Neural tube defects (NTD) are the second most prevalent congenital anomaly in the United States, second only to cardiac malformations. Three factors have played a significant role in the assessment and prevention of this disorder in developed countries:
- The widespread use of maternal screening programs to identify pregnancies at high risk.
- Sonographic imaging combined with amniocentesis for diagnosis of affected fetuses.
- Administration of folic acid supplements for prevention of the disorder.
It's recommended 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.
A study that surveyed national screening policies for 18 European countries in 2004 reported the overall prenatal detection rate for NTD was 88 percent (range 25 to 94 percent) and detection rates were highest in those countries with standards determined by a national screening policy.
The American College of Medical Genetics recommends use of maternal serum alpha-fetoprotein and/or ultrasound for detection of neural tube defects between 15 and 20 weeks of gestation.
1) Alpha-fetoprotein
Historically, maternal serum alpha-fetoprotein (AFP) has been used as a screening test for open NTDs. AFP 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. 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. Amniotic fluid AFP levels are measured to aid in diagnosis of NTDs.
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. 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.
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. 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.
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. 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. 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.
Studies have consistently demonstrated the utility of MSAFP screening for detection of fetuses with NTDs. A meta-analysis of 22 studies including 684,112 second trimester women calculated overall sensitivity and specificity of 75.1 and 97.7, respectively. The detection rate for anencephaly is even higher: greater than 95 percent.
The risk of an affected fetus when the MSAFP is >2.5 MoMs is 4.5 percent. 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.
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.
- Gestational age — Screening can be performed between 15 to 20 weeks of gestation; however, optimal detection of NTDs is between 16 and 18 weeks. Knowledge of gestational age is critical to interpretation of MSAFP. An incorrect gestational age will falsely raise or lower the reported MoM, which is based upon gestational age.
- Maternal weight — Maternal weight affects MSAFP screening because of dilution of AFP in the larger blood volume of heavier women. Correction for maternal weight increases the detection rate for NTDs. Maternal weight should be measured and reported to the MSAFP laboratory on the day of testing.
- Diabetes mellitus — The prevalence of NTDs is higher in women with diabetes mellitus and their MSAFP level is 15 percent lower than in nondiabetics. For these reasons, there is a lower threshold MSAFP value (eg, approximately 1.5 MoM) to obtain the same sensitivity of detection of NTDS as in nondiabetic women. The presence of maternal diabetes should always be noted on the MSAFP laboratory requisition.
- Fetal anomalies — NonNTD fetal defects can be associated with an elevated MSAFP. There is direct correlation between the degree of MSAFP elevation and the frequency of anomalies. In one study, the risk was 3 percent at a level of 2.5 MoMs and 40 percent at a level >7.0 MoMs. Abdominal wall defects are commonly associated with elevated MSAFP levels. One representative series reported MSAFP was raised in 89 percent of fetuses with omphalocele and in 100 percent of fetuses with gastroschisis. Fetal congenital nephrosis, teratomas, and benign obstructive uropathy can also be associated with elevated MSAFP levels.
- Multiple gestation — The concentration of MSAFP is proportional to the number of fetuses, thus the upper limit for a twin pregnancy is twice (eg, 4 to 5 MoMs) that of a singleton gestation.
- Race — The MSAFP level is 10 percent higher in black women. Thus, an adjustment based upon race should be made by the laboratory when calculating MSAFP results.
- Fetal viability — Fetal death raises the MSAFP value. This is not of diagnostic concern except in cases of multiple gestation with a viable and a nonviable fetus. MSAFP results are not interpretable in this situation.
2) Ultrasound
Ultrasound is also an effective technique for detecting NTDs, and can potentially detect more NTDs than MSAFP. In fact, in many places, traditional two-dimensional ultrasound has superseded MSAFP testing as a screening tool.
Detection rates are influenced by gestational age and type of NTD. For example, first trimester studies generally have reported detection rates greater than 90 percent for anencephaly and 80 percent for encephalocele, but lower rates for spina bifida (44 percent). Second trimester ultrasound scanning increases the detection rate of spina bifida to approximately 92 to 95 percent.
References: UTD