he incidence of neural-tube defects (NTDs) is 0.9 per 1000 live births, and they are second only to cardiac anomalies as the most frequent structural fetal malformation (Chap. 13, p. 270). Some NTDs, as well as congenital heart defects, are associated with speciic mutations. One example is the 677C -+=T substitution in the gene that encodes methylene tetrahydrofolate reductase. For this and similar gene defects, the trial conducted by the Medical Research Council Vitamin Study Research Group (1991) showed that preconceptional folic acid therapy significantly reduced the risk for a recurrent NTD by 72 percent. More importantly, because more than 90 percent of neonates with NTDs are born to women at low risk, Czeizel and Dudas (1e992) showed that supplementation reduced the a priori risk of a irst NTD occurrence. It is currently recommended, therefore, that all women who may become pregnant take daily 400 to 800 j1g of folic acid orally before conception and through the irst trimester (U.S Preventive Services Task Force, 2009). Folate fortiication of cereal grains has been mandatory in the United States since 1998, and this practice has also resulted in decreased neural-tube defect rates (Williams, 2015). Despite the demonstrated benefits of folate supplementation, only half of women have taken folic acid supplementation periconceptionally (de Jong-van den Berg, 2005; Goldberg, 2006). The strongest predictor of use appears to be consultation with a health-care provider before conception.
More than 600 mutations have been identified in the phenylalanine hydroxylase gene. The inherited defect in phenylalanine metabolism exempliies diseases in which the fetus may not be at risk to inherit the disorder but may be damaged by maternal disease. Specifically, mothers with phenylketonuria (PKU) who eat an unrestricted diet have abnormally high blood phenylalanine levels. his amino acid readily crosses the placenta and can damage developing fetal organs, especially neural and cardiac tissues (Table 8-3).
TABLE 8-3. Frequency of Complications in the Offspring of Women with Untreated Phenylketonuria
Data from American Academy of Pediatrics: Matenal phenylketonuria, Pediatrics 2008 \ug;122(2):445-449.
No offspring II Proband is II -2
Adopted out of a family
FIGURE 8-2 Symbols used for pedigree construction. (Modified with permission from Thompson MW, Mcinnes RR, Huntington FW (eds):
Number of children of sex indicated
Carrier of X-linked recessive trait
Twins of unknown zygosity
Genetics in Medicine, 5th ed. Philadelphia, Saunders, 1991o.)
With appropriate preconceptional counseling and adherence to a phenylalanine-restricted diet before pregnancy, the incidence of fetal malformations is dramatically reduced (Camp, 2014; Vockley, 2014). Therefore, the phenylalanine concentration is ideally normalized 3 months before conception and then maintained throughout pregnancy (American College of Obstetricians and Gynecologists, 2017b). The target phenylalanine blood concentration is 120 to 360 �mol/L (Camp, 2014).