Universal Down syndrome testing… are we ready?

In January 2007, the American College of Obstetricians and Gynecologists (ACOG) introduced new guidelines for the screening of fetal chromosomal abnormalities. These guidelines have generated controversy because of the abrupt change compared with prior practice standards. The new guidelines state that all patients should now be offered invasive testing rather than employing the previously recommended cut-off age of 35 years. These same guidelines also mandate that all patients who register in the first trimester be offered a first-trimester screening strategy and that each patient undergo extensive counseling regarding all available testing strategies, incorporating the detection and the false-positive rates of each. This editorial examines these guidelines and questions whether the resources are in place in the current healthcare setting to meet these goals. Areas of need are identified and possible solutions are proposed. The goal of these suggestions is to meet the new guidelines, as well as to provide a structured approach to further antenatal genetic testing as it becomes available.

Prenatal genetic screening has been an area undergoing rapid change over the past 20 years. One of the areas that has undergone the most significant change is the clinical approach to the antenatal diagnosis of Down syndrome. Prior to 1984, a woman’s risk was solely determined by her age. A strong positive correlation had been shown between advancing age and risk, with a 20-year-old woman’s risk of having a live born with Down syndrome being one in 1667, compared with a 45-year-old woman’s risk of one in 45 [1]. Based on this correlation, an age-related risk at 35 years of age was used as an arbitrary cut-off point to determine when to offer invasive testing. The reason for this age being chosen was that it reflected a maternal risk of one in 204 of having a live birth of a chromosomally abnormal fetus, which was roughly equivalent to the procedure-related loss risk of an amniocentesis at that time. Although women over 35 years of age are at an elevated risk for chromosomal abnormalities, the majority of Down syndrome infants are born to women under 35 years (who have the majority of babies) and therefore the search for a screening test in this population continued.

In 1984, an association was reported between low maternal serum α-fetoprotein (MSAFP) and women who subsequently delivered Down syndrome infants [2]. Using maternal age in correlation with low MSAFP enabled 30% of fetuses with Down syndrome to be identified prenatally [3]. The triple screen was subsequently introduced, which combined human chorionic gonadotropin (hCG) and unconjugated estriol screening with MSAFP screening, to improve detection rates for Down syndrome to 70%, while maintaining a false-positive rate of 5%. The quadruple screen followed, which integrated maternal inhibin A levels into the formula, thereby increasing the detection rate for Down syndrome to 80% at the standard 5% false-positive rate [4].

Although these serum markers proved a significant advancement over prior testing based strictly on age, screening in women younger than 35 years of age was limited to after the first trimester. Restricting the timing of Down syndrome testing to the second trimester could cause a woman faced with a difficult decision undue pain and suffering. A woman in the second trimester who elects not to continue the pregnancy may have added impediments to her right to choose. She may be unable to ‘conceal’ the pregnancy after 12 weeks’ gestation and therefore would have to inform others of her decision, and it may be difficult to find practitioners who could provide termination services in the second trimester in her community. The introduction of first-trimester screening ameliorated many of these issues. This technology, which relies on nuchal translucency combined with free β-hCG and pregnancy-associated plasma protein-A screening, provides a detection rate, in large clinical trials, of 82–87% for Down syndrome with a false-positive rate of 5% [5].

Physicians caring for pregnant women were suddenly faced with a multitude of tests incorporated into several screening strategies. In the face of new technologies, many practicing obstetricians look toward ACOG to provide guidance on the new technologies and how to incorporate them into their daily practice. In January 2007, ACOG published the practice bulletin addressing screening for fetal chromosomal abnormalities [6]. This guideline, although composed to help provide guidance to practitioners, has generated some controversy. The reason for the controversy is the abrupt change it has brought about in clinical practice and the impact it has on the patient, physician and healthcare system as a whole.

The recommendation that has been most controversial is that “maternal age of 35 years alone should no longer be used as a cut-off to determine who is offered screening versus who is offered invasive testing” [6]. This approach is further enforced by ACOG when they state that “all women, regardless of age, should have the option of invasive testing” [6]. One can appreciate ACOG’s goal of increasing patient autonomy by providing this option to all patients. However, the impact of such a substantial policy change should be appreciated on all levels prior to implementing a clinical practice guideline.

The patient, with her new autonomy, may have lost an important reference point in navigating this maze of tests. Although the age-related risk cut-off of 35 years may have left some individuals feeling they were ‘high-risk’, it helped patients to determine when invasive testing might be warranted. Now, since all women will have the option of invasive testing, they will be asked to make a decision weighing the risks and benefits of a procedure that they may not fully understand or, equally importantly, to understand the alter-native noninvasive screening tests. Unfortunately, some women may look at this test not as an option but as a recommendation; ‘if my physician is offering this to me, that must mean I need to have it done’.

From the standpoint of fetal risk, this change in policy may lead to an increase in the loss rate of normal fetuses. With universal invasive testing, one may presume that many low-risk patients will now undergo either chorionic villus sampling or genetic amniocentesis. The problem is that there is a fetal loss rate associated with each of these procedures and, therefore, a higher number of chromosomally normal fetuses will be lost as a result of universal invasive testing. Some experts may argue that, based on the First- and Second-Trimester Evaluation of Risk trial data [7], the loss rate with amniocentesis is much lower than the original statistic of one in 200. Although this is encouraging, it is important to remember that this low loss rate was obtained in tertiary-care centers with maternal–fetal medicine experts performing the majority of the procedures. Whether this lower procedure-related loss rate is maintained in large-scale testing has yet to be determined.

These new guidelines place a substantial burden on the practicing physician. The physician of today is under substantial time and financial constraints and these new guidelines mandate extensive patient counseling. The new guidelines require that a woman be provided with “information about the detection and false-positive rates, advantages, disadvantages and limitations, as well as the risks and benefits of diagnostic procedures that should be available to patients so that they can make an informed decision” [6]. Some may argue that this can be provided with a patient information packet, but the guidelines then go on to require that “counseling should be provided regarding the specific detection rates and false-positive rates of the screening strategy or strategies they are considering” [6]. When one considers the time it takes today to explain the risks and benefits of an amniocentesis to a patient who was formerly classified as a high risk, one can appreciate the extensive time that will be required for counseling in the future. A physician is now obligated to discuss with each patient the detection and false-positive rates of first-trimester screening, second-trimester screening, sequential screening, integrated screening, chorionic villus sampling and amniocentesis, as well as the risks associated with those tests that are invasive.

The wider healthcare system is bound to feel the impact of these new guidelines. One of the options that is mentioned is that it may be reasonable to refer some patients to genetic counselors or maternal–fetal medicine experts. This is particularly relevant when one examines the ever-increasing number of prenatal screening tests that are offered to the patient. These guidelines imply that a patient should be counseled on the other diagnostic tests (e.g., fragile-X, sickle cell, cystic fibrosis, Jewish genetic diseases, thalessemia, sickle cell disease) that are available with screening and especially if the patient is now given the option of invasive testing. This almost surely mandates a consultation with a genetic counselor prior to deciding on a testing strategy, to perform a pedigree and explain the testing that is available and applicability of each test to the individual patient. Although these healthcare providers are capable of providing the level of counseling necessary, this option is not always available. In the USA today, there is a shortage of perinatal centers, with one state having no maternal–fetal medicine physicians within its borders. Therefore, a physician practicing in these underserved areas is forced not only to deal with the extended counseling requirements but also to arrange follow-up testing, which may not be readily available.

This touches upon yet another area that may prove challenging, that is, the recommendation that all patients who register during the first trimester be offered first-trimester screening. This assumes that there is widespread availability of centers that have the ability to perform nuchal translucency ultrasound examinations. There are extensive requirements and a testing process to obtain certification to offer this screening modality. Even if a certified center is recognized in a community, the larger problem is that many regions do not have individuals trained to perform chorionic villus sampling. This may lead to a patient with an abnormal result being forced to wait 5 weeks for an amniocentesis to determine whether her child is affected by a chromosomal abnormality. Patients with abnormal results may opt to travel substantial distances at significant cost to undergo chorionic villus sampling or opt to terminate owing to anxiety and an unwillingness to wait until 15 weeks’ gestation for an amniocentesis.

The authors of these new guidelines should be commended for attempting to provide guidance to the practicing obstetrician, while understanding the importance of patient autonomy. The problem, which one can appreciate with the recommended approach, is that these guidelines may not be feasible in today’s healthcare setting. In order for them to be met, it requires that patients have easy access to centers capable of performing first-trimester screening and individuals capable of providing chorionic villus sampling when an elevated risk is determined. The guidelines also assume that physicians will be afforded time and be properly reimbursed for the extensive counseling requirements placed upon them. The risk of invasive testing on a wide-scale basis must be assessed so that the patient is presented with the true risks and benefits of an invasive procedure that may now be offered to all gravidas. The most important aspect of these recommendations is the cost–benefit analysis, which has yet to be determined. These current guidelines will result in substantial cost increases with an undetermined benefit. In today’s healthcare setting of limited resources, will the cost be determined to be justifiable in the long run, particularly when it will probably result in a trade-off with lost services in other aspects of prenatal care?

Key issues

•	The American College of Obstetricians and Gynecologists introduced new guidelines for antenatal screening of chromosomal abnormalities.
•	Invasive testing should be offered to all women, regardless of age.
•	The arbitrary cut-off age of 35 years is no longer a valid criterion for offering testing.
•	Any patient registering before 12 weeks´ gestation should be offered a first-trimester screening strategy.
•	The current number of perinatal centers is insufficient to meet the new guidelines.
•	Owing to the expanding number of antenatal diagnostic modalities, now and in the near future, universal genetic counseling will probably become necessary.