Down syndrome, also known as trisomy 21, is a disorder caused by a chromosomal abnormality. It is the most common single cause of birth defects including mental retardation. Women who are over the age of 35 or who have a previously affected pregnancy are at the highest risk. Interestingly however, 80% of babies born with Down syndrome are born to mothers under 35. There is no preventative measure or cure for this condition.

Prenatal screening first became available over 20 years ago and has been evolving ever since. Up until the early 1980s, maternal age and history was the only screening modality available. This changed in the mid 1980s when Cuckle⁽¹⁾ demonstrated that combining maternal age with maternal serum alpha-fetoprotein increased the detection rate substantially. If patients were deemed to be at increased risk, an amniocentesis may be performed. This allowed detection of Down syndrome midway through the second trimester. Ultimately, this evolved into quadruple screen which is typically done at 15-18 weeks. With this test, four serum markers, MSAFP, hCG, estriol and inhibin, are measured, yielding a 75% detection and 5% false positive rate. The desire came for earlier as well as more efficient detection, leading investigators to search for one method of screening.

First trimester screening first came to light in the early 1990s when Nicolaides reported an association between thickened nuchal translucency (NT) and aneuploidy⁽²⁾.

Nuchal translucency is a sonographic finding examining the subcutaneous tissue at the back of the fetal neck. The NT is a collection of fluid that is appears as an echolucent line (Fig. 1). There are strict designated criteria to ensure proper measurement (Table 1).

Combining nuchal translucency with maternal age provided earlier detection of those pregnancies at higher risk for aneuploidy with 80% detection⁽³⁾.

In 1996, Wald et al⁽⁴⁾ set out to determine the value of serum screening between 8 and 14 weeks. Seven potential markers were evaluated. Two markers, PAPP-A and free Beta hCG were found to be discriminatory for Down syndrome affected pregnancies. A low PAPP-A value and high free Beta hCG were seen in affected pregnancies. Using both analytes in combination with age provided a 62% detection rate. Although detection rates were similar, patients had the benefit of earlier screening and ultimately, more options. Wald used mathematical models to combine data from three established datasets: serum markers and nuchal translucency measurements. Using these models, it was determined that using either serum markers or NT alone in the first trimester were not more effective than second trimester screening. However, combining the results of NT and serum markers increased the detection rate to 80%.

The next step was examining this combination outside the models and within a population of women. The First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening Study Group (BUN Study Group)⁽⁶⁾ was designed to evaluate and test this combination. This multicenter study obtained first trimester serum analytes in combination with the measured NT in over 8500 patients, between 74 and 97 days gestation, using. Blood samples were sent to the same laboratory. Nuchal translucency measurements were obtained according to specific standards set by the Nicolaides and the Fetal Medicine Foundation. The results were monitored for quality control.

Using the combination of serum and ultrasound screening, this study obtained a detection rate of 79% for Down syndrome. The false positive rate was 5 percent. These results were consistent with the previously proposed mathematical models and confirmed by the OSCAR trial⁽⁷⁾ which prospectively looked at over 30,000 pregnancies with first trimester serum and NT screening. The OSCAR trial reported a 90% detection rate.

The FASTER (First and Second Trimester Evaluation of Risk) trial⁽⁸⁾ was a multicenter study screening over 38,000 patients, measuring not only NT and first trimester serum analytes but also second trimester serum analytes. Maternal age was taken into account for all tests. In this study, the patients were not made aware of the findings from the first trimester screens. Once all the data was collected, the information was analyzed in multiple combinations (Table 2). The goal was to not only compare first and second trimester screening, but to describe combinations that may provide the best detection.

This trial confirmed that in the first trimester, the combination of NT and serum is more effective than either alone. At 11 weeks, the detection rate for Down syndrome was 70% using nuchal translucency alone. This increased to 87% when PAPP-A and free Beta hCG was added. This finding was statistically significant and clearly supports using the combined markers when assessing first trimester risk. The fully integrated model yielded the best detection rate at 96%. The major disadvantage of the fully integrated testing is that the patient is not made aware of the first trimester results. The risk is not completely calculated until after the second trimester screen. This not only removes the option of CVS for early diagnosis but affects management option for the patient if it is decided not to continue the pregnancy. The stepwise sequential allows for calculation of risk after the first trimester. If the first trimester screen is negative, the patient would then undergo the quadruple screen with a new risk calculated. If the first trimester screen is positive, it is early enough for the patient to have a CVS for further assessment. Even with the positive screen the patient can choose to forego CVS and have the second trimester quadruple screen with a new calculated risk. If the quadruple screen is positive, the patient can then undergo amniocentesis for further evaluation. The detection rate for the stepwise sequential is 95%. The FASTER trial also demonstrated that detection rates are best if done at 11-12 weeks.

There are multiple options from which physicians and patients may choose. Regardless of the method chosen, nuchal translucency is integral in optimizing the screening for Down syndrome. First trimester screening has become increasingly available and is likely to be implemented into standard practice.

There may be some foreseeable obstacles with this approach . Once the first trimester risk is calculated, proper counseling will be needed. This can take up a substantial portion of office time and not every practitioner has a genetics counselor easily accessible. If screen is positive, the patient has the option of invasive testing i.e. CVS. In experienced hands, the procedure related loss rate for CVS is approximately 0.5-1%, which is equivalent to the risk of second trimester amniocentesis. It will be essential that if first trimester screening is done, CVS is an available option. This may not be the case in all parts of the country and it may be necessary for referral centers to be formed. If the CVS should reveal an aneuploid fetus and the desire is to not continue the pregnancy, earlier terminations are safer than later in the second trimester. If the screen is negative, the quadruple screen is done and will calculate a new risk for the patient. At this point if positive, the patient has the option of amniocentesis.

Which option is ultimately chosen will depend on several factors. The first depends on when the patient presents for prenatal care. If she presents after 14 weeks then quadruple screen will still serve well for this patient. For those patients that come for early prenatal care, the options available should be discussed with the patient. Some patients, e.g. women over 35, may decide to go straight to invasive testing. For other patients, the best option is dependant on what the patient would do with the information.

If the patient is not comfortable with CVS or if it is not immediately available the fully integrated screen would offer the best detection rate. If the patient would undergo CVS, the first trimester combined may be best with the stepwise sequential if the first trimester screen is negative. Ultimately, all the options allow the provider match each patient with an effective screening tool that can fit their specific needs.

Table 1. Requirements for a proper nuchal translucency (Fetal Medicine Foundation)

Crown rump length (CRL) between 45 and 84mm Sagittal section of the fetus i.e. clearly visualized profile The fetus should be in neutral position i.e. not hyperextended or flexed Only the head and thorax should be included in the picture The widest part of the translucency should be measured Measurements should be along the inner borders of the translucency, not within the fluid The amnion must be visualized and distinguishable from fetal skin More than one measurement should be obtained with the maximum recorded

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Table 2. Combinations of first trimester screening tests
Name	Tests	Detection rate
Nuchal Translucency alone	Nuchal Translucency (NT)	70%
First trimester serum screen alone	PAPP-A and Free Beta hCG	70%
First trimester combined	NT + 1st trimester serum	87%
Second trimester serum (quadruple screen)	MSAFP, hCG, Estriol, Inhibin	81%
Independent sequential	NT + 1st trimester serum with risk calculated, then quadruple screen with each independent risk calculated	94% *(11% false positive)
Stepwise sequential	NT + 1st trimester serum with risk calculated, then quadruple screen with final risk including first and 2nd trimester results	95%
Serum integrated	PAPP-A in 1st + quadruple screen in the 2nd trimester with one risk calculated	88%
Fully integrated	PAPP-A in and NT in the 1st + quadruple in the 2nd trimester with one risk calculated	96%

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References

1. Cuckle HS, Wald NJ, Thompson SG. Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and alpha fetal protein level. British Journal of Obstetrics and Gynecology 1987; 94(5):387-402.
2. Nicolaides KH, Azar G, Byrne D et al. Fetal nuchal translucency: ultrasound screening for chromosomal defects in the first trimester of pregnancy. British Medical Journal 1992;304:867-9.
3. Snijders RL, Noble P, Sebire N et al. UK multicenter project on assessment of risk of trisomy 21 by maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation. Lancet 1998;352:343-6.
4. Wald NJ, George L, Smith D et al. Serum screening for Down’s syndrome between 8 and 14 weeks of pregnancy. British Journal of Obstetrics and Gynecology 1996;103:407-12.
5. Wald NJ, Hackshaw AK, Combinin ultrasound and biochemistry in first trimester screening for Down’s syndrome. Prenatal Diagnosis 1997;17(9):821-9.
6. Wapner R, Thom E, Simpson JL et al. First trimester screening for trisomies 21 And 18. New England Journal of Medicine 2003;349(15):1405-13.
7. Avgidou K, Papageorghiou A, Bindra R et al. Prospective first trimester screening For trisomy 21 in 30,564 pregnancies. American Journal of Obstetrics and Gynecology 2005;192(6): 1761-7.
8. Malone FD, Canick JA, Ball RH et al. First trimester of second trimester, or both, for Down’s syndrome. New England Journal of Medicine 2005;353(19):2001-11

June, 2006

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