Selected risk factors for NTDs are listed in Table 14-1, and

genetic factors represent the largest category. Isolated NTDs display

multifactorial inheritance. The recurrence risk is approximately
3 to 5 percent if a couple has previously had a child with
either anencephaly or spina bifida, 5 percent if either parent was
born with an NTD, and as high as 10 percent if a couple has
two affected children. Importantly, almost 95 percent of NTDs
develop in the absence of a family history. Polymorphisms in
the methylene tetrahydrofolate reductase gene, which leads to
impaired homocysteine and folate metabolism, have been associated
with increased risk for anencephaly and spina bifida, as
well as for cardiac malformations (Aneji, 2012; Harisha, 2010;
Munoz, 2007; Yin, 2012). NTDs are a component of more
than 80 genetic syndromes, many including other anomalies
that may be amenable to prenatal diagnosis (Milunsky, 2004).
Other risk factors for NTDs include hyperthermia, medications
that disturb folic acid metabolism, and hyperglycemia
from insulin-dependent diabetes. Although the exact mechanism
by which diabetes causes these anomalies is unknown,
rodent studies have found that oxidative stress from embryonic
hyperglycemia is associated with apoptosis in the developing
neural tube (Li, 2012; Sugimura, 2009; Yang, 2008).
The risk for these defects is also increased in certain racial or
ethnic groups as well as in populations from selected geographical
regions. For example, recent data from population-based
registries indicate an NTD prevalence of 1.0 to 1.3 per 1000
births in the United Kingdom, which compares with 0.9 per
1000 in the United States (Cragan, 2009; Dolk, 2010). In the
United States, the risk may be twice as high among Mexicanborn
women (Velie, 2006).