Fetal Evaluation and Prenatal Diagnosis



Fetal Evaluation and Prenatal Diagnosis


Andrew J. Healy

Tracy Shevell

Mary E. D’Alton



Serious birth defects, often genetically determined, complicate the lives of 3% of newborns and their respective families. These disorders account for 20% of deaths during the newborn period, surpassing prematurity as the leading cause of neonatal mortality and contributing to an even higher percentage of the serious morbidity in infancy and childhood. The cost of neonatal intensive care is staggering; higher still are the costs of rehabilitation programs for the severely handicapped. The impact on an affected family is perhaps immeasurable.

With growing recognition of the frequency and importance of congenital disorders as well as social trends toward delayed parenthood and smaller family sizes, prenatal diagnosis plays an important role in the management of many pregnancies. The goal of prenatal diagnosis is to provide anatomic, genetic, physiologic, and biochemical information about the fetus, thereby facilitating maximum reproductive choices for the parents.


INDICATIONS FOR PRENATAL DIAGNOSIS

Both general and specific risk factors must be ascertained to determine if a pregnancy has an increased risk of a diagnosable fetal disorder. The American College of Obstetricians and Gynecologists (ACOG) recommends the use of a questionnaire to elicit genetic information that may help elucidate these factors. Counseling before prenatal diagnosis is of critical importance. The central issue is balancing the risk of an abnormal child against the risk associated with an investigative or interventional procedure. Prospective parents must understand the concept of excluding or establishing a specific diagnosis with a high reliability but without complete certainty. One of the most important goals in genetic counseling is to help patients understand the reproductive options that are available. A person’s previous experience, ethnicity, cultural background, and religious beliefs may affect his or her acceptance of prenatal diagnosis and the choices made following the diagnosis of an abnormality. Counseling should be nondirective and concentrate on the accurate presentation of all the facts and options available. Common indications for prenatal counseling and diagnosis are summarized in Box 22.1.


General Factors

Numeric chromosomal abnormalities occur with increased frequency with advancing maternal age (Table 22.1). Standard
practice is to offer prenatal cytogenetic diagnosis to all women who will be 35 years or older at their delivery date. Testing for biochemical markers in maternal serum identifies patients at risk for certain cytogenetic and structural abnormalities. Alpha-fetoprotein, the major protein of early fetal life, is synthesized in the fetal liver and yolk sac. Open neural tube and ventral wall defects are associated with exposed fetal membrane and blood vessel surfaces, which increase the level of alpha-fetoprotein in amniotic fluid and maternal serum. Low levels of maternal serum alpha-fetoprotein and unconjugated estriol are associated with trisomies 21 and 18.



BOX 22.1 Indications for Prenatal Testing



  • General factors


  • Maternal age greater than or equal to 35 at time of delivery


  • Maternal serum alpha-fetoprotein concentration


  • Triple screening (maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol)


  • Specific factors


  • Previous child with structural defect or chromosomal abnormality


  • Stillbirths, neonatal deaths


  • Parent with structural abnormality


  • Parent with balanced translocation


  • Inherited disorders (cystic fibrosis, metabolic disorders, sex-linked recessive disorders)


  • Maternal medical disease (diabetes, phenylketonuria)


  • Teratogen exposure (ionizing radiation, anticonvulsant medicines, lithium, isotretinoin, alcohol)


  • Infections (rubella, toxoplasmosis, cytomegalovirus)


  • Ethnic factors























    Disorder Ethnic Group Screening Test
    Tay-Sachs disease Ashkenazi Jews, French Canadians Decreased serum, hexosaminidase A
    Sickle cell anemia Black Africans, Mediterraneans, Arabs, Indo-Pakistanis Presence of sickling in hemolysate followed by confirmatory hemoglobin electrophoresis
    Thalassemia Mediterraneans, Southern and Southeast Asians, Chinese Mean corpuscular volume less than 80 fL (alpha and beta) followed by confirmatory hemoglobin electrophoresis

The single marker that yields the highest detection rate for Down syndrome is human chorionic gonadotropin, which is significantly elevated in this syndrome. The combined use of the markers human chorionic gonadotropin, unconjugated estriol, maternal serum alpha-fetoprotein, and maternal age leads to detection of approximately 60% of cases of Down syndrome, with a false-positive rate of 6.6%. The use of ultrasonography to verify gestational age reduces the false-positive rate to 3.8%.

Maternal serum alpha-fetoprotein screening should be offered to women at 16 to 20 completed weeks of pregnancy. Careful evaluation of gestational age is of critical importance because maternal serum alpha-fetoprotein values increase steadily throughout the second trimester. Because of population differences in median maternal serum alpha-fetoprotein values, laboratories must take into account variables such as race, multiple gestations, diabetes mellitus, and maternal weight when determining results. Most centers in the United States utilize a cutoff of 2.0 to 2.5 times the median for the general population screened for neural tube defects. Invasive procedures such as amniocentesis may give rise to maternal alpha-fetoprotein elevations; therefore, blood samples for screening markers should be obtained before amniocentesis is performed.








TABLE 22.1. MATERNAL AGE AND ESTIMATED RATES OF CHROMOSOMAL ABNORMALITIES AT TIME OF EXPECTED LIVE BIRTH
















































































Maternal Age Risk for Down Syndrome Total Risk for Chromosomal Abnormalities
20 1/1,667 1/526
25 1/1,250 1/476
30 1/952 1/385
35 1/385 1/202
36 1/295 1/162
37 1/227 1/129
38 1/175 1/102
39 1/137 1/82
40 1/106 1/65
41 1/82 1/51
42 1/64 1/40
43 1/50 1/32
44 1/38 1/25
45 1/30 1/20
46 1/23 1/16
47 1/18 1/13
48 1/14 1/10
49 1/11 1/7
Modified from Hook EB. Rates of chromosome abnormalities at different gestational ages. Obstet Gynecol 1981;58:282; Hook EB, Cross PK, Schreinemacher MS. Chromosomal, abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249:2034.

Dimeric inhibin A represents an additional serum analyte consistently reported to enhance the detection rate of Down syndrome when included in second-trimester screening. In a large prospective study assessing 1,256 patients, inhibin A performed extremely well; with a fixed false-positive rate, up to 23% more cases of Down syndrome were detected than with the traditional multiple-marker screening test. Using alpha-fetoprotein, estriol, total human chorionic gonadotropin, and inhibin A, along with maternal age, 70% of cases of Down syndrome were detected for a 5% false-positive rate. Using this “quad-screen” could lead to fewer genetic amniocenteses than the traditional triple screen; therefore, measuring this analyte may lower the cost per Down syndrome pregnancy identified.


Specific Factors

Following the birth of a child with trisomy 21, the likelihood that a subsequent child will have a similar chromosomal abnormality is approximately 1%. The recurrence rate for neural tube defects is 2% to 5%, compared with a general population risk of 1 to 2 per 1,000 births. The general recurrence risk of a cardiac defect is 2% to 4%, compared with the general population risk of 4 to 8 per 1,000 live births. If a parent has spina bifida, congenital heart disease, or a known chromosome translocation or inversion, an increased chance exists that a child will have a related defect. Antenatal diagnosis is possible
for many inborn errors of metabolism, almost all of which are transmitted in an autosomal recessive fashion. Maternal diabetes and maternal phenylketonuria are associated with an increased risk of fetal malformations. Other known teratogens include ionizing radiation, drugs, and maternal infections.


Ethnic Factors

The gene frequencies of various genetic disorders differ among geographic population groups. Carrier detection programs can be applied to different ethnic groups at risk for specific diseases (e.g., for Tay-Sachs disease in Ashkenazi Jewish populations, hemoglobinopathies in African Americans, and thalassemia in people of Mediterranean origin). The populations involved and the methods of screening are listed in Box 22.1.


Multifetal Gestations

Multifetal gestations have increased dramatically over the past generation, mainly resulting from advancements in artificial reproductive techniques (ARTs). These pregnancies are at greater risk for preterm delivery, and as a result contribute significantly to perinatal morbidity and mortality. In an effort to improve neonatal outcome, mainly through prolonging gestational age of delivery, select hospitals throughout the country offer multifetal reduction. This procedure involves the termination of one or more fetuses in a multifetal pregnancy in the effort to optimize outcome for the remaining fetus(es). Occasionally a multifetal pregnancy may include an aneuploid or anomalous fetus. Under these conditions, a selective termination is performed in which a particular fetus is targeted for termination.

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Jul 24, 2016 | Posted by in PEDIATRICS | Comments Off on Fetal Evaluation and Prenatal Diagnosis

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