Affect of Smoking on PAPP-A Levels in First Trimester Screening for Aneuploidy
Tuesday, March 25, 2008
Kenneth F. Trofatter, Jr., MD, PhD
• At Wed Mar 19, 09:32:00 PM 2008, Anonymous said…
Hi everyone. I am Jean, 33 years old, a Singaporean Chinese, now 15-week pregnant. I am a non-smoker.
I had my 1st trimester screening at 11 week 6 days. The screening test has however misclassified me as a smoker. I wonder how this would have affected the risk estimation outcome.
The test results are as follows:-
NT scan : 1mm
hCG: 0.62 MoM
PAPP-A: 0.58 MoM
Risk for Trisomy 21 is 1/8000
Risk for Trisomy 13+18 is 1/14000
The risk is low despite the lower than normal PAPP-A & hCG. Also, would wrongly being classified as a smoker reduce my PAPP-A and hCG MoM ratio ?
Anyone have any ideas? I intend to bring this up to my Obs at the 16th week appointment too.
Regards,
Jean•
At Thu Mar 20, 06:43:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…
To Jean Mar 19: Your question is excellent. I will elaborate on my comments below, but to give you a brief answer to your question, smoking significantly reduces PAPP-A and, to a lesser degree, hCG in first trimester screening. Most laboratories do perform a 'correction factor’ for smokers but I do not know what that factor actually is. In your case that means, you are probably at greater risk than indicated by your final results, but even if that risk was doubled (and I cannot believe the correction factor is more than 10-20%), you would still be at very low risk for trisomy 21 and trisomies 18/13. For peace of mind, you could ask your doctors to call the lab and get a corrected result based on the fact you are not a smoker and that was reported in error. Thanks again for the great question and let us know how your pregnancy turns out!
Dr T
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As we have discussed in a previous post, PAPP-A is produced by the placental trophoblasts, especially, by the extravillous cytotrophoblasts (Handschuh, et al., Placenta 2006;27 suppl A:S127-34). It is a ‘protease’ for insulin-like growth factor (IGF) binding proteins 4 and 5 (Boldt and Conover. Growth Horm IGF Res. 207;17:10-18). This means it has the ability to help release IGF from these binding proteins so that it is free to interact with its cell receptor (Laursen, et al., Mol Endocrinol 2007;21:1246-57). IGF is thought to play an important role in trophoblast invasion and hence the early development and vascularization of the placenta and the placental bed. These early events in placental development are critical to pregnancy outcome and, when abnormal, are associated with miscarriage, intrauterine growth restriction (IUGR) of the baby, pregnancy-induced hypertensive disorders, fetal death in utero, premature delivery, and even cesarean section for indications of fetal or maternal compromise.
Data suggest that low levels of PAPP-A, resulting in less release of IGF, could be a pathway by which early abnormalities of placentation culminate in these poor pregnancy outcomes. Spencer and colleagues (Ultrasound Obstet Gynecol 2006;28:637-43) evaluated first trimester markers in 54,722 chromosomally normal singleton pregnancies. At the 5th percentile of PAPP-A (0.415 MoM), the odds ratios for fetal loss before 24 weeks, at or above 24 weeks, and at any gestational age were 3.3, 1.9, and 2.8. In other words, there was about a three-fold risk of losing a baby with low PAPP-A levels. Cowans and Spencer (Prenat Diagn 2007;27:264-71) recently confirmed the association between low PAPP-A and small for gestational age birth weight babies as well. Indeed, they found a linear relationship between the severity of growth restriction and the decrease in PAPP-A levels – in other words, the lower the PAPP-A, the smaller the babies at any gestational age. Several other studies confirm the association of the other ‘pregnancy complications’ noted above with low levels of PAPP-A. For example, as a spin-off of the results in the First and Second Trimester Evaluation of Risk (FASTER) trial, it was found that women with PAPP-A at or below the 5th percentile “were significantly more likely to experience fetal loss at < or = 24 weeks gestation, low birth weight, preeclampsia, gestational hypertension, preterm birth (P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption (P < .02)” (Dugoff, et al., Am J Obstet Gynecol 2004; 191:1446-61).
I am not sure if smoking was factored into the analysis of pregnancy outcome risk in the FASTER trial when the group of low PAPP-A women were evaluated, because in recent years, smoking, as an independent risk factor, while it may be associated overall with smaller babies, is also correlated with a decreased risk for preeclampsia! However, over the past decade, smoking by itself, has also been found to be correlated with lower PAPP-A levels. In 1999, Spencer reported an analysis of 3111 singleton pregnancies in which first trimester screening was performed and found a 15% reduction in PAPP-A in smokers compared to nonsmokers (Prenat Diagn 1999;19:1065-6). Subsequent studies confirmed this 15-20% reduction of PAPP-A during first trimester maternal serum marker evaluation in smoking pregnant women around the world (deGraaf, et. Al., Prenat Diagn 2000;20:186-9; Spencer, et al., Prenat Diagn 2003;224:169-73; Ardawi, et. al., Prenat Diagn 2007;27:303-11). In a recent study of 92,287 nonsmokers and 13,976 smokers, Kagan and colleagues (Prenat Diagn 2007;27:849-53) were able to confirm a ‘dose-dependent’ effect of cigarette smoking on first trimester PAPP-A levels.
In another very recent article, Miron and colleagues (Prenat Diagn 2008;28:180-5) reported that smoking was associated with decreases in both PAPP-A and free β-hCG in dried blood specimens in first trimester, but also appeared to be correlated with an increase in detection of trisomy 18! This raises the interesting possibility that smoking, just as it inexplicably decreases the occurrence of preeclampsia later in gestation, might also increase survival of babies with trisomy 18 in early pregnancy – most of which are typically miscarried before the end of first trimester!
Dr T
Labels: aneuploidy screening in first trimester, first trimester screening, PAPP-A
29 Comments:
At Wed May 07, 04:54:00 PM 2008,
TRay said…
Hi Dr. T....
I'm 41 years old and 15 weeks pregnant. Genetic testing results are as follows at 13.5 weeks:
NT: 2.6
Crown Rump: 71.7
No defects found
hCG: 1.79
PAPP-A: 1.42
Down Syndrome risk 1:28
Recently stopped smoking.
Please help me to understand these results. I'm so scared.
Thanks... TRay
At Thu May 08, 09:36:00 AM 2008,
TRay said…
Hi Dr. T.... I know you haven't had a chance to respond to my first post, but I wanted to ask more specific questions. As you know my PAPP-A level was 1.42 MoM and my hCG level was 1.79 Mom. I can't find anywhere on the internet a "normal" margin for these readings. I've seen many blogs with levels significantly lower than mine so I'm at a loss as to what is an acceptable level. Can you please tell me where my numbers fall in the whole scheme of things. As I said, I'm 41 and was 13.5 weeks pregnant at my first screening. The doctor has scheduled an amnio for me next week on the 15th of May and I'll be 15 weeks at the time. Thanks so much for any help you can give me. Also, my NT was 2.6 and my Crown Rump was 71.7. Thanks for your help! TRay :)
At Fri May 09, 08:21:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To TRay: Your age alone risk for aneuploidy in first trimester is about 1 in 42 for Down syndrome and 1 in 22 for all chromosomal abnormalities. (if you will be 42 at the time of your due date those risks are 1 in 32 and 1 in 17 respectively). Your Down's risk appears to be driven by your age and the modestly high NT measurement, not the hCG and PAPP-A levels. Although the final choice is yours, an amniocentesis at 15-16 weeks would be the quickest way to give you a final answer. I wish you luck and let us know what you find out. Dr T
At Sat May 10, 07:26:00 AM 2008,
TRay said…
Hi Dr. T... You have no idea how happy I am for your response. Thank you for taking the time to review my post and ease my mind. I will still be 41 when I deliver in November (just turned 41 in April). I've been trying to research the PAPP-A levels and the hCG levels as compared to mine and couldn't find where mine were off the charts or weird. When the girl was doing my ultrasound, she had several measurements for the NT as the baby moving around like a wild thing, with the largest one being 2.6. Hopefully it is just an angle issue. :) In any regard, I am going on Thursday for the Amnio so once I get the results I'll let you and the readers know. Thanks again for your help! You are a blessing to so many of us worried moms-to-be! :)
At Tue May 13, 06:47:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
Thank you for the kind words TRay and best of luck. We will all be pulling for you! Dr T
At Thu May 22, 11:43:00 AM 2008,
Anonymous said…
Hi Dr. T,
I am 36 years old, and my first trimester screen gave me a risk of Downs at 1:242 based on the bloodwork (NT was normal, but PAPP-A MoM was .5, and HcG was 1.7). I just had my 20-week ultrasound today, which evidenced a soft marker (small calcification on the heart), but otherwise everything else was normal. Was wondering how much this additional marker increases my risk (and/or how much to worry about it?)... thanks!
Anonymous
At Thu May 22, 02:01:00 PM 2008,
TRay said…
Hi Dr. T.... Okay... here's the scoop... I had an appointment for my amnio and decided at the appointment that I didn't want to have it. Instead we did the second part of my testing (blood and ultrasound) as I knew I could have the amnio at any time during the pregnancy. The ultrasound was perfect AND the ultrasound girl pulled my other pictures from the previous ultrasound and said that they sent in a picture with a NT measurement of 2.6, however it was one picture. All the other ones were at 1.6. I asked the doctor why they sent in the large one and he said that was standard, however the tech said that in theory the best angle shot should be sent in and that one read 1.6. In any regard, my blood work came back PERFECT and my chances of a 1:28 of a downsyndrome baby went up to a 1:400!!!! I'm so happy right now. I am going in in 3 weeks for an ECO on the baby's heart, but so far everything looks great. As a recap to new readers, I originally had the following stats that put me in a 1:28 chance:
I'm 41 years old and my genetic testing results were as follows at 13.5 weeks:
NT: 2.6
Crown Rump: 71.7
No defects found
hCG: 1.79
PAPP-A: 1.42
Down Syndrome risk 1:28
So, for you moms out there that get weird numbers and results, make sure you double check them! My risk was high basically due to my age (apparently I'm an old hag!) and the NT scan at 2.6 which was one shot out of 10 that was a bad angle. Keep your chins up... the risks are ONLY a statistic and NOT a diagnostic on your baby!!!
At Sun May 25, 05:55:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous May 22: Personally, I tend to completely ignore echogenic intracardiac foci, particularly, if they are single, small and not accompanied by any other abnormmalities. At most, some providers will increase your risk for Down syndrome by 1.4-fold, but even then, aall things else being equal, I would still ignore it! Chances are that the baby will be just fine. Let me know how things turn out! Dr T
At Sun May 25, 06:09:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To TRay: Congratulations. Glad you stuck things out. Odds are that everything will be just fine. Let us know when you have the baby in your arms. Many readers have appreciated your saga! Best wishes! Dr T
At Mon Aug 04, 11:09:00 AM 2008,
Anonymous said…
Hi Dr. T,
I'm 33 years old and 14 weeks pregnant. NT testing results at 13.2 weeks are as follows:
NT: 2.8
Crown Rump: 71 mm
hCG: 2.21
PAPP-A: .79
Down Syndrome risk 1:15
I lied and told the tech that I stopped smoking (I was too ashamed to tell her the truth). I regularly cheat (1-6 cigs/day).
How would that affect my results? I realize that factoring in smoking would make my PADD-A a little better, but does that also make my hCG results worse? Do my results reflect a "typical" pattern for Downs?
Thanks... Lori
At Wed Aug 06, 02:22:00 PM 2008,
Anonymous said…
Hi Dr. T ~
I will be 39 yrs old at time of delivery and had the NT done at 12 wks 6 days according to LMP.
NT 1.9
crown rump 70mm
nasal bone present on sonogram
hCG .59
PAPP-A 2.04
DS risk 1:64
After searching the internet, am I accurately understanding that the presence of a nasal bone at this point in pregnancy almost negates my DS risk being high? My sonographer is very experienced in Dallas and told me he would be very surprised to see DS after doing the sonogram regardless of the blood results, which then of course came back with an increased risk and now have me very worried. Are there any other reasons for the high hCG and low PAPP-A pattern? I have a 3 year old whose NT came back within the normal range. Thank you for any input you have.
TT
At Thu Aug 07, 07:08:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Lori: The high hCG and upper limits NT and the difference in MoMs between the hCG and PAPP-A (as well as your age) are primarily driving your risk. The PAPP-A level is actually reassuring. I would not even consider trying to make any adjustments based on your smoking history. At this level, some form of invasive diagnostic procedure is usually recommended - but the final choice is yours. Good luck and let us know what you find out! Dr T
At Thu Aug 07, 07:11:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To TT: I am curious. Are you sure you didn't get the MoMs on the hCG and the PAPP-A reversed? That is an unusual combination of maternal serum results. And, if they are correct, the presence of the nasal bone and the PAPP-A result would give me some comfort, however, you will have to make your decisions regarding the need for an invasive diagnostic study on the COMPOSITE result you were given and not the individual tests. Good luck and please let us know what you find out! Dr T
At Thu Aug 14, 10:10:00 AM 2008,
Gill said…
Hiya,
I am emailing from London, and having had FTS done in Bangkok I'm finding it difficult to get anyone to properly explain the risks to me. We have an amnio booked in on Tuesday at which I will be over 16 weeks, but I can't bear the thought that it could be an unnecessary process. I am trying to find out what the PAPP A and HCG levels mean, ie what is a 'normal' range but can't seem to find anything. Can you help...??
Age: 35 years old
NT at 13 weeks: 1.6mm
Nasal bone: Present
PAPP A: 0.69 MoM
HCG: 1.9 MoM
My risk came out at 1:780 BUT in this particular hospital in Bangkok, they work out my risk on AGE alone being 1:190 and the midwife in London showed me a chart with a risk on age alone based on 1: 266.
Could this difference between the countries be increasing my risk and what do the hormone levels really mean...?!
If you could help me on this that would be great!!
Gill.
At Thu Aug 14, 07:21:00 PM 2008,
Anonymous said…
Hi Dr. T~
I did get the hCG and PAPP-A results backwards. Here is the correct info:
Age at delivery:39
NT 1.9
crown rump 70mm
nasal bone present on sonogram
hCG 2.04
PAPP-A .59
DS risk 1:64
I think I'm going to wait until the 18 week full body sonogram and make a decision then about the amnio. If no soft markers show up, could I rest easier without the amnio? I can't even imagine miscarrying a healthy baby (which I have a 98% chance of having even with my poor numbers on blood work) b/c I was trying to find out if my baby had DS. Is my hCG compared to PAPP-A level that alarming to you?
Thanks for your input.
TT
At Sat Aug 16, 07:37:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Gill: Your risk is 1 in 780 and that is MUCH more reliable than any counseling based on age alone. tell the doctors you are not going to have the amnio, unless YOU relally want to. The difference between the countries is not the test results, it is the doctors and their approach to patient care. Best wishes! Dr T
At Sat Aug 16, 07:40:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To TT: A completely normal sonogram can at least halve your risk. At some point you and YOU alone will have to decide what level of risk you can live with without knowing for sure. We do not make that decision for you. Dr T
At Thu Aug 21, 12:05:00 PM 2008,
Anonymous said…
Hi Dr. T,
Just wanted to update you. I had an amnio and both the FISH and final results showed that everything is normal! I am so happy! The nurse said that now I really shouldn't have anything to worry about, but the blood test results still concern me. Given the high hcG (2.21) and the large NT (2.8), is there anything else I should be concerned about that WON'T show up on the amnio results, such as heart defects due to the high NT? If so, what other test would I want to consider?
Thanks so much,
Lori
At Wed Aug 27, 05:58:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
Lori: As Rosanne Rosanadanna (I know, before your time) used to say, "There's always something." Sure there is, but odds are in your favor everything will be fine. Try to relax, enjoy the rest of the pregnancy, and let us know how things turn out! Don't forget us now! Dr T
At Wed Sep 03, 10:54:00 AM 2008,
Paula said…
Hi Dr T
Wonder if you could give me your opinion on my results please as we are in a bit of a quandry. 14 month old daughter had NT of 1.7mm and all ok. Hosp now do combined test, and at 12w5d my blood and scan restults were:
NT 1.3mm
HCG 1.3
PAPP-A .33MM
I am 37 in October and we have been told our risk is 1:240. Would you suggest an amnio or CVS in our case, or should we not worry?
Thanks so much
Paula
At Mon Sep 15, 08:01:00 AM 2008,
Anonymous said…
Hi
I am 43yrs of age and had a NT scan at 12wk 3 days the results show
crown rump lenght 60.2
NT 1.4 mm
free b-hcg 1.4 equiv to 0.037
papp-a 0.102 equiv to 0.104
i was given the background risks of T21 1:46, T18 1:546, T13 1:1286
the adjusted risks were
T21 1:56, T18 1:38, and T13 1:121
we are considering an amnio and do not know which way to turn at present.
thanks
cathy
At Tue Sep 23, 06:30:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To cathy: I have not seen the results of the serum marker screens expressed that way, but it appears that both the hCG and the PAPP-A are low. That is what is increasing the risk for trisomies 18 and 13. Both are such serious chromosomal abnormalities that we would recommend that you have an amnio done, but the final decision is yours alone to make. Best wishes and please let us know what you find out. Dr T
At Thu Oct 02, 11:36:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Paula Sept 3: Sorry I have not responded sooner, but the folks at Healthline have just sent me your query. At a 1 in 240 risk in first trimester (which is less than half your age alone risk), I would ordinarily offer either an amniocentesis or simply a 'genetic sonogram' at 18-20 weeks. If that is completely normal, your risk for Down syndrome is reduced AT LEAST another 50%. Good luck and let us know how things turn out. Dr T
At Sun Nov 02, 12:51:00 AM 2008,
Tony said…
Hello Doc:
Here's our scenario....
39 years old
1st viable pregnancy (2 previous miscarriages at 8, 10 weeks)
We also cannot find any range on the internet which tells us how far "abnormal" these results might be:
NT: 1.8 (made at 11w4d)
hCG: 6.430 (told very high)
PAPP-A: .818
T18 risk: <1:5,000
DS T21 risk: 1:48
My wife has been vegetarian for about a year and I've read this might be a reason for the significantly elevated HCG.
Can you offer some opinions on this data?
Thank you so much.
Tony (husband)
At Tue Nov 04, 02:36:00 PM 2008,
Anonymous said…
hello Dr.T,
i am 29 years old and 14 weeks pregnant. i got following test results at 12 weeks.
nt 1.5
papp-a .37
hcg - 0.21
the lab said my risk of trusomy 18 & 31 was 1 in 5 . can u help me with these results please. i am absolutely petrified
thank you
ks
At Fri Nov 07, 05:42:00 PM 2008,
JPC said…
Hi Dr T.,
I am 38, baby is due around my 39th birthday.
Thankfully, I had a negative screen result this week which I am very happy about. I just wondered why my PAPP-A would be so low? I occasionally smoke, but no more than a few puffs to 1/2 a cigarette a day, if that much...less because I have been so severely nauseated with morning (all day) sickness. Below are my results:
12 weeks, 4 days
nasal bone present
no defects
saw arms,hands and legs
NT 1.8 mm
CRL 57.0 mm
Heart rate 160
Free HCG 0.495
PAPP-A 0.328
My scores were:
1:497 for Trisomy 21
1:268 for Trisomy 13+18
Do these look like good results to you? I was concerned with the low serum levels. An amnio was not recommended based on these results, but I am still considering.
Thank you kindly for your insight,
JPC
At Mon Nov 24, 09:20:00 AM 2008,
Gen said…
Hello Dr T
I am 28 yrs old and pregnant with my first child after 2 miscarriages and finding out I have hetero MTHFR. After my first trimester screening at 12 weeks exactly my results were a normal NT test and a normal HCG level, but my Pappa was 0.5. This gave me a 1/290 risk for down syndrome the same as a 35 yr old. I am going back next week for some additional blood work to decide then after those results come in if I will do an amniocentesis or not. But my question is - I have read a bit on what a low Pappa can mean when it comes to IUGR and preeclampsia, but could it mean the baby has something else wrong with it besides trisomy 21, like another trisomy. And also just wondering what you think about the low pappa and my age and the real risk of a genetic problem. Thanks
At Fri May 08, 04:08:00 AM 2009,
Anonymous said…
Hi Dr. T,
I'm 33 years old.
East Asian.
I conceived through IVF. Singleton.
My results are as follows at 12wks 3 days.
NT: 2.0mm
CRL: 61.4mm
hCG: 0.559MoM
PAPP-A: 0.270 MoM
Background risk: 1:404
Ultrasound risk: 1:1094
Biochemistry risk: 1:62
Adjusted risk: 1:165
Doctor advised me to go for the amniocentesis test at 16wks. Is that necessary?
How about DS, is the risk considered high given the results?
Both my PAPP-A and hCG are low. Why is it so low? Should I be concerned?
Worried Mum
At Sun May 24, 02:37:00 AM 2009,
Snehal said…
Hello Dr. T
I'm 30 years old and 12 weeks pregnant. Genetic testing results are as follows at 11 weeks + 2 days.
FHR - 164 bpm
Crown rump length: 56.2 mm
NT - 1.4 mm
Nasal Bone Present
hCG - 1.676 MoM
PAPP-A - 0.243 MoM
Trisomy 21 (Down's Synd) - 1:100
Adjusted Risk US - 1:4690
Adjusted Risk BC - 1:17
Adjusted Risk - 1:100
Trisomy 18 - 1:18676
Trisomy 13 - 1: 25646
Non Smoker (neither self nor husband)
No hypertension
BMI 20.2
Anxious to find out if I should do an amnio. Still have some time to decide since the doc is recommending amnio at 16th week.
Please advise the options available
Thanks - Krish (Singapore)
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