Down syndrome screening marker levels in women with a previous aneuploidy pregnancy

BACKGROUND: In Down syndrome screening programmes, women with a previous affected pregnancy are assumed to have the same marker distribution as those without a family history. This assumption needs to be tested. METHODS: Information on previous aneuploidy pregnancies was routinely sought on the test request forms in three centres, Leeds, Romford and the Fetal Medicine Centre, London. For each woman with a previous aneuploidy (case), five unaffected pregnancies to women without a history were selected as controls. The markers tested included maternal serum free beta-human chorionic gonadotrophin (hCG), pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein, unconjugated estriol and ultrasound nuchal translucency thickness. RESULTS: There were 375 cases: 303 with previous Down syndrome, 63 with Edwards syndrome and 9 with Patau's syndrome. There was a statistically significant difference between cases and controls, in the distribution of free beta-hCG and PAPP-A levels, adjusted for gestation. On average, free beta-hCG was increased by 10% in a subsequent pregnancy after aneuploidy (p < 0.005, Wilcoxon rank sum test) and for PAPP-A the increase was 15% (p < 0.0001). No other marker was significantly different. CONCLUSION: Risk calculation algorithms need to be modified to take account of the increased marker levels. Until data from sufficient affected pregnancies are available for study, it would be prudent to assume that the same increase as in unaffected pregnancies applies.     

Maternal serum hyperglycosylated human chorionic gonadotrophin (HhCG) in the first trimester of pregnancies affected by Down syndrome,using a sialic acid-specific lectin immunoassay

In a series of 54 cases of pregnancies complicated by Down syndrome and 224 unaffected pregnancies we examined maternal serum levels of hyperglycosylated human chorionic gonadotrophin (HhCG) in samples collected in the first trimester (11-13 weeks) using a sialic acid-specific lectin immunoassay. We compared these levels with those of other potential first trimester serum markers [free beta-hCG, pregnancy-associated plasma protein A (PAPP-A) and total hCG (ThCG)] and modeled detection rates and false-positive rates of various biochemical markers in conjunction with fetal nuchal translucency (NT) and maternal age using an maternal age standardized population. Maternal serum HhCG in cases of Down syndrome were significantly elevated (median MoM 1.97) with 24/54 (44%) of cases above the 95th centile for unaffected pregnancies. Free beta-hCG was also elevated (median MoM 2.09) with 33% of cases above the 95th centile. PAPP-A levels were reduced (median MoM 0.47) with 38% below the 5th centile. ThCG levels, whilst elevated (median MoM 1.34), had only 20% of cases above the 95th centile. Maternal serum HhCG levels were not correlated with fetal NT but showed significant correlation with ThCG and free beta-hCG and with PAPP-A in the Down syndrome group (r=0.536). Maternal serum HhCG levels in cases with Down syndrome had a significant correlation with gestational age, increasing as the gestation increased. When HhCG was combined together with fetal NT, PAPP-A and maternal age, at a 5% false-positive rate the modeled detection rate was 83%, some 6% lower than when free beta-hCG was used and some 4% better than when ThCG was used. Maternal serum HhCG is unlikely to be of additional value when screening for Down syndrome in the first trimester.     

Between pregnancy biological variability of first trimester markers of Down syndrome and the implications for screening in subsequent pregnancies: an issue revisited

OBJECTIVES: To assess the level of correlation of first trimester biochemical and biophysical markers of Down syndrome between different pregnancies in the same individual. To assess the impact that between pregnancy biological variability has on the likelihood that women who are at increased risk in a first pregnancy being also at increased risk in a subsequent pregnancy. METHODS: During a three period women attending the OSCAR clinic at Harold Wood Hospital have had the opportunity to have first trimester screening for Down syndrome and other aneuploidies using the maternal serum biochemical markers free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A) in conjunction with fetal nuchal translucency (NT) thickness and maternal age. Of the 111,105 women undergoing such screening, the computer records were examined for women who had more than one pregnancy. The results from 1002 women with two normal singleton pregnancies were available for analysis. Marker correlations (as MoM) were established between the pregnancies and the proportion of women likely to be at increased risk in each pregnancy estimated, as was the likelihood of women being at increased risk in both pregnancies. RESULTS: For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r = 0.0959, p > 0.10). For maternal serum free beta-hCG MoM a significant correlation was found (r = 0.3976, p < 0.001), as was also found for PAPP-A MoM (r = 0.4371, p < 0.001). CONCLUSION: The implication for such between pregnancy marker association is that women who have an increased risk of Down syndrome in one pregnancy are two or three times more likely to repeat this event in their next pregnancy. This information may be useful in counselling women when undergoing first trimester screening in a subsequent pregnancy.     

Pregnancy associated plasma protein-A2: A novel biomarker for down syndrome

IntroductionIn an effort to improve prenatal screening for Trisomy 21, we evaluated pregnancy associated plasma protein-A2 (PAPP-A2) as a potential novel second trimester biomarker for Trisomy 21.MethodsTrisomy 21 and normal control mid-trimester placental samples were subjected to quantitative rt PCR analysis of seven genes we had previously found to be differentially expressed in Trisomy 21 placentae. The localization and differential expression of PAPP-A2 in second trimester placentae from normal and Trisomy 21 pregnancies was determined by immunohistochemistry. PAPP-A2 maternal serum protein levels in ten Trisomy 21 and ten diploid pregnancies were compared by Western blotting. Maternal serum PAPP-A2 levels were measured in 30 Down syndrome cases and 142 normal controls, using ELISA. Regression analysis was used to determine the correlation of PAPP-A2 with other existing markers of Trisomy 21.ResultsPAPP-A2 (aka PLAC 3) mRNA and protein expression were both increased in Down syndrome placentae as compared to diploid placentae. PAPP-A2 was also increased in maternal serum from Down syndrome pregnancies as compared to diploid pregnancies. PAPP-A2 expression correlated weakly with established markers.DiscussionThis work takes advantage of our previously performed systematic approach to the discovery of novel maternal serum biomarkers for Trisomy 21, using cDNA microarray analysis. Beginning with the validation of the microarray results, we have tracked PAPP-A2 overexpression in Down syndrome from placental mRNA to maternal serum protein.ConclusionPAPP-A2 could serve as an additional maternal serum marker in prenatal screening for Trisomy 21.     

Low PAPP-A levels between 11 and 13(+6) weeks of gestation and the risk of preeclampsia

PAPP-A is one of the 2 biochemical markers of the first trimester Down syndrome serum screening. In Bulgaria this screening was first performed in 2006. The threshold values for evaluation of the risk of development of preeclampsia used by the researchers vary in a wide range. Nevertheless in the last several years the most used value is 0.4 MoM. The aim of represented study is evaluate the low PAPP-A levels as a marker for development of preeclampsia alone, or in combination with some risk factors. The data of 194 singleton pregnancies that underwent a first trimester Down syndrome screening between January 2008 and June 2009 had been analyzed. Twenty three patients (11.6%) developed preeclampsia, of which 8 required delivery before 34th gw. The control group includes 134 women who had term deliveries of healthy babies. Nine out of 23 (39%) patients with preeclampsia, 5 out of 8 (62.5%) patients with early onset preeclampsia and 42 out of 134 (30.4%) controls had PAPP-A levels below 0.4 MoM. These levels are associated with relative risk for development of preeclampsia of 1.5 times. Low PAPP-A levels in the first trimester were associated with a low prognostic value for development of preeclampsia and early preeclampsia before 34th gw. When low PAPP-A levels are added to the maternal age and especially results of Doppler evaluation of the uterine arteries significant prognostic value improvement was observed.     

The effect of cigarette or sheesha smoking on first-trimester markers of Down syndrome

Objective  To investigate the influence of cigarette or sheesha smoking on first-trimester markers of Down syndrome.
Design  A prospective observational study.
Setting  Primary care centres and antenatal clinics of Maternity and Children Hospital, King Abdulaziz University Hospital and New Jeddah Clinic Hospital, Jeddah, Saudi Arabia.
Population  Women with a singleton pregnancy who were either nonsmokers ( n = 1736) or cigarette smokers ( n = 420) or sheesha smokers ( n = 181).
Methods  Fetal nuchal translucency thickness (fetal NT), maternal serum free beta-human chorionic gonadotrophin (free β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) were measured at 11 weeks 0 days to 13 weeks 6 days of gestation in all women. Women were grouped according to smoking status, confirmed by maternal serum cotinine measurements, and analyte levels between groups were compared.
Main outcome measures  Fetal NT, maternal serum free β-hCG, PAPP-A and cotinine measurements.
Results  Compared with nonsmoking women, fetal NT was significantly increased and free β-hCG and PAPP-A levels were significantly decreased in both cigarette and sheesha smokers. There were significant relationships between all three markers and the number of sheeshas consumed per day.
Conclusions  Cigarette and sheesha smoking significantly affect first-trimester markers of Down syndrome (fetal NT, free β-hCG and PAPP-A). Correction for this effect in women who smoke might improve the effectiveness of first-trimester screening for Down syndrome in these women. The underlying mechanism(s) relating smoking to the changes in first-trimester markers require further studies.     

First trimester screening for Down syndrome in rhesus negative women

OBJECTIVES: To explore the effect of maternal rhesus status on first-trimester screening markers for Down syndrome. METHODS: We accessed a database of singleton pregnancies undergoing first-trimester genetic screen with maternal Rh status documented and pregnancy outcome information available. Excluded were cases of fetal chromosomal or structural abnormalities, or maternal systemic disease. Results of maternal serum pregnancy-associated plasma protein A (PAPP-A) and beta-human chorionic gonadotrophin (beta-hCG) adjusted for gestational age were compared between Rh-negative and Rh-positive women with p < 0.05 considered significant. RESULTS: Two thousand two hundred and two pregnancies fulfilled the study criteria, and 160 of them (7%) were Rh negative. Only free beta-hCG corrected multiples of the median (MoM) values were statistically increased in Rh-negative women (p < 0.009). Using a cut-off of 1:300, screen-positive rates of maternal serum biochemistry were not significantly different between Rh-negative and Rh-positive women (12.5 vs 10.4%, p = 0.41). CONCLUSION: The present study focused on measurements of beta-hCG and PAPP-A in the sera of women with Rh-negative blood group. Women with Rh-negative blood type have similar first-trimester serum PAPP-A MoM values as Rh-positive women, but significantly higher beta-hCG MoM values. However, there was no significant difference in the screen-positive rate for Down syndrome between the two groups.     

Maternal serum pregnancy-associated plasma protein-A and free beta-human chorionic gonadotrophin in pregnancies conceived with fresh and frozen-thawed embryos from in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVE: Maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) are useful markers in the screening of Down syndrome in the first trimester. We investigated the effect of intracytoplasmic sperm injection (ICSI), freezing and thawing of embryos on the levels of these two analytes in assisted reproduction pregnancies. METHODS: We recruited 149 women who conceived after assisted reproduction with fresh embryos (92 from conventional IVF and 57 from ICSI), 85 women who conceived with frozen-thawed embryos (54 from conventional IVF and 31 from ICSI) and 401 women with spontaneous conceptions as controls. The concentrations of PAPP-A and free beta-hCG were measured between 10 and 14 weeks and were converted to multiples of medians (MoM) for comparisons. RESULTS: Median PAPP-A MoMs were significantly reduced in ICSI pregnancies in the fresh and frozen-thawed embryo subgroups (0.70 and 0.66 MoM respectively) and in the IVF fresh embryo subgroups (0.83 MoM), as compared to controls (1.00 MoM). Free beta-hCG MoM was significantly reduced in the IVF fresh embryos subgroup (0.87 MoM), but not in the other three subgroups. CONCLUSION: Further studies for exploring the underlying pathophysiology and adjustment in the marker levels for screening of Down syndrome are warranted in pregnancies conceived after assisted reproduction.     

Practical strategies in contingent sequential screening for Down syndrome

OBJECTIVE: To design and assess the performance of protocols for contingent sequential Down syndrome screening that can be implemented in practice. METHODS: Protocols were designed in which all women received first-trimester measurement of nuchal translucency (NT) together with maternal serum pregnancy-associated plasma protein-A (PAPP-A) and either free beta- or total human chorionic gonadotrophin (hCG). Those women with borderline Down syndrome risks received follow-up second-trimester maternal serum involving double, triple, or quadruple serum screening markers: alpha-fetoprotein, free beta-hCG or total hCG, unconjugated estriol and inhibin-A. Specific ranges of risks were used to define the borderline group. Separate protocols were developed for the United Kingdom and the United States to reflect differences in commonly used tests, cut-offs, and the gestational age at testing. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling with Monte Carlo simulation. RESULTS: Proposed protocols based on first-trimester NT, PAPP-A and free beta-hCG or total hCG, followed by selective use of second-trimester quadruple markers can result in a 91% detection rate and 2.1% false-positive rate for the United Kingdom and a detection rate of 89% and false-positive rate of 3.1% for the United States. For both countries, over 60% of affected pregnancies would be detected in the first trimester and less than 20% of women would require a second-trimester Down syndrome risk assessment. Use of alternative cut-offs to define those with borderline risks or different combinations of second-trimester markers also yielded high detection rates and low false-positive rates. CONCLUSION: With appropriate patient counselling, it should be possible to provide highly effective Down syndrome screening using contingent sequential protocols.     

Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study

OBJECTIVES: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening. METHODS: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG). RESULTS: PAPP-A was lower among cases than controls (0.47 MoM) in the first trimester (at an average of 12.5 weeks); in the second trimester, it was not different (0.91 MoM). Using repeated measures of PAPP-A alone, 21 of 34 cases were detected (62%, 95%CI 44% to 78%) with 5% false positives. At an observed 2% false-positive rate, the detection rates (DR) for the quadruple (69%) and serum integrated (69%) tests were lower than for the repeated measures test (75%). Modelled performance at 12 weeks was similar to these observed findings (70, 75, and 82%, respectively). If the first-trimester samples were collected at 10 weeks, however, DR would be higher (70, 81, and 91%, respectively). CONCLUSIONS: Adding a repeated measure of PAPP-A to existing serum markers improves Down syndrome screening to levels that are currently obtainable only by including ultrasound measurement of nuchal translucency (NT). Serum-based screening has the advantages of higher availability and reliability at a lower cost, resulting in a more effective screening strategy. A serum-based repeated measures test has a place in routine Down syndrome screening.     

Comparison of serum markers in first-trimester down syndrome screening

OBJECTIVE: To estimate patterns of total hCG and inhibin A levels in the late first trimester of Down syndrome pregnancies, compare them with that of free beta-hCG, and assess screening performance of these markers individually and in combination with pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency. METHODS: Seventy-nine matched case-control sets of maternal serum samples (each Down syndrome case matched to 5 controls) from 11 through 13 completed weeks of gestation were taken from the sample bank of the First and Second Trimester Evaluation of Risk Consortium, a population-based study, and assayed for levels of free beta-hCG, total hCG, and inhibin A. Distribution characteristics and correlations of the multiples of the median values were estimated in cases and controls. Screening performance for each marker, alone and in combination with PAPP-A, nuchal translucency, and maternal age, was calculated. RESULTS: Median multiples of the median levels of free beta-hCG, total hCG, and inhibin A in cases were more elevated as gestation increased from 11 to 13 weeks, with univariate detection rates of 31%, 23%, and 29%, respectively, at a 5% false-positive rate. At 12 weeks, the multivariate detection rates at a 5% false-positive rate for nuchal translucency and PAPP-A (with maternal age) with either free beta-hCG, total hCG, or inhibin A were 84%, 83%, and 85%, respectively. The improvement in performance from nuchal translucency and PAPP-A to any of the three-marker tests was significant, while performance of any of the three-marker combinations was not significantly different from each other. CONCLUSION: Although levels of free beta-hCG in affected pregnancies were higher earlier than the levels of either total hCG or inhibin A, there was no significant difference in screening performance when either of the three markers was used with nuchal translucency and PAPP-A at 11-13 weeks of pregnancy. LEVEL OF EVIDENCE: II-2.     

Higher median levels of free beta-hCG and PAPP-A in the first trimester of pregnancy in a Chinese ethnic group. Implication for first trimester combined screening for Down's syndrome in the Chinese population

OBJECTIVE: To study the effect of ethnic Chinese on the medians of free beta-hCG and PAPP-A in the first trimester of pregnancy. METHODS: The data of 943 women undergoing first trimester combined screening for fetal Down syndrome were analysed to derive the Chinese-specific medians. The calculated risk of Down syndrome based on these Chinese-specific medians was compared with that based on the original algorithm of the Fetal Medicine Foundation (FMF). RESULTS: The maternal serum levels of multiples of median of free beta-hCG and PAPP-A were significantly higher among the Chinese than among the Caucasians. The weight-adjusted gestation-specific medians were developed. Without adjustment for ethnicity, the original FMF algorithm underestimated the risk of Down syndrome by a median of 1%. Adjustment by ethnicity increased the false-positive rate by 10% (from 5.3 to 5.9%). CONCLUSION: Ethnic Chinese have a significantly higher maternal serum level of free beta-hCG and PAPP-A in the first trimester, which could not be explained by differences in maternal weight. Adjustment for ethnicity may be necessary for these biochemical markers in a first trimester screening program.     

Down syndrome biochemical markers and screening for preeclampsia at first and second trimester: correlation with the week of onset and the severity

OBJECTIVES: To estimate the combined screening performance of first and early second trimester prenatal serum markers for Down syndrome, in screening for the development of preeclampsia, and analyze the correlation among marker levels, week of onset, and severity of the disease. METHODS: A retrospective cohort study was carried out on 32 women with preeclampsia and 3044 controls. Serum samples from these pregnancies were assayed for pregnancy-associated plasma protein-A (PAPP-A), alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotrophin (hCG), and inhibin-A. A likelihood ratio and the odds of being affected given a positive result (OAPR) of various combinations of markers were calculated and receiver operating characteristic (ROC) curves analysis was performed. RESULTS: In the pregnancies that subsequently developed preeclampsia, first trimester PAPP-A concentration was significantly lower and concentrations of early second trimester inhibin-A and hCG significantly elevated. Levels of early second trimester uE3 and AFP were not significantly altered. We also found that inhibin-A correlates with both onset of the disease and the severity. CONCLUSION: Down syndrome biochemical markers levels are altered in those patients who subsequently developed preeclampsia and may be a useful screening test for preeclampsia. Inhibin-A is the most predictive marker and correlates with the severity of subsequent preeclampsia and inversely with the week of occurrence of preeclampsia.     

Early vaginal bleeding and first-trimester markers for Down syndrome

OBJECTIVES: To assess the effect of early vaginal bleeding on first-trimester markers for Down syndrome. METHODS: A retrospective study was conducted on 2330 normal singleton fetuses who underwent first-trimester combined screening for Down syndrome based on ultrasound and maternal serum markers. Fetal nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-hCG and the false-positive rate of the test were compared between pregnancies with (n = 253) and without (n = 2077) a history of early vaginal bleeding. RESULTS: The mean +/- SD log(10) MoM for NT, PAPP-A and free beta-hCG was -0.024 +/- 0.101, 0.007 +/- 0.244, 0.047 +/- 0.273 and -0.011 +/- 0.108, -0.006 +/- 0.223, 0.008 +/- 0.264 in pregnancies with and without a history of early vaginal bleeding, with a p value of 0.07, 0.40 and 0.03 respectively. The false-positive rate was 2.4% and 3.6% (p = 0.33). CONCLUSIONS: An earlier episode of vaginal bleeding is associated with an increase in maternal serum free beta-hCG levels at first-trimester combined screening for Down syndrome. However, this phenomenon is unlikely to significantly affect the false-positive rate of the test.     

Co-variables in first trimester maternal serum screening

The objective of this study was to determined the influence of maternal weight, maternal smoking habits, gravidity, parity and fetal gender on the level of maternal serum marker used in first trimester screening for Down syndrome. A total of 2449 singleton unaffected pregnancies from two centres were studied. Maternal serum free beta-human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP) concentrations had been measured in all pregnancies, and pregnancy associated plasma protein (PAPP)-A levels had been measured in 924. All results were expressed as multiples of the gestation specific median (MoM) values after regression, using each centre's own medians. Information on maternal weight was available in 2259 pregnancies, on self-reported current cigarette smoking in 1364 (of whom 117 (8.6%) were smokers), on gravidity in 1371, parity in 1303 and fetal gender in 253. All three markers showed a statistically significant negative association with maternal weight (p<0.0005) and in the subsequent analyses MoM values were weight adjusted using standard methods. The median PAPP-A level in smokers was 0.81 MoM, a significant reduction (p<0.005); free beta-hCG was also reduced (median 0.89 MoM) but not significantly (p=0.17), and AFP was unaltered. The median AFP level in primagravidas was highly significantly greater than that in gravid women (p<0.0005). In PAPP-A the reverse effect was seen but it did not reach statistical significance (p=0.15) and there was no effect for free beta-hCG. Results of a similar magnitude and direction were found for parity. The median level of free beta-hCG was higher (p=0.0005), and the median AFP lower in female pregnancies. Maternal weight and, for PAPP-A, maternal smoking are important first trimester screening co-variables. Gravidity, parity and fetal gender also seem to influence one or more first trimester markers.     

First-trimester maternal dried blood Down syndrome screening marker levels in early pregnancy loss

OBJECTIVE: To determine the association of free beta hCG and PAPP-A measured during first-trimester Down syndrome risk assessment with early pregnancy loss when blood is drawn prior to scheduled ultrasound. METHODS: Maternal dried blood samples were collected prior to the ultrasound exam for Down syndrome risk assessment. Free beta hCG and PAPP-A levels in 55 patients who experienced loss of pregnancy prior to their scheduled ultrasound appointment were compared to 6464 control pregnancies using logistic regression. RESULTS: Low levels of free beta hCG and PAPP-A were associated with increased risk of early pregnancy loss. The detection rate of early pregnancy loss for a fixed 5% false-positive rate using free beta alone, PAPP-A alone and a combination of the two were 47, 36 and 49%, respectively. CONCLUSION: Free beta hCG and PAPP-A can identify pregnancies at increased risk for early pregnancy loss. More studies are needed to determine whether further evaluation of these pregnancies prior to the scheduled ultrasound is warranted.     

Accuracy of Down syndrome risks produced in a first-trimester screening programme incorporating fetal nuchal translucency thickness and maternal serum biochemistry

Over the past three years approximately 12 000 women have been screened in the first trimester through our OSCAR programme, which utilizes fetal NT and maternal serum free beta-hCG and PAPP-A. During this time 30 cases of Down syndrome were identified either prenatally or postnatally. Using an established procedure the accuracy of predicted risk for Down syndrome was assessed in a population of 30 cases of Down syndrome and 11 758 unaffected pregnancies. The correlation between predicted risk and prevalence of Down syndrome was very high (r=0.9995). It is concluded that risks produced by the Fetal Medicine Foundation combined risk algorithm agree very closely with Down syndrome prevalence and can be used with confidence when counselling women of their risk.     

The impact of correcting for smoking status when screening for chromosomal anomalies using maternal serum biochemistry and fetal nuchal translucency thickness in the first trimester of pregnancy

OBJECTIVES: To evaluate the influence of cigarette smoking status on maternal serum free beta-hCG, PAPP-A and fetal nuchal translucency (NT) thickness at 11 to 14 weeks of gestation in a large cohort of women screened prospectively for chromosomal anomalies. METHODS: Information on maternal cigarette smoking status, maternal age, maternal serum biochemical marker levels and fetal NT were collected from the prenatal screening computer records in two OSCAR screening centres. Data was available from 32,730 unaffected pregnancies and from 124 with Down syndrome. Statistical analysis of the marker levels in the smoking and non-smoking group were carried out. The impact on false-positive rate of correcting for smoking status was assessed from a modelling exercise. RESULTS: Prevalence of smoking was significantly affected by maternal age with an overall incidence of 11.5%, which varied from 35% in women under 20 to 7% in women over 35. In the unaffected population, the median free beta-hCG MoM was significantly lower in the smoking group (0.97 vs 1.00) as was that for PAPP-A (0.84 vs 1.02). The standard deviation of the log(10) MoM free beta-hCG was lower in the smoking group and that for PAPP-A was higher in the smoking group. The difference in median marker levels did not seem to be related to the number of cigarettes smoked per day. In the group with Down syndrome, the median MoM free beta-hCG was not significantly different in the smokers (1.69 vs 1.86) as was that for PAPP-A (0.53 vs 0.57). Fetal delta NT was not significantly different in the unaffected smokers (0.11 vs 0.0 mm) or in those with Down syndrome (1.96 vs 2.25 mm). In the smoking group, when screening using maternal serum biochemistry and age alone, the false-positive rate was 6.17%, compared to 4.67% in an age-matched group of non-smokers. Correcting for smoking status by dividing the measured MoM by the median found in the smoking group resulted in the false-positive rate falling to 4.40%. When screening using NT, maternal serum biochemistry and age, the false-positive rate in smokers was 4.48%, which reduced to 3.46% after correction-in line with the 3.76% in the non-smoking group. The impact on detection rate was too small to be accurately measured. CONCLUSIONS: The impact of smoking on first-trimester biochemical marker levels does not seem to be dose related. Whilst correcting first-trimester biochemical markers for maternal smoking status has little impact at the population level for detection rates, a considerable reduction in false-positive rate can be achieved, reducing the level to that seen in non-smokers. However, the effect on the individual patient-specific risk can be substantial and could certainly make a difference to the patient's decision on whether to have an invasive test.     

First trimester screening for Down syndrome and assisted reproduction: no basis for concern

In pregnancies obtained after assisted reproduction the false-positive rate of second trimester Down syndrome (DS) screening is increased by 1.5-3-fold. This may cause an increase in the number of amniocenteses and the fetal loss rate. The present study for the first time examined whether assisted reproductive technologies affect the results of first trimester screening. The markers PAPP-A, free beta-hCG and the nuchal translucency (NT) thickness were examined at 12-14 weeks' gestation. Screening markers in 47 in vitro fertilisation (IVF), 63 ovulation induction (OI) and 3026 spontaneously conceived singleton pregnancies were compared. The MoM (multiples of the median) value in the IVF pregnancies was 1.02 (95% CI: 0.85-1.22) for PAPP-A, 1.14 (95% CI: 0.95-1.37) for beta-hCG and 0.97 (95% CI: 0.89-1.05) for NT; the MoM value in the OI pregnancies was 0.89 (95% CI: 0.76-1.05) for PAPP-A, 1.08 (95% CI: 0.93-1.25) for beta-hCG and 1.02 (95% CI: 0.95-1.11) for NT. The first trimester marker values in assisted reproductive pregnancies and spontaneously conceived pregnancies were not significantly different. Estimated false-positive rates for a risk cut-off of 1:400 varied from 4.7% in IVF pregnancies to 5.1% in OI pregnancies. Therefore the false-positive rate in Down syndrome screening should be independent of the method of conception.     

Maternal serum marker medians in Aboriginal Canadian women

OBJECTIVES: The study evaluates the differences between Aboriginal and Caucasian women in the levels of maternal serum markers used in second-trimester Down syndrome screening (alpha-fetoprotein, unconjugated estriol, and total human chorionic gonadotrophin). METHODS: A case-control study compared the levels of serum markers in 401 Aboriginal women and 1565 matched controls selected from 7717 Caucasian women. The cases and controls were screened in a single centre and matched for maternal age, parity, and sample date. Women with multiple pregnancies and pregnancies associated with Down syndrome, open neural tube defects, trisomy 18, and insulin-dependent diabetes mellitus as well as women without weight recorded were excluded from the study. RESULTS: No differences in the levels of maternal serum alpha-fetoprotein and total human chorionic gonadotrophin were observed between the two groups. Maternal serum unconjugated estriol was 12% higher in Aboriginal women. DISCUSSION: Since Aboriginal women make up only a small proportion of women screened, correcting the level of uE3 for this group will have little effect on the overall screening performance. However, if these results are confirmed by further study, individual centres may consider making this correction, so optimal screening performance can be achieved in Aboriginal women.