Maternal Serum Free beta-hCG Research Articles

Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening

IntroductionExtreme levels of either PAPP-A or free β-hCG may be a serious clinical concern. A multicentre study was carried out to determine the frequency and clinical consequences of high (minimum 2,0 MoM) maternal (PAPP)-A and free beta hCG. MethodsA total number of 8591 patients with singleton pregnancies between 11 + 0–13 + 6 weeks of gestation were enrolled. A total number of 612 cases with first trimester serum level of PAPP-A corresponding to ≥ 2,0 MoM and/or free β-hCG to ≥ 2,0 MoM were included in the statistical analysis. All serum samples were analysed with Roche (Cobas) or Kryptor (Brahms) devices. A retrospective analysis of perinatal outcomes was conducted. ResultsValues of PAPP-A ≥ 2,0 MoM and free β-hCG < 2.0 MoM were detected in 48,5% of patients (n = 297), free β-hCG ≥ 2,0 MoM and PAPP-A concentration < 2,0 MoM in 38,1% of patients (n = 233) and both PAPP-A and free β-hCG ≥ 2,0 multiple of median in 13,4% of patients (n = 82). The highest PAPP-A and free β-hCG concentrations were 19,2 MoM and 16,3 MoM respectively. Patients with both PAPP-A and free β-hCG above 2,0 MoM had a slightly higher (but statistically not significant) prevalence of history of low birthweight (8,3%). DiscussionPregnancy outcomes in women with normal ultrasound findings and high PAPP-A /free β-hCG concentration are good. Higher prevalence of pregnancy complications was not detected in either extremely high PAPP-A and free β-hCG concentration groups. In cases of normal ultrasound and isolated high (even extreme) biochemical markers levels the counselling should be comforting.

A risk prediction model for fetal hypospadias by testing maternal serum AFP and free beta-HCG

ObjectiveWe aimed to determine the correlation between serum alpha-fetoprotein (AFP), the free human chorionic gonadotropin beta subunit (free beta-HCG) in pregnant women during the mid-trimester, and fetal hypospadias, and tried to establish a risk prediction model. MethodsA multi-center case-control study was conducted. We divided the fetuses into two groups (69 with fetal hypospadias and 62 without fetal hypospadias). Time-resolved immunofluorescence was used to determine the serum levels of AFP and free beta-HCG. The best cut -value and area under curve (AUC) were determined based on the Receiver operating characteristics (ROC) curve, and the diagnostic value of AFP and free beta-HCG was evaluated. ResultsThe level of AFP in the study group was 1.14 multiple of Median(MOM), which was higher than in the control group (0.96 MOM); the difference was significant (Z = 2.831, P = .005). Similarly, the free beta-HCG level was 1.30 MOM in the study group, and was also significantly higher than in the control group (0.84 MOM; Z = 3.131, P = .004). We used the AFP and free beta-HCG levels separately to predict fetuses with hypospadias, and the AUCs were 0.644 (95% Confidence interval (CI): 0.5500.737, P = .005) and 0.659 (95% CI: 0.5650.752, P = .002), respectively. According to the ROC curve, the best cut-off values for AFP and free beta-HCG were 0.945 MOM and 1.275 MOM, respectively. When we combined the AFP level with the free beta-HCG level, the AUC was 0.700 (95% CI: 0.610–0.789, P < .001), with a sensitivity of 0.551 and a specificity of 0.855. ConclusionCombined screening for fetal hypospadias with maternal serum AFP and free beta-HCG levels during the early second trimester has high sensitivity and specificity, which can be used as a new marker.

Maternal serum alpha fetoprotein and free β-hCG of second trimester for screening of fetal gastroschisis and omphalocele

To assess the detection of maternal serum alpha fetoprotein (MSAFP) and free beta-HCG levels of second trimester for screening of fetal gastroschisis and omphalocele. Clinical data of 622 639 pregnant women from 5 prenatal screening centers in Hangzhou during October 2007 and September 2016 were analyzed retrospectively. Thirty cases of gastroschisis and 30 cases of omphalocele diagnosed by ultrasonography and postmortem findings were enrolled in the study and 116 cases of pregnant women with normal fetal development during the same period were selected as control group. The cut-off value and area under ROC curve (AUC) of MSAFP and free β-hCG for diagnosis of fetal gastroschisis and omphalocel were analyzed. MSAFP levels of women with fetal gastroschisis and omphalocele were 4.41 (0.88-11.69) MOM and 2.31 (0.72-23.20) MOM, which were significantly higher than that of control group[0.98 (0.41-2.26) MOM, all P<0.01]. Free β-hCG level of women with fetal gastroschisis was 1.25 (0.35-19.94) MOM, which was significantly higher than that of control group[0.86 (0.17-6.11) MOM, P<0.05). But there were no significant difference in free β-hCG between fetal omphalocele group[1.03(0.21-8.95)]and control group (P>0.05). The AUCs of MSAFP for diagnosis of gastroschisis and omphalocele were 0.897 (95% CI:0.822-0.972) and 0.852(95% CI:0.762-0.942), respectively (all P<0.01). Taking 1.655 MOM as the cut-off value of MSAFP for abdominal wall defects (gastroschisis and omphalocele), the sensitivity was 68.30%, specificity was 99.60% and Youden index was 0.649. MSAFP of second trimester is a better biomarker than free β-hCG in screening abdominal wall defects.

Is maternal renal disease a cause of elevated free β‐hCG in first trimester aneuploidy screening?

To asses whether supra elevated levels of maternal serum free beta hCG in the first trimester are associated with impaired renal function. A cohort of 553 women with maternal serum free beta-hCG greater than 5 multiple of median (MoM) with a single euploid fetus was matched with a control of the same maternal age (+/-1 year), ethnic origin and with a free beta-hCG within the range 0.50-1.50 MoM. Screening samples were analysed for serum creatinine and estimated glomerular filtration rate was calculated. Renal function in the two groups was compared. The database was examined to find outcomes registered as known renal disease amongst the high free beta-hCG group. In the group with a supra elevated free beta-hCG MoM there was a significant reduction in estimated glomerular filtration rate (eGFR) (122.85, 95% CI 120.43-124.74 vs 118.80, 95% CI 114.90-121.59; p = 0.009) suggesting a small but increased risk of renal disease. The presence of renal disease should also be considered as one potential cause of supra elevated levels of free beta-hCG in addition to the possibility of paternally derived triploidy and trisomy 21.

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.

Effect of deviation of nuchal translucency measurements on the performance of screening for trisomy 21

To examine the effect of deviations in median nuchal translucency thickness (NT) and the spread in measurements on the performance of screening for trisomy 21 by maternal age and fetal NT, and by maternal age, fetal NT and maternal serum biochemistry. We simulated the NT and multiples of the median values for pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) for 500 000 euploid and 500 000 trisomy 21 pregnancies at 12 weeks of gestation. Detection rates for trisomy 21 and false-positive rates were calculated without adjustments in NT and by adding or subtracting values ranging from 0.1 to 1.0 mm to each observed measurement. In addition, the effects of variation in the scatter of NT measurements were examined by applying a multiplicative factor ranging from 0.5 to 2 to the SD. The detection rate of trisomy 21 for a fixed false-positive rate of 3% in screening by maternal age and fetal NT was 72%, and in screening by maternal age, fetal NT and serum free beta-hCG and PAPP-A it was 86%. A consistent underestimate or overestimate in the measured NT reduced the detection rate of trisomy 21 for a fixed-false positive rate. At a fixed screen-positive cut-off an underestimate in fetal NT reduced the detection rate whereas an overestimate in NT increased the false-positive rate. A widening in the scatter of measurements had only a small impact on the detection rate but it caused a major increase in the false-positive rate. High performance of screening necessitates appropriate measurement of fetal NT. This paper demonstrates the effect of deviations in the median and SD of NT from the expected on the performance of screening and can form the basis of audit of results of individual sonographers.

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.

Early first‐trimester free β‐hCG and PAPP‐A serum distributions in monochorionic and dichorionic twins

In the Netherlands, prenatal screening for trisomy 21 in the first trimester of pregnancy for singletons is conducted through a combined test based on maternal age, nuchal translucency measurement and maternal serum free beta-hCG and PAPP-A. In our clinic risk calculations in twins are currently based on the NT of both fetuses instead of the combined test. In this study we looked at differences in early first-trimester free beta-hCG and PAPP-A between mono- and dichorionic twins. A total of 202 twin pregnant women participated in the study and agreed to donate first-trimester serum for research. The data of 200 twins with normal outcome were used for setting up reference values for free beta-hCG and PAPP-A. Trisomy 21 was identified in the two remaining pregnancies. The overall median weight-corrected MoM was 1.99 for free beta-hCG, and 2.14 for PAPP-A in all twins. Monochorionic twins have a significantly lower free beta-hCG weight-corrected MoM (1.53 vs 2.11; Mann-Whitney U, p=0.002) and a significantly lower PAPP-A weight-corrected MoM (1.59 vs 2.40; Mann-Whitney U, p=0.003) compared to dichorionic. This study strengthened the need to make a distinction between mono- and dichorionic twins for the risk calculation in Down syndrome screening as biochemical markers are significantly lower in monochorionic than in dichorionic twins.

A New Approach to Calculating the Risk of Chromosomal Abnormalities with First-Trimester Screening Data

First-trimester screening at 11 - 14 weeks has been proven to be very useful in the early detection of chromosomal defects. The aim of this project was to develop a CE-certified new risk calculation program (PRC = Prenatal Risk Calculation) using a nationwide database. The database underlying the new risk calculation procedure was established in Germany from 2003 through 2006. Overall, the database includes measurements from 70,030 pregnant women having given birth to healthy children. Following consideration of all pregnancies associated with a chromosomally abnormal outcome, the sample size was 451. The algorithm used for calculating the risk of a chromosomally abnormal outcome comprises the following variables: maternal age, crown-rump length (CRL) (restricted to a range from 45 - 84 mm or, equivalently, 11 + 1 - 14 + 0 weeks of gestation), nuchal translucency (NT), as well as the maternal serum parameters PAPP-A (pregnancy associated plasma protein A) and free beta-hCG (free human chorionic gonadotropin). In a preliminary cross-validation study, we applied both the new algorithm and the FMF UK program to an independent sample containing n = 40,568 pregnancies with negative outcome, n = 187 cases of trisomy 21, n = 34 trisomies 18 and n = 13 trisomies 13. Using the primary sample of 70,030 pregnancies with a negative outcome, reference bands were constructed for the sonographic parameter fetal nuchal translucency and the biochemical parameters PAPP-A and free beta-HCG. Instead of MoM values we used "degree of extremeness" (DoE) values. This statistical parameter has been proven to give more precise results than the MoM measure because it assesses the deviation of the actual measurement value from the centre of the reference band expressed as a multiple of the width of the respective band section. The result of the risk calculation is visualized by means of a traffic light graph which allows the patient to comprehend her individual risk at first glance. The red color indicates a high risk, green a low risk, and yellow represents a moderate risk. In our preliminary cross-validation study the detection rate obtained for the German algorithm was 86.6 % for trisomy 21, 94.1 % for trisomy 18 and 92.4 for trisomy 13. The corresponding detection rates obtained with the same data by the FMF UK program were 86.1 %, 82.3 % and 69.2 % throughout. The false-positive rate was 5.0 % throughout. The new risk calculation procedure of the FMF Germany (PRC) has been made available as a CE-certified computer program. In screening for trisomy 21 it yields results comparable to those of the program used by the FMF UK. Regarding the diagnosis of trisomy 13 and 18, even higher detection rates are currently achieved with the German algorithm. Program, data base and license key are available free of charge to registered members of the FMF Germany.

Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free -hCG and pregnancy-associated plasma protein-A

A beneficial consequence of screening for trisomy 21 is the early diagnosis of trisomies 18 and 13. Our objective was to examine the performance of first-trimester screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and maternal serum-free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A). Prospective screening for trisomy 21 by maternal age, fetal NT, free beta-hCG and PAPP-A at 11(+0)-13(+6) weeks in singleton pregnancies, including 56 376 normal cases, 395 with trisomy 21, 122 with trisomy 18 and 61 with trisomy 13. Risk algorithms were developed for the calculation of patient-specific risks for each of the three trisomies based on maternal age, NT, FHR, free beta-hCG and PAPP-A. Detection (DR) and false positive rates (FPR) were calculated and adjusted according to the maternal age distribution of pregnancies in England and Wales in 2000-2002. The DR and FPR were 90% and 3%, respectively, for trisomy 21, 91% and 0.2% for trisomy 18 and 87% and 0.2% for trisomy 13. When screen positivity was defined by an FPR of 3% on the risk for trisomy 21 in conjunction with an FPR of 0.2% on the maximum of the risks for trisomies 13 and 18, the overall FPR was 3.1% and the DRs of trisomies 21, 18 and 13 were 91%, 97% and 94%, respectively. As a side effect of first-trimester screening for trisomy 21, approximately 95% of trisomy 13 and 18 fetuses can be detected with an 0.1% increase in the FPR.

First‐trimester screening for trisomy 21 by free beta‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A: impact of maternal and pregnancy characteristics

To use multiple regression analysis to define the contribution of maternal variables that influence the measured concentration of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), and the interaction between these covariates, in first-trimester biochemical screening for trisomy 21. This was a multicenter study of prospective screening for trisomy 21 by a combination of fetal nuchal translucency thickness, and maternal serum free beta-hCG and PAPP-A at 11 + 0 to 13 + 6 weeks of gestation. In the pregnancies subsequently found to have trisomy 21 and in those with no obvious chromosomal abnormality, we used multiple regression analysis to account for pregnancy characteristics that influence the measured concentrations of free beta-hCG and PAPP-A. We fitted Gaussian distributions to the distribution of log multiples of the median (MoM) values in trisomy 21 and in unaffected pregnancies. There were 491 cases of trisomy 21 and 96 803 chromosomally normal pregnancies. Compared with values in Caucasian women, those who were parous, non-smokers and those who conceived spontaneously, PAPP-A was 57% higher in women of Afro-Caribbean origin, 3% higher in South Asians, 9% higher in East Asians, 2% higher in nulliparous women, 17% lower in smokers and 10% lower in those conceiving by in-vitro fertilization (IVF). Free beta-hCG was 12% higher in women of Afro-Caribbean origin, 9% lower in South Asians, 8% higher in East Asians, 2% higher in nulliparous women, 4% lower in smokers and 9% higher in those conceiving by IVF. In screening for trisomy 21 by maternal age and serum free beta-hCG and PAPP-A the estimated detection rate was 65% for a false-positive rate of 5%. In first-trimester biochemical screening for trisomy 21 it is essential to adjust the measured values of free beta-hCG and PAPP-A for maternal and pregnancy characteristics.

OP25.05: First trimester combined screening for trisomy 21 in a predominantly Chinese population

To examine the effectiveness of first-trimester fetal Trisomy 21 (T21) screening using a combination of maternal age, nuchal translucency (NT), maternal serum free beta-hCG and PAPP-A levels in a predominantly Chinese population in Hong Kong. A prospective study performed in a university fetal medicine unit over a three and a half-year period. Consecutive women who underwent the combined screening for T21 between 11 and 13 + 6 weeks of gestation were recruited. NT was measured according to the criteria set by the Fetal Medicine Foundation (FMF). Maternal serum biochemistry was measured by Kryptor analyzer. Risk of T21 was calculated using FMF's algorithm. Fetal karyotyping was advised when the risk was 1 : 300 or above for T21, or 1 : 150 for T13/18. All subjects were followed up for pregnancy and fetal outcome. Among the 9333 women who underwent the screening program, 99% were Chinese and 173 women had a twin pregnancy, with a total of 9506 fetuses. 27.1% of the women were at or above 35 years old. 558 fetuses were screened positive (5.98%) for T21 (with or without increased risk for T13/18). Another 18 cases were positive for T13/18 only, making a total of 576 (6.17%). There were a total of 26 cases of T21, of which two were screened negative (detection rate of 92.3%). There were five cases of T13, 12 cases of T18, 10 cases of monosomy X, and six cases of other chromosomal abnormalities; all were screened positive. The overall positive predictive value for chromosomal abnormality was 1 in 9.9. First-trimester combined screening for fetal T21 is highly effective among Chinese subjects.

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.

Dose dependency between cigarette consumption and reduced maternal serum PAPP‐A levels at 11–13+6 weeks of gestation

To examine whether in smokers there is a significant dose dependency between the number of cigarettes per day and levels of free ss-hCG and pregnancy-associated plasma protein A (PAPP-A) at 11-13(+6) weeks of gestation. This was a retrospective analysis of the maternal serum free ss-hCG and PAPP-A levels in relation to the maternal smoking status in 109 263 chromosomally normal singleton pregnancies that had undergone first-trimester screening for Down syndrome by a combination of fetal nuchal translucency thickness and maternal serum biochemistry. There were 95 287 nonsmokers and 13 976 cigarette smokers. The overall median PAPP-A MoM among cigarette smokers was 0.827, which was 19.6% lower than the value of 1.029 in nonsmokers (p < 0.0001 for log(10) MoM). The respective values for beta-hCG MoM were 1.003 for smokers and 1.035 for nonsmokers (p < 0.0001 for log(10) MoM) which corresponds to a reduction of 3.1%. There was a significant inverse relationship between the number of cigarettes per day and the level of PAPP-A MoM (r = 0.989, p < 0.0001) but not the level of free beta-hCG MoM (r = 0.733; p = 0.098). Using a statistical modeling approach we found that the screen-positive rate when correcting the PAPP-A MoM by an all or nil smoking factor was reduced by only 0.1% (3.75 vs 3.85%) when compared to correcting with a factor related to the smoking dose per day. In first-trimester screening for Down syndrome by maternal serum PAPP-A and free beta-hCG the impact of correcting for the dose dependant rather than the all or nil effect of smoking is marginal. However, a dose dependent correction improves the accuracy of the individual patient-specific risk.

Maternal serum free ß‐hCG and PAPP‐A in patients with habitual abortion‐influence on first‐trimester screening for chromosomal abnormalities

To explore if maternal serum free beta-hCG and pregnancy-associated plasma protein A (PAPP-A) levels in the first-trimester of pregnancy are altered in patients with habitual abortions and if there is an effect on first-trimester screening for Down syndrome. A retrospective study was conducted on 913 normal singleton fetuses that underwent first-trimester combined screening for Down syndrome. Maternal serum PAPP-A and free beta-hCG were compared between patients with (n = 64) and without habitual abortions (n = 849). The medians +/- SD log(10) MoM of PAPP-A and free beta-hCG +/- SD in patients with and without habitual abortions were 0.063 +/- 0.28 versus - 0.014 +/- 0.27 and - 0.001 +/- 0.27 versus - 0.018 +/- 0.31, with a p value of 0.042 and 0.87, respectively. The screen positive rate setting the cut off at 1:350 looking at the background risk for trisomy 21 was 71.4% in women with and 81.2% in women without habitual abortion, after combined first-trimester screening it was 7.8% in women with and 10.1% in women without recurrent abortion. Patients with habitual abortions have slightly increased maternal serum PAPP-A levels in the first-trimester. This marginal difference seems not to effect risk calculation in combined first-trimester screening for trisomy 21.

Influence of maternal systemic lupus erythematosus on first‐trimester combined screening for chromosomal abnormalities

To explore the effect of maternal systemic lupus erythematosus (SLE) on first-trimester screening markers for Down syndrome. A retrospective study was conducted on 1150 normal singleton fetuses that underwent first-trimester combined screening for Down syndrome. Fetal delta nuchal translucency (NT), maternal serum PAPP-A and free beta-hCG were compared between pregnancies with SLE (n = 10) and without preexisting maternal disease (n = 1140). The medians +/- SD for delta NT, log(10) MoM of PAPP-A and free beta-hCG +/- SD in pregnancies with SLE and without maternal disease were - 0.18 +/- 0.29 versus - 0.18 +/- 0.33, 0.005 +/- 0.32 versus 0.02 +/- 0.26, and 0.22 +/- 0.19 versus - 0.014 +/- 0.28, with a p value of 0.7, 0.98 and 0.03, respectively. Patients with preexisting SLE have increased maternal serum-free beta-hCG levels in the first-trimester. But, because of the multimodal procedure of risk calculation there is no significant difference in the screen-positive rate after the combined first-trimester screening for trisomy 21.

Comparing First Trimester Screening Performance: Routine Care Gynaecologists’ Practices vs. Prenatal Centre

To evaluate and compare the screening performance for fetal trisomy 21 in the first trimester of pregnancy in general gynaecologists' practices and specialised centres for prenatal care in Germany. This study included 15,026 serum samples analysed in our laboratory for free beta-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks of gestation between 1.1.2000 and 31.12.2003. Fetal risk for trisomy 21 was calculated using nuchal translucency (NT) values and crown-rump-lengths (CRL), measured either in general gynaecologists' practices or in a tertiary level prenatal centre. The detection rate for a fixed risk cut-off (1:300) and a fixed false-positive rate (5 %) was calculated for NT, serum biochemistry, maternal age and the combination of these components. The estimated risk for trisomy 21 based on maternal age, fetal NT and maternal serum free beta-hCG and PAPP-A was 1 in 300 or greater in 5.1 % (362 of 6897) and 8 % (329 of 3840) of normal pregnancies, and in 78.9 % (15 of 19) and 88.5 % (23 of 26) of those with trisomy 21. For a fixed false-positive rate of 5 %, the respective detection rates of screening for fetal Down's syndrome by maternal age and serum free beta-hCG and PAAP-A, maternal age and fetal NT and by maternal age, fetal NT and maternal serum biochemistry were (general gynaecologists' practices/prenatal centre) 68.4/69.2 %, 42.1/65.4 % and 78.9/88.5 %, respectively. The screening results are satisfactory in both general gynaecologists' practices and a prenatal centre.

Does vaginal bleeding influence first‐trimester markers for Down syndrome?

To examine the effect of early vaginal bleeding on first-trimester screening markers for Down syndrome. A retrospective study was conducted on 1755 normal singleton fetuses that underwent first-trimester combined screening for Down syndrome on the basis of ultrasound and maternal serum markers. Fetal delta-nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG were compared between pregnancies with (n = 252) and without (n = 1503) an episode of vaginal bleeding. Subgroup analysis for the intensity of bleeding (spotting n = 191; light n = 32; heavy n = 29) was performed. The median +/- SD (log(10)) for delta-NT, multiple of medians (MoM) PAPP-A and MoM free beta-hCG (corrected for maternal weight, smoking and ethnicity) was - 0.17 +/- 0.62, 1.10 +/- 0.28, 1.1 +/- 0.28 and - 0.15 +/- 0.51, 0.98 +/- 0.26, 0.94 +/- 0.3 in pregnancies with and without a history of early vaginal bleeding, which were not significantly different. Exclusion of patients with spotting from the vaginal bleeding group revealed significantly higher maternal serum free beta-hCG MoM values (median +/- SD (log(10))) compared to patients without bleeding, 1.29 +/- 0.27 vs 0.96 +/- 0.3(p = 0.011). Screen-positive (cut off of 1:350) rate after combined first-trimester screening was 28.1% in patients with light vaginal bleeding and 8.4% in patients without bleeding (p = 0.001). Light vaginal bleeding before first-trimester combined screening for Down syndrome leads to a higher screen-positive rate after combined first trimester screening, without a significant difference in serum levels of the screening markers.

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.

First‐trimester combined screening for trisomy 21 in a predominantly Chinese population

To examine the effectiveness of first-trimester fetal trisomy 21 screening using a combination of maternal age, nuchal translucency thickness (NT) and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels in a predominantly Chinese population in Hong Kong. This was a prospective study over a 1.5-year period of 2990 women who underwent combined screening for trisomy 21 between 11+0 and 13+6 weeks of gestation in a university fetal medicine unit. NT was measured according to the criteria set by The Fetal Medicine Foundation (FMF), maternal serum free beta-hCG and PAPP-A levels were measured, and the risk of trisomy 21 was calculated using The FMF's algorithm. Fetal karyotyping was advised when the risk was 1 : 300 or above. All subjects were followed up for pregnancy and fetal outcome. Of the 2990 women who underwent the screening program, 99% were Chinese. There were 57 twin pregnancies, giving a total of 3047 fetuses. Thirty-one percent of the women were 35 years old or above. One hundred and eighty-five (6.1%) fetuses were screen-positive; this included 14 cases of trisomy 21 and 17 cases of other chromosomal abnormalities. The positive predictive value was 16.7%. Among the 2862 screen-negative fetuses, only 18 (0.6%) cases had an unknown fetal outcome. There were no cases in which trisomy 21 was missed and the infant was liveborn. First-trimester combined screening for fetal trisomy 21 is highly effective among Chinese subjects.