Fruit of the Womb
Fruit of the Womb

Affect of Smoking on PAPP-A Levels in First Trimester Screening for Aneuploidy

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The reader below underwent combined first trimester screening for aneuploidy. The composite result was very reassuring with regard to her risks for Down syndrome and trisomies 18/13, however, she also observed that both her PAPP-A (Pregnancy-Associated Plasma Protein-A) and hCG levels were “low,” a combination that often accompanies an ‘increased risk’ for trisomy 18. She then also noted that she had been misclassified on the report form as a “smoker” and wondered if this had given her a result that was falsely reassuring. This is an excellent question and worthy of a full response so that other readers might appreciate another source of relatively low maternal serum markers in first trimester and the importance of honesty in their responses to questions related to smoking during pregnancy!

• 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 ?-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
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About the Author

Dr. Trofatter is an expert on maternal-fetal medicine.

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