Provider FAQs

What proteins are used in first trimester screening?
Free β-human chorionic gondadotropin (freeBeta) and pregnancy associated plasma protein-A (PAPP-A), are measured in maternal blood. Low levels of PAPP-A are associated with chromosomal defects (aneuploidy), such as trisomy 18 and 21. FreeBeta is the most sensitive biochemical marker for Down Syndrome (DS (trisomy 21) and an elevation of this marker is common for these pregnancies. In addition, low levels of freeBeta are associated with trisomy 18. Intact beta hCG is not an adequate marker for aneuploidy in the first trimester (1 to 1.2 Mom) and should not be used for First Trimester Screening.

What ultrasound measurements are used in 1st trimester screening?
The fetal crown-rump length (CRL) and the Nuchal Translucency (NT) are measured. The CRL is used to estimate gestational age in FTS (not LMP, BPD, etc.). NT is a fluid filled area found on the back of the neck of all fetuses. NT is a strong predictor of chromosomal, heart and other defects, as well as a marker for other medical conditions.

Do the professionals measuring have to have specific training?
YES! To insure accurate NT measurements and to maintain quality control, each provider must attend an Official Fetal Medicine Foundation (FMF) sponsored course and obtain an FMF NT Practical Certificate before submitting very precise NT measurements for First Trimester Screening to GeneCare to combine with the biochemical tests. USA National FMF NT Standard for NT measurement has been proven in all studies to significantly increase the accuracy of screening. Once a certificate has been obtained, then maintenance of quality control is achieved by external audit of each sonographer's NT median analysis and films quarterly and annually. GeneCare helped set and meets the USA National FMF NT Standard and uses the FMF database to provide accurate prenatal screening results. All studies have shown other methods of NT measurement do not meet this standard.

If an NT measurement is larger or smaller than average why send a blood sample for biochemistry analysis? Instead, can we just say an NT is either larger than average or small?
NT measurements naturally change with gestational age and the final risk assessment is based on maternal age, weight, and previous pregnancy history. To interpret the significance of an NT measurement, mathematical calculations (a delta NT and FMF fetal risk analysis) must be performed with all these factors taken into account. It is not practical to do these calculations in an ultrasound room. In addition, the biochemistry analysis reduces the screen positive rate (SPR) from 8.3% with NT alone to 2.4% and increases the detection rate (DR) from 80% to 91%. Your patients deserve the best screening available, which is not possible without biochemical assessment. The same is true for small as well as large NTs. No NT is too small to combine with biochemistry. Small NTs can be associated with increased biochemical test risks results which must be combined to raise the detection rate to 91% @ 2.4% screen positive rate (SPR).

How large does an NT have to be to be considered a marker for potential fetal heart defects?
About 1% of patients have an NT ≥ 3.5mm (≥ 99th centile) between 11-13 weeks which is used as the cutoff for making a referral for fetal echocardiogram and fetal anomaly scan at a later gestational age. Heart evaluations and fetal anomalies can detect 40% of fetal heart defects and many other anomalies during the first and second trimester.

Is Nuchal Translucency increased with unbalanced chromosomal translocation fetuses?
A study by Cheng (Obstet Gynecol 2005; 105:1058-62) shows a significantly greater NT measurement in unbalanced translocation fetuses compared with the balanced chromosomal translocation group and the normal karyotype group. Therefore, an increased NT may increase the risk that the fetus might have an unbalanced translocation.

What is the correct gestational age to do screening?
The most accurate anomaly scanning results are achieved between CRL 45-84mm (11w0d - 13w6d) but not before or after. Dating is by CRL, not LMP, BPD, etc. Chromosomal screening can be performed at 38-84mm but is not suggested because it is too early to do the anomaly scan.

Is First Trimester Screening only for advanced maternal age patients?
No. FTS is intended to screen LOW RISK patients (call to discuss ICD codes). FTS should be offered to ALL Low Risk Patients. Screening is also effective at evaluating the risk for DS and T-18 for AMA patients. All AMA patients should be routinely offered genetic counseling and diagnostic testing (CVS or amniocentesis). AMA patients who have declined amniocentesis should be counseled that prenatal screening for two chromosomal abnormalities is not a substitute for diagnostic testing for all chromosomal abnormalities. If AMA patients have FTS, their risk for other chromosomal abnormalities will still be raised. General ICD codes are available for precise CRL measurements to 0.1mm and fetal assessment.

Should we add second trimester chromosomal screening as a follow up to First Trimester Screening?
No. Second trimester chromosomal prenatal screening is not recommended because as a follow up test it cannot be accurate. Each patients risk before screening (prior risk) is adjusted by FTS. Because labs doing 2nd trimester "follow up screening do not use each patients adjusted prior risk, and cannot revise their second trimester database to account for the >90% decreased Down Syndrome and >97% T-18 prevalence, f/up second trimester risks report can not be accurate. 2nd trimester screening will more than triple the SPR to 17% (NICHD BUN, 2002) and will make patients unnecessarily anxious. The positive predictive value decreases significantly, more than 5 fold, resulting in 5 times as many unnecessary amniocenteseses. Over 250 CVS or Amniocentesis will be required to diagnose 1 affected fetus vs. only 17 to detect an affected fetus with FTS.

What is the recommended follow up?
Since FTS is not designed to detect spina bifida, AFP only is the recommended follow-up biochemical screening test for patients who have had an FTS test. A second trimester ultrasound may also be offered as a follow-up test for spina bifida. First Trimester Screening patients should never have their test repeated, because regression to the mean will result in inaccurate testing.

The ACOG 2007 Practice Bulletin seems to advocate Sequential screening.  Do we need to switch to Sequential screening rather than doing First Trimester NT/NB/freeBeta/PAPP-A screening?

No, the ACOG did not recommend a specific type of prenatal screening test.  While Sequential screening is listed as having a projected high detection rate, in real world clinical practice the detection rate is only slightly above that of the quad screen, somewhere between 82-85% (Okun, N., et al. 2007).  The Sequential and Integrated projected detection rates need to be adjusted to include the 12-33% of patients who dropped out in the observational FASTER and SURUSS trials to more accurately estimate the detection rate in clinical practice.  Also, the Sequential 5% screen positive rate is higher than 2.3% with Early Screen.  One step Early Screen has 10-13% higher risk detection than two step Sequential screening without withholding known risks and provides benefits precluded by Sequential screening.

 It is also important to consider other factors when choosing a prenatal screening test.  Physicians should obtain from each laboratory documentation of their own detection and screen positive rates before choosing a laboratory so the physicians can quote accurate information to their patients (ACOG).  The only prenatal screening tests on the ACOG Bulletin list for which detection and screen positive rates have been documented in multiple large prospective trials and by laboratories in the USA are FMF NT/Nasal Bone/dried blood/freeBeta/PAPP-A screening, AFP/freeBeta, and the triple screen.  The other tests on the list have only recently become available in the USA.  Labs offering these other tests need time to acquire prospective outcome data to be able to document their own detection and screen positive rates.

 GeneCare has documented the performance of each of our tests and provides references to ensure accurate genetic counseling for patients regarding the performance of our tests.  The first trimester prenatal screening tests offered by GeneCare have the highest detection rates and yields and the lowest screen positive rates of all available tests.  These statistics have been documented both by our center, the 23 FMF accredited prospective, evidence-based medicine studies on 177,996 patients and 2 NIH trials.  Note that the ACOG bulletin acknowledges the recommendation to consider Integrated, Sequential, and Contingent testing is based on limited or inconsistent scientific evidence (level B).  The current basis for these 3 tests is projections from modeled data.  Real world prospective clinical studies are needed to determine the performance of two-step tests which are complicated by the withholding of known risks from patients and physicians.

First Trimester Dried Blood/NT/freeBeta/PAPP-A has 91% DS detection and 2.3% screen positive rate.  Adding nasal bone raises detection to 95% at 2% screen positives.  Trisomy 18/13 has 97 and 98% detection, respectively.  As a result, GeneCare's one-step First Trimester Prenatal Screening tests are earlier, safer, and more effective than other screening tests.  For patients and physicians who want to add a Quad Test in the second trimester, GeneCare combines a dried blood First Trimester Test and a liquid blood Quad Test with Full Disclosure of test results in the first and second trimester.  This screening test avoids the significant disadvantages of Withholding Sequential and Integrated testing because the patient and physician receive all the benefits of First Trimester Screening.  Contact GeneCare for more information. 

The ACOG 2007 Practice Bulletin recommends first trimester NT/freeBeta/PAPP-A screening as an effective screening test for Down syndrome in the general population.  Does this mean first trimester screening should be offered to all patients?

Yes, all patients should be offered NT/Nasal Bone (NB)/dried blood freeBeta/PAPP-A screening.  Screening should be provided with genetic counseling regarding the differences between diagnostic and screening tests.  We would not recommend prenatal screening as equal to diagnostic amniocentesis because screening does not diagnose all chromosomal abnormalities and, unlike amniocentesis, has both false positive and false negative test results.  Although the opinion indicates that 35 years of age should no longer be used as a criterion for offering amniocentesis, it is still important to inform patients that their risk of having a baby with a chromosome abnormality increases with age.  Patients may elect diagnostic testing based on their age and/or other risk factors.

Does the bulletin also recommend that amniocentesis be offered to patients of all ages due to new studies showing increased procedure safety?

Yes, the bulletin has now opened the option of amniocentesis to all patients.  A meta-analysis reported the possible risk of a procedure-related miscarriage maybe lower than 1/200.  Patients should be counseled about their age related risk for all chromosomal abnormalities and the benefits of diagnostic amniocentesis compared to prenatal screening for several chromosomes.  The benefits and limitations of each approach should be provided to patients.  Patients who are at increased risk due to age, family history, or ultrasound exam should be informed that their risk is higher than that of patients without these concerns and that diagnostic amniocentesis and CVS are available.

The ACOG 2007 Practice Bulletin suggests the Down syndrome detection rate of first trimester screening might be similar to the second trimester quad screen.  Is this correct?

No.  Compared to quad screen, Early Screen has a 20-30% higher Down syndrome detection rate, less than half the screen positive rate and a 31-37% higher trisomy 18 detection rate.  The quad screen Down syndrome detection rate is 65-80% at 5-8% screen positive rate (SPR) and the trisomy 18 detection rate is 60% at 0.5-1% SPR.  First Trimester NT/dried blood freeBeta/PAPP-A prenatal screening (Early Screen) in the United States has an accepted DS detection rate of 91% at 2.3% SPR and the detection rate for trisomy 18/13 is 97% at 0.4% SPR.  Quad screen does not provide a trisomy 13 risk assessment.

 One of the most critical principles of interpreting prenatal screening studies is to not mix prospective FMF standardized studies with modeled non-FMF studies.  The bulletin quoted data on non-FMF averaged NT measurements combined with liquid blood freeBeta/PAPP-A which is a research test based on modeled data that is not performed in the USA.  The only first trimester prenatal screening tests based on prospective non-modeled data that are offered in the USA are 1) the NT/dried blood freeBeta/PAPP-A test (Early Screen) and 2) this same test with Nasal Bone assessment added to raise the detection rate from 91% to 95% at 2% SPR.  It is not accurate in the USA to quote the non-FMF averaged NT/liquid blood freeBeta/PAPP-A detection rates from the bulletin, the SURUSS or the FASTER trials because no laboratory in the USA actually performs that screening test.  The bulletin should have quoted the international consensus data from the 22 FMF NT/freeBeta/PAPP-A studies on over 177,996 patients and the NB standardized studies which accurately provide documented prospective data for the first trimester NT/NB/freeBeta/PAPP-A tests performed in the USA.

 Early Screen is the only documented test which provides patient-specific risk assessments for singletons, twins, multiples, and patients with diabetes, at all ages for Down syndrome and trisomy 18/13 risk assessments with external NT, NB, and TF audit; the 11-13 Week Scan for heart defects and other fetal anomalies; and perinatal risk assessment for optimal pregnancy management.

Did the ACOG 2007 Practice Bulletin quote projected detection rates based upon modeled data for screening tests?

Yes.  Historically, projected detection rates based on modeled data have not been as accurate as evidence-based data from multiple large prospective clinical trials due to inherent observational trial problems.  For example, NT measurements have been determined to be more precise in prospective interventional trials where the measurement is critical to patient care.  The detection rates documented by international FMF standardized NT and NB assessments are significantly higher than in non-FMF observational studies.  The USA FMF NT detection rate is 80% at a 5% screen positive rate, compared to 60% in non-FMF trials.  The detection rate for FMF NT/dried blood freeBeta/PAPP-A is 91% at 2.3% screen positive rate, not 82% from non-FMF trials using liquid blood and averaged non-FMF NT measurements.  Furthermore, the projected detection rates for Integrated, Sequential, and Contingent screening must be modified to take into account the effect of those patients who dropped out between the first and second trimester.  The 12% FASTER and 33% SURUSS dropout rates reduce the projected detection rates to 82-89%.  Beyond the problems associated with modeled versus prospective data, there are other practical problems with implementing hCG and two-step screening which should be carefully reviewed before implementing screening programs and providing genetic counseling.

The ACOG 2007 Practice Bulletin quoted the freeBeta MOM (1.98) and the PAPP-A MOM (0.43) but did not provide documentation that hCG is an effective marker in the first trimester.  Do we have proof that hCG can be used as effectively as freeBeta in first trimester prenatal screening?

 No.  While freeBeta has been conclusively determined to be a strong marker based on all international studies, hCG has been determined to be ineffective.  The ACOG Bulletin does not provide documentation to prove hCG is effective.  In fact, meta-analysis of all prospective international studies have documented hCG to be less effective than freeBeta and to have only 1.2 MOM in the 23 studies on 14,924 patients, demonstrating hCG's ineffectiveness as a Down syndrome and trisomy 18 screening marker.  The most accurate way to compare markers is to test each marker on the same patient blood sample.  All prospective studies where hCG and freeBeta were tested in the same patients have documented that hCG has an 8.8% lower detection rate than freeBeta.  The SURUSS trial is based on only 438 patients at 11-13 week, 6 days who had non-FMF averaged NT/liquid blood/PAPP-A with freeBeta or hCG testing, too small a study for evidence-based medicine.  The SURUSS trial reported that hCG had a lower detection rate than freeBeta.  Furthermore, data from the SURUSS and FASTER trials cannot be used to determine the freeBeta detection rate in the USA because no USA laboratory performs the liquid blood freeBeta testing using the same assay, database, and non-FMF algorithm.  In the USA, freeBeta is provided as a dried blood test using a different assay and the very large FMF database and algorithm which shows 10% higher detection rate than non-FMF studies.  Additionally, the small retrospective FASTER study on hGC and freeBeta is based on samples frozen over five years.  Historically, retrospective studies using frozen samples studies have not been as reliable as prospective studies and do not meet the criteria for evidence-based medicine.  This type of small retrospective frozen sample study cannot be used to prove hCG is effective.  The international literature has conclusively documented hCG is an ineffective research marker.  For all these reasons, the non-FMF SURUSS and FASTER studies cannot be used to negate the large prospective evidence-based international FMF literature.

In comparing prenatal screening tests, is it more important to look at the comprehensive first trimester FMF Pregnancy Management Protocol or to limit the comparison to only the performance of prenatal chromosome screening tests?

Pregnancy management has been improved dramatically by the implementation of the FMF protocol in the USA and internationally.  Patients are better served by concentrating on improving overall pregnancy management provided by the first trimester FMF protocol rather than only focusing on the detection or screen positive rates for prenatal chromosome screening test.  For example, the promotion of non-FMF two-step Integrated, Sequential, or Contingent testing is based on the limited premise that withholding known risks from the first trimester might reduce the screen positive rate.  This theory negates the real benefits of screening in the first trimester.  In the USA, the most effective way to decrease the screen positive rate is to switch from liquid to dried blood which cuts the screen positive rate in half.  In addition, using the most effective first trimester markers (NT/NB/freeBeta/PAPP-A) with the FMF algorithm has produced higher detection rates and lower screen positive rates than other combinations of less effective markers in an hCG or two-step screening strategy.  Prospective non-modeled studies are not available to document a benefit of non-FMF NT (hCG or ITA or inhibin A) PAPP-A, Sequential, Contingent, or Integrated screen test over first trimester FMF NT/NB/dried blood freeBeta/PAPP-A chromosome detection or screen positive rate advantage over first trimester Early Screen and the FMF Pregnancy Management Protocol, the most compelling concern should be which prenatal chromosome screening, ultrasound anomaly, and perinatal risk assessment protocol provides the optimal pregnancy management.  The answer is the FMF Pregnancy Management Protocol and first trimester Early Screen.

The FMF Pregnancy Management Protocol provides the highest chromosome detection rates and yields (the number of procedures required to identify one affected fetus) with the lowest screen positive rates.  It also provides the 11-13 Week Scan, the detection of 40% of fetal heart defects, many other anomalies, and perinatal risk assessment at 11-13 weeks.  Patients strongly prefer one-step first trimester screening in all 11 surveys (references available).  First trimester screening provides earlier, safer, and more accurate risk assessments and it offers the patient the most options.  First Trimester Early Screen is practical, has a 33% cost effective advantage over other screens, and is covered by the majority of insurance providers.

Does the 2007 ACOG Practice Bulletin recommend that second trimester ultrasound markers be interpreted in the context of a patient's age, history, and serum screening results?

Yes.  The FMF Pregnancy Management Protocol will aid in following this recommendation.  The FMF protocol includes: 1) First trimester NT/NB/freeBeta/PAPP-A screening, the 11-13 Week Scan, ONTD risk assessments by ultrasound or MSAFP only, perinatal risk assessment, and second trimester fetal anomaly and echocardiogram for patients with an NT measurement >3.5mm with normal karyotype.  2) The second trimester targeted fetal ultrasound exam is recommended for fetal evaluation for ultrasound markers and other benefits.

What does the future hold for prenatal chromosome screening, ultrasound anomaly and fetal heart evaluation and assessment of perinatal risk?

Patient surveys show women strongly prefer First Trimester Prenatal Screening because of the significant advantages to them, most important of which is privacy and early first trimester options.  The Fetal Medicine Foundation and the FMF USA have played significant roles in improving patient care by implementing the comprehensive first trimester FMF Pregnancy Management Protocol to improve patient care in these areas.  The future will include 5 ultrasound markers for which FMF accreditations will be provided to ensure QA and external audit for consistent and accurate assessment.  These 5 markers are nuchal translucency, nasal bone, tricuspid flow, ductus venosus, and frontal maxillary facial angle.  In addition to proven first trimester markers, freeBeta and PAPP-A, other markers may be added in the next few years.

 The current DS detection rate using NT/NB/dried blood freeBeta/PAPP-A is 95% with 2% screen positive rate.  The addition of more markers will raise detection and yield and lower the screen positive rate.  First trimester screening will continue to be the most accepted and effective method of prenatal screening because patients can receive a full risk assessment during a single first trimester office visit.  In the second trimester, we will continue to offer ONTD screening by ultrasound or MSAFP and the genetic ultrasound exam.  Advanced in ultrasound technology will improve detection of fetal anomalies and other pregnancy risks.  Markers are being developed which may be added to first trimester screening to identify preterm, preeclampsia, and other problems further improving patient care.