM 2007, Anonymous said…
Hi, my wife just miscarried our 7 week old baby. Her hCG levels were about 2,000 at that time. The doctors said that her levels were pretty low when we did the first the pregnancy test two weeks ago. My question is could we have been able to prevent this miscarriage if they placed her on progesterone supplements early on in the pregnancy? Could there have been anything we could have done to prevent this miscarriage?

• At Fri Dec 21, 06:00:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Dec 20: Progesterone probably would not have helped at the point it was found to be “low” and may actually have been contraindicated. If you have had other children, the most likely reason for the miscarriage is that the baby was chromosomally abnormal. Most of those babies are lost in first trimester. If this was a first pregnancy, or if your wife has any other medical problems, there may be other explanations - usually hormonal or immunologic in nature. I am sorry for your loss, but this is one situation in which you should not kick yourselves for having done anything 'wrong.' Miscarriage is always sad - wondering what was, what could have been, and what could we have done different, but if there are no underlying medical conditions to have contributed to the miscarriage, then the odds are you will be successful in the future. My thoughts and best wishes are with you. Thanks for reading!
Dr T

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As a focus for further discussion related to these queries, let’s start with progesterone. Following ovulation, what’s left of the follicle (the corpus luteum) begins to make the hormone progesterone that helps to prepare (decidualize) the lining of the uterus (the endometrium) to receive the fertilized egg, aiding attachment and implantation of the early embryo. With implantation, the fetal trophoblast cells start producing the hormone hCG that sends a ‘message’ back to the corpus luteum to ‘stay healthy and keep making progesterone.’ Production of progesterone by the corpus luteum is necessary to support the development of the placenta during the first 7-8 weeks of the pregnancy. After that point under normal circumstances, the placenta itself takes over progesterone production at a level sufficient to maintain the pregnancy.

Decreased progesterone production following ovulation or inadequate production of hCG or placental progesterone has been found to accompany pregnancy abnormalities that result in miscarriage. Defective production of these hormones may precede by weeks the identification or loss of an abnormal pregnancy (Hahlin, et al., Hum Reprod 1990;5:622–626) or ectopic (tubal) pregnancy (Yeko, et al., Fertil Steril 1987;48:1048–1050; Ledger, et al., Hum Reprod 1994;9:157–160). Indeed, there is good evidence to suggest that serum progesterone measured in early pregnancy is the most reliable single predictor of pregnancy outcome in natural conceptions (Al-Sebai, et al., Br J Obstet Gynaecol 1995;102:364–369; Daily, et al., Am J Obstet Gynecol 1994;171:380–383) even in the absence of a pregnancy detected by ultrasound (Elson, et al., Utrasound Obstet Gynecol 2003;21:57–61). Ioannides and colleagues (Human Reprod 2005;20:741-6) demonstrated that even in IVF pregnancies supplemented with progesterone, a single serum progesterone on day 14 post-oocyte retrieval and fertilization (4 weeks gestation), could “highly (but not completely) differentiate between normal and abnormal pregnancies.” Women with viable intrauterine pregnancies “had significantly higher serum progesterone levels (median: 430, 95%CI: 390–500 nmol/l) compared to those who had either an abnormal pregnancy (72, 48–96 nmol/l; P<0.001) or failed to conceive (33, 28–37 nmol/l; P<0.001).” It is interesting to point out that as the result of their findings, they hypothesized “that endogenous progesterone is already sufficient in viable pregnancies and that exogenous progesterone administration will not rescue a pregnancy destined to result in a miscarriage.”

Although progesterone is highly effective at differentiating normal from abnormal pregnancies, it is still not routinely used at most institutions for this purpose because of the expense, inexperience of provider interpretation, and the more widespread availability and high reliability of quantitative hCG testing. hCG can usually be detected by routine blood assays within 10-11 days following conception (7-8 days by highly sensitive assays) and in the urine at 12-14 days (just preceding or coincident with the time of expected menstruation). Serial quantitative blood testing of hCG is a useful approach to evaluation of early intrauterine pregnancy viability and ectopic pregnancies. In 80-90% of normal pregnancies, hCG levels will double every 48-72 hours, peak at 8-11 weeks gestation and then fall off to a stable lower level for the rest of the pregnancy.

If hCG levels are low for a calculated gestational age, this can indicate a nonviable or ectopic pregnancy. However, it is generally recommended that decisions regarding viability not be made by a single hCG level alone. It could be low simply because the pregnancy is not quite as far along as expected (e.g., in circumstances when women ovulate later in their cycles than expected or are not “sure” of their last menstrual period) or as the result of normal variation in hCG levels in different women and different pregnancies. More ominous are situations in which the hCG is not rising appropriately over time.

However, at low levels of hCG, the woman is rarely in immediate danger, even if she has an ectopic pregnancy, so the prudent approach in situations in which the pregnancy is desired is to simply wait, repeat the hCG levels periodically, every 2-3 days, and perform an ultrasound to look for evidence of an intrauterine pregnancy when the hCG level is at the point where that becomes possible. Usually a gestational sac can be seen within the uterine cavity between 4 and 5 weeks and when the hCG is in the range of 1000-2000 mIU/mL. By 6 weeks, a ‘fetal pole’ is usually visible and the hCG is > 5000 mIU/mL; and by 7 weeks, fetal cardiac activity is readily detectable and the hCG is > 20,000. I can relate many personal experiences with patients who started out with an unexpectedly low hCG that went on to have normal, healthy pregnancies, so patience is a virtue under these circumstances.

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