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%.     

Screening for triploidy by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In 25 cases of triploidy at 10-14 weeks of gestation, compared with 947 controls, the median multiple of the median (MoM) fetal nuchal translucency (NT) thickness was significantly increased (1.89 MoM), and maternal serum total and free beta-human chorionic gonadotrophin (hCG) were increased (3.13 MoM and 4.59 MoM respectively), alpha fetoprotein (AFP) was increased (2.14 MoM), and pregnancy associated plasma protein A (PAPP-A) was decreased (0.12 MoM). There are two types of triploidy. In type I, where the additional chromosome set is of paternal origin, the placenta is partially molar and the fetus is relatively well-grown. Type II, where the extra chromosome set is of maternal origin, is characterized by a small normal looking placenta and severe asymmetrical fetal growth restriction. In type I triploidy there was increased fetal NT (2.76 MoM), maternal serum total hCG (4.91 MoM), free beta-hCG (8.04 MoM), and AFP (3.22 MoM), and mildly decreased PAPP-A (0.75 MoM). In type II triploidy fetal NT was not increased (0.88 MoM), and there was a decrease in maternal serum total hCG (0.16 MoM), free beta-hCG (0.18 MoM), PAPP-A (0.06 MoM) and AFP (0.77 MoM). We conclude that a large proportion of triploidy cases of both phenotypes could be identified in the first trimester using NT, maternal serum free beta-hCG and PAPP-A with a combination of trisomy 21 risk and an atypicality approach.     

Diagnosis and prediction of parental origin of triploidies by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 11-14 weeks of gestation

The study objective was to determine the parental origin of triploidy in relation to findings from early risk assessment in a combined screening program between 2004 and the end of 2006. Triploidy was diagnosed in six chorion villus samples and two samples from missed abortions. After informed consent, quantitative fluorescence polymerase chain reaction analysis was performed on the five cases where we received blood from both parents and tissue from fetuses. In four cases the origin of the triploidy was paternal and in one maternal, in accordance with previous findings in type I and type II triploidies. Finding triploidy is possible by risk assessment (ultrasound and double test), and thereby women may have the opportunity for early termination of pregnancy.     

Screening for trisomy 13 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In 42 cases of trisomy 13 at 10-14 weeks of gestation, compared with 947 controls, the median multiple of the median (MoM) of maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy associated plasma protein A (PAPP-A) was significantly decreased (0.506 MoM and 0.248 MoM respectively), whilst fetal nuchal translucency was increased (2.872 MoM). In 38% and 71% of cases of trisomy 13 maternal serum free beta-hCG and PAPP-A was below the 5th centile of the appropriate normal range for gestation and in 62% of cases the nuchal translucency was above the 95th centile. When combined together in a multivariate algorithm with maternal age, 90% of cases of trisomy 13 could be detected at a 0.5% false positive rate or 84% at a 0.1% false positive rate. We conclude that specific trisomy 13 risks should be part of developing risk algorithms combining maternal serum biochemistry and nuchal translucency for use in first trimester screening alongside those for trisomy 21 and trisomy 18.     

Screening for trisomy 18 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In a study of 50 cases of trisomy 18 compared with 947 controls we have found the median multiple of the median (MoM) of maternal serum free beta human chorionic gonadotrophin to be significantly decreased (0.281 MoM) in samples collected between the 10th and 14th week of gestation. Similarly, maternal serum pregnancy associated plasma protein A (PAPP-A) levels are also decreased (0.177 MoM), whilst the median nuchal translucency is significantly higher (3.272 MoM). Free beta-hCG MoM was less than the 5th centile of normal in 64 per cent of cases of trisomy 18 and for PAPP-A was less than the 5th centile in 78 per cent of cases. Also, in 78 per cent of cases the nuchal translucency was above the 95th centile. When combined together in a multivariate algorithm with maternal age, we predict that 89 per cent of cases of trisomy 18 could be detected at a 1 per cent false-positive rate. We conclude that specific trisomy 18 risks should be part of developing risk algorithms combining maternal serum biochemistry and nuchal translucency for use in first trimester screening alongside those for trisomy 21.     

Circulating levels of pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin (hCG) in intrauterine and extrauterine pregnancies

Summary. Pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin (hCG) have been measured in the plasma of pregnant and non-pregnant women attending the outpatient clinic for suspicion of pregnancy. The plasma concentrations obtained were grouped into intrauterine or extrauterine pregnancies and compared with values obtained in non-pregnant patients with similar periods of amenorrhoea. Patients with ectopic pregnancies had slightly lower PAPP-A levels and significantly lower hCG concentrations than those in women with normal intrauterine pregnancies. Non-pregnant women had very low hCG and PAPP-A levels compared with those in pregnant patients. These data suggest that in patients with extrauterine pregnancies the poorly sustained ectopic trophoblast is unable to produce normal concentrations of hCG and probably PAPP-A and that the slightly diminished levels of PAPP-A in ectopic pregnancies might be derived from a decidual production.     

The influence of smoking on the pregnancy-associated plasma protein A,free beta human chorionic gonadotrophin and nuchal translucency

Objective To analyse the effects of smoking on first trimester parameters used in prenatal screening for Down's Syndrome.
Design A chart study.
Setting Primary care centres and maternity clinics of the participating universities' and central hospitals.
Population Three thousand and one hundred fifteen women screened by nuchal translucency measurement and 4436 women screened by maternal serum samples. Only normal singleton pregnancies were included.
Methods The mean multiples of median of pregnancy associated plasma protein A (PAPP-A), free beta human chorionic gonadotrophin (β-hCG) and nuchal translucency were compared by independent samples t test after logarithmic transformation of the data between smokers and non-smokers.
Main outcome measures PAPP-A and free β-hCG concentrations and nuchal translucency measurements.
Results PAPP-A was significantly reduced and nuchal translucency increased if the mother smoked. The smokers were more frequently considered as being at high risk for Down's Syndrome.
Conclusions Correcting PAPP-A median for smokers down by 20% might improve the accuracy of the risk evaluations given to individual women. If the association between increased nuchal translucency and smoking can be confirmed, it poses interesting questions as to the reasons for increased nuchal translucency among normal pregnancies.     

Abnormal human chorionic gonadotropin (hCG) trends after transfer of multiple embryos resulting in viable singleton pregnancies

Purpose

The purpose of this study is to investigate whether abnormal hCG trends occur at a higher incidence among women conceiving singleton pregnancies following transfer of multiple (two or more) embryos (MET), as compared to those having a single embryo transfer (SET).

Methods

Retrospective cohort study was performed of women who conceived singleton pregnancies following fresh or frozen autologous IVF/ICSI cycles with day 3 or day 5 embryo transfers between 2007 and 2014 at a single academic medical center. Cycles resulting in one gestational sac on ultrasound followed by singleton live birth beyond 24 weeks of gestation were included. Logistic regression models adjusted a priori for patient age at oocyte retrieval and day of embryo transfer were used to estimate the Odds Ratio of having an abnormal hCG rise (defined as a rise or <?66% in 2 days) following SET as compared to MET.

Results

Among patients receiving two or more embryos, 6.1% (n?=?84) had abnormal hCG rises between the first and second measurements, compared to 2.7% (n?=?17) of patients undergoing SET (OR 2.16, 95% CI 1.26–3.71). Among patients with initially abnormal hCG rises who had a third level checked (89%), three-quarters had normal hCG rises between the second and third measurements.

Conclusions

Patients who deliver singletons following MET were more likely to have suboptimal initial hCG rises, potentially due to transient implantation of other non-viable embryo(s). While useful for counseling, these findings should not change standard management of abnormal hCG rises following IVF. The third hCG measurements may clarify pregnancy prognosis.

     

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.     

Cystic hygromas, nuchal edema, and nuchal translucency at 11-14 weeks of gestation

OBJECTIVE: To estimate the incidence of septations in fetuses with increased nuchal translucency (NT) thickness, and to investigate the relationship between the length and thickness of the translucency and whether the length or septations provide useful information concerning the fetal karyotype in addition to that provided by the NT thickness alone. METHODS: We examined 386 fetuses with NT thickness equal to or above the 95th percentile for crown-rump length (CRL). A transverse suboccipitobregmatic section of the fetal head was taken to determine whether the sonolucency was septated, and a midsagittal longitudinal section was used to measure NT thickness, CRL, the longitudinal distance between the occiput and the lower end of the sonolucency toward the fetal sacrum (NT length) and the length between the occiput and the sacral tip (spinal length). Logistic regression analysis was used to investigate the effect on abnormal karyotype of CRL, NT thickness, and percentage of NT length to spinal length. RESULTS: Septations within the translucency were observed in all fetuses. The fetal karyotype was abnormal in 83 (21.5%) pregnancies, and multiple regression showed that the only significant independent predictor of abnormal karyotype was fetal NT thickness. CONCLUSION: Septations within the translucency can be seen in all fetuses, and therefore this feature cannot be used to distinguish between increased NT and cystic hygromas. The length of the translucency is related to its thickness and does not give useful information concerning the fetal karyotype in addition to that provided by the NT thickness alone. LEVEL OF EVIDENCE: II-2.     

First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial)

OBJECTIVE: The purpose of this study was to determine whether maternal serum levels of pregnancy-associated plasma protein A, free-beta subunit human chorionic gonadotropin, or nuchal translucency size are associated with obstetric complications. STUDY DESIGN: Data were obtained from the First and Second Trimester Evaluation of Risk trial. Pregnancy-associated plasma protein A and free-beta subunit human chorionic gonadotropin levels were analyzed, and nuchal translucency was measured between 10 weeks 3 days and 13 weeks 6 days of gestation in 34,271 pregnancies. RESULTS: Women with pregnancy-associated plasma protein A of < or =5th percentile were significantly more likely to experience spontaneous fetal loss at < or =24 weeks of gestation, low birth weight, preeclampsia, gestational hypertension, preterm birth ( P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption ( P < .02). Nuchal translucency at > or =99th percentile and free-beta subunit human chorionic gonadotropin at < or =1st percentile were associated with an increased risk of spontaneous loss at < or =24 weeks of gestation (adjusted odds ratios, 3.90, 3.62, respectively; P < .001). CONCLUSION: Low pregnancy-associated plasma protein A levels in the first trimester were associated strongly with a number of adverse pregnancy outcomes. Low free-beta subunit human chorionic gonadotropin levels and large nuchal translucency were both associated with early fetal loss.     

First trimester screening for Down's syndrome using maternal serum PAPP-A and free β=hCG in combination with fetal nuchal translucency thickness

The aim of this study was to evaluate the potential effectiveness of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free β-hCG in combination with nuchal translucency thickness in first trimester screening for Down's syndrome. Maternal serum levels of PAPP-A and free β-hCG were assayed in stored sera from 32 Down's syndrome and 200 unaffected pregnancies. Fetal nuchal translucency was measured by ultrasound at the time of blood sampling. Screening of Down's syndrome using a combination of maternal age, PAPP-A, free β-hCG and nuchal translucency would achieve a detection rate of 75.8% for a false positive rate of 5%.     

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.     

Combined measurement of fetal nuchal translucency, maternal serum free beta-hCG, and pregnancy-associated plasma protein A for first-trimester Down's syndrome screening.

PURPOSE: It has been proposed that first-trimester Down's syndrome screening has a higher detection rate compared to second-trimester biochemical screening. This study investigated the accuracy of Down's syndrome screening during gestational weeks 10 to 13 using the combination of fetal nuchal translucency (NT) measurement with maternal serum concentrations of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). METHODS: A total of 1,514 women with singleton pregnancies were enrolled in this study. Fetal NT was measured using the criteria published by the Fetal Medicine Foundation. Maternal serum concentrations of free beta-hCG and PAPP-A were determined by microtiter-plate ELISA. Down's syndrome risk was calculated using multivariate Gaussian distribution and Alpha software. RESULTS: Seventeen (1.12%) of the 1514 screened pregnancies had a fetal NT of at least 3 mm, and 41.2% of these had a poor pregnancy outcome, including four fetal aneuploidies. The odds of a fetal aneuploidy when the NT was greater than 2.0 multiples of median (MoM) was 90, when serum PAPP-A concentration was less than 0.45 MoM, it was 8.6, and when serum free beta-hCG concentration was greater than 2.2 MoM, it was 4.7. Using a risk cut-off level of 1 in 400, nine of 10 fetal aneuploidies were identified with a 4.7% false-positive rate, including two with trisomy 21, one with trisomy 18, and three with Turner's syndrome. CONCLUSIONS: This study demonstrated that Down's syndrome screening using the combined test in the first trimester had a higher detection rate than that of serum screening in the second trimester. Implementation of NT measurement in the first trimester provides substantial advantages for Down's syndrome detection and early diagnosis of fetal structural abnormalities.     

Human chorionic gonadotropin (hCG) plasma levels at oocyte retrieval and IVF outcomes

Purpose

The aim of our study was to ascertain the influence of hCG levels at oocyte pick-up on IVF outcomes, and their relationship with clinical parameters.

Methods

A prospective study was performed including 473 women undergoing IVF, aged under 40 years. Blood samples to analyze hCG levels were obtained at the time of follicular aspiration, 36 h after the administration of 250 μg of recombinant hCG.

Results

Neither the numbers of oocytes obtained or fertilized, nor the pregnancy rate, were correlated with hCG levels. Moreover, hCG values were very similar in women who did and did not become pregnant (123.3 ± 48.7 and 117.5 ± 44.7 mUI/mL). Cases in which no oocytes were recovered after follicular aspiration had similar hCG levels to those in which more than 1 oocyte was obtained. On the other hand, hCG levels were negatively related to body mass index, weight, and age.

Conclusions

These data indicate that after the administration of 250 μg of recombinant hCG, hCG levels are not responsible for failure to recover oocytes. Specifically, there was no correlation between plasma hCG levels and the number of oocytes obtained or other markers of IVF outcome. There was, however, an inverse relationship with BMI, body weight and age.