The incidence of major abnormalities apparent at birth is 2 to 3 percent. These anomalies cause a significant portion of neonatal deaths, and more than a fourth of all pediatric hospital admissions result from genetic disorders (Lee and colleagues, 2001). Prenatal diagnosis is the science of identifying structural or functional abnormalities—birth defects—in the fetus. With this information, clinicians hope to provide appropriate counseling and optimize outcome. In some cases, fetal therapy can be used to improve the intrauterine environment. Therapy may include blood product transfusion, administration of medication transplacentally or via the fetal circulation, laser or radiofrequency ablation of vascular anastomoses, amnioreduction, shunt placement, or more extensive fetal surgery.
Birth defects can arise in at least three ways. The most common type of structural fetal abnormality is a malformation—an intrinsic abnormality “programmed” in development, regardless of whether a precise genetic etiology is known. An example is spina bifida. The second type is a deformation caused when a genetically normal fetus develops abnormally because of mechanical forces imposed by the uterine environment. An example is an otherwise normal limb that develops contractures because of prolonged oligohydramnios. The third type is a disruption, which is a more severe change in form or function that occurs when genetically normal tissue is modified as the result of a specific insult. An example is damage from an amnionic band causing a cephalocele or limb-reduction abnormality.
Sometimes multiple structural or developmental abnormalities occur together in one individual. A cluster of several anomalies or defects can be a syndrome, meaning that all the abnormalities have the same cause—for example, trisomy 18 (see Chap. 12, Trisomy 18). Anomalies also may comprise a sequence, meaning that all developed sequentially as result of one initial insult—for example, oligohydramnios leading to pulmonary hypoplasia, limb contractures, and facial deformities. Finally, a group of anomalies may be considered an association, in which particular anomalies occur together frequently but do not seem to be linked etiologically—for example, VATER, association of vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial dysplasia. It is readily apparent that classification of fetal anomalies can be challenging, and reclassification may be required.
Neural-Tube Defects (NTDs)
The open neural-tube defects include anencephaly, spina bifida, cephalocele, and other rare spinal fusion (schisis) abnormalities. Features of these anomalies are reviewed in Chapter 16 (Normal and Abnormal Fetal Anatomy). As a class, these defects of neurulation occur in 1.4 to 2 per 1000 pregnancies and are the second most common class of birth defect after cardiac anomalies (American College of Obstetricians and Gynecologists, 2003). In the 1970s, Brock and associates (1972, 1973) observed that pregnancies complicated by a NTD had higher levels of alpha-fetoprotein (AFP) in maternal serum and amnionic fluid. This formed the basis for the first maternal serum screening test for a birth defect.
The results of a landmark trial were reported by Wald and associates (1977), who described the United Kingdom Collaborative Study on Alpha-Fetoprotein in Relation to Neural-Tube Defects. This study demonstrated the efficacy of maternal serum AFP screening for NTDs. Maternal serum AFP concentration at 16 to 18 weeks was found to exceed 2.5 multiples of the median (MoM) in 88 percent of women carrying fetuses with anencephaly and in 79 percent with spina bifida (Wald and co-workers, 1977). These benefits were subsequently confirmed by others and adopted in the United States and Europe by the mid-1980s (Burton, 1983; Haddow, 1983; Milunsky, 1980, and all their co-workers).
Risk Factors for Neural-Tube Defects
Almost 95 percent of NTDs occur in the absence of recognized risk factor or family history—hence the need for routine screening. There are, however, specific risk factors, some of which are listed in Table 13-1. Genetic causes are the largest category, and NTDs are multifactorial disorders (Chap. 12, Examples of Multifactorial or Polygenic Defects). The recurrence risk is approximately 4 percent if a couple has previously had a child with either anencephaly or spina bifida, 5 percent if either parent was born with a NTD, and as high as 10 percent if a couple has two affected children. One etiology for this in some populations is a common mutation in the methylene tetrahydrofolate reductase (MTHFR) gene—677C→T—which leads to impaired homocysteine and folate metabolism and increases the risk for NTDs and probably cardiac malformations (Dalal, 2007; Grandone, 2006; Munoz, 2007, and all their colleagues). NTDs are also a component of more than 80 genetic syndromes, many of which include other fetal anomalies amenable to prenatal diagnosis (Milunsky and Canick, 2004).
Table 13-1. Some Risk Factors for Neural-Tube Defects
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Table 13-1. Some Risk Factors for Neural-Tube Defects
- Family history—multifactorial inheritance
- MTHFR mutation—677C→T
- Syndromes with autosomal recessive inheritance
- HARDE—hydrocephalus–agyria–retinal dysplasia–encephalocele
- Trisomy 13
- Trisomy 18
Exposure to certain environmental agents
- Hot tub or sauna
- Fever (controversial)
Geographical region—ethnicity, diet, other factor
- United Kingdom
- Southern Appalachian United States
Other risk factors for NTD include environmental exposures, such as hyperthermia; certain medications, especially those that disturb folic acid metabolism; and hyperglycemia from insulin-dependent diabetes. Although the exact mechanism by which diabetes causes a NTD is unknown, research in rodents has focused on the role of embryonic hyperglycemia causing increased oxidative metabolism (Loeken, 2005; Zhao and Reece, 2005). In mice, oxidative stress leads to decreased expression of one or more genes involved in neuroepithelial and neural crest development, effectively arresting the process of neural-tube closure.
There are also certain racial/ethnic groups, as well as populations living ...