Serum Free Beta-human Chorionic Gonadotropin Research Articles

Effect of Maternal Hepatitis B Carrier Status on First-Trimester Markers of Down Syndrome

Up to 10% of women of reproductive age in our country are carriers of hepatitis B virus. This study examined whether maternal hepatitis B carrier status has any effect on markers used in first-trimester screening for Down syndrome. Records for 2 major Taiwanese hospitals were retrospectively examined to identify women with singleton pregnancies resulting in normal live births from June 2002 through 2008. Maternal hepatitis B data were used to define 3 groups: seronegative women, inactive carrier women, and active carrier women. Women with active or inactive carrier status were significantly older than seronegative women. The results of the study show that maternal hepatitis B carrier status does not influence first-trimester levels of maternal serum free beta-human chorionic gonadotropin (free beta-hCG) multiples of the median (MoM), pregnancy-associated plasma protein A (PAPP-A) MoM, and median fetal nuchal translucency and screening false-positive rate; therefore, correction in the risk calculation algorithm for maternal hepatitis B carrier status is not necessary.

Correlation between First-Trimester Maternal Serum Markers, Second-Trimester Uterine Artery Doppler Indices and Pregnancy Outcome

Aims: The aim of this study was to assess the correlation between first trimester maternal serum free beta-human chorionic gonadotropin (fBHCG), pregnancy-associated plasma protein A (PAPPA), second-trimester uterine artery (UA) Doppler measurements and adverse pregnancy outcomes. Methods: Serum levels of PAPPA and fBHCG were determined at the first trimester, and patients underwent bilateral UA Doppler assessments at 20–25 weeks of gestation. A serum PAPPA level <0.4 MoM was termed as low and the abnormal Doppler findings were the presence of bilateral notches and RI >0.52 (mean) or unilateral notch and RI >0.66 (90th percentile). Results: Mean PAPPA level was significantly lower in cases with unilateral or bilateral notches (1.09; 0.79 and 0.80 MoM for 0, 1 and 2 notches, p < 0.001). Fifty-two cases (12.8%) had a low PAPPA level; in this group the incidence of abnormal Doppler was significantly higher (34.6 vs. 18.4%, p = 0.011). In the presence of abnormal Doppler in a case with a low serum PAPPA the risk of pregnancy-induced hypertension (OR = 4.56, p = 0.0067), low birth weight (OR = 6.8, p = 0.0002) and the risk of at least one complication (OR = 7.6, p = 0.00001) were significantly high. Conclusion: Combination of first- and second-trimester findings might improve the efficiency of screening for pregnancy complications.

Maternal serum human placental growth hormone at 11 to 13 weeks in trisomy 21 and trisomy 18 pregnancies

To investigate the maternal serum concentration of human placental growth hormone (hPGH) in trisomy 21 and trisomy 18 pregnancies at 11 to 13 weeks of gestation and to examine the possible association between fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). The maternal serum concentration of hPGH at 11 to 13 weeks was measured in a case-control study from 28 pregnancies with fetal trisomy 21, 28 with trisomy 18 and 112 pregnancies with euploid fetuses. The median hPGH multiple of the median (MoM) in trisomy 21 and trisomy 18 pregnancies were compared with euploid pregnancies. Serum hPGH was significantly lower in trisomy 21 (0.93 MoM) and trisomy 18 (0.62 MoM) compared to euploid pregnancies (1.02 MoM). There was a significant association between serum hPGH and PAPP-A in both the euploid (r = 0.258, p = 0.006) and trisomy 21 pregnancies (r = 0.410, p = 0.030) but not in trisomy 18 pregnancies (p = 0.445). In the first trimester, serum hPGH in trisomy 21 and trisomy 18 pregnancies is reduced. This is the opposite of findings in previous studies reporting that in the second trimester, trisomy 21 and 18 pregnancies have increased hPGH.

P11.02: First-trimester combined screening for aneuploidy in a Brazilian population from a private center in Rio de Janeiro: a preliminary study

The aim of this study was to assess the effectiveness of first-trimester screening using a combination of maternal age, nuchal translucency thickness (NT) and maternal serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels for aneuploidy in a Brazilian population in Rio de Janeiro. This was a retrospective study of 546 women who underwent combined screening for aneuploidy between 11 + 0 and 13 + 6 weeks of gestation in a fetal medicine unit in Rio de Janeiro (Perinatal Group—Laranjeiras). NT was measured according to the criteria set by the Fetal Medicine Foundation (FMF). Maternal serum free β-hCG and PAPP-A levels were measured, and the risk of aneuploidy was calculated using The FMF's algorithm. Fetal karyotyping was advised when the risk was 1: 100 or above. All subjects were followed up for pregnancy and fetal outcome. Among the 546 women who underwent the screening program, 37% were 35 years old or above. 15 fetuses (2,7%) were screen positive; this included 2 cases of trisomy 21 and 1 case of trisomy 18. The sensibility was 75% and the specificity was 98%; the positive predictive value was 21%, and the negative predictive value was 99.5%. Among the 545 screen negative fetuses, there was only one case in which aneuploidy was missed and the infant was live born. First-trimester combined screening for aneuploidy was highly effective in the Brazilian population analyzed in this preliminary study.

P11.18: Impact of ductus venosus assessment in screening Down syndrome protocols

Screening by combination of nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotropin (beta hCG) and pregnancy-associated plasma protein-A (PAPP-A) is an effective strategy to detect Down syndrome. Our objective is to estimate the improvement in screening efficiency when ductus venosus (DV) Doppler studies are added to existing Down syndrome (DS) screening protocols. First-trimester combined screening for DS was prospectively carried out, from February 2007 to January 2009, in 4408 singleton pregnancies at 11 + 0 to 13 + 6 gestational weeks, including maternal age, biochemistry (beta hCG and PAPP-A) and nuchal translucency. Ductus venosus pulsatility index for veins was calculated at the same time. The maternal serum biochemistry was measured using the Kryptor analyzer (Brahms Diagnostica) in a two-step strategy. The detection rate (DR) and false-positive rates (FPR) for standard screening strategy (maternal age, NT and biochemistry) and the same strategy but including DV assessment were calculated. The mean maternal age was 33 (range 18–46) years. The mean gestation age at blood test was 71 (+/− 10) days. The mean gestation age at scan was 12,6 (range 10,5–13.6) weeks. The population included 35,8% over 35 years. Down syndrome was identified in 16 pregnancies. At a fixed 1% FPR, the DR for trisomy 21 at screening time was 68,8% for standard screening strategy and 81,3% when including DV assessment, respectively. Compared to the standard DS screening strategies, DV assessment can improve screening efficiency by significantly reducing the false-positive rate. Early evaluation of DV can be introduced to standard DS screening strategies in experienced centers as a first level screening test to reduce invasive test rate derived from the extended existing DS screening protocols.

OP02.08: Tricuspid regurgitation in screening pregnancies at 11 + 0 to 13 + 6 weeks of gestation

To investigate the performance of first-trimester screening for aneuploidies, but also for the pregnancy outcome, by including assessment of tricuspid blood flow in the combined test of maternal age, fetal nuchal translucency (NT) thickness and serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein A (PAPP-A). Screening by the combined test was performed in singleton pregnancies, between 11 + 0 to 13 + 6 weeks of gestation. In all cases tricuspid flow was assessed to determine if there was tricuspid regurgitation. It was noted as final parameters: chromosomal defects, fetal intrauterine demise, major cardiac anomalies, perinatal death. Were included 727 pregnancies, 720 with chromosomally normal fetuses or the delivery of a phenotypically normal baby—euploid group, 5 with trisomy 21, 1with trisomy 18, 1 with trisomy 13. Tricuspid regurgitation was observed in 1,4% (10 cases) of the 720 euploid fetuses and 40% (2 cases) of the fetuses with trisomy 21 and in both cases of fetuses with trisomies 18 and 13. The prevalence increases for chromosomal defects, fetal death, and major cardiac anomalies if there is tricuspid regurgitation. It may be assumed that in a screening policy based on maternal age, fetal NT, serum free beta-hCG and PAPP-A, the assessment of tricuspid flow in all pregnancies would increase the detection rate of trisomies, and also could change the management of pregnancies with normal euploid babies. Assessment of tricuspid flow could improve the performance of first-trimester screening for trisomies. Could also become a tool in assessment the risk in pregnancy. There is need to confirm this, by further studies, of a larger sample of cases.

Prospective validation of first‐trimester combined screening for trisomy 21

To examine the performance of the new algorithm in screening for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). This was a prospective screening study for trisomy 21 in singleton pregnancies at 11 + 0 to 13 + 6 weeks of gestation using an algorithm combining maternal age, fetal NT thickness based on the mixture model for the assessment of NT, and maternal serum free beta-hCG and PAPP-A based on a multiple regression model for the assessment of serum biochemistry. The NT measurements were performed by 60 operators who had obtained The Fetal Medicine Foundation certificate of competence in the 11-13-week scan. The study population consisted of 19 614 pregnancies with a normal karyotype or delivery of a phenotypically normal baby (euploid group) and 122 cases of trisomy 21. In the euploid fetuses the NT was above the previously defined 50(th), 95(th) and 99(th) centiles in 10 033 (51.2%), 618 (3.2%) and 123 (0.6%) cases and the respective values for trisomy 21 were 117 (95.9%), 94 (77.0%) and 57 (46.7%). The median fetal NT was within 0.1 mm of the expected in 47 (78.3%) of the 60 sonographers and within 0.2 mm in all. In the euploid fetuses the median free beta-hCG was 1.0 (range, 0.1-29.4) multiples of the median (MoM) and the median PAPP-A was 1.0 (range, 0.2-3.3) MoM. The median MoM values were 1.0 or close to 1.0 MoM for each subgroup of pregnancy characteristics, including gestations of 11, 12 and 13 weeks, maternal weight of < 60 kg, 60-80 kg and > 80 kg, different ethnic origins, cigarette smokers and non-smokers, natural conception and in vitro fertilization. For a false-positive rate of 3%, the detection rate of trisomy 21 in screening by maternal age and fetal NT was 81% (95% CI, 73-89%), by maternal age and maternal serum biochemistry it was 63% (95% CI, 56-72%) and by combined screening based on maternal age, fetal NT and maternal serum biochemistry it was 90% (95% CI, 84-96%). This study has validated the new risk algorithm and demonstrated that in combined screening for trisomy 21 based on maternal age, fetal NT and free beta-hCG and PAPP-A the detection rate is about 90% for a 3% false-positive rate.

First‐trimester fetal nasal bone length in an ethnic Chinese population

To determine reference ranges of fetal nasal bone length (NBL) in a Chinese population and to assess the value of NBL measurement in screening for chromosomal defects in the first trimester. In this prospective study the fetal profile was examined and the fetal NBL and crown-rump length (CRL) were measured in Chinese women presenting with singleton pregnancies for first-trimester screening for aneuploidy between January 2004 and June 2007. Screening was performed on the basis of nuchal translucency (NT) measurement and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A levels. NBL was measured in 7543 fetuses, of which 7517 were euploid. The best fit equation for median NBL in euploid fetuses in relation to CRL was: NBL (mm) = 0.4593 + (0.0186 x CRL(mm)). The NBL for gestational age (GA, in days) was given by the equation NBL(mm) = 0.2392 + (0.0027 x GA). There was no correlation between log(10)(NBL multiples of the median (MoM)) and log(10)(NT MoM) in unaffected pregnancies (r = - 0.009; P = 0.43). Only two of the 11 cases with trisomy 21 had an NBL outside the 5(th) or 95(th) centiles of the reference range for euploid fetuses. Reference ranges for NBL in a Chinese population suitable for screening for aneuploidy between 11 and 13 + 6 weeks' gestation have been derived. The NBL in Chinese fetuses is similar to that of other ethnic groups. However, unlike the determination of presence vs. absence of the nasal bone, NBL measurement is unlikely to further improve screening for aneuploidy.

Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation

To investigate the performance of first-trimester screening for aneuploidies by including assessment of ductus venosus flow in the combined test of maternal age, fetal nuchal translucency thickness, fetal heart rate, and serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Screening by the combined test was performed in singleton pregnancies, including 19 614 with euploid fetuses, 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and eight with Turner syndrome. In all cases the a-wave in the fetal ductus venosus flow was assessed. We examined the performance of two screening strategies: first, assessment of the a-wave in all patients and, second, first-stage screening using the combined test in all patients followed by second-stage assessment of the a-wave only in those with an intermediate risk of one in 51 to one in 1000 after the first stage Reversed a-wave was observed in 3.2% of the euploid fetuses, and in 66.4%, 58.3%, 55.0% and 75.0% of fetuses with trisomies 21, 18 and 13 and Turner syndrome, respectively. Inclusion of ductus venosus flow in all pregnancies would detect 96%, 92%, 100% and 100% of trisomies 21, 18 and 13 and Turner syndrome, respectively, at a false-positive rate of 3%. The same detection rates were achieved with the two-stage strategy at a false-positive rate of 2.6%, in which it was necessary to assess the ductus venosus in only 15% of the total population. Assessment of ductus venosus flow improves the performance of first-trimester screening for aneuploidies.

Medians and correction factors for biochemical and ultrasound markers in Chinese women undergoing first‐trimester screening for trisomy 21

To establish normative values and distribution parameters of first-trimester maternal serum free beta-human chorionic gonadotropin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A) and fetal nuchal translucency (NT) thickness in Chinese women and to examine the effects of covariates on their levels. Maternal serum free beta-hCG, PAPP-A and fetal NT were measured in 9762 women presenting for first-trimester combined screening for Down syndrome at 11 to 14 weeks of gestation. Individuals' markers were converted to multiples of the median (MoM) using expected medians estimated by performing a weighted regression analysis. Multivariate regression analysis was performed to assess the influence of maternal weight, parity, ethnicity, chorionicity in twin pregnancies, smoking, insulin-dependent diabetes and mode of conception on individual marker MoM levels. Both free beta-hCG and PAPP-A median values demonstrated an exponential relationship with gestational age in days. Multivariate regression analysis indicated that free beta-hCG MoM was statistically significantly dependent on maternal weight (P < 0.0001) and chorionicity in twin pregnancy (both monochorionic and dichorionic P < 0.0001), that PAPP-A MoM was dependent on maternal weight (P < 0.0001), parity (P < 0.0001), chorionicity in twin pregnancy (both monochorionic and dichorionic P < 0.0001) and mode of conception (P = 0.002), and that fetal NT-MoM was dependent on maternal weight (P = 0.0006) and mode of conception (P = 0.012). Normative values have been generated to allow conversion of NT, free beta-hCG and PAPP-A to their MoM equivalents and correction factors have been determined to adjust for maternal and pregnancy characteristics for use in ethnic Chinese women undergoing first-trimester screening for aneuploidy.

Fetal nasal bone in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation

To investigate the performance of first-trimester screening for aneuploidies by including assessment of the fetal nasal bone in the combined test of maternal age, fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Screening by the combined test was performed in singleton pregnancies, including 19,614 with euploid fetuses, 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and eight with Turner syndrome. In all cases the fetal nasal bone was assessed and classified as present or absent. We examined the performance of two screening strategies: firstly, assessment of the nasal bone in all patients and secondly, first-stage screening using the combined test in all patients followed by second-stage assessment of the nasal bone only in those with an intermediate risk of 1 in 51 to 1 in 1000 after the first stage. To validate the new risk algorithm we used a second independent dataset of 19 651 fetuses, including 139 with trisomy 21. The nasal bone was absent in 2.6% of the euploid fetuses, 59.8% with trisomy 21, 52.8% with trisomy 18, 45.0% with trisomy 13 and in none of the fetuses with Turner syndrome. Respective figures for an absent nasal bone in the validation population, which contained fewer Black women, were 0.6%, 62.6%, 55.3%, 35.3% and 41.7%. In a screening policy based on maternal age, fetal NT, FHR, serum free beta-hCG and PAPP-A, for a fixed risk cut-off of 1 : 100, the false-positive rate was 3.0%. The standardized detection rates were 91% for trisomy 21 and 100% for trisomy 18, trisomy 13 and Turner syndrome, respectively. Assessment of the nasal bone in all pregnancies reduced the false-positive rate to 2.5% without changing the detection rate. A detection rate of 93% was achieved with the two-stage strategy at a false-positive rate of 2.4% in which it was necessary to assess the nasal bone in only 15% of the total population. In the validation dataset, screening by the combined test and using a risk cut-off of 1 : 100 detected 90% of the cases with trisomy 21 for a false-positive rate of 4%. Inclusion of the nasal bone increased the detection rate to 92% for a false-positive rate of 2.9%. Contingent screening detected 92% of cases for a false-positive rate of 2.9%. Assessment of the fetal nasal bone improves the performance of first-trimester screening for trisomy 21.

Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11 + 0 to 13 + 6 weeks of gestation

To investigate the performance of first-trimester screening for aneuploidies by including assessment of tricuspid blood flow in the combined test of maternal age, fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein A (PAPP-A). Screening by the combined test was performed in singleton pregnancies, including 19 614 with chromosomally normal fetuses or the delivery of a phenotypically normal baby (euploid group), 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and eight with Turner syndrome. In all cases tricuspid flow was assessed to determine if there was tricuspid regurgitation. We examined the performance of two screening strategies: firstly, assessment of tricuspid flow in all patients and secondly, first-stage screening using the combined test in all patients followed by second-stage assessment of tricuspid flow only in those with an intermediate risk of 1 in 51 to 1 in 1000 after the first stage. Tricuspid regurgitation was observed in 0.9% of the euploid fetuses and 55.7%, 33.3% and 30% of the fetuses with trisomies 21, 18 and 13, respectively, and in 37.5% of those with Turner syndrome. In a screening policy based on maternal age, fetal NT, FHR, serum free beta-hCG and PAPP-A, for a fixed false positive rate of 3% the standardized detection rates were 91% for trisomy 21 and 100% for trisomy 18, trisomy 13 and Turner syndrome. Assessment of tricuspid flow in all pregnancies would increase the detection rate of trisomy 21 to 96%, and the detection rates of trisomy 18, trisomy 13 and Turner syndrome would be 92%, 100% and 100%, respectively. The same detection rates were achieved with the two-stage strategy-in which it was necessary to assess tricuspid flow in only 15% of the total population-at a false positive rate of 2.4%. Assessment of tricuspid flow improves the performance of first-trimester screening for trisomy 21.

Screening for trisomy 18 by maternal age, fetal nuchal translucency, free β‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A

To derive a model and examine the performance of first-trimester screening for trisomy 18 by maternal age, fetal nuchal translucency (NT) thickness, and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Prospective combined screening for trisomy 21 was performed at 11 + 0 to 13 + 6 weeks in 56 893 singleton pregnancies, including 56 376 cases of euploid fetuses, 395 with trisomy 21 and 122 with trisomy 18. The measured free beta-hCG and PAPP-A were converted into a multiple of the median (MoM) and then into likelihood ratios (LR). Similarly, the measured NT was transformed into LRs using the mixture model of NT distributions. In each case the LRs for NT and the biochemical markers were multiplied by the age and gestation-related risk to derive the risk for trisomy 21 and trisomy 18. Detection rates (DRs) and false-positive rates (FPRs) were calculated by taking the proportions with risks above a given risk threshold. In screening with the algorithm for trisomy 21, at a FPR of 3%, the estimated DRs of trisomies 21 and 18 were 89% and 82%, respectively. The use of an algorithm for trisomy 18 identified 93% of affected fetuses at a FPR of 0.2%. When the algorithm for trisomy 21 was used and screen positivity was fixed at a FPR of 3%, and in addition the algorithm for trisomy 18 was used and screen positivity was fixed at a FPR of 0.2%, the overall FPR was 3.1% and the DRs of trisomies 21 and 18 were 90% and 97%, respectively. A beneficial side effect of first-trimester combined screening for trisomy 21 is the detection of a high proportion of fetuses with trisomy 18. If an algorithm for trisomy 18 in addition to the one for trisomy 21 is used, more than 95% of trisomy 18 fetuses can be detected with a minor increase of 0.1% in the overall FPR.

Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A

To derive a model and examine the performance of first-trimester combined screening by maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Prospective combined screening for trisomy 21 was carried out at 11 + 0 to 13 + 6 weeks in 56,771 singleton pregnancies, including 56,376 cases with a normal karyotype or delivery of a phenotypically normal baby (unaffected group) and 395 cases with trisomy 21. The blood test and ultrasound scan were carried out in the same visit. In each case the maternal age-related risk for trisomy 21 at term was calculated and adjusted according to the gestational age at the time of screening to derive the a-priori risk. The measured NT was transformed into a likelihood ratio using the mixture model of NT distributions. The measured free beta-hCG and PAPP-A were converted into a multiple of the median (MoM) for gestational age, adjusted for maternal weight, ethnicity, smoking status, method of conception and parity, and a likelihood ratio was subsequently calculated. The likelihood ratios for NT and for the biochemical markers were multiplied by the a-priori risk to derive the patient-specific risk. Detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000-2002. These standardized rates were compared with detection and false-positive rates estimated using Monte Carlo methods to sample from the modeled Gaussian distributions. The performance of screening based on the model was in good agreement with that observed in our population. In a strategy for first-trimester combined screening where the blood test and scan are carried out in the same visit it was estimated that, for false-positive rates of 3% and 5%, the detection rates were 92% and 94%, respectively, at 11 weeks, 85% and 90% at 12 weeks, and 79% and 83% at 13 weeks. In an alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, the estimated detection rates were 94% and 96% for false-positive rates of 3% and 5%, respectively. The aim of the first-trimester scan is not just to screen for trisomy 21 but also to diagnose an increasing number of fetal malformations. In this respect the ability to visualize fetal anatomy is better at 12-13 weeks than at 11 weeks. Consequently, the ideal gestation for combined testing in the same visit would be 12 weeks. An alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, is associated with higher detection rates of trisomy 21. However, the cost of two-stage screening would be higher and, in addition, the potential advantage in terms of detection rate may be eroded by the likely increased non-compliance with the additional step.

The Use of Nuchal Translucency in Contemporary Obstetric Practice

Nuchal translucency sonography is the most powerful single prenatal marker for Down syndrome. Its detection rate is 75% at a 5% false-positive rate. The combination of nuchal translucency and maternal serum-free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A can identify 85% to 90% of fetuses with Down syndrome for a false-positive rate of 5%. This method can also identify more than 90% of fetuses with trisomies 18 and 13, Turner syndrome, and triploidy for a screen-positive rate of 1%.

First‐trimester ultrasound and biochemical markers of aneuploidy and the prediction of preterm or early preterm delivery

To examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict preterm delivery. We examined 54 722 singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the median (MoM) of the expected normal median for a pregnancy of the same gestation and the measurements of fetal NT were expressed as the difference (delta) from the normal median NT for crown-rump length. The association between free beta-hCG, PAPP-A and delta NT and the incidence of preterm delivery before 37 weeks or early preterm delivery before 34 weeks was assessed by comparing the relative incidence at a number of MoM or delta NT cut-offs and at various centile cut-offs. At various marker levels the likelihood ratios (LR) for preterm delivery and early preterm delivery were also calculated after excluding other adverse pregnancy complications. The risk of preterm delivery increased with decreasing maternal serum PAPP-A. In the 3132 cases delivering before 37 weeks the PAPP-A MoM was 0.91 and in the 1060 cases delivering before 34 weeks the PAPP-A MoM was 0.90. At the 5th centile of the normal outcome group for PAPP-A (0.415 MoM) the odds ratios for delivery before 37 weeks and before 34 weeks were 1.92 and 2.35, respectively. The respective values for the 5th centile of free beta-hCG (0.41 MoM) were 1.18 and 1.08 and for the 95th centile of delta NT they were 0.91 and 0.77, respectively. Low levels of maternal serum PAPP-A are associated, in the absence of an abnormal karyotype, with an increased risk of preterm or early preterm delivery. The LR profiles provided at various levels of PAPP-A may be of some help in counseling women with such results and may raise awareness among healthcare professionals for increased surveillance in such cases.

Combining fetal nuchal fold thickness with second‐trimester biochemistry to screen for trisomy 21

To assess second-trimester screening for trisomy 21 by combining ultrasound nuchal fold (NF) measurement with maternal serum biochemistry. NF, maternal serum alpha-fetoprotein (AFP) and free beta-human chorionic gonadotropin (beta-hCG) were determined concurrently at 14-19 weeks' gestation in a study population comprising 1813 women with singleton pregnancies, including 1257 unselected women undergoing serum screening for trisomy 21 (1999-2002), and 556 high-risk pregnancies prior to amniocentesis (2003-2005), 402 of whom had positive serum screening tests. The results were expressed in multiples of the gestation-specific normal median (MoMs). There were 1799 unaffected singleton pregnancies, and their NF values approximately fitted a log Gaussian distribution over a wide range. There was a weak but statistically significant correlation between log NF and log AFP (r = - 0.069, P < 0.005) and the correlation coefficient between log NF and log free beta-hCG was even smaller and not statistically significant (r = 0.038, P = 0.11). Among the seven trisomy 21 pregnancies, the median NF level was 1.53 MoM (geometric mean 1.75 MoM), a highly statistically significant increase compared with unaffected pregnancies (P < 0.0001, one-tail Wilcoxon Rank Sum Test). In pregnancies referred because of positive serum screening tests (391 unaffected, seven cases of trisomy 21, one of monosomy X and three other chromosomal anomalies) the use of NF to modify the serum screening risk would have reduced the invasive procedures in unaffected pregnancies by 46% without affecting the detection rate of trisomy 21 or other anomalies. Statistical modeling predicted that adding NF to AFP and free beta-hCG would increase detection more than would adding unconjugated estriol as well as inhibin-A, an analyte that is difficult to measure with precision. The addition of NF measurement to second-trimester biochemical markers improves screening performance, and could overcome drawbacks in the implementation of inhibin-A assay in clinical practice.

First‐trimester biochemical markers of aneuploidy and the prediction of small‐for‐gestational age fetuses

To examine the clinical utility of the first-trimester biochemical markers of aneuploidy in their ability to predict subsequent delivery of a small-for-gestational age (SGA) infant. We examined singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the expected normal median (MoM) for a pregnancy of the same gestation. The association between free beta-hCG and PAPP-A and the incidence of SGA were assessed by comparing the relative incidence at MoM cut-offs and birth-weight centile cut-offs. At various marker levels the likelihood ratios (LR) for SGA were also calculated after excluding other adverse pregnancy complications. There were 46,262 pregnancies resulting in live births with birth weight at or above the 10(th) centile, and 3,539 below the 10(th) centile for gestation (SGA). There was a significant inverse association between the risk for SGA and maternal serum PAPP-A MoM but not free beta-hCG MoM. At the 5(th) centile of the normal outcome group for PAPP-A (0.415 MoM) the odds ratios for SGA below the 10(th), 5(th) and 3(rd) centiles of normal were 2.70, 3.21 and 3.66 and the respective detection rates for SGA were 12.0%, 14.0% and 16.0%. Low levels of maternal serum PAPP-A are associated, in the absence of an abnormal karyotype, with an increased risk for subsequent delivery of an SGA infant.

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

To investigate the influence of cigarette or sheesha smoking on first-trimester markers of Down syndrome. A prospective observational study. Primary care centres and antenatal clinics of Maternity and Children Hospital, King Abdulaziz University Hospital and New Jeddah Clinic Hospital, Jeddah, Saudi Arabia. Women with a singleton pregnancy who were either nonsmokers (n = 1736) or cigarette smokers (n = 420) or sheesha smokers (n = 181). Fetal nuchal translucency thickness (fetal NT), maternal serum free beta-human chorionic gonadotrophin (free beta-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. Fetal NT, maternal serum free beta-hCG, PAPP-A and cotinine measurements. Compared with nonsmoking women, fetal NT was significantly increased and free beta-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. Cigarette and sheesha smoking significantly affect first-trimester markers of Down syndrome (fetal NT, free beta-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.

Maternal serum free‐β‐chorionic gonadotrophin, pregnancy‐associated plasma protein‐A and fetal nuchal translucency thickness at 10–13+6 weeks in relation to co‐variables in pregnant Saudi women

To establish normative values and distribution parameters of first-trimester screening markers, namely, fetal nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), at 10 to 13(+6) weeks of gestation in Saudi women and to evaluate the effect of co-variables including maternal body weight, gravidity, parity, fetal gender, twin pregnancy, smoking and ethnicity on these markers. A cohort of Saudi women (first cohort n = 1616) with singleton pregnancies prospectively participated in the present study, and fetal NT together with maternal serum free beta-hCG and PAPP-A were determined at 10 to 13(+6) weeks of gestation. The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and normative values were established, and correction for maternal body weight was made accordingly. The influence of various co-variables was examined using the data collected from the first and the second (n = 1849) cohorts of women and 62 twin pregnancies, and compared with other studies. All markers exhibited log-normally distributed MoMs. Gestational age-independent normative values were established. Maternal body weight was corrected, particularly for maternal free beta-hCG and PAPP-A using standard methods. Fetal NT showed a negative relationship with increasing gravidity (r = -0.296) or parity (r = -0.311), whereas both free beta-hCG and PAPP-A exhibited a significant positive relationship. There was a significant increase in the MoM of free beta-hCG in female fetuses. Smoking decreased MoM values of free beta-hCG (by 14.6%; P < 0.01) and PAPP-A (by 18.8%; P < 0.001). Twin pregnancy showed significant increases in MoM values of free beta-hCG (by 1.87-fold) and PAPP-A (by 2.24-fold), with no significant changes in fetal NT MoM values. Fetal NT MoM values were lower in Africans and Asians but higher in Orientals, as compared to Saudi women (P < 0.05; in each case). MoM values (body weight-corrected) of free beta-hCG were 25.2% higher in Africans and 19.4% higher in Orientals but 6.8% lower in other Arabian and Asian (by 5.8%) women as compared to Saudi women (P < 0.05; in each case). The normative values and distribution parameters for fetal NT, maternal serum free beta-hCG and PAPP-A were established in Saudi singleton pregnancies, the maternal body weight together with smoking, twin pregnancy and ethnicity being important first-trimester screening co-variables. Gravidity, parity and fetal gender are also considered to influence one or more of the first-trimester markers examined.