Effect of fetal gender on first trimester markers and on Down syndrome screening.

OBJECTIVES: The purpose of the present study was to evaluate whether a gender-related difference exists in first trimester markers used for Down syndrome screening, namely nuchal translucency (NT), maternal serum pregnancy-associated plasma protein-A (PAPP-A), and free beta-human chorionic gonadotrophin (beta-hCG), and whether this has an influence on screening performance. METHODS: A total of 1325 patients with a singleton pregnancy underwent combined first trimester screening at 10-13 weeks' gestation. Maternal serum PAPP-A and free beta-hCG were analyzed by fluoroimmunoassay, nuchal translucency (NT) was measured by transvaginal sonography. Only patients with normal outcomes and known fetal gender were included in the study. Data were categorized by gestational age and by fetal gender. RESULTS: There were no significant gender-related differences in NT and PAPP-A levels. However, free beta-hCG was significantly higher (p=0.00004) in the presence of a female fetus than in the presence of a male fetus. Women with female fetuses had a higher median calculated Down syndrome risk (1:5490) compared to those having males (1:6451). This difference was not, however, statistically significant. CONCLUSION: First trimester free beta-hCG is significantly higher in pregnancies with a female fetus.     

Between pregnancy biological variability of first trimester markers of Down syndrome: implications for screening in subsequent pregnancies.

In a group of 149 women who had undergone routine first trimester screening using fetal nuchal translucency thickness (NT) and maternal serum free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) in two consecutive pregnancies the within person between pregnancy biological variability of these markers has been assessed. For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r=0.0800). For maternal serum free beta-hCG MoM a significant correlation was observed (r=0.4174) as was also found for PAPP-A MoM (r=0.3270). The implications for such between pregnancy marker association is that women who have an increased risk of Down syndrome in their first pregnancy are 1.5-2 times more likely to repeat this event in their next pregnancy. This observation may be useful in counselling women in the first trimester screening of a subsequent pregnancy.     

Fetal facial sonographic markers for second trimester Down syndrome screening in a Thai population

Objective

To assess the efficacy of using facial sonographic markers for screening fetuses in the second trimester for Down syndrome (DS) in a high-risk Thai population.

Method

Frontomaxillary facial angle (FMF) and nasal bone length (NBL) were measured prospectively in pregnant women at high-risk for DS who were undergoing genetic amniocentesis from November 2008 to October 2009. The receiver operator characteristic (ROC) curves were constructed to assess the screening efficacy of FMF angle and NBL.

Result

A total of 460 pregnant women were recruited, and a mid-sagittal facial profile was obtained for 403 fetuses. There were 386 fetuses with normal chromosomes, 10 fetuses with DS, 1 fetus with trisomy 13, and 1 fetus with trisomy 18. The remaining 5 fetuses had balanced translocation (n = 2), deletion (n = 1), and mosaic Turner (n = 2). Two different combinations of FMF angle and biparietal diameter to nasal bone length (BPD:NBL) ratio for DS screening in the second trimester achieved 50% and 90% detection rates and 4.4% and 14.0% false positive rates, respectively.

Conclusion

The combination of FMF angle and BPD:NBL ratio has a high sensitivity and specificity for screening for DS in the second trimester in a high-risk Thai population.     

Inaccurate estimation of risk in second trimester serum screening for Down syndrome among women who have already had first trimester screening

Problems can arise in prenatal screening for Down syndrome when tests are performed in the first and second trimester and some women who have a negative first trimester test have a second trimester serum test. The second test result does not usually take account of the previous one being negative. Even if it does, it is often inaccurate. Using published data the extent of the error was examined. The age-specific risk of an affected pregnancy in such women will be lower than if no first trimester test had been performed. The distributions of the screening markers in affected and unaffected pregnancies will be different from those in unscreened women. If the appropriate age-specific risk and marker distributions are not used, error will arise. For example, a 35-year-old woman with nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (hCG) levels at the normal median would have a risk of 1 in 6500. If she then had the Triple Test with alpha-fetoprotein (AFP), unconjugated oestriol, and hCG levels of 0.7, 0.7 and 1.5 multiples of the median (MoM), respectively, her risk, ignoring the previous result, would be overestimated (1 in 95 compared with the correct estimate of 1 in 705). If the previous result was included, but the age-specific risk and second trimester marker distributions were not revised, her risk would be underestimated (1 in 820). If the correct age-specific risk and screening marker distributions were used, risk estimates would be accurate, but two tests would be less efficient than integrating all the screening information into a single test. The practice of offering second trimester serum screening to women who have already been screened is best avoided.     

First trimester screening for Down syndrome in multiple pregnancy

The incidence of twins, triplets, and high-order multiples has increased substantially in the last two decades secondary to fertility treatments and to delayed childbearing. Prenatal diagnosis in these patients is challenging. Options for screening tests are limited. First trimester screening for Down syndrome in patients with multiples appears promising. This paper will review the advantages of first trimester screening in this high-risk patient population.     

Maternal serum screening for Down syndrome in the first trimester: experience from Belarus.

We have carried out a large retrospective study of alpha-fetoprotein (AFP), free-beta human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein (PAPP-A) in the first trimester of pregnancy. Unlike other studies all women had routine ultrasound dating, carried out during a nuchal translucency measurement project. A total of 13,477 serum samples were tested for AFP and 11,659 for free beta-hCG. A subset of 1564 samples from unaffected pregnancies were also tested for PAPP-A on a case-control basis. All three markers were also determined in 31 samples from pregnancies with Down syndrome. Equations were derived to express results in multiples of the median using both gestational age and crown rump length and to adjust for maternal weight. Statistical modelling with Gaussian distribution parameters obtained in the study were used to predict the detection rate for a 5 per cent false-positive rate. The predicted rates were: 73.7 per cent for all three markers; 69.1 per cent for PAPP-A and free beta-hCG; 47.4 per cent for PAPP-A and AFP; 57.6 per cent for free beta-hCG and AFP. As these rates are similar to those in the second trimester, health planners may now want to consider a change in policy from second-trimester to first-trimester screening with biochemical markers.     

Agreement between predicted risk and prevalence of Down syndrome in first trimester nuchal translucency screening

The agreement between predicted risks of Down syndrome and observed prevalence was investigated in a population of 11,847 singleton pregnancies screened by first trimester nuchal translucency at a single institution. Twenty-seven cases of Down syndrome were observed; 20 were detected prenatally by nuchal translucency and maternal age screening, three by other means and four postnatally. The screened women were grouped according to their predicted risk of having an affected pregnancy, and this was compared with the observed prevalence. A significant correlation between predicted and observed prevalences was noted, thus demonstrating that risk estimates for Down syndrome based on first trimester nuchal translucency screening are accurate.     

First trimester Down syndrome screening: public health implications

Down syndrome (DS) screening has been an integral part of routine prenatal screening for the last three decades. Recent efforts have been directed at developing additional non-invasive prenatal screening techniques that could not only improve sensitivity of prenatal screening, but also be employed in the first trimester to offer earlier diagnostic and interventional opportunities. Nuchal translucency has proven to be an effective and cost-effective screening test that, when combined with serum markers (hCG and pregnancy-associated plasma protein [PAPP-A]) in the first and/or second trimester, broadens the diagnostic possibilities and improves the diagnostic capabilities of current prenatal DS screening methods. Despite the potential benefits, significant operational issues regarding access to and availability of such testing may limit its widespread application and necessitates the maintenance of both non-sonographic and second trimester screening methods. The implementation of first trimester DS testing requires the development and maintenance of nationally standardized quality control systems to ensure the reliability of serum and ultrasound measurements and the accurate assessment of risk. Future efforts to improve prenatal screening should continue to emphasize the need for improved access to all aspects of prenatal care, stress the importance of provider education and the necessity for extensive patient counseling, and reinforce the role of patient education and choice.     

Diagnosis of fetal acrania during the first trimester nuchal translucency screening for Down syndrome.

OBJECTIVES: Prenatal screening during the first-trimester using fetal nuchal translucency (NT) measurement and maternal serum levels of free beta-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) has become an established method for the detection of fetal Down syndrome. Increasing evidence has shown that some of the fetal structural abnormalities could be identified during NT scanning. Second trimester maternal serum alpha-fetoprotein (MSAFP) measurements and ultrasound scans have been widely used in clinical practice to identify fetal neural tube defects (NTDs). In this study, we evaluated the effectiveness of early diagnosis of fetal acrania during NT scanning. METHODS: We reviewed the medical records of 5890 pregnancies that were delivered in our hospital between January 1, 1999 and January 31, 2001. Among them, 3600 pregnant women received NT-based Down syndrome screening at 10-13 weeks' gestation. Pregnancies with fetal NTDs were evaluated and their maternal serum levels of free beta-hCG and PAPP-A were compared with those of the normal control pregnancies. RESULTS: Seven of the 3600 pregnancies were identified with fetal acrania and all of them were detected during first-trimester NT scanning. Among the seven cases, five had measurements of maternal serum concentration free beta-hCG and PAPP-A concentration, yet there were not significant difference between the pregnancies with fetal acrania and those of the control pregnancies (PAPP-A, 1.13 vs. 0.96; free beta-hCG, 1.10 vs. 1.06; P>0.05). Two of the seven affected patients did not have maternal serum biochemical measurements due to the immediate termination of pregnancies. CONCLUSIONS: We demonstrated that pregnancies with fetal acrania could be easily identified at the time of NT scanning. Careful ultrasound inspection of fetal structure during NT measurements at 10-13 weeks of gestation provides an encouraging advantage for early diagnosis of fetal acrania.     

First trimester screening for Down syndrome in rhesus negative women

OBJECTIVES: To explore the effect of maternal rhesus status on first-trimester screening markers for Down syndrome. METHODS: We accessed a database of singleton pregnancies undergoing first-trimester genetic screen with maternal Rh status documented and pregnancy outcome information available. Excluded were cases of fetal chromosomal or structural abnormalities, or maternal systemic disease. Results of maternal serum pregnancy-associated plasma protein A (PAPP-A) and beta-human chorionic gonadotrophin (beta-hCG) adjusted for gestational age were compared between Rh-negative and Rh-positive women with p < 0.05 considered significant. RESULTS: Two thousand two hundred and two pregnancies fulfilled the study criteria, and 160 of them (7%) were Rh negative. Only free beta-hCG corrected multiples of the median (MoM) values were statistically increased in Rh-negative women (p < 0.009). Using a cut-off of 1:300, screen-positive rates of maternal serum biochemistry were not significantly different between Rh-negative and Rh-positive women (12.5 vs 10.4%, p = 0.41). CONCLUSION: The present study focused on measurements of beta-hCG and PAPP-A in the sera of women with Rh-negative blood group. Women with Rh-negative blood type have similar first-trimester serum PAPP-A MoM values as Rh-positive women, but significantly higher beta-hCG MoM values. However, there was no significant difference in the screen-positive rate for Down syndrome between the two groups.     

Comparison and integration of first trimester fetal nuchal translucency and second trimester maternal serum screening for fetal Down syndrome

BACKGROUND: It is uncertain whether first trimester nuchal translucency (NT) is more effective than the well-established second trimester serum screening for fetal Down syndrome or whether their combination works best. We report data from a large multicentre non-interventional trial in which all subjects underwent both first and second trimester screening. METHODS: All women who attended the obstetric clinic before 15 weeks' gestation were recruited. An ultrasound examination was performed at 10 to 14 weeks to measure the NT. The nuchal measurements were not acted upon unless the fetus showed gross features of hydrops fetalis. All women had serum alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) assay at 15 to 20 weeks. The Down syndrome risk assigned by serum screening was disclosed and amniocentesis was offered if this assigned risk was >or=1:250 or if the women were 35 years and older. The efficacy of different combinations of screening markers was compared. RESULTS: Between January 1997 and August 2000, 17 590 women were recruited (19% >or=35 years old). After excluding subjects who miscarried, defaulted the serum test and other reasons, 16 237 pregnancies were analysed. Of these, 35 pregnancies were affected by Down syndrome (2.2 cases per 1000 pregnancies). At a false-positive rate of 5%, the detection rate of Down syndrome by NT alone, NT and age, serum hCG, AFP and age, and NT, hCG, AFP and age were 61%, 69%, 73% and 86%, respectively. CONCLUSION: Integration of NT and second trimester serum AFP and hCG assay yielded the best screening efficacy for Down syndrome.     

Between pregnancy biological variability of first trimester markers of Down syndrome and the implications for screening in subsequent pregnancies: an issue revisited

OBJECTIVES: To assess the level of correlation of first trimester biochemical and biophysical markers of Down syndrome between different pregnancies in the same individual. To assess the impact that between pregnancy biological variability has on the likelihood that women who are at increased risk in a first pregnancy being also at increased risk in a subsequent pregnancy. METHODS: During a three period women attending the OSCAR clinic at Harold Wood Hospital have had the opportunity to have first trimester screening for Down syndrome and other aneuploidies using the maternal serum biochemical markers free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A) in conjunction with fetal nuchal translucency (NT) thickness and maternal age. Of the 111,105 women undergoing such screening, the computer records were examined for women who had more than one pregnancy. The results from 1002 women with two normal singleton pregnancies were available for analysis. Marker correlations (as MoM) were established between the pregnancies and the proportion of women likely to be at increased risk in each pregnancy estimated, as was the likelihood of women being at increased risk in both pregnancies. RESULTS: For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r = 0.0959, p > 0.10). For maternal serum free beta-hCG MoM a significant correlation was found (r = 0.3976, p < 0.001), as was also found for PAPP-A MoM (r = 0.4371, p < 0.001). CONCLUSION: The implication for such between pregnancy marker association is that women who have an increased risk of Down syndrome in one pregnancy are two or three times more likely to repeat this event in their next pregnancy. This information may be useful in counselling women when undergoing first trimester screening in a subsequent pregnancy.