An estimated 95% of infants with NTDs are born into families with no prior history of this malformation. The first developed noninvasive serum analyte- based screening test measures the amount of maternal serum α- fetoprotein (MSAFP) to identify pregnancies at increased risk for a fetal open NTD, including open spina bifida, anencephaly, and encephalocele not covered by skin. These are associated with high amounts of AFP in the amniotic fluid. AFP is a fetal glycoprotein produced mainly in the liver, secreted into the fetal circulation, and excreted through the fetal kidneys (see also Amniocentesis, later). AFP also leaks into the amniotic fluid when the fetal skin is breached. Because AFP enters the maternal bloodstream via the placenta, membranes, and maternal- fetal circulation, MSAFP is also elevated, which is the basis for using MSAFP measurements at ~16 weeks (15– 21 weeks) to screen for open NTDs. There is considerable overlap between the range of MSAFP concentrations in unaffected pregnancies and those where the fetus has an open NTD (Fig. 1), and the sensitivity of MSAFP screening to detect an increased risk for fetal open NTDs depends on statistically defined cutoff values. As shown in Fig. 1, if the cutoff for an elevated concentration is defined as 2.5 multiples of the median (MoM) value in unaffected pregnancies (which is 1 MoM), one can estimate that 80% of fetuses with open NTDs are detected and 20% remain undetected. However, lowering the cutoff to improve sensitivity would be at the expense of reduced specificity, thereby increasing the number of unaffected pregnancies that would be interpreted as high risk (false- positive rate). An elevated MSAFP concentration is not specific to a pregnancy with an open NTD. As listed in Table 1, there are many other causes of high MSAFP, most of which can be distinguished from open NTDs by fetal ultrasonography, which should be offered when MSAFP is increased. Combining MSAFP screening with detailed diagnostic ultrasonography approaches the accuracy for the detection of open NTDs of ultrasonography combined with amniocentesis to measure AFP in amniotic fluid. Thus it is acceptable to offer ultrasound examination (at 18 weeks) paired with an MSAFP assay to first- degree, second- degree, or more distant relatives of individuals with NTDs instead of amniocentesis. MSAFP measurement has now become integrated in a second trimester multiple serum analyte screen for fetal trisomies, but far more women now have first trimester trisomy screening with serum analytes and ultrasound, or more recently with cell- free DNA analysis. Thus providers should remember to offer these women screening for open NTDs by ultrasound with or without MSAFP. Currently, in expert centers, NTDs are increasingly diagnosed by a screening anatomy ultrasound alone, without MSAFP.
Fig1. Maternal serum α- fetoprotein (AFP) concentration, expressed as multiples of the median, in normal fetuses, fetuses with open neural tube defects, and fetuses with Down syndrome. (Redrawn from Wald NJ, Cuckle HS: Recent advances in screening for neural tube defects and Down syndrome. In Rodeck C, editor: Prenatal diagnosis, London, 1987, Bailliére Tindall, pp 649– 676.)
Table1. Findings Associated With Elevated α- Fetoprotein Concentration
