Fetal Assessment and Prenatal Diagnosis
Louise E. Wilkins-Haug
Linda J. Heffner
I. GESTATIONAL-AGE ASSESSMENT
is important to both the obstetrician and pediatrician and must be made with a reasonable degree of precision. Elective obstetric interventions such as chorionic villus sampling (CVS) and amniocentesis must be timed appropriately. When premature delivery is inevitable, gestational age is important with regard to prognosis, the management of labor and delivery, and the initial neonatal treatment plan.
The clinical estimate of gestational age is usually made on the basis of the first day of the last menstrual period. Accompanied by physical examination, auscultation of fetal heart sounds and maternal perception of fetal movement can also be helpful.
Ultrasonic estimation of gestational age. During the first trimester, fetal crownrump length can be an accurate predictor of gestational age. Crown-rump length estimation of gestational age is expected to be within 7 days of the true gestational age. During the second and third trimesters, measurements of the biparietal diameter (BPD) and the fetal femur length best estimate gestational age. Strict criteria for measuring the cross-sectional images through the fetal head ensure accuracy. Nonetheless, owing to normal biologic variability, the accuracy of gestational age estimated by BPD decreases with increasing gestational age. For measurements made at 14 to 20 weeks of gestation, the variation is up to 11 days; at 20 to 28 weeks, the variation is up to 14 days; and at 29 to 40 weeks, the variation can be up to 21 days. The length of the calcified fetal femur is often measured and used in validating BPD measurements or used alone in circumstances where BPD cannot be measured (e.g., deeply engaged fetal head) or is inaccurate (e.g., hydrocephalus).
II. PRENATAL DIAGNOSIS OF FETAL DISEASE
continues to improve. The genetic or developmental basis for many disorders is emerging, along with increased test accuracy. Two types of tests are available: screening tests and diagnostic procedures. Screening tests, such as a sample of the mother’s blood or an ultrasound, are noninvasive but relatively nonspecific. A positive serum screening test, concerning family history, or an ultrasonic examination that suggests anomalies or aneuploidy may lead patient and physician to consider a diagnostic procedure. Diagnostic procedures, which necessitate obtaining a sample of fetal material, pose a small risk to both mother and fetus but can confirm or rule out the disorder in question.
Screening by maternal serum analysis during pregnancy individualizes a woman’s risk of carrying a fetus with a neural tube defect (NTD) or an aneuploidy such as trisomy 21 (Down syndrome) or trisomy 18 (Edward syndrome).
Maternal serum alpha-fetoprotein (MSAFP) measurement between 15 and 22 weeks’ gestation screens for NTDs. MSAFP elevated above 2.5 multiples
of the median for gestation age occurs in 70% to 85% of fetuses with open spina bifida and 95% of fetuses with anencephaly. In half of the women with elevated levels, ultrasonic examination reveals another cause, most commonly an error in gestational age estimate. Ultrasonography that incorporates cranial or intracranial signs, such as changes in head shape (lemon sign) or deformation of the cerebellum (banana sign) that are secondary to the NTD, increase the sensitivity of ultrasound for the visual detection of open spinal defects.
Second-trimester aneuploidy screening: MSAFP/triple panel/quad panel. Low levels of MSAFP are associated with chromosomal abnormalities. Altered levels of human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and inhibin are also associated with fetal chromosomal abnormalities. On average, in a pregnancy with a fetus with trisomy 21, hCG levels are higher than expected and uE3 levels are decreased. A serum panel in combination with maternal age can estimate the risk of trisomy 21 for an individual woman. For women younger than 35 years, 5% will have a positive serum screen, but the majority (98%) will not have a fetus with aneuploidy. However, only approximately 70% of fetuses with trisomy 21 will have a “positive” maternal triple screen (MSAFP, hCG, uE3) compared with 80% with a positive quad screen (MSAFP, hCG, uE3, inhibin). Trisomy 18 is typically signaled by low levels of all markers.
First-trimester serum screening. Maternal levels of two analytes, pregnancy-associated plasma protein-A (PAPP-A) and hCG (either free or total), are altered in pregnancies with an aneuploid conception, especially trisomy 21. Similar to second-trimester serum screening, these values can individualize a woman’s risk of pregnancy complicated by aneuploidy. However, these tests need to be drawn early in pregnancy (optimally at 9—10 weeks) and even if abnormal, detect less than half of the fetuses with trisomy 21.
First-trimester nuchal lucency screening. Ultrasonographic assessment of the fluid collected at the nape of the fetal neck is a sensitive marker for aneuploidy. With attention to optimization of image and quality control, studies indicate a 70% to 80% detection of aneuploidy in pregnancies with an enlarged nuchal lucency on ultrasonography. In addition, many fetuses with structural abnormalities such as cardiac defects will also have an enlarged nuchal lucency.
Combined first-trimester screening. Combining the two first-trimester maternal serum markers (PAPP-A and beta hCG) and the nuchal lucency measurements in addition to the maternal age detects 80% of trisomy 21 fetuses with a low screen positive rate (5% in women younger than 35 years). This combined first-trimester screening provides women with a highly sensitive risk assessment in the first trimester.
Combined first- and second-trimester screening for trisomy 21. Various approaches have been developed to further increase the sensitivity of screening for trisomy 21 while retaining a low screen positive rate. These approaches differ primarily by whether they disclose the results of their first-trimester results.
Integrated screening is a nondisclosure approach, which achieves the highest detection of trisomy 21 (97%) at a low screen positive rate (2%). It involves a first-trimester ultrasound and maternal serum screening in both the first and second trimester before the results are released.
Sequential screening. Two types of sequential screening tools exist. Both are disclosure tests, which means that they release those results indicating a high risk for trisomy 21 in the first trimester, but then go on to further screen either
the entire remaining population in the second trimester (stepwise sequential) or only a subgroup of women felt to be in a medium risk zone (contingent sequential). With contingent sequential screening, patients can be classified as high, medium, or low risk for Down syndrome in the first trimester. Low-risk patients do not return for further screening as their risk of a fetus with Down syndrome is low. When the two types of sequential tests are compared, they have similar overall screen positive rates of 2% to 3%, and both have sensitivities of over 90% for trisomy 21 (stepwise, 95%; contingent, 93%).
Use of ultrasound following serum screening for aneuploidy. Second-trimester ultrasound targeted for detection of aneuploidy has been successful as a screening tool. Application of second-trimester ultrasound that is targeted to screen for aneuploidy can decrease the a priori maternal age risk of Down syndrome by 50% to 60%, as well as the risk conveyed by the second-trimester serum screening. Recently, second-trimester ultrasound following first-trimester screening for aneuploidy has likewise been shown to have value in decreasing the risk assessment for trisomy 21.
In women with a positive family history of genetic disease, a positive screening test, or at-risk ultrasonographic features, diagnostic tests are considered. When a significant malformation or a genetic disease is diagnosed prenatally, the information gives the obstetrician and pediatrician time to educate parents, discuss options, and establish an initial neonatal treatment plan before the infant is delivered. In some cases, treatment may be initiated in utero.
Chorionic villus sampling (CVS). Under ultrasonic guidance, a sample of placental tissue is obtained through a catheter placed either transcervically or transabdominally. Performed at or after 10 weeks’ gestation, CVS provides the earliest possible detection of a genetically abnormal fetus through analysis of trophoblast cells. Transabdominal CVS can also be used as late as the third trimester when amniotic fluid is not available or when fetal blood sampling cannot be performed. Technical improvements in ultrasonographic imaging and in the CVS procedure have brought the pregnancy loss rate very close to the loss rate after second-trimester amniocentesis, 0.5% to 1.0%. The possible complications of amniocentesis and CVS are similar. CVS, if performed before 10 weeks of gestation, can be associated with an increased risk of fetal limbreduction defects and oromandibular malformations.
Direct preparations of rapidly dividing cytotrophoblasts can be prepared, making a full karyotype analysis available in 2 days. Although direct preparations minimize maternal cell contamination, most centers also analyze cultured trophoblast cells, which are embryologically closer to the fetus. This procedure takes an additional 8 to 12 days.
In approximately 2% of CVS samples, both karyotypically normal and abnormal cells are identified. Because CVS-acquired cells reflect placental constitution, in these cases, amniocentesis is typically performed as a followup study to analyze fetal cells. Approximately one-third of CVS mosaicisms are confirmed in the fetus through amniocentesis.
Amniocentesis. Amniotic fluid is removed from around the fetus through a needle guided by ultrasonic images. The removed amniotic fluid (˜20 mL) is replaced by the fetus within 24 hours. Amniocentesis can technically be performed as early as 10 to 14 weeks’ gestation, although early amniocentesis (<13 weeks) is associated with a pregnancy loss rate of 1% to 2% and an increased incidence
of clubfoot. Loss of the pregnancy following an ultrasonograph-guided second-trimester amniocentesis (16—20 weeks) occurs in 0.5% to 1.0% cases in most centers, so they are usually performed in the second trimester.
Amniotic fluid can be analyzed for a number of compounds, including alpha-fetoprotein (AFP), acetylcholinesterase (AChE), bilirubin, and pulmonary surfactant. Increased levels of AFP along with the presence of AChE identify NTDs with more than 98% sensitivity when the fluid sample is not contaminated by fetal blood. AFP levels are also elevated when the fetus has abdominal wall defects, congenital nephrosis, or intestinal atresias. In cases of isoimmune hemolysis, increased levels of bilirubin in the amniotic fluid reflect erythrocyte destruction. Amniotic fluid bilirubin proportional to the degree of hemolysis is dependent upon gestational age and can be used to predict fetal well-being (Liley curve) (see Chap. 26
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