The phrase “screening for genetic disorders” generally refers to two forms of genetic testing. One approach is screening the patient and/or spouse to determine their carrier status for common genetic disorders, such as cystic fibrosis. Secondly, the genetic screening may refer to techniques that assess the likelihood the fetus is affected by a genetic condition or birth defect, such as Down syndrome (DS) or spina bifida. Although both are termed “screening,” the concepts behind each approach are significantly different.

Screening for carrier status can either be directed to certain high-risk groups, or can be population based. Carrier screening for specific ethnic groups has been covered in Chapter 6 on Preconception Counseling. The approaches described previously for the patient contemplating a pregnancy are the same ones used for the pregnant patient. However, depending on the patient’s gestational age, concurrent testing of the patient and her spouse may be necessary to provide adequate time for prenatal diagnosis, should both parents be found to be carriers of the genetic condition in question.

Population based screening, on the other hand, means that every pregnant woman, regardless of her ethnic background, is offered carrier screening. At the time of the writing of this book, only cystic fibrosis falls in this category. Although more common in individuals with northern European heritage, the mutant gene is found in all populations. This factor and the pluralistic nature of US society has lead the American College of Obstetricians and Gynecologists (ACOG) to suggest that all women should be offered carrier screening for cystic fibrosis.¹ One drawback to the current recommendation is that the recommended panel of mutations that should be tested for is based on the most common mutations in the “Caucasian” population, and may, therefore, detect very few carriers in an Asian populations.

In all forms of genetic screening, but especially in carrier screening, both the patient and the physician need to be well versed in the benefits and limitations of the testing. Using our Caucasian patient example, we know that the incidence of CF carriers in this population is 1 in 29. There are nearly 2000 mutations that have been found to cause cystic fibrosis, but testing for the 23 common mutations will detect approximately 90% of the carriers. If the patient is negative for the common CF mutations, her chances of having a child with CF are quite low, but it is not zero. Should she be found to carry a CF mutation, and her spouse have negative testing, their risk of having an affected child is approximately one in a thousand. Although a low risk, it is significantly higher than the population incidence of CF (1 in 3000 births).

The key points in counseling the patient about carrier screening is that she should be provided information on the clinical features and natural history of the disorder, the benefits and limitations of the testing, and the options available to her, should she and her spouse both be carriers of the genetic condition. For any new genetic disorder to be introduced on a population-wide basis, the carrier frequency should be significantly high (eg, the 1 in 29 incidence of CF) and be comparably high in all ethnic groups. Likewise, the screening test itself must be relatively inexpensive, detect most of the carriers (ideally 95% or greater), and the test results must be easily interpretable by the practicing physician.

Screening has been defined as “the identification, among apparently healthy individuals, of those who are sufficiently at risk for a specific disorder to justify a subsequent diagnostic test or procedure.”² It can be said that the first screening test for genetic disease in the fetus was the use of the patient’s birth date to determine the at-risk category for pregnancies complicated by a fetal chromosomal disorder. When introduced as a criterion for offering amniocentesis, the screen positive rate would have been 5% (the percent of pregnant women age 35 or greater in the US population in the early 1970s) with a detection rate of approximately 30% (the number of DS children born to women above the age of 35). It is important to note here that screening for genetic diseases in pregnancy has not followed the conventional screening terminology of sensitivity, specificity, false positive, and false negative. Even when using the term “false positive” the author most commonly is actually describing the “screen positive” rate. Screen positive refers to the number of individuals in the population who have a positive screening test, and includes both the true positives and the false positives. Because the incidence of true positives is quite low, the screen positive and false positive rates are essentially the same, and used interchangeably by most authors. Pregnancy screening programs use a second measure, known as detection rate (the percentage of true positives that are found using the screening algorithm), which is synonymous with sensitivity. To put our maternal age example into a current context the screen positive rate would be 15% to 20% (the percentage of US pregnancies in women aged 35 or older) for a similar detection rate of between 30% and 40% for DS. By any measure, this approach to screening would have no validity. Since the early 1980s, there have been many attempts to define serum and ultrasound markers that would more accurately delineate the at-risk population for DS, as well as other birth defects. This chapter will focus on three of these approaches for DS screening to outline the principles, as well as the benefits and limitations, of screening.