First trimester Down’s syndrome screening marker values and cigarette smoking: new data and a meta-analysis on free β human chorionic gonadotophin, pregnancy-associated plasma protein-A and nuchal translucency

J Med Screen 2008;15:204-206
doi:10.1258/jms.2008.008049
© 2008 Medical Screening Society

 

This Article
Right arrow
Abstract

Freely available
Right arrow
Figures Only
Right arrow

Full Text (PDF)

Right arrow
Alert me when this article is cited
Right arrow
Alert me if a correction is posted
Services
Right arrow
Email this article to a friend
Right arrow

Similar articles in this journal

Right arrow
Similar articles in PubMed
Right arrow
Alert me to new issues of the journal
Right arrow
Download to citation manager
Right arrow
Citing Articles
Right arrow
Citing Articles via HighWire
Right arrow

Citing Articles via Web of Science (2)

Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow
Articles by Bestwick, J. P
Right arrow
Articles by Wald, N. J
Right arrow Search for Related Content
PubMed
Right arrow
PubMed Citation
Social Bookmarking

What’s this?


Short Communications


Jonathan P Bestwick, Statistician 
,


Wolfson Institute of Preventive Medicine, Barts and the London Queen Marys School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ


Wayne J Huttly, Antenatal screening manager
,


Wolfson Institute of Preventive Medicine, Barts and the London Queen Marys School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ


Nicholas J Wald, Professor
,


Wolfson Institute of Preventive Medicine, Barts and the London Queen Marys School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ

Correspondence to: Jonathan P Bestwick, Wolfson Institute of Preventive Medicine Barts and the London Queen Marys School of Medicine and Dentistry Charterhouse Square London EC1M 6BQ; j.p.bestwick{at}qmul.ac.uk


Objectives To examine the effect of smoking on three first trimester screeningmarkers for Down’s syndrome that constitute the Combined test,namely nuchal translucency (NT), pregnancy-associated plasmaprotein-A (PAPP-A) and free β human chorionic gonadotophin(free β-hCG) and to use the results to determine whichof these markers need to be adjusted for smoking and by howmuch.

Methods The difference in the median multiple of the median (MoM) valuesin smokers compared to non-smokers was determined for NT, PAPP-Aand free β-hCG in 12,517 unaffected pregnancies that hadroutine first trimester Combined test screening. These resultswere then included in a meta-analysis of published studies andthe effect of adjusting for smoking on screening performanceof the Combined test was estimated.

Results The results using the routine screening data were similar tothe summary estimates from the meta-analysis of all studies.The results from the meta-analysis were; median MoM in smokerscompared to non-smokers: 1.06 NT (95% confidence interval 1.03to 1.10), 0.81 PAPP-A (0.80 to 0.83) and 0.94 free β-hCG(0.89 to 0.99). The effect of adjusting for smoking on the Combinedtest is small, with an estimated less than half percentage pointincrease in the detection rate (the proportion of affected pregnancieswith a positive result) for a 3% false-positive rate (the proportionof unaffected pregnancies with a positive result) and less than0.2 percentage point decrease in the false-positive rate foran 85% detection rate.

Conclusion Adjusting first trimester screening markers for smoking hasa minimal favourable effect on screening performance, but itis simple to implement and this paper provides the adjustmentfactors needed if a decision is made to make such an adjustment.


Cigarette smoking in pregnancy influences levels of serum markers used in screening for Down’s syndrome, although there is no evidence of an association between the birth prevalence of Down’s syndrome and smoking.1

In the early second trimester of pregnancy, human chorionic gonadotrophin (hCG; total hCG and the free ß subunit) and inhibin-A are materially influenced by smoking. The median total hCG multiple of the median (MoM) in smokers has been estimated to be 0.822 (18% lower than non-smokers), the median free β-hCG MoM to be 0.80 (20% lower than non-smokers), and the median inhibin-A MoM to be 1.62 (62% higher than non-smokers).1 Alphafetoprotein and unconjugated oestriol are less influenced by smoking, with median MoM values in smokers of 1.05 and 0.96, respectively. Adjusting for smoking can be simply achieved by dividing a smoker’s observed MoM value for a particular marker by the median value of that marker in smokers.1

In the late first trimester, two serum markers, free ß-hCG and pregnancy-associated plasma protein-A (PAPP-A) and an ultrasound marker, nuchal translucency (NT), measured between about 11 and 13 weeks of gestation constitute the Combined test. Published studies have shown a lower free ß-hCG median MoM in smokers than non-smokers with estimates ranging from no difference to 13% lower,37 lower PAPP-A levels with median MoM values ranging from about 15% to 25% lower in smokers37 and higher NT values ranging from no difference to 16% higher in smokers.3,5,7,8 The range of estimates prompted us to examinethe levels of these first trimester markers in our own dataand include these in a meta-analysis of published results toprovide more precise estimates of the effect of smoking thanis possible from the results of individual studies.

Measurements of free ß-hCG, PAPP-A and NT, together with a record of smoking status were collected on 12,517 unaffected pregnancies as part of routine first trimester Combined test screening at the Wolfson Institute of Preventive Medicine between 1 January 2003 and 30 September 2007. There were too few in women who smoked and also had an affected pregnancy with Down’s syndrome to investigate the effect of smoking on screening markers in affected pregnancies. In our data, approximately 8% of women smoked, with Caucasian women most likely to smoke (8.8%) followed by Afro-Caribbean women (7.7%), Oriental women (2.3%) and women of South Asian origin (1.1%). Smokers were, on average, younger (32 versus 35 years of age at expected date of delivery), had first trimester screening at the same gestational age (88 days) and, contrary to previous observations,5 smokers were on averagethe same weight as non-smokers (68 kg). This may have been dueto the general decline in smoking over time being less evidentin certain groups such as the relatively poor and overweight.

Table 1 shows the median MoM value for the three markers according to smoking status, with the median MoM in non-smokers set to 1.00 for each marker. The median PAPP-A MoM in smokers was 20% lower than that in non-smokers (P < 0.001). The median free β-hCG MoM was 4% lower than non-smokers and the median MoM for NT was 3% higher in smokers, both small differences, but nonetheless statistically significant (P = 0.011 and P < 0.001, respectively). The standard deviations for each marker were similar in smokers and non-smokers. As previously found, there was a minor statistically significant dose-response relationship in our data for PAPP-A79, but most of the effect wasbetween smokers and non-smokers and the dose response relationshipwas not clinically useful (the median MoM in women who smokeda few cigarettes per day was only marginally higher than inheavy smokers).



View this table:
[in this window]
[in a new window]
Table 1 Median free β-human chorionic gonadotrophin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency (NT) multiple of the median (MoM) values measured at 10 to 13 weeks gestation in smokers compared to non-smokers (median set to 1.00 MoM)

 

Figure 1 shows the results of a meta-analysis for each marker (including our current results with those previously published) using a random effects model,10 again setting the median MoM in non-smokers to 1.00. For each marker, studies that did not provide an estimate of the standard deviation in smokers were assigned the pooled estimate for that marker.4,8The summary estimate for PAPP-A was a median MoM of 0.81 insmokers (19% lower than non-smokers), close to our estimateof 0.80 MoM. The summary estimate for free ß-hCG was 0.94MoM (6% lower) and for NT was 1.06 (6% higher), also both closeto our estimates of 0.96 and 1.03, respectively. For each marker,the median MoM in smokers was statistically significantly differentfrom the median value in non-smokers (1.00 MoM).



View larger version (17K):
[in this window]
[in a new window]
Figure 1 Published studies of free β-human chorionic gonadotrophin (free β-hCG), pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency (NT) measured at 10–13 weeks gestation in pregnancies of women who smoke compared to women who do not smoke, showing the median multiple of the median (MoM) value and number of pregnancies in each study, together with a pooled estimate of the median with 95% CI and the median in non-smokers (solid line, median set to 1.0 MoM)

 

Among women screened at the Wolfson Institute the Combined test false-positive rate was 8.6% (1,058/12,517), close to the 8.9% expected on the basis of the age distribution of the women screened and ignoring their smoking habits (using a 1 in 250 term risk cut-off). The false-positive rate in smokers was 11.1% (108/969), statistically significantly higher than the false-positive rate in non-smokers (8.4%, 969/11,558 P = 0.003).

Table 2 shows the predicted effect on the detection and false-positive rates of the Combined test with and without adjustment for smoking (using the results from the meta-analysis) according to the prevalence of smoking (10%, 20% and 30%) and without. Modelling was performed by simulation and with adjustments to marker MoM values for smoking as previously described.1,11 The effect of adjusting for smoking is small with no more than a half percentage point increase in the detection rate for a 3% false-positive rate and no more than a 0.2 percentage point decrease in the false-positive rate for an 85% detection rate. At a fixed risk cut-off of 1 in 250, adjusting for smoking results in a small decrease in both the detection and false-positive rates. Similar modelling applied to the Integrated test (first trimester NT, PAPP-A and second trimester AFP, uE3, hCG and inhibin-A) showed a similar marginal improvement in screening performance, using the adjustment factors taken from these results and those previously published.1



View this table:
[in this window]
[in a new window]
Table 2 Screening performance of the Combined test (markers measured at 11 completed weeks gestation) adjusting marker MoM values for smoking and without adjusting for smoking according to prevalence of smoking. Detection rate (DR) for a 3% false-positive rate (FPR), FPR for an 85% DR and DR and FPR for specified risk cut-off

 

Whilst adjusting MoM values in smokers has a negligible effecton the overall screening performance, this paper provides theadjustment factors needed if a decision is made to adjust firsttrimester screening markers for smoking.

 

 

 

Accepted for publication July 11, 2008.




REFERENCES

Go to previous sectionTop

 REFERENCES


  1. Rudnicka AJ, Wald NJ, Huttly W, Hackshaw AK. Influence of maternal smoking on the birth prevalence of Down’s syndrome and on second trimester screening performance. Prenat Diagn 2002;22:893–7[Medline]
  2. Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down syndrome. J Med Screen 1997;4:181–246[Medline]
  3. Spencer K. The influence of smoking on maternal serum PAPP-A and free beta hCG levels in the first trimester of pregnancy. Prenat Diagn 1999;18:225–34
  4. de Graaf IM, Cuckle HS, Pajkrt E, et al. Co-variables in first trimester maternal screening. Prenat Diagn 2000;20:186–9[Medline]
  5. Niemimaa M, Heinonen S, Seppala M, Ryynanen M. The influence of smoking on the pregnancy-associated plasma protein A, free β human chorionic gonadtophin and nuchal translucency. BJOG 2003;110:664–7[Medline]
  6. Kagan KO, Frisova V, Nicolaides KH, Spencer K. Dose dependency between cigarette consumption and reduced maternal serum PAPP-A levels at 11-13 + 6 weeks of gestation. Prenat Diagn 2007;27:849–53[Medline]
  7. Ardawi MSM, Nasrat HA, Rouzi AA, et al. The effect of cigarette or sheesha smoking on first-trimester markers of Down syndrome. BJOG 2007;114:1397–401[Medline]
  8. Miron P, Cote YP, Lambert J. Effect of maternal smoking on prenatal screening for Down syndrome and trisomy 18 in the first trimester of pregnancy. Prenat Diagn 2008;28:180–5[Medline]
  9. Yigiter A, Kavak Z, Bakirci N, Gokaslan H. Effect of smoking on pregnancy-associated plasma protein A, free β-human chorionic gonadtophin, and nuchal translucency in the first trimester of pregnancy. Advances in Therapy 2006;23:131–8[Medline]
  10. DerSimonian R, Laird N. Meta-analysis in Clinical Trials. Controlled Clinical Trials 1986;7:177–88[Medline]
  11. Wald NJ, Bestwick JP, Morris JK. Cross-trimester marker ratios in prenatal screening for Down syndrome. Prenat Diagn 2006;26:514–23[Medline]


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What’s this?






This article has been cited by other articles:

Home page J Med ScreenHome page

G. Lambert-Messerlian, G. E Palomaki, and J. A Canick
Adjustment of serum markers in first trimester screening
J Med Screen,

June 1, 2009;

16(2):

102 – 103.

[Abstract]
[Full Text]
[PDF]


 

This Article
Right arrow
Abstract

Freely available
Right arrow
Figures Only
Right arrow

Full Text (PDF)

Right arrow
Alert me when this article is cited
Right arrow
Alert me if a correction is posted
Services
Right arrow
Email this article to a friend
Right arrow

Similar articles in this journal

Right arrow
Similar articles in PubMed
Right arrow
Alert me to new issues of the journal
Right arrow
Download to citation manager
Right arrow
Citing Articles
Right arrow
Citing Articles via HighWire
Right arrow

Citing Articles via Web of Science (2)

Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow
Articles by Bestwick, J. P
Right arrow
Articles by Wald, N. J
Right arrow Search for Related Content
PubMed
Right arrow
PubMed Citation
Social Bookmarking

What’s this?

 

 

Leave a Comment