Special Feature: Contemporary Prenatal Diagnosis
Special Feature
Contemporary Prenatal Diagnosis
By John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, Associate Editor for OB/Gyn Clinical Alert
In 1985 5.6% of pregnant patients were 35 years of age or older, and in 2002 that figure rose to 12.5%. It is estimated that last year 20% of the pregnant population was older than 34 years of age.
Today’s women of advanced maternal age (AMA) are very interested in having as much non-invasive diagnostic information available to them before deciding whether to have an invasive procedure, and today the scope of prenatal testing has expanded to allow these patients reasonably reliable estimates of their risk of having fetuses with trisomy 21 and trisomy 18.
This Special Feature will focus on the most contemporary forms of prenatal diagnosis and how they can be used to provide the most accurate risk assessment for those wishing non-invasive diagnostic information. In addition, the risks and benefits of various invasive procedures will be discussed.
Invasive Procedures
Second trimester amniocentesis. The risk of amniocentesis most frequently quoted is 1 in 200. This emanated from a vintage NIH study that was published in 1976. Interestingly, this figure, as indicated below, still represents the estimated procedure-related risk based on the available published literature.
There is only 1 randomized clinical trial in the literature involving 4066 women who were 34 years of age or younger. The fetal loss rate in the amniocentesis group, up until 26 weeks of gestation, was 17 per 1000, compared with 7 per 1,000 in the control group. The derived 1% procedure-related risk took some by surprise, but that study has stood up to heavy scrutiny because the numbers were reasonable, the operators were very experienced, and the procedures were all performed under ultrasound guidance.
Several uncontrolled studies have yielded loss rates after second trimester amniocentesis, ranging between 1.9 and 4.9 percent. To evaluate procedure-related loss rate from contemporary mid-trimester amniocentesis, Seeds et al analyzed data from 29 studies, each including more than 1000 patients having mid-trimester amniocentesis.1 In the 29 studies totaling 33,795 patients, the raw loss rate was 2.5%, which, compared with the loss rate in the above controls, gave a procedure-related loss rate of 0.7%.
Given the lack of randomized data, it is difficult to precisely quote a risk for amniocentesis, but it is clear that: 1) experience plays a role in procedure-related losses; 2) with the exception of unpublished data from 1 large non-randomized study (the FASTER trial) suggesting a lower amniocentesis risk, available published information points towards a procedure-related risk of 1 in 200; 3) the spontaneous second trimester loss rate (up until 26 weeks) is about 0.5%.2,3
Early amniocentesis. When chorionic villus sampling (CVS) emerged as an option for early prenatal diagnosis, only a few operators were trained in this invasive technique. However, many were trained in amniocentesis. In order to comply with their patients’ requests for early diagnostic information, some clinicians began offering amniocentesis between 11 and 14 weeks.
Simply put, this option represents the least safe test for invasive prenatal diagnosis. Randomized trials show a doubling of fetal loss compared with CVS and standard amniocentesis, as well as an unacceptable incidence of clubbed foot.
Chorionic villus sampling. Brambati was the first to exploit the idea of sampling placental tissue in the first trimester by threading a catheter through the cervix and directing the tip under ultrasound guidance into the placenta.4,5 The greatest problem in assessing the risk of CVS stems from the difficulty in sorting out spontaneous loss rates, which drop as pregnancy progresses through the first trimester and early second trimester. Raw loss rates after CVS have varied between 1.6 and 3.4 percent in experienced centers in the United States.
Two reports suggested a high rate of transverse limb defects with CVS. However, this was only in patients having CVS too early (< 10 weeks). After this time, there is no increase in this complication. We have been quoting to our patients a procedure-related loss rate of CVS, performed at 10 to 13 weeks, to be about 1%. And, realizing that the paucity of randomized data does not allow us to provide more precise information, we have indicated that this risk is slightly higher than amniocentesis, as concluded by the authors of a review of the Cochrane Database.6
Non-invasive Prenatal Diagnosis
First trimester ultrasound. In 1992, Nicolaides reported on the association between an enlarged nuchal translucency (NT) and fetal chromosome abnormalities. After compulsively organizing a multicenter screening program, which involved careful standardization of the methods and regimented operator training, the group reported their results in a prospective study involving 96,127 patients.7 The calculation of fetal Down syndrome risk was based on the patient’s age, the crown-rump length, and the NT measurement. At a false-positive rate of 5%, the detection rate for trisomy 21 was 77%. The first study initiated in the United States had discouraging results with a sensitivity for the above method of only 31%. However, combined data in unselected patient populations put together by Malone and D’Alton8 showed a 77.3% sensitivity in the 316,311 patients pooled from 30 studies. Also, the BUN study involving 8514 patients had a sensitivity of 69% at a false-positive rate of 5%. This US study, as well as the soon-to-be-published FASTER trial data, bears out the efficacy of this method in an American population.
Inherent in the accuracy of NT screening is the necessity to have experienced, specially trained sonographers utilizing standardized protocols when performing the ultrasound examinations.
First trimester biochemistry. Two analyses that have seemed most effective in the first trimester are pregnancy-associated plasma protein A (PAPP-A) and the beta subunit of human chorionic gonadotropin (b-hCG), both placental products. When used together, they have a 62% sensitivity for trisomy 21 at a 5% screen-positive rate.
NT and biochemistry in combination. It is clear that the addition of biochemistry enhances the predictive value of NT (the combined test). Combined data from 8 published studies involving 59,857 patients yielded an 82% sensitivity for trisomy 21 at a 5% screen positive rate.
Nasal bone. Since fetuses with Down syndrome tended to have small nasal bones, Cicero et al9 began investigating presence or absence of fetal nasal bone in the second trimester as a possible diagnostic tool for the diagnosis of this condition. In their first publication, they found that 73% of fetuses with Down syndrome had absent nasal bones, compared with only 0.5% of the normal population. In their expanded data, they found that 67% of Down syndrome fetuses had absent nasal bones and there were ethnic variations in their results. The good news was that nasal bone findings were independent of NT. In fact, the addition of the nasal bone evaluation increased the sensitivity of the combined tests from 89% to 97% with a screen-positive rate of 5%.
It should be mentioned that recent unpublished data from the FASTER trial do not bear out this high sensitivity for fetal nasal bone in the first trimester.
Second trimester biochemistry. In Down syndrome, maternal serum alpha-fetoprotein levels tend to be low, total hCG levels tend to be high, and estriol values generally are low. The combination of these 3 analytes (triple screen) has a sensitivity of 67% (as noted in the BUN study). In an AMA population, the sensitivity of the triple screen can exceed 85%, but this is at a screen positive rate of about 14%.
The addition of a fourth analyte (generally inhibin-A, another placental product) clearly enhances the sensitivity of the test by 5-7%.
Based on the above-mentioned trials, sufficient data have emerged to fashion 3 different approaches to prenatal diagnosis using first trimester ultrasound and first and second trimester biochemical information. Since the titles for these programs below are descriptive and concepts are just now evolving, their names may well change.
1. Integrated screen—this represents the protocol used in the FASTER trial and consists of first trimester NT and PAPP-A and a second trimester quad screen. The controversial part of this scheme is that the patient is not informed of the first trimester results until all the information is in. She gets one answer a few days after the second trimester blood is drawn. Through analysis of existing data, this method gives a 96% sensitivity at a 5% screen-positive rate.
2. Independent sequential screen—this consists of a combined screen of NT, PAPP-A, and b-hCG, which is performed in the first trimester, and the patient is apprised of the results immediately. The result of second trimester biochemistry is then given to the patient, which is independent of the first trimester result and based on a pretest risk of age alone. The reported sensitivity of this technique in the BUN study, using a triple screen, was 98% with an overall screen-positive rate of 17%. However, when using extrapolated data to give parallel results, this technique would have resulted in the sensitivity of 87% with a screen positive of 5%. With the quad screen, the sensitivity figure would be higher.
3. Dependent sequential screen—risk is derived from the combined first trimester test (NT and PAPP-A with or without hCG) which is given to the patient. She then goes into her second trimester quad screen with a new pretest risk, which is not based on her age but on the result of the first trimester test. The second result would then yield a lower false-positive rate than the independent screen described above. With modeling from the FASTER data, this would yield a sensitivity of 95% with a screen-positive rate of 5%.
A variation of the above dependent sequential theme is a contingency approach in which a preset first trimester numerical risk would be used as a threshold below which no further testing would be required. This would make sense from a cost standpoint and could diminish patient angst.
Increased Nuchal Translucency in Euploid Fetuses
Fetuses with NT measurements that are above the 95th percentile need further diagnostic attention, even if invasive procedures indicate a normal karyotype. A number of fetal abnormalities too long to list have been reported to be associated with increased NT. These include abnormalities of the fetal heart, ventral wall, central nervous system, and fetal skeleton.
Fetal cardiac abnormalities are common, with or without the above multiple anomaly syndromes. When NT measures above 3.5 mm, the risk of cardiac defects increase 30 fold. Our approach to fetuses with large NTs and normal karyotypes is to perform a very detailed ultrasound in the second trimester (after ruling out any obvious first trimester structural abnormalities by transvaginal ultrasound) and to add a detailed fetal echocardiogram at about 20 weeks. If these examinations are negative, then the risk of fetal anomalies drops almost to baseline levels.
Genetic Sonogram
This has been covered in detail in other Clinical Alerts. It is composed of a detailed ultrasound examination to rule out fetal short limbs, major anomalies, and markers for Down syndrome. Data from 9 recent studies suggest a sensitivity of the genetic sonogram being between 59% and more than 90%. Pooled data from an 8-center study showed an average sensitivity of the genetic sonogram of 71.6%. This and other studies also suggest that the genetic sonogram has independent diagnostic value, since it performed as well in patients with abnormal biochemistry, as well as in those of AMA.10-12
Current results in the literature suggest that centers with large patient numbers and accurate outcome data can calculate their own likelihood ratios. Then, using Bayes theorem, an adjusted risk can be estimated for a given patient after a negative genetic sonogram. For example, a 25-year-old woman with a pretest value of 1 in 280, having a reassuring sonogram in a center generating a likelihood ratio of 0.3, would be adjusted downward to a risk of 8 in 840 (0.3 × 280).
Programs, yet to establish their own sensitivity and specificity values, but following a carefully standardized protocol for a genetic sonogram, could add a conservative cushion by simply adjusting the pretest risk downward by half after a negative genetic sonogram. The FASTER trial has shown that the few trisomy 21 fetuses not screened in with an integrated test were picked up in more than 8000 patients in the study having a genetic sonogram, giving a 100% sensitivity for Down syndrome when the ultrasound was added to the integrated testing scheme.
Conclusion
Progress in prenatal diagnosis has been exponential over the last decade and there is reason to believe that the dots of progress will continue to be connected along the same pathway in the next decade. Ultrasound technology is exploding as evidenced by recent advent of 3D and 4D methods. Investigators are better trained and bench science is becoming more automated. Soon, invasive techniques will be needed for patients who are only at the very highest risk for severe fetal abnormalities.
References
- Seeds JW, et al. Am J Obstet Gynecol. 2004;191:607-615.
- Philip J, et al. Obstet Gynecol. 2004;103(6):1164-1173.
- The Canadian Early and Mid-trimester Amniocentesis Trial (CEMAT) Group. Lancet. 1998;351(9098):242-247.
- Brambati B, et al. Prenat Diag. 1988;8(8):609-617.
- Brambati B, et al. Prenat Diag. 1998;18(3):255-266.
- Alfirevic Z, et al. Cochrane Pregnancy and Childbirth Group. Cochrane Database of Systematic Reviews, 2005.
- Snijders RJ, et al. Lancet. 1998;352(9125):343-346.
- Malone FD, et al. Obstet Gynecol. 2003;102(5 Pt 1):1066-1079.
- Cicero S, et al. Lancet. 2001;358(9294):1665-1667.
- Wapner R, et al. N Engl J Med. 2003;349(15):1405-1413.
- Hobbins JC, et al. J Ultrasound Med. 2003;22(1):33-38.
- Hyett J, et al. BMJ. 1999;318(7176):81-85.
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