Methods of Prenatal Diagnosis



Case 1: A 35-year-old, gravida 1, presents for prenatal care at 8 weeks’ gestation. How do you counsel her regarding her risks for genetic conditions in her fetus, and her options for prenatal screening and/or diagnosis?

Historically prenatal diagnosis was offered to all women who would be age 35 or greater at delivery. The exact reason that age 35 was chosen in the United States (in the United Kingdom age 37 was chosen) is not entirely clear, but it was not because there is a biological difference between women above, and those below, age 35 that causes a sudden increase in the risk of chromosome abnormalities in their offspring. Likewise, the age cut-off was not chosen to balance the risk of a chromosomal abnormality with the risk of procedure-related pregnancy loss, as the guidelines were established before the early studies were done to assess procedure related risk. The best explanations are those based on logistics: what resources were available to provide cytogenetic studies to the population of women. In the early 1970s when amniocentesis was introduced into practice the limited number of cytogenetic laboratories available in the United States could provide testing for about 5% of the pregnant population. At that time only 5% of the pregnant population was 35 or older at birth. Whatever the actual reason for defining age 35 or greater as “advanced maternal age,” it became the US standard of care until 2007 when the American College of Obstetricians and Gynecologists (ACOG) declared that age 35 should no longer be used as a criteria for whether a patient should be offered invasive prenatal testing.1

Although the risk of chromosomal abnormalities such as Down syndrome (DS) does increase with maternal age, using maternal age as a screening criterion results in a very poor screening testing. With approximately 15% of the US population age 35 or older, there would be a 15% “false positive” rate to detect about 30% of DS fetuses. In 1975, when no other screening methods were available, a 5% false positive with a 30% detection was a more reasonable approach.

In counseling the patient described above, it is important to present the risk in terms that are understandable to the patient. Table 9-1 presents the risks of DS and all chromosomal abnormalities at both mid-trimester and at birth. At age 35 the mid-trimester risk (the standard time for most testing) of DS is 1/270, and for all chromosomal abnormalities 1/100. Giving these numbers as fractions or percentages (0.3% and 1%) is not truly understood by most patients. Putting these numbers in concrete terms, such as “1 in every 100 women of your age will have a chromosome abnormality in their pregnancy,” is more likely to convey the information in a way to allow an informed decision. The counseling session should include some discussion of the natural history of the disorders that are included in the category of “all chromosomal abnormalities.” By the late first and early second trimester, only five maternal age-associated chromosome aneuploidies are likely to be present in a viable pregnancy (trisomies 13, 18, and 21, and the sex chromosome aneuploidies, 47,XXY and 47,XXX). Turner syndrome (45,X) is not associated with advancing maternal age. Finally, the counseling session should emphasize that increasing maternal age is only associated with a risk of nondisjunction (chromosome abnormalities), and not with any other genetic conditions. Having provided to the patient this brief discussion of her risks, attention can be turned to the various diagnostic and screening options available to her. It is important to remember that “doing nothing” also is an appropriate option, given the 99% likelihood that the pregnancy is not complicated by DS, or one of the other aneuploidies.

TABLE 9-1.

Age-Related Risk of Trisomy 21 and all Chromosome Abnormalities




The “gold standard” in prenatal diagnosis is amniocentesis, having now been a part of the medical practice for nearly 50 years. It is generally performed between 16 and 18 weeks’ gestation for genetic diagnosis, but can be performed at later gestational ages, if clinically indicated. Studies of amniocentesis done prior to 14 weeks’ gestation have found higher fetal loss rates (corrected for earlier gestational age), and an increased incidence of positional limb abnormalities, such as club foot. Current indications for offering amniocentesis, which are also the indications for prenatal diagnosis in general, are outlined in Table 9-2

TABLE 9-2.

Indications for Amniocentesis

In counseling a patient regarding the risks and benefits of amniocentesis, the greatest benefit is quite precise genetic information, approaching 100% reliability for the common indications for amniocentesis. The most common reason for a misdiagnosis is contamination of the amniotic fluid sample by maternal cells obtained as the needle passes through maternal tissue before entering the amniotic cavity. This risk can be minimized by discarding the first 1 to 2 mL of amniotic fluid withdrawn, which should clear the needle tip of any potential maternal tissue.

The most significant risk of amniocentesis is procedure-related fetal loss. Despite nearly a half century since its introduction, the true risk of fetal loss directly related to amniocentesis remains unknown. The first US study funded by the National Institute of Health found that the overall fetal loss rate was 3.5% compared to a 3.2% loss rate in the control group, a difference that was not statistically significant.2 Despite this lack of statistical significance, a number of textbooks begin stating that the risk of amniocentesis was 0.5% or less, which ultimately became “the risk of spontaneous abortion following amniocentesis is one in 200.” The only randomized study of the risk of amniocentesis, performed by Tabor and colleagues did find a statistically significant risk of pregnancy loss following amniocentesis of approximately 1%.3 Since this study from the mid-1980s a number of observational studies have been published, each failing to find a significant difference in pregnancy loss in patients undergoing amniocentesis.4,5 However, each study has consistently shown a higher, albeit not statistically significant, risk for the amniocentesis group compared to the control groups. For purpose of counseling a patient considering amniocentesis, the best approach may be to state that the risk of pregnancy loss following amniocentesis is quite low, likely in the range of 1 loss for every 500 to 1000 procedures performed. If the procedure is performed by an experienced operator using continuous ultrasound guidance, there should be no other maternal or fetal risks associated with amniocentesis.

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Jan 12, 2019 | Posted by in OBSTETRICS | Comments Off on Methods of Prenatal Diagnosis
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