ETIOLOGY AND RISK FACTORS — The majority of NTDs are isolated malformations of multifactorial origin (ie, traits/conditions influenced by both environmental and genetic factors):

Folic acid deficiency — Adequate folate is critical for cell division due to its essential role in the synthesis of nucleic and certain amino acids. Folic acid deficiency has been implicated in the development of NTDs (folate sensitive NTDs) and folate supplementation has been shown to reduce the risk of NTDs. (See "Prevention of neural tube defects", section on Relationship between folate and NTDS).

Environmental factors — The frequency of NTDs is increased with exposure to certain environmental factors, such as drugs (valproic acid, carbamazepine, folic acid antagonists), hyperthermia, diabetes mellitus, obesity [13-17]. While some of the environmental associations are weak, or suffer from poor methodological studies, others (valproic acid) are quite strong. (See "Risks associated with epilepsy and pregnancy", section on Effect of antiepileptic drugs on the fetus).

Genetic factors — A genetic factor is suggested by the observations that NTDs have a high concordance rate in monozygotic twins, are more frequent among first degree relatives, and are more common in females than males [18]. NTDs also occur as part of several genetic syndromes (eg, Meckel-Gruber) and may be associated with the MTHFR variant (See "Prevention of neural tube defects", section on MTHFR variant and NTDS).

The risk of recurrence for NTDs is approximately 2 to 4 percent when there is one affected sibling [19-23]. With two affected siblings, the risk is approximately 10 percent [24]. The risk of NTD according to family history is illustrated in the table (show table 1). The risk of recurrence appears to be higher in countries such as Ireland where the prevalence if NTDs is high [25].

The recurrence risk for anencephaly is estimated at 2 to 5 percent [26]. Isolated encephaloceles have not been shown to be familial. However, encephaloceles may be part of specific genetic syndromes if there are associated anomalies; the inheritance pattern is autosomal recessive in these cases. As an example, the risk of recurrence for an encephalocele with Meckel Gruber syndrome (posterior encephalocoele, cleft palate, and polydactyly) is 25 percent.

There is a high prevalence of karyotypic abnormalities among fetuses with NTDs, especially in the presence of other congenital anomalies [27-30]. As an example, a series evaluating the frequency of chromosomal abnormalities in pregnancies with fetal NTDs found these abnormalities in 6.5 percent of affected cases (4/167 fetuses with an isolated NTD and 9/33 fetuses with a NTD and associated anomalies) [27]. Other series reported a similar (7 percent) or higher (13 percent) rate of chromosomal abnormalities in fetuses with NTDs, particularly when there were associated anomalies [28-30]. Trisomy 18 was the most common aneuploidy detected. These data support the use of fetal karyotyping as an aid in diagnostic evaluation and recurrence risk counseling.

Deformation — Some cases of encephalocele may be due to disruptive factors, such as amniotic bands.

Vitamin B12 deficiency — Serum vitamin B12 levels have also been noted to be lower in pregnancies complicated by NTDS [31-33]. A systematic review found serum vitamin B12 concentration was 38 ng/L lower in such pregnancies [31]. A relationship between vitamin B12 deficiency and NTDS may result from a vitamin B12 associated functional state of folate deficiency or hyperhomocysteinemia [33-35]. The relationship between maternal vitamin B12 status and NTDs needs further study before any clinical recommendations can be made.

SCREENING — We recommend offering screening for NTDs to all pregnant women. Early diagnosis of affected pregnancies allows couples the option of pregnancy termination or an opportunity to prepare for the birth of a child.

Alpha-fetoprotein — Alpha fetoprotein (AFP) is the maternal serum marker used in screening for NTDs. It is a fetal specific globulin, synthesized by the fetal yolk sac, gastrointestinal tract, and liver. The function of AFP is unknown, although data suggest that it may be involved in immunoregulation during pregnancy. Another function may be as an intravascular transport protein because of its similarity to albumin.

AFP can be measured in maternal serum, amniotic fluid, and fetal plasma. The maternal serum AFP (MSAFP) concentration is much lower than that in amniotic fluid or fetal plasma. It rises in early pregnancy, peaks between 28 and 32 weeks of gestation, and then falls (show figure 3). Increasing fetoplacental permeability and advancing gestation may explain the rise in MSAFP that occurs when amniotic fluid and fetal serum concentrations are declining.

AFP is secreted by the fetal kidney into the urine and then excreted into the amniotic fluid. The concentration of amniotic fluid AFP (AFAFP) is highest early in pregnancy, peaks between 12 and 14 weeks of gestation, then declines until it becomes undetectable at term (show figure 2). Amniotic fluid AFP levels are measured to aid in diagnosis of NTDs. (See "Prenatal diagnosis" below).

The concentration of fetal plasma AFP peaks between 10 and 13 weeks of gestation, then declines exponentially from 14 to 32 weeks, and falls even more dramatically near term (show figure 1) [36]. The fall in AFP can be explained by both decreased fetal synthesis and a dilution effect due to increasing fetal blood volume. There is no clinical role for measurement of AFP in fetal plasma.

Screening protocol — MSAFP screening at 15 to 20 weeks of gestation should be offered to all pregnant women as it is an effective method for detecting NTDs [15]. AFP screening is primarily intended for the detection of open spina bifida and anencephaly, but can also uncover several nonneural fetal abnormalities (eg, ventral wall defects, tumors, dermatologic disorders, congenital nephrosis, aneuploidy). It does not detect closed spina bifida. (See "Pregnancy complications predicted by second trimester maternal serum screening").

MSAFP results are expressed as multiples of the median (MoM) for each gestational week because these values are easy to derive, more stable, and allow for interlaboratory variation. The median value, rather than the mean, is used because it is not influenced by occasional outlying values. A value above 2.0 to 2.5 MoM is designated an abnormal result, depending upon the laboratory's preference for balancing the detection and false-positive rates in their population.

A first elevated test may be repeated because as many as 30 percent of moderately elevated MSAFP results will be below the threshold level upon repeating the test and such findings are not associated with an increased frequency of false-negative NTD diagnoses [37]. If the elevation persists, then the next step is to obtain a specialized ultrasound examination to further assess whether a NTD, or other anomaly, is present [15]. An advanced gestational age, patient anxiety, or a significantly elevated value may preclude repetition of the test, in which case sonography should be obtained expeditiously. (See "Ultrasound examination" below).

Sensitivity and specificity — Studies have consistently demonstrated the utility of MSAFP screening. Overall, the detection rate for open NTDs is 75 to 90 percent, with a greater than 95 percent detection rate for anencephaly. The risk of an affected fetus when the MSAFP is >2.5 MoMs is 4.5 percent [38]. The positive predictive value of an MSAFP level between 2.5 and 2.9 MoMs for NTDs is 1.45 percent; with an MSAFP level greater than 7 MoMs, the positive predictive value goes up to 13.5 percent.

Two representative examples are provided below:

A British collaborative study compared 18,684 singleton and 163 twin pregnancies without NTDs to 381 singleton pregnancies with fetal NTDs [37]. The authors established expectations for detection rates and defined 16 to 18 weeks of gestation as the most efficient time to screen. A MSAFP of greater than 2.5 MoMs at 16 weeks of gestation detected 82 percent of open spina bifida and 95 percent of anencephaly, with a false-positive rate of 2 to 5 percent.
An American series including 13,486 women with singleton pregnancies reported elevated MSAFP levels were 90.9 percent sensitive and 96 percent specific for spina bifida and 100 percent sensitive and 96 percent specific for anencephaly [39,40].
Factors affecting interpretation — Many factors influence the correct interpretation of MSAFP results. These include: gestational age, maternal weight, ethnicity, maternal diabetes mellitus, fetal viability, exclusion of other anomalies, and multiple pregnancy.
multiple gestation with a viable and a nonviable fetus. MSAFP results are not interpretable in this situation