Free beta-hCG Levels Research Articles

First‐trimester ultrasound and biochemical markers of aneuploidy and the prediction of impending fetal death

To examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict future fetal loss. 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, 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 for a pregnancy of the same gestation (MoM) and the measurements of fetal NT were expressed as the difference (delta) from the normal median NT for crown-rump length (CRL). The association between free beta-hCG, PAPP-A and delta NT and the incidence of fetal loss prior to 24 weeks, at or after 24 weeks or at any time, 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 ratio (LR) for fetal loss was also calculated. The rate of fetal loss increased with decreasing maternal serum free beta-hCG and PAPP-A and increasing delta NT. At the 5th centile of the normal outcome group for free beta-hCG (0.41 MoM) the odds ratio for fetal loss before 24 weeks, at or above 24 weeks and at any gestation was 3.1, 1.8 and 2.6, respectively. The respective values for the 5th centile of PAPP-A (0.415 MoM) were 3.3, 1.9 and 2.8 and for the 95th centile of delta NT they were 2.5, 1.9 and 2.2, respectively. There was almost no correlation between reduced levels (<or=0.50 MoM) of PAPP-A and reduced levels of free beta-hCG in either the normal pregnancy group (r = 0.041) or the group with fetal death (r = 0.072), indicating relatively independent prediction by either biochemical marker. Low levels of maternal serum PAPP-A and free beta-hCG and increased fetal NT are associated, in the absence of an abnormal karyotype, with an increased risk of impending fetal death. The likelihood ratio profiles provided at various levels of PAPP-A or free beta-hCG may be of some help in counseling women with such results and raise awareness among health-care professionals for increased surveillance in such cases.

Does a “vanishing twin” affect first-trimester biochemistry in Down syndrome risk assessment?

The purpose of this study was to evaluate the impact of spontaneous reduction in multifetal pregnancy on first-trimester maternal serum biochemistry. We evaluated first-trimester pregnancy associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin levels in singleton euploid pregnancies. Biochemical values in pregnancies with evidence of spontaneous reduction were compared to other singleton pregnancies. Mann-Whitney U, Student t test, Fisher exact test, and logistic regression analysis were used for statistical comparison. There were 41 cases (0.9%) of spontaneous reduction. Though spontaneous reduction was not associated with different levels of either analyte, reduction within 4 weeks was associated with higher levels of both PAPP-A (1.79 vs 1.18; P = .002) and free beta-hCG (1.28 vs 0.96; P = .03) compared with other pregnancies. Spontaneous reduction was associated with a higher frequency of PAPP-A >95th %ile (17.1 vs 4.7%; P = .003) and free beta-hCG >95th %ile (17.1% vs 5.0%; P = .004). Logistic regression identified independent associations between spontaneous reduction and both high PAPP-A and high free beta-hCG. Recent spontaneous reduction is associated with higher values of PAPP-A and free beta-hCG. These differences have the potential to affect risk assessment for fetal aneuploidy.

Nuchal Translucency and First-Trimester Screening

irst-trimester screening for Down syndrome has become a commonly used approach in prenatal genetic diagnosis. The drive behind the development of earlier, reliable methods of genetic screening and risk assessment is the ability to provide the parents with more options at an earlier gestational age. Currently, this involves the sonographic evaluation of fetal nuchal translucency (NT) in combination with maternal serum levels of free beta-hCG and PAPP-A to provide a risk assessment for Down syndrome.1 This is referred to as combined first-trimester screening. Based on a survey of US maternal-fetal medicine specialists in 2001, of the 543 respondents, 46% used NT sonography and 27% used first-trimester maternal serum screening for Down syndrome.3 The term "nuchal translucency" refers to the fluid-filled space between the back of the fetal neck and the overlying skin.4 It has been noted that fetuses with Down syndrome, as well as other forms of aneuploidy, have increased edema in this area, resulting in an increased NT measurement.4 Based on seminal work by Nicolaides and others, measurement ofNT in fetuses between 11 and 14 weeks has been used since the early 1990's to provide earlier risk assessment of fetuses with aneuploidy.5 Initial results indicated detection rates comparable to second-trimester maternal serum screening.' However, three recent large trials, including the US-based Firstand SecondTrimester Evaluation of Risk (FASTER) trial, the North American-based First Trimester Maternal Serum Biochemistry and Ultrasound Fetal Nuchal Translucency Screening (BUN) Study, and the European-based Serum, Urine, and Ultrasound Screening Study (SURUSS) Trial have demonstrated that combined screening in the first trimester outperforms both NT and first-trimester serum screening when performed separately, with detection rates for Down syndrome ranging from 79%87% at a false positive rate of 5% 6 This compares favorably with performance of second-trimester serum screening, also referred to as the "quad" screen, which utilizes maternal serum levels of unconjugated estriol, free human chorionic gonadotropin, alpha-fetoprotein, and inhibin A, with a detection rate of 81%.7 Furthermore, the detection rate for trisomy 18 with the combined screen was comparable to the quad screen.8 There are still a number of issues which limit the use ofNT. The technical expertise required to obtain reliable and reproducible images has proven challenging. Furthermore, patients must have access to providers who are capable of performing first-trimester chorionic villus sampling when a patient screens positive. There is still no consensus as to the most efficient or

Prediction of pre‐eclampsia by uterine artery Doppler ultrasonography and maternal serum pregnancy‐associated plasma protein‐A, free β‐human chorionic gonadotropin, activin A and inhibin A at 22 + 0 to 24 + 6 weeks' gestation

To investigate the potential value of combining uterine artery Doppler ultrasonography with the measurement of maternal serum pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (beta-hCG), activin A and inhibin A at 22 + 0 to 24 + 6 weeks' gestation, in the prediction of pregnancies that subsequently develop pre-eclampsia. The maternal serum PAPP-A, free beta-hCG, activin A and inhibin A concentrations at 22 + 0 to 24 + 6 weeks' gestation were measured in samples obtained from women with singleton pregnancies who participated in a screening study for pre-eclampsia by transvaginal color flow Doppler measurement of the uterine artery pulsatility index (PI). A search was made of the database to identify those who subsequently developed pre-eclampsia (n = 24) and a group of controls with normal outcome (n = 144). Regression analysis was performed to establish any relationship between the biochemical markers themselves and between the biochemical markers and uterine artery mean PI. A multivariate Gaussian model combining various biochemical markers with uterine artery mean PI was developed using standard statistical modeling techniques and the performance of such models in discriminating cases with pre-eclampsia was evaluated by receiver-operating characteristics curve (ROC) analysis. In the pre-eclampsia group, compared to the controls, the uterine artery mean PI and the maternal serum levels of PAPP-A, free beta-hCG, activin A and inhibin A were significantly increased. The predicted detection rates of pre-eclampsia, for a false positive rate of 5%, was 50% by uterine artery mean PI, 5% by PAPP-A, 10% by free beta-hCG, 35% by inhibin A and 44% by activin A. Screening by a combination of uterine artery mean PI and maternal serum activin A and inhibin A could detect 75% and 92% of patients who subsequently developed pre-eclampsia, for false positive rates of 5% and 10%, respectively. Screening for pre-eclampsia by uterine artery PI at 22 + 0 to 24 + 6 weeks' gestation can be improved by measurement of activin A and inhibin A levels.

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

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. 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. 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. 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.

The efficacy of first-trimester PAPP-A and free βhCG levels for predicting adverse pregnancy outcome

To determine whether first-trimester measurements of maternal serum PAPP-A and free beta hCG levels were associated with adverse pregnancy outcomes. First trimester maternal serum free beta hCG and PAPP-A were measured in 490 singleton pregnancies. Pregnancies were followed by the fetal-maternal unit, and predictive efficacy of these markers for small for gestational age (SGA) babies, gestational diabetes mellitus and hypertensive disorders were analyzed by cut-off values determined by using a ROC analysis, and also, by using the fifth percentile as the cut-off value. The sensitivities for PAPP-A in predicting pregnancies with a SGA baby and those complicated by a hypertensive disorder were 49% and 73%, respectively, when optimal cut-off values were used. Specificities were 76% and 65%, respectively. Serum free beta hCG had no predictive value for individual pregnancy outcomes. Efficacy of first trimester maternal serum markers in predicting adverse pregnancy outcome is low. Even after optimization of cut-off values, these markers do not appear to be clinically acceptable as an effective tool for screening for adverse pregnancy outcomes.

Screening for trisomy 21 by fetal tricuspid regurgitation, nuchal translucency and maternal serum free β-hCG and PAPP-A at 11 + 0 to 13 + 6 weeks

To examine whether in pregnancies with fetal trisomy 21 the level of maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation is independent of the presence or absence of tricuspid regurgitation and to estimate the performance of a screening test that combines tricuspid regurgitation with fetal nuchal translucency (NT) thickness and serum free beta-hCG and PAPP-A. The study population comprised 77 trisomy 21 and 232 chromosomally normal fetuses from singleton pregnancies at 11 + 0 to 13 + 6 weeks of gestation. In all cases the fetal karyotype was determined by chorionic villus sampling (CVS), which was carried out at the request of the parents after first-trimester screening for trisomy 21 by fetal NT and maternal serum free beta-hCG and PAPP-A. Immediately before chorionic villus sampling, fetal echocardiography was performed and the presence or absence of tricuspid regurgitation was determined by pulsed wave Doppler ultrasonography. The distribution of fetal NT, maternal serum free beta-hCG and PAPP-A in trisomy 21 fetuses with absent and present tricuspid regurgitation was examined. We examined two screening strategies: first, integrated first-trimester screening in all patients and second, first-stage screening of all patients using fetal NT and maternal serum free beta-hCG and PAPP-A followed by second-stage assessment of tricuspid regurgitation only in those with an intermediate risk of 1 in 101 to 1 in 1000 after the first stage. Tricuspid regurgitation was observed in 57 (74.0%) of the trisomy 21 fetuses and in 16 (6.9%) of the chromosomally normal fetuses. There were no significant differences in median maternal age, median gestational age, free beta-hCG multiples of the median (MoM) and PAPP-A MoM in trisomy 21 fetuses with and without tricuspid regurgitation. The modeled detection rates of trisomy 21 for fixed false positive rates of 1%, 2% and 5% in screening by maternal age, fetal NT thickness and maternal serum free beta-hCG and PAPP-A and assessment of tricuspid flow in all cases were 87%, 90% and 95%. In the two-stage approach, the estimated detection rate was 91% and the false positive rate was 2.6%. There is no relationship between tricuspid regurgitation and the levels of maternal serum free beta-hCG and PAPP-A in cases with trisomy 21. An integrated sonographic and biochemical test at 11 + 0 to 13 + 6 weeks can potentially identify about 90% of trisomy 21 fetuses for a false-positive rate of 2-3%.

OC26.06: First trimester maternal serum level of pregnancy associated plasma protein A is an independent factor of fetal maxillary bone length

To derive a normogram of fetal maxillary bone length for a Chinese population and to study whether first trimester maternal serum levels of pregnancy associated plasma protein A (PAPP-A) is an independent factor of fetal maxillary bone length. This was a prospective study of 607 Chinese women with a singleton pregnancy who attended our first trimester screening for Down syndrome programme. The subjects had the fetal crown-rump length (CRL), nuchal translucency, maxillary bone length, maternal serum PAPP-A and free beta-hCG (fβ-hCG) levels measured. A normogram of maxillary bone length was derived using normal pregnancies without date problem. The correlations between maxillary length, CRL, PAPP-A and fβ-hCG levels were studied, after correction for gestational dependency using z-score transformation for the ultrasound markers (z-MAX and z-CRL), and logarithmic transformation of multiple of medians (MoM) for the biochemical markers. Positive correlations were further analysed with multiple regression. The mean gestational age at screening was 124 weeks (SD: 4 days). Curve estimation analysis showed that a linear relationship fit best between maxillary bone length and CRL (r = 0.826; p < 0.001), and between maxillary length and gestational age (r = 0.754; SD = 0.71; p < 0.001). There were significant positive correlations between z-MAX and z-CRL (r = 0.627; p = < 0.001), z-MAX and log10PAPP-Amom (r = 0.239; p = < 0.001). Multiple regression analysis showed that both z-CRL (p = < 0.001) and log10PAPP-A < STARTSUBmom (p = 0.048) were independent factors for z-MAX. Both CRL and maternal levels of PAPP-A are independent factors for the fetal maxillary length measured during the first trimester. The positive correlation between PAPP-A levels and fetal maxillary length is consistent with the known biological function of PAPP-A on bone growth. This association must be adjusted for when both PAPP-A and maxillary length are combined for screening of Down syndrome.

First-Trimester Down Syndrome Screening: Component Analytes and Timing for Optimal Performance

The most effective first-trimester Down syndrome screening protocol in current use employs three independent markers: maternal serum levels of PAPP-A and free beta hCG, and measurement of fetal nuchal translucency (NT). Eleven weeks appears to be the optimum gestational age for performing first trimester DS risk assessment. Although the discrimination of free beta hCG improves with increasing gestational age and is greatest at 13 weeks, PAPP-A and NT perform optimally at 10 and 11 weeks, respectively. In addition to accurate pregnancy dating, first trimester screening performance is improved by using a consistent NT measurement technique, NT cut-offs adjusted for gestational age or crown-rump length, and possibly center- or operator-specific NT medians. Whether or not absence or presence of the nasal bone adds to screening accuracy is a matter of some debate. Finally, because enlarged NT has been associated with cardiac defects and other structural anomalies, even in euploid fetuses, its presence should prompt a targeted second trimester ultrasound examination.

Triploidy identified through second‐trimester serum screening

To describe the maternal serum marker patterns of triploid pregnancies and estimate the second-trimester prevalence of triploidy. Forty-two cases of triploidy were identified in six serum screening programmes, five in the United Kingdom, one in Canada. This study describes the serum marker patterns, serum screening results for Down syndrome, trisomy 18 and open neural tube defects, and maternal age of these triploidy cases. The risk cut-off levels were > or = 1 in 250 for Down syndrome, > or =2.5 MoMs alpha-fetoprotein for open neural tube defects and > or =1:100 for trisomy 18 screening. The estimated second-trimester prevalence of triploidy was based on 22 triploidy cases ascertained in 599 934 pregnancies from three routine screening programmes, which attempted complete ascertainment of aneuploidy cases. The observed second-trimester rate of triploidy was 0.37 per 10 000 fetuses. Two different serum marker patterns were seen in triploid pregnancies, distinguished from each other by typically very high or very low levels of total hCG or free beta-hCG. The median maternal ages were respectively 33 years for triploidy with human chorionic gonadotrophin levels < 1.0 MoM, and 26 years for those with hCG levels > or =1.0 MoM. Fifty-seven percent of the pregnancies with a triploid fetus had a risk estimate > or =1:100 for trisomy 18 alone, 10% had an alpha-fetoprotein > or =2.5 MoM, 5% were screen positive for Down syndrome alone, and 19% had an increased risk or positive results for more than one anomaly. The simultaneous use of maternal serum tests designed to screen prenatally for Down syndrome, neural tube defects, and an increased risk of trisomy 18 resulted in a screen-positive result for 90% of pregnancies with triploidy.

Maternal serum biochemistry at 11-13+6 weeks in relation to the presence or absence of the fetal nasal bone on ultrasonography in chromosomally abnormal fetuses: an updated analysis of integrated ultrasound and biochemical screening

Screening for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) at 11-13(+6) weeks of gestation is associated with a detection rate of 90%, for a false-positive rate of 5%. Recent evidence suggests that in about 70% of fetuses with trisomy 21 the nasal bone is not visible at the 11-13(+6) week scan and that the frequency of absence of nasal bone differs in different ethnic groups. In addition, there is a relationship between absent nasal bone and nuchal translucency thickness. In a preliminary study we showed that while PAPP-A levels were lower and free beta-hCG levels were higher in trisomy 21 fetuses with an absent nasal bone, this difference was not statistically different. In fetuses with trisomy 13 and trisomy 18, there is also a high (57 and 67%) incidence of an absent nasal bone. The aim of this present study was to extend our examination of whether the level of maternal serum biochemical markers is independent of the presence or absence of the nasal bone in cases with trisomy 21 and to ascertain if any differences exist in cases with trisomies 13 and 18. This study data comprised 100 trisomy 21 singleton pregnancies at 11-13(+6) weeks of gestation from our previous study and an additional 42 cases analysed as part of routine OSCAR screening. A total of 34 cases with trisomy 18 and 12 cases with trisomy 13 were also available. Ultrasound examination was carried out for measurement of fetal NT and assessment of the presence or absence of the fetal nasal bone. Maternal serum free beta-hCG and PAPP-A were measured using the Kryptor rapid random access immunoassay analyser (Brahms Diagnostica AG, Berlin). The distribution of maternal serum free beta-hCG and PAPP-A in chromosomally abnormal fetuses with absent and present nasal bone was examined. The nasal bone was absent in 29 and present in 13 of the new trisomy 21 cases and in 98 (69%) and 44 respectively in the combined series. For the trisomy 18 cases, the nasal bone was absent in 19 (55.9%) cases and in 3 (25%) of cases of trisomy 13. There were no significant differences in median maternal age, median gestational age, NT delta, free beta-hCG MoM and PAPP-A MoM in trisomy 21 fetuses with and without a visible nasal bone, and similarly for those with trisomies 13 or 18. For a false-positive rate of 5%, it was estimated that screening with the four markers in combination with maternal age would be associated with a detection rate of 96% of cases with trisomy 21. For a false-positive rate of 0.5%, the detection rate was 88%. There is no relationship between an absent fetal nasal bone and the levels of maternal serum PAPP-A or free beta-hCG in cases with trisomies 13, 18 or 21. An integrated sonographic and biochemical test at 11-13(+6) weeks can potentially identify about 88% of trisomy 21 fetuses for a false-positive rate of 0.5%.

First-trimester nuchal translucency and maternal serum free beta-hCG and PAPP-A can detect triploidy and determine the parental origin.

To evaluate the levels of first-trimester screening markers in triploid pregnancies and to determine the parental origin of triploidy. During the five-year study period, 12322 patients with singleton pregnancies underwent combined first-trimester screening using nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotrophin (free beta-hCG) and pregnancy associated plasma protein-A (PAPP-A) at 10 to 14 weeks' gestation. Maternal serum markers and NT were evaluated in cases of triploidy. Molecular analysis was performed using polymorphic markers to establish the parental source of triploidy. Eight cases of triploidy were detected at a rate of at least 1 in 1540. All cases were electively terminated early in gestation or resulted in spontaneous miscarriage. Two patterns of first-trimester markers emerged: type I, characterized by extremely high levels of free beta-hCG and elevated NT; and type II, characterized by very low levels of PAPP-A and free beta-hCG with normal NT. Molecular analysis demonstrated that type I triploidy is of paternal origin (diandric) and type II is of maternal origin (digynic). On the basis of these results, it may be possible to detect triploid pregnancies in the first trimester and determine their origin using combined first-trimester screening.

Early vaginal bleeding and first-trimester markers for Down syndrome.

To assess the effect of early vaginal bleeding on first-trimester markers for Down syndrome. 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. 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). 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.

Biochemical screening for Down syndrome in pregnancies following renal transplantation.

To assess the performance of the double marker test [free beta-human chorionic gonadotrophin (beta-hCG) and alpha-fetoprotein (AFP)] as a screening test for Down syndrome in pregnant patients who had a prior renal transplant. A retrospective study. The Fetal Medicine Unit, Royal Free Hospital, London, UK. Detailed records of 14 post-renal transplant pregnancies were obtained from the Renal Unit of our hospital where the patients were followed up. The serum concentrations of urea, creatinine, free beta-hCG and AFP at the time of the double marker test were recorded, with a cut-off point of 1:250 for the double marker test. A control group of 14 normal pregnancies matched for age, parity and gestational age was used. The Mann-Whitney U-test and t-tests of unequal variance were applied to compare parameters of the study and the control groups. Two patients in each group were high risk for Down syndrome and amniocentesis revealed normal karyotype. No babies with Down syndrome were delivered in either group. Regression analysis showed significant correlation between free beta-hCG and urea concentrations (p<0.001) and free beta-hCG and creatinine concentrations (p<0.001), but not for AFP. The present study demonstrates that residual renal function alterations persisting after renal transplantation can affect the levels of free beta-hCG and AFP, thus resulting in false-positive screening for Down syndrome. First trimester nuchal translucency (NT) measurement in combination with second trimester ultrasonographic markers can be used in these patients, or alternatively the free beta-hCG levels should be corrected according to the serum creatinine levels.

Serum free beta-HCG and alpha-fetoprotein levels in IVF, ICSI and frozen embryo transfer pregnancies in maternal mid-trimester serum screening for Down's syndrome.

The aim of this study was to compare the maternal mid-trimester free beta-HCG and alpha-fetoprotein (AFP) levels in pregnancies conceived by assisted reproduction technology and spontaneous pregnancies in Down's syndrome screening. The influence of the number of embryos transferred and the amount of gonadotrophins used on the marker levels was also evaluated. The study population consisted of 58 IVF, 32 ICSI and 26 frozen embryo transfer (FET) singleton pregnancies. The levels of beta-HCG and AFP were compared with the control group of 6548 singleton spontaneous pregnancies. The false positive rate (FPR) in the Down's syndrome screening was 19% overall in assisted reproductive technology pregnancies, being highest (30.8%) in the FET group. The free beta-HCG multiples of the median (MoM) values were statistically significantly elevated only in the FET group (1.33 MoM; P = 0.012). A positive correlation between the number of embryos transferred and the marker levels was observed in the IVF group. No correlation was found between the amount of gonadotrophin medication used and the marker levels. The present data confirm that the overall FPR in the serum screening for Down's syndrome in assisted reproduction pregnancies is high, resulting in unnecessary invasive procedures.

First-trimester screening for trisomy 21 in singleton pregnancies achieved by assisted reproduction.

The possible effect of assisted reproduction on first-trimester screening for trisomy 21 was examined by fetal nuchal translucency thickness (NT), maternal serum free beta-human chorionic gonadotrophin (HCG) and pregnancy-associated plasma protein-A (PAPP-A). Parameters were measured at 11-14 weeks in 411 singleton pregnancies achieved by controlled ovarian stimulation, including 220 that had undergone IVF. Results were compared with 1233 singleton pregnancies conceived spontaneously. In the IVF pregnancies, the median fetal NT was not significantly different from that in controls, whilst the median free beta-HCG was significantly increased, and PAPP-A was significantly decreased. In the intracytoplasmic sperm injection group, fetal NT and free beta-HCG values were not significantly different from those in controls, but PAPP-A was significantly decreased. In those pregnancies achieved by ovarian stimulation, neither fetal NT, free beta-HCG nor PAPP-A were significantly different from the control group. In IVF pregnancies, screening for trisomy 21 by fetal NT, maternal serum free beta-HCG and PAPP-A levels may be associated with a 1.2% higher false-positive rate than in natural conception.

Maternal serum levels of dimeric inhibin A in pregnancies affected by trisomy 21 in the first trimester.

Dimeric inhibin A was measured in maternal serum samples from 45 pregnancies affected by trisomy 21 and 493 samples from unaffected pregnancies at 10-14 weeks of gestation. Inhibin A levels in affected pregnancies were compared with levels of free beta-hCG and PAPP-A in the same series. In the trisomy 21 group, the median multiple of the median (MoM) inhibin A was not significantly elevated (1.28 vs 1.00) with only 15.5% being above the 95th centile. In contrast, the median MoM free beta-hCG was significantly increased (2.05 vs 1.00) with 36% above the 95th centile and PAPP-A was significantly reduced (0.49 vs 1.00) with 42% below the 5th centile. Inhibin A levels in the trisomy 21 group were significantly correlated with gestational age such that median levels rose from 1.04 at 11 weeks to 1.30 at 12 weeks and 1.67 at 13 weeks. These findings suggest that first trimester biochemical screening for trisomy 21, which is currently optimised using maternal serum free beta-hCG and PAPP-A and fetal nuchal translucency, will not benefit from the inclusion of inhibin A.

The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free ?-hCG and PAPP-A at 10-14 weeks of gestation

In a study of 2923 normal pregnancies and 203 pregnancies affected by trisomy 21 we have shown a significant difference in the median MoM of the markers: fetal nuchal translucency, maternal serum free beta-hCG and PAPP-A in the presence of a female fetus compared with a male fetus. For maternal serum free beta-hCG levels are higher by 15% if the fetus is chromosomally normal and by 11% if the fetus has trisomy 21. For maternal serum PAPP-A the levels in chromosomally normal fetuses are 10% higher in the presence of a female fetus and 13% higher if the fetus has trisomy 21. In contrast, fetal nuchal translucency is 3-4% lower in both chromosomally normal and trisomy 21 female fetuses. The consequence of such changes when screening for trisomy 21 will be a reduction in the detection rate in female fetuses by a factor of 1-2%. Correction of risk algorithms for fetal sex, however, is probably not feasible, since ultrasound detection of fetal sex is only 70-90% accurate in the 10-14 week period.

The influence of smoking on maternal serum PAPP-A and free beta hCG levels in the first trimester of pregnancy.

In an analysis of 3111 singleton pregnancies routinely screened in the first trimester with nuchal translucency, free beta hCG and pregnancy associated plasma protein A (PAPP-A) smoking has been found to occur in 20.8 per cent of pregnant women. When the individual marker levels were assessed in smokers and non-smokers, levels of PAPP-A were reduced in smokers by some 15 per cent. Despite free beta hCG levels being reduced by 10-14 per cent in the second trimester of smoking women, in the first trimester period this is not evident. Simulation studies would suggest that in smokers the detection of trisomy 21 using free beta hCG, PAPP-A and maternal age will be reduced by some 5 to 6 per cent compared with that of the general population.

Prediction of pre-eclampsia with maternal mid-trimester total renin, inhibin A, AFP and free beta-hCG levels.

We wanted to study if maternal serum mid-trimester total renin, inhibin A, AFP or free beta-hCG levels predict the development of pre-eclampsia. Maternal serum alpha-fetoprotein (AFP) and human chorion gonadotrophin (beta-hCG) were evaluated in the screening programme for Down syndrome in 4356 patients prospectively. Data on pregnancy outcome were available in 1242 women. Pregnancy-induced hypertension (PIH) developed in 69 women, 282 women with uneventful pregnancy outcome were selected for controls. Serum total renin and inhibin A levels were measured retrospectively in the trisomy screening samples of 69 and 30 patients who later developed PIH, and in 282 and 7 patients, respectively, who had an uneventful pregnancy outcome. No significant differences were found in the levels of maternal mid-trimester serum total renin, inhibin A or free beta-hCG levels between PIH and healthy women. The multiples of the median (MoM) of AFP values were significantly higher in the subgroup of patients who later developed severe pre-eclampsia than in patients with mild pre-eclampsia or gestational hypertension and healthy pregnant women. Maternal mid-trimester serum levels of total renin, inhibin A and free beta-hCG are not predictive for development of PIH. High mid-trimester serum AFP values may help in the prediction of severe pre-eclampsia.