EARLYSCREEN First Trimester Screening

First Trimester EARLY SCREEN^®

Pregnancy Management Program

Nuchal Translucency / Nasal Bone / Dried Blood freeBeta / PAPP-A Prenatal Screening

11-13 Week Fetal Ultrasound Exam

GeneCare has introduced new tests to detect more types of birth defects earlier in pregnancy. Our prenatal screening tests identify mothers whose fetus (unborn baby) may be at increased risk of having a chromosomal disorder like Down syndrome and trisomy 18/13.  In 1998, we introduced EARLY SCREEN, the earliest, safest, and most accurate first trimester prenatal screening test at 11-13w6d for Down syndrome, trisomy 18/13, and other chromosomal abnormalities, birth defects, and perinatal risk.  FMF accredited Nasal Bone (NB) assessment was added in 2002. GeneCare helped develop the FMF USA National NT/NB/freeBeta/PAPP-A standard screening Protocol which has been implemented in the United States and over 80 countries, and is the national and international Standard of Care for first trimester screening.  GeneCare provides the highest detection rates and lowest screen positive rates for Down syndrome and trisomy 18/13 screening. 

Although risks for Down syndrome and trisomy 18/13 can be generated with either the biochemical or the NT measurement alone, the detection rates (DR) are 10% higher and the screen positive rate (SPR) is 50% lower when both are combined. NT and NB accredited sonographers and physicians assure accurate NT/NB assessments that meet the FMF USA National NT and NB standard to combine with freeBeta / PAPP-A. The following tables show the benefit of combining the strongest markers:

Table 1: Performance of freeBeta/PAPP-A between 24-84mm CRL (9w1d and 13w6d) gestation.

Table 2: Performance of NT/freeBeta/PAPP-A between 45-84mm CRL (11w to 13w6d) gestation.

*Table 3: Performance of NT/NB/freeBeta/PAPP-A

* Screen positive rate (SPR).  This rate decreases with ultrasound confirmation of gestational age, dried blood, accredited NT/NBs, and use of the FMF algorithm.
** Number of amniocentesis or CVS procedures necessary to identify one affected fetus

Screening Comparison Criteria:  Screening programs are judged by these criteria:

Detection Rate:  The detection rate is the percentage of affected fetuses identified to be at increased risk by the test.  Screening programs try to raise detection without raising the screen positive rate.

Screen Positive Rate:  The Screen Positive Rate (SPR) is the percentage of women reported to have an increased risk of Down syndrome or trisomy 18/13. Our screening program has the lowest SPR.  Early Screen has a 2.3% SPR, lower than the SPR for triple, integrated, sequential, or quad screens, which means fewer unnecessarily anxious women, reduced medical time and cost, and fewer diagnostic amniocentesis and CVS procedures, but with higher detection.

Yield:  Yield is the number of diagnostic procedures required to identify one affected fetus. This variable is a function of both the detection rate and the screen positive rate and provides a critical measure of a program's performance. Screening programs try to decrease the number of diagnostic tests needed to identify the same number of affected fetuses.  Most women that are referred for CVS/amniocentesis because of an increased screening risk, have healthy babies. First Trimester NT/freeBeta/PAPP-A screening has a 1 in 17 yield, the highest of any prenatal screening test.

Patient Preference:  Eleven FMF study surveys of women's opinions found that the majority of pregnant women prefer first trimester screening. (Kornman et al., 1997, Mononi et al., 1999)

First Trimester Markers

FreeBeta hCG:  The freeBeta hCG level in the blood of women carrying fetuses with Down syndrome is increased to 2.0 multiple of the median (MoM) compared to 1.0 MoM for unaffected fetuses.  FreeBeta is significantly reduced for trisomy 18/13 fetuses with a 0.18 MoM.  FreeBeta and PAPP-A are the most specific and sensitive first trimester markers for Down syndrome and trisomy 18/13.  The medical literature has conclusively documented Intact hCG (alpha+beta hCG) is ineffective at 9w to 13w 3d with only a 1.2 MoM.

PAPP-A:  Pregnancy Associated Plasma Protein A (PAPP-A), also produced by the placental trophoblasts, is significantly reduced for Down syndrome and trisomy 18/13 fetuses.  The median MoMs are 0.44 and 0.32, respectively, which raises detection while decreasing screen positives.

Nuchal Translucency/Nasal Bone:   The most important breakthrough in birth defect screening is the FMF and FMF USA standardization of NT and NB ultrasound assessments which are combined with dried blood freeBeta/PAPP-A for prenatal chromosome, fetal anomalies, and perinatal risk screening.  NT is the echo-free space between the skin and the soft tissue overlying the cervical spine that presents only during the first trimester of pregnancy. NT is increased in fetuses with chromosomal and other abnormalities, cardiac defects, certain genetic syndromes, and perinatal risks.  The nasal bones are assessed for presence, hypoplasis/absence. 

Early non-FMF studies used 2 to 6 mm NT cut offs which reduced detection.  Because fixed NT cutoffs, averaged NT’s, center-specific NT’s, MoM NT’s, and non-accredited NT’s are less accurate, we use the Operator-Specific FMF Standard protocol of combining the largest of 3 NT’s measured to 0.1mm accuracy by accredited sonographers with other risk factors to produce a delta NT before combining the data with nasal bone / freeBeta / PAPP-A. 

The Fetal Medicine Foundation and Kings College researchers in London established NT/NB/TF standardization. NT detects 80% of Down syndrome, with higher detection for trisomies 13 and 18. Studies of the FMF standard protocol have proven that the lower Non-FMF NT detection rates of other studies are due to personnel not measuring NT to the FMF standard. The London data has been confirmed by centers around the world after each center received FMF accreditation and followed the FMF protocol.  FMF Standard NT measurements should be analyzed by an FMF algorithm laboratory using the FMF interpretive software to calculate accurate risks for chromosomal abnormalities. 

Nuchal Translucency, Nasal Bone, and Tricuspid Regurgitation Certificates
To combine NT measurements with dried blood freeBeta/PAPP-A, physicians and sonographers must have an FMF USA or NTQR NT certificate.  To combine NB or Tricuspid Flow (TF) assessment with dried blood/PAPP-A, the physician or sonographer must have a current FMF USA Nasal Bone or Tricuspid Flow certificate.  To obtain NB or TF certificates, the operator must first obtain an FMF NT certificate.  GeneCare provides non-profit CME / CEU First Trimester Prenatal Screening and Ultrasound Diagnosis, Nuchal Translucency, Nasal Bone, Tricuspid Flow (TF), Ductus Venosus (DV), Fronto Maxillary Facial Angle (FMF-A) courses with hands-on training and continuing external audit. For more information on courses and certificates, please contact customer service with questions. 

The blood sample for freeBeta/PAPP-A is drawn between 24-84mm CRL (9 weeks to 13w6d). NT/NB are assessed between 45-84 mm CRL (11 weeks 1 day to 13w6d). 

Who Should be Offered First Trimester Prenatal Screening?
First Trimester NT/NB/freeBeta/PAPP-A screening should be offered to all pregnant women who are at low risk for the disorders being screened (ACOG, ACMG, NICHD, 2004). Therefore, the screening programs described here are for women who are under 35 years of age at the time of delivery and who do not have a positive history of an ONTD or chromosomal abnormality. Women who are over 34 years or have a positive medical history should consider diagnostic CVS or amniocentesis for prenatal chromosome testing in order to diagnose 99.9% of all chromosomal abnormalities. Screening is not a substitute for amniocentesis, because: 1) It does not give a diagnosis,  2) It estimates a risk for only 3 chromosomal abnormalities, 3) It will miss many of the hundreds of other types of chromosomal abnormalities, 4) It may falsely reassure some patients who still have an increased chromosomal abnormality risk due to age.  

High risk patients should be counseled that screening does not address their total chromosomal risk, eg. the fetal chromosome risk of a 35 year old woman includes 1.  Down syndrome and trisomy 18/13 (about 50% of the total screening risk) plus 2.  hundreds of other chromosomal abnormalities (50% of the total risk). A within normal range screening report can adjust half of the age related chromosome risk, which leaves about half of the fetal chromosomal abnormality risk not addressed. Genetic counseling is suggested for all high risk patients to help them understand why screening is not a substitute for diagnostic CVS/amniocentesis chromosomal analysis. This test is not necessary for a patient who decides to have an amniocentesis.

Twins:  First Trimester NT / Nasal Bone / freeBeta / PAPP-A screening should be offered to all low risk women who are carrying twins to detect 80% of DS pregnancies. Nuchal translucency and NB screening is equally sensitive in both singleton and multiple pregnancies.  Adding biochemistry reduces the screen positive rate from 12.4% to 7.2% for twins.  Adding NB to NT should raise detection from 80% to 84%.

Open Neural Tube Defects (ONTDs):  Because First trimester screening tests does not screen for ONTDs, women who receive a First Trimester Screening report which does not show an increased chromosomal risk should have an AFP (alpha-fetoprotein) dried blood screening test after 13w 3d or an ultrasound exam at 16-20 weeks to obtain 98% detection of ONTDs.  Women who receive an increased risk First Trimester report can elect to have amniocentesis with an amniotic fluid AFP test to detect greater than 99% of ONTDs and most open abdominal wall defects. Women who have CVS should have an AFP or ultrasound exam in the second trimester.

CVS and Amniocentesis:  Women with an increased risk for a chromosomal abnormality because of First Trimester screening or ultrasonographic findings are offered CVS or amniocentesis. CVS and amniocentesis may be associated with a small increased risk of miscarriage.  CVS and amniocentesis has been shown to be safe when performed by experienced physicians using continuous ultrasound guidance. The choice of procedure is usually made on the basis of local availability, provider, experience, and the patient’s preference. Both procedures are offered through GeneCare's network of consultants.

Optimal Screening Protocol:  Maximum screening efficiency for Down syndrome, Trisomy 18/13 and ONTDs is achieved through first trimester NT/NB/dried blood freeBeta/PAPP-A screening and the 11-13 Week Scan, followed by AFP Only or targeted fetal ultrasound for spina bifida in the second trimester.

References available upon request.