Second-trimester maternal pregnancy-associated plasma protein a and inhibin a levels in fetal trisomies

OBJECTIVE: The aim of this study was to determine whether fetal trisomy is associated with altered levels of second-trimester maternal pregnancy-associated plasma protein A (PAPP-A) and inhibin A. METHODS: Maternal serum PAPP-A and inhibin A concentrations were measured at 15-17 weeks of gestation in 14 singleton pregnancies with fetal trisomy and in 56 matched pregnant controls. RESULTS: PAPP-A levels in the trisomy group were significantly lower than in controls. The inhibin A level with fetal trisomy 21 was slightly higher than the control group, but levels were not different between trisomies 18 and 13 and controls. CONCLUSION: Fetal trisomies 21, 18, and 13 are associated with a reduction in second-trimester maternal PAPP-A levels; trisomies 18 and 13 are not associated with increased inhibin A levels, unlike trisomy 21.     

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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%.     

Second-trimester levels of pregnancy-associated plasma protein-A and free beta-hCG in pregnancies with trisomy 13

OBJECTIVE: To examine the levels of free beta-human chorionic gonadotrophin (free beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in second-trimester maternal serum from pregnancies affected by trisomy 13 and compare these with the known reduced levels of these markers in first-trimester cases in an attempt to better understand the pathophysiology of changes in marker levels in chromosomally abnormal pregnancies between the first and second trimester. METHODS: Using the Kryptor immunoassay system, we measured free beta-hCG and PAPP-A in 32 singleton pregnancies affected by trisomy 13 between 14 and 20 weeks of gestation. Using medians established in a previous study, these results were compared against 450 normal singleton pregnancies over the same gestational range. The data were combined with data from 82 cases of trisomy 13 previously examined in the first trimester (11-13 weeks) and an analysis of analyte trend was performed. RESULTS: The median free beta-hCG in multiples of the appropriate gestational median (MoM) in the second-trimester samples was not significantly different from the controls (1.15 (95% CI 0.827-1.651) vs 1.00). The median PAPP-A MoM in the second-trimester samples was significantly lower (p<0.001) than in controls (0.25 (95% CI 0.164-0.373) vs 1.00). Seventy-eight percent of cases were below the 5th centile of normal for PAPP-A. The combined cases in the first trimester had a median free beta-hCG MoM of 0.58 (95% CI 0.454-0.668) and a median PAPP-A MoM of 0.26 (95% CI 0.218-0.320). For PAPP-A, there was no significant change in median across the gestational period of 11 to 20 weeks, whilst for free beta-hCG, there was a significant increase with gestation (r=0.458, p<0.001). CONCLUSIONS: Although PAPP-A levels are reduced in trisomy 13 pregnancies in the second trimester, this isolated lower marker value is unlikely to be of value in screening for trisomy 13 in the second trimester. The aetiology of reduced levels of PAPP-A in cases with trisomy 13 may be similar to that in cases with trisomy 18, but different from that in cases with trisomy 21 since the temporal pattern in trisomies 13 and 18 are different from that in trisomy 21.     

Cribado de aneuploidía en gestación gemelar: resultados de la aplicación del test combinado

Objective

To evaluate the effectiveness of the Combined Test for trisomy 21 screening in twin pregnancies. To assess the performance of biochemical markers and nuchal translucency (NT) measurement in pregnancies with euploid fetuses and in twin pregnancies with one or two affected fetuses. To compare the value of markers according to chorionicity and the mode of conception.

Material and methods

Retrospective study including 161 twin pregnancies. Maternal serum fß-hCG and PAPP-A were determined at 8 to 12 weeks and fetal NT was measured at 11 to 14 weeks. The individual risk of trisomy 21 was calculated in each fetus using the Combined Test. In monochorionic pregnancies, the single risk for the pregnancy was obtained with the largest NT. An invasive diagnostic procedure was offered when the risk was 1:250 or more in one or both of the fetuses.

Results

All trisomy 21 pregnancies were identified (three pregnancies and four fetuses) by the combined testfor a false-positive rate of 6.4% of pregnancies and 3.5% of fetuses. The median fß-hCG level, expressed in MoM, was 1.72 and the median PAPP-A level was 2.01. The median NT was 1.05 MoM. Both fß-hCG and PAPP-A levels were significantly decreased in monochorionic pregnancies and PAPP-A was significantly decreased in pregnancies resulting from assisted reproduction. No significant differences were observed in NT measurement between monochorionic and dichorionic fetuses or between those conceived naturally or by assisted reproduction.

Conclusions

The combined test shows high sensitivity and specificity in screening for trisomy 21 in twin pregnancies. The differences obtained in the biochemical markers according to chorionicity or the mode of conception require confirmation in further studies with a larger number or cases.     

Screening for trisomy 21 in twin pregnancies in the first trimester using free beta-hCG and PAPP-A, combined with fetal nuchal translucency thickness

In the first trimester of pregnancy the biochemical markers free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) are used for the prenatal screening of trisomy 21, either alone or in combination with nuchal translucency (NT) thickness. In this study, I have analysed the distribution of these biochemical markers in 159 twin pregnancies and compared this with 3466 singleton pregnancies. On average free beta-hCG values are 2.099 times greater in twins than in singletons and PAPP-A some 1.86 times greater. The width of the analyte distribution in twins is very similar to that in singleton pregnancies. Using statistical modelling techniques I have predicted that at a 5% false positive rate the detection rate in twins discordant for trisomy 21 will be 52% and in twins concordant for trisomy 21 will be 55%, if correction for twin pregnancy is carried out using the 'pseudo risk' approach. The detection rate using biochemical parameters is less than that achievable for twins using NT (75%). However, the combination of NT and maternal serum biochemistry will give detection rates approaching 80%. These rates are some 10% less than in singleton pregnancies, but nevertheless combining NT and biochemistry will allow high rates of detection of affected twins with the benefit of ultrasound and NT being able to specifically locate the affected twin. Twin screening using both modalities should be considered when introducing first trimester screening.     

Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation

Objective To determine the prevalence of increased fetal nuchal translucency thickness in twin pregnancies and to evaluate screening for trisomy 21 by a combination of translucency thickness and maternal age.
Design Prospective screening study at 10 to 14 weeks of gestation.
Setting Fetal Medicine Centre.
Population 22,518 self-selected pregnant women at 10 to 14 weeks of gestation, including 21,477 singleton and 448 twin pregnancies with live fetuses.
Methods Fetal nuchal translucency thickness was measured by ultrasound examination at 10–14 weeks. Sensitivity and false positive rates of screening for trisomy 21 by a combination of fetal nuchal translucency thickness and maternal age were calculated.
Main outcome measures Prevalence of increased nuchal translucency thickness and detection of trisomy 21.
Results In the 448 twin pregnancies the nuchal translucency thickness was above the 95th centile of the normal range (for crown-rump length in singletons) in 65/896 fetuses (7.3%), including 7/8 (88%) with trisomy 21. Increased translucency was also present in four fetuses with other chromosomal abnormalities. In the chromosomally normal twin prebmancies the prevalence of increased nuchal translucency was higher in fetuses from monochorionic (8.4%; 16/190) than in those with dichori-onic pregnancies (5.4%; 37/688). The minimum estimated risk for trisomy 21, based on maternal age and fetal nuchal translucency thickness, was 1 in 300 in 19.5% (175/896) of the twins including all eight of those with trisomy 21.
Conclusions In twin pregnancies the sensitivity of fetal nuchal translucency thickness in screening for trisomy 21 is similar to that in singleton pregnancies, but the specificity is lower because translucency is also increased in chromosomally normal monochorionic twin pregnancies.     

The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free beta-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.     

Maternal serum levels of placental proteins after in vitro fertilisation and their implications for prenatal screening

OBJECTIVES: To determine whether the serum levels of pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific beta(1)-glycoprotein (SP1), placental lactogen (hPL) and human chorionic gonadotrophin (hCG) are different in pregnancies obtained after in vitro fertilisation (IVF) and embryo transfer (ET) in comparison to spontaneous pregnancies. Assessment of the need to establish normal medians for biochemical trisomy screening in IVF pregnancies. METHODS: The population comprised 96 IVF-ET pregnancies, of which 79 came from fresh gonadotrophin-stimulated cycles and 17 from embryo transfers without gonadotrophin stimulation (natural cycle IVF, frozen embryo transfers), and 156 spontaneous pregnancies. A single blood sample was obtained between 7 + 0 and 16 + 3 weeks. PAPP-A, SP1, hPL and hCG were quantified and the levels compared between gonadotrophin-stimulated IVF, steroid-only- or non-stimulated IVF, and controls with respect to gestational age using non-parametric statistical analysis. RESULTS: PAPP-A and hPL levels were reduced after stimulated IVF in early gestation (before 10 pregnancy weeks); SP1 followed the same trend without reaching statistical significance. hCG tended to be increased after IVF treatment including non-gonadotrophin-stimulation cycles, and also beyond 10 pregnancy weeks. CONCLUSION: Reduced PAPP-A with increased hCG yields an increased risk in screening for foetal trisomy 21. We confirm recently published observations but do not recommend the establishment of normal medians for IVF pregnancies since the extent of the deviations is varying according to the different stimulation protocols and dosages of gonadotrophins used.     

A comparison between maternal serum free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A levels in first-trimester twin and singleton pregnancies

OBJECTIVES: To determine the levels of first-trimester free beta-human chorionic gonadotrophin (free betahCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT) in twin pregnancies. METHODS: The study included 93 patients with twin pregnancy and 4,977 with singletons who underwent first-trimester testing using free betahCG, PAPP-A and NT at 10-13 weeks of gestational age. RESULTS: In twin pregnancies, the maternal serum free betahCG level was 2.18 higher and the PAPP-A level was 2.38 higher than in singleton pregnancies. These marker levels were significantly higher than the expected 2.0 multiples of the median (MoM). In contrast, NT values did not differ between twins and singletons. CONCLUSION: These data may be used to establish first-trimester combined screening for twin pregnancies.     

Placental protein and hormone measurements in twin pregnancy

Summary. Maternal serum levels of human placental lactogen (hPL), schwangerschaftsprotein 1 (SP1), pregnancy-associated plasma protein A (PAPP-A), placental protein 5 (PP5) and total oestriol (E3) were measured serially in 35 twin pregnancies during the third trimester. Eighteen pregnancies had major complications including dysmaturity of one or both fetuses in nine, premature labour in six, and placental abruption in three. Serum levels of all five variables were higher than in singletons, this distinction being greatest for hPL and lowest for SP1 and E3. The levels of hPL, PP5 and E3 just before delivery were significantly correlated with the total birthweight, a correlation with placental weight being evident only for hPL and PP5. A significant correlation between the five biochemical variables at 33–34 weeks was only seen between hPL and PAPP-A. Protein and hormone levels in. the abnormal twin pregnancies were not apparently different from those in the normal twin pregnancies. These data suggest that only hPL levels biochemically reflect this extreme of fetal and placental growth, but that neither the levels of hPL nor any of the other biochemical indices examined are altered in abnormalities in twin pregnancy     

Placental protein and hormone measurements in twin pregnancy

Maternal serum levels of human placental lactogen (hPL), schwangerschaftsprotein 1 (SP1), pregnancy-associated plasma protein A (PAPP-A), placental protein 5 (PP5) and total oestriol (E3) were measured serially in 35 twin pregnancies during the third trimester. Eighteen pregnancies had major complications including dysmaturity of one or both fetuses in nine, premature labour in six, and placental abruption in three. Serum levels of all five variables were higher than in singletons, this distinction being greatest for hPL and lowest for SP1 and E3. The levels of hPL, PP5 and E3 just before delivery were significantly correlated with the total birthweight, a correlation with placental weight being evident only for hPL and PP5. A significant correlation between the five biochemical variables at 33-34 weeks was only seen between hPL and PAPP-A. Protein and hormone levels in the abnormal twin pregnancies were not apparently different from those in the normal twin pregnancies. These data suggest that only hPL levels biochemically reflect this extreme of fetal and placental growth, but that neither the levels of hPL nor any of the other biochemical indices examined are altered in abnormalities in twin pregnancy.     

First-trimester screening for trisomy 21 in twin pregnancy: does the addition of biochemistry make an improvement?

OBJECTIVE: To evaluate the effectiveness of the addition of first-trimester biochemistry to fetal nuchal translucency (NT) measurement in the Combined Test when screening for trisomy 21 in twin pregnancies. METHODS: Maternal serum free beta-hCG and PAPP-A were determined at 8 to 12 weeks and fetal NT was measured at 11 to 14 weeks. The individual risks were estimated for each of the fetuses using both NT screening alone and the Combined Test. An invasive diagnostic procedure was offered when the risk was 1:250 or over in either one of the fetuses. In the first period, only the results of NT screening were clinically applied. After previous analysis, the Combined Test was introduced into clinical practice. RESULTS: In the two-and-a-half-year study period, a complete follow-up was obtained in 100 twin pregnancies. Three fetuses (two pregnancies) with trisomy 21 were detected by both methods. The false-positive rate achieved by NT screening (14.3% of pregnancies and 8.6% of fetuses) was substantially reduced when first-trimester biochemistry was added in the Combined Test (5.1% of pregnancies and 3.6% of fetuses). CONCLUSION: The Combined Test appears to maintain the detection rate achieved by NT screening for trisomy 21 in twin pregnancies, but false-positive rates and invasive diagnostic procedures are reduced.     

Management of twin pregnancies with fetal trisomies

Objective To examine options of management and outcome of twin pregnancies affected by fetal trisomies.
Design Retrospective study.
Setting Research Centre for Fetal Medicine.
Population Twenty-seven twin pregnancies affected by fetal trisomy.
Methods A computer search was made of our database for twin pregnancies concordant or discordant for trisomies. The data were reviewed for gestation at diagnosis of the chromosomal abnormality, management and pregnancy outcome.
Main outcome measures Pregnancy management and outcome in relation to type and gestation at diagnosis of the trisomies.
Results There were seven cases where both fetuses were trisomies and in these the parents opted for termination of pregnancy; termination was also performed in another pregnancy where one fetus had trisomy 18 and the chromosomally normal co-twin had a major facial cleft. In 19 cases one fetus had either trisomy 21 (   n = 14  ) or trisomy 18 (   n = 5  ) and the other was normal. Selective fetocide was carried out in 13 of 14 pregnancies discordant for trisomy 21 and in one of the five with trisomy 18. In the four cases discordant for trisomy 18 that were managed expectantly, the trisomic baby died in utero or in the neonatal period, whereas the normal co-twin was liveborn at 33 to 40 weeks (median 37). In the 14 cases of selective fetocide, the chromosomally normal co-twin was live born at 24 to 41 weeks of gestation (median 38), and there was a nonsignificant inverse correlation between the gestation at fetocide and gestation at delivery.
Conclusions In twin pregnancies discordant for fetal trisomies the main determinant in deciding whether to perform selective fetocide or adopt expectant management is the degree of lethality of the chromosomal defect.     

First-trimester nuchal translucency measurement and echocardiography at 16 to 18 weeks of gestation in prenatal detection for trisomy 18

BACKGROUND: Trisomy 18, the second most common autosomal trisomy, has the highest incidence of congenital heart disease of all chromosomal abnormalities. This study assessed the use of nuchal translucency (NT) measurement and fetal echocardiography at 16 to 18 weeks of gestation in prenatal detection for trisomy 18. METHODS: Screening for chromosomal aneuploidy using fetal NT measurement was performed at 10 to 14 weeks of gestation. Detailed fetal echocardiography was performed at 16 to 18 weeks of gestation immediately before genetic amniocentesis for fetal karyotyping in singleton pregnancies with increased fetal NT thickness. RESULTS: Of the 3151 singleton pregnancies included in our study, 171 cases (5.4%) of increased (> or =3.0 mm) NT were noted. Fetal chromosomal abnormalities were identified in 22 (12.9%) of these pregnancies, including 9 with trisomy 21, 5 with trisomy 18, 4 with 45,X and 4 with unbalanced structural abnormalities. Major defects of the heart and the great arteries were identified in 13 (7.6%) of these pregnancies with increased NT. These included eight pregnancies that also had the diagnosis of chromosomal aneuploidy. Among the 22 fetuses with confirmed aneuploidy, all 5 fetuses with trisomy 18, 1 of the 4 fetuses with 45,X and 2 of the 9 fetuses with trisomy 21 had increased fetal NT thickness associated with abnormal fetal echocardiography findings. CONCLUSIONS: Screening for Down syndrome and cardiac defects using first-trimester fetal NT measurement in combination with fetal echocardiography at 16 to 18 weeks of gestation is a feasible and sensitive procedure for the prenatal detection of trisomy 18.     

Evidence for blood chimerism in dizygotic spontaneous twin pregnancy discordant for Down syndrome

BACKGROUND: A monochorionic-diamniotic placenta (MCDAP) is rare in dizygotic (DZ) twinning. All reported cases have been documented in pregnancies achieved by the induction of ovulation alone or during the IVF cycle. METHODS AND RESULTS: We report a spontaneous pregnancy in a 39-year-old patient with evidence of MCDAP in DZ twins, discordant for trisomy 21. The first and second-trimester sonographic scans indicated male twins with MCDAP. Amniocentesis, performed because of advanced maternal age, revealed a normal karyotype in one fetus, and trisomy 21 in the other. Molecular studies, performed in order to confirm the zygosity and chorionicity, demonstrated that the fetuses were DZ. In order to identity the affected twin, a detailed sonographic examination was repeated, but no abnormal findings associated with Down syndrome were demonstrated in any of the fetuses. Therefore, umbilical cord blood samples were obtained from both fetuses. Chromosomal analysis revealed in both fetuses two cell lines: a normal cell line of 46,XY and a 47,XY,+ 21 cell line, in 65 and 80% of the cells, respectively. This result was independently confirmed by both FISH and G-banding. DNA extracted from both cord blood samples demonstrated an admixture of two distinct genotypes in each sample. CONCLUSIONS: We propose that this case represents a monochorionic-dizygotic twin pregnancy with blood chimerism. The most plausible mechanism underlying this phenomenon is placental fusion early in pregnancy, resulting in an architecturally single placenta originating from two distinct zygotes. The newly formed blood vessels created anastomoses between the DZ twins and allowed reciprocal blood chimerism between the normal and the trisomic twin.     

Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome

OBJECTIVE: Low levels of maternal serum pregnancy associated plasma protein-A (PAPP-A) have been linked to chromosome anomalies such as trisomy 21, 13 and 18, triploidy and sex chromosome aneuploidy. Low levels of PAPP-A have also been implicated in spontaneous miscarriage. The purpose of this study was to evaluate whether low levels of first trimester PAPP-A are predictive of other adverse pregnancy outcomes. STUDY DESIGN: The study included patients with singleton pregnancies who underwent combined first trimester screening using nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotrophin (free beta-hCG) and PAPP-A at 10-13 weeks' gestation. Patients with chromosome aberrations or fetal anomalies were excluded. Serum marker levels were expressed as gestational age-specific multiples of the median (MoMs). The incidences of various adverse pregnancy outcomes (spontaneous preterm labor, fetal growth restriction (FGR), proteinuric and non-proteinuric pregnancy induced hypertension (PIH), intrauterine fetal demise, oligohydramnios, spontaneous miscarriage and placental abruption) were evaluated, according to maternal PAPP-A MoM levels. RESULTS: Of the 1622 patients in the study, pregnancy complications were observed in 184 (11.3%). Patients with PAPP-A < or =0.25 MoM had significantly higher rates of FGR (RR = 3.12), proteinuric PIH (RR = 6.09), spontaneous miscarriage (RR = 8.76). No statistically significant differences were noted for other adverse outcomes evaluated Women with PAPP-A < or =0.50 MoM also had significantly higher rates of FGR (RR = 3.30) and spontaneous miscarriage (RR = 3.78). CONCLUSIONS: We conclude that decreased levels of first trimester maternal serum PAPP-A are predictive not only of chromosome anomalies but also of adverse pregnancy outcome.     

Monitoring of postimplantation embryo viability following successful in vitro fertilization and embryo transfer by measurement of placental proteins

Serum levels of pregnancy-associated plasma protein A (PAPP-A), human chorionic gonadotropin (hCG), and pregnancy-specific beta 1-glycoprotein (SP1) were measured in 21 women after successful in vitro fertilization and embryo transfer. Of the 21 pregnancies, 14, including 1 twin gestation, progressed successfully to term. The remaining seven, composed of tubal (n = 3), anembryonic (n = 1), and spontaneously aborted (n = 3) pregnancies, failed during the first half of pregnancy. Placental protein measurement was of no diagnostic value in the detection of anembryonic pregnancy. Similarly, measurement of hCG and SP1 could not readily distinguish tubal ectopic from normal intrauterine pregnancies. By contrast, the predictive value (38.9%) of a depressed PAPP-A level in conjunction with superior diagnostic sensitivity (70%) and relative risk factor (23.6) proved to be of greater diagnostic value in this potentially lethal condition. In the absence of ultrasonography, the biochemical diagnostic indices were comparable in the prediction of spontaneous abortion. However, in the presence of a live fetus, PAPP-A levels were consistently depressed (sensitivity, 91.7%) many weeks before pregnancy demise. The relative risk factor of depressed PAPP-A levels was 29 times greater than the risk associated with a depressed hCG level. These findings further demonstrate the potential diagnostic value of PAPP-A measurement for monitoring postimplantation embryo viability.     

Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency,absent fetal nasal bone,free beta-hCG and PAPP-A at 11 to 14 weeks

BACKGROUND: 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 to 14 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 11th- to 14th-week scan (Cicero et al., 2001). The aim of this study was to examine whether fetal NT thickness and the level of maternal serum biochemical markers is independent of the presence or absence of the nasal bone, and to estimate the performance of a screening test that integrates the two sonographic and the two biochemical markers. METHODS: This was a retrospective case-control study comprising 100 trisomy 21 and 400 chromosomally normal singleton pregnancies at 11 to 14 weeks of gestation. 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 GmbH, Berlin). The distribution of fetal NT, maternal serum free beta-hCG and PAPP-A in trisomy 21 fetuses with absent and present nasal bone was examined. RESULTS: The nasal bone was absent in 69 and present in 31 of the trisomy 21 fetuses. 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. 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 97%. For a false-positive rate of 0.5%, the detection rate was 90.5%. CONCLUSIONS: An integrated sonographic and biochemical test at 11 to 14 weeks can potentially identify about 90% of trisomy 21 fetuses for a false-positive rate of 0.5%.     

Serum parameters and nuchal translucency in first trimester screening for fetal chromosomal abnormalities

Objective To assess the relation between serum parameters and nuchal translucency in pregnancies affected by fetal aneuploidy in the first trimester.
Design Retrospective study of different serum parameters collected prior to chorionic villus sampling and measurement of nuchal translucency in relation to fetal aneuploidy.
Setting Switzerland (German and Italian sector) and Bregenz, Austria.
Population One thousand one hundred and fifty-one women aged 25 to 44 years at 10 to 13 weeks of gestation undergoing chorionic villus sampling, mostly for advanced maternal age. Fetal aneuploidy was found in 23 pregnancies including four cases of trisomy 21, five of trisomy 18 and one case of trisomy 13.
Main outcome measure Fetal karyotype, serum levels of free β-hCG, pregnancy-associated plasma protein A (PAPP-A) and alpha-fetoprotein and the measurement of nuchal translucency.
Results Serum PAPP-A was decreased in all common chromosomal abnormalities. Free β-hCG levels were increased in trisomy 21 but decreased in trisomy 18, whereas alpha-fetoprotein was low in trisomy 21, 18 and other chromosomal abnormalities. Nine of twenty-three abnormal embryos had evidence of an increased nuchal translucency. Nuchal translucency, however, did not seem to be associated with any alteration in the levels of the biochemical parameters in either chromosomally normal or abnormal embryos. A low serum PAPP-A or an increased nuchal translucency was seen in two-thirds of all pregnancies with chromosomal abnormalities.
Conclusion A nuchal translucency 3 mm and depressed serum PAPP-A levels have a good predictive value in the detection of fetal aneuploidy at 10 to 13 weeks of pregnancy. Serum free 0-hCG and alpha-fetoprotein levels may give additional information. An increased nuchal translucency was not-associated with altered serum parameters. This would allow these different markers to be used in combination.     

Maternal serum free β-hCG at 10 to 14 weeks of gestation in trisomic twin pregnancies

Maternal serum free β-hCG was measured at 10 to 14 weeks of gestation in 136 normal twin pregnancies and in 12 twin pregnancies where one or both fetuses had trisomy 21. The values were compared with a normal range from 4181 singleton pregnancies. In the normal twins the median free β-hCG (65 ng/mL) was about twice as high as in singletons (34 ng/mL z =−12.1,   P < 0.0001  ). In the trisomy 21 group the median free β-hCG (95 ng/mL) was significantly higher than in normal twins ( z = 2.1,   P < 0.05  ). However, only one of the trisomic pregnancies had a level above the 95th centile. In twin pregnancies maternal serum free β-hCG at 10 to 14 weeks of gestation is unlikely to be useful in the prediction of fetal trisomy 21.