Gestational age — Screening can be performed between 15 to 20 weeks of gestation; however, optimal detection of NTDs is between 16 and 18 weeks. Knowlee of gestational age is critical to interpretation of MSAFP (show figure 4). An incorrect gestational age will falsely raise or lower the reported MoM, which is based upon gestational age. (See "Ultrasound examination" below and see "Indications for diagnostic obstetrical ultrasound examination").
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 [41]. 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 [42].
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 [43]. 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.
PRENATAL DIAGNOSIS — Pregnancies that screen positive (a value above 2.0 to 2.5 MoM) require further evaluation to determine whether a NTD, or other abnormality, is present. All such pregnancies should undergo ultrasound examination to confirm gestational age, fetal viability, number of fetuses (see "Factors affecting interpretation" above) and to perform a detailed fetal anatomic survey.

Ultrasound examination — Ultrasound is an effective technique for detecting NTDs, and can potentially detect more NTDs than MSAFP [44]. The diagnosis of anencephaly is based upon the absence of brain and calvarium superior to the orbits on coronal views of the fetal head. The sonographic diagnosis of this condition is highly accurate and should not be missed on any routine second or third trimester ultrasound examination. The sensitivity of sonographic diagnosis of other NTDS is high, but depends in part upon the size and location of the defect, the position of the fetus, the volume of amniotic fluid, maternal habitus, and the skill and equipment of the sonographer. (See "Ultrasound diagnosis of neural tube defects").

Amniocentesis — As discussed above, ultrasound examination may be diagnostic of a NTD. However, ultrasound findings may be uncertain or show an apparently normal fetus. In these cases, further evaluation is usually indicated. Amniotic fluid AFP (AFAFP) and amniotic fluid acetylcholinesterase (AChE) are the primary biochemical tests performed on amniotic fluid for detection of open neural tube defects. AChE is an enzyme contained in blood cells, muscle, and nerve tissue. An elevation of both AFP and AChE values suggests an open fetal NTD with 96 percent accuracy and a false positive rate of 0.14 percent [3]. Blood contamination of the amniotic fluid sample is responsible for one-half of false-positive AChE results. (See "Amniocentesis: Technique and complications")

Sonographic versus amniotic fluid diagnosis — Some authors have suggested that the rate of detection of NTDs by ultrasound examination alone may preclude the need for amniocentesis [45-48]. These findings are illustrated by the following examples.

In one study of over 2000 women with an elevated MSAFP, sonography alone was 97 percent (66 of 68 cases) sensitive and 100 percent (2189 cases) specific in diagnosing an open NTD [46]. Suspicious findings on sonography led to an amniocentesis for confirmation of NTD in the two cases of NTD not specifically diagnosed on ultrasound examination.
A second series of 905 pregnancies found that 49 neural tube defects were correctly diagnosed by ultrasound alone; one was not [47]. The sensitivity, specificity, and positive and negative predictive values of ultrasound evaluation for the detection of NTDs were 98, 100, 100, and 99.9 percent, respectively. Forty-three other abnormal fetuses were also detected in patients with an elevated MSAFP, including 19 with abdominal wall defects, seven with findings suggestive of chromosomal abnormalities, five with urinary tract abnormalities, one with a cardiac abnormality, and 11 others; two fetuses with chromosomal abnormalities were not detected. The authors felt that ultrasound could be used reliably to detect NTDs, thereby avoiding the risks of amniocentesis.
A review of the ultrasound findings in 51 consecutive fetuses with pathologically confirmed spina bifida, encephalocele, gastroschisis, or omphalocele calculated the sensitivity of ultrasonography for these diagnoses and the probability of an affected fetus in women with a given level of MSAFP and a normal second trimester sonogram at their facility [45]. These four types of anomalies were correctly identified in all 51 cases, yielding a sensitivity of 100 percent. The probability of an affected fetus ranged from 0.01 to 0.15 percent for MSAFP levels ranging from 2.0 to 3.5 MoMs, respectively. The authors concluded that this level of risk was less than the reported risk of a procedure related spontaneous abortion after amniocentesis (0.3 to 0.5 percent) and, therefore may lead some women with an elevated MSAFP to decide not to proceed with amniocentesis.
Cost-benefit analyses have revealed savings of approximately $36 to $49 million dollars in annual savings if ultrasound examination replaced amniocentesis for the diagnosis of NTD [49].
In contrast, a series of 161 cases of open spina bifida identified by the California Maternal Serum Alpha-Fetoprotein Screening Program reported 8 percent of NTDs were not diagnosed by the initial ultrasonographic evaluation and three defects were not recognized until birth [50]. The authors concluded that ultrasonography was not sufficiently sensitive to forego amniocentesis. Small encephaloceles and spina bifida may be missed with ultrasonography and factors cited above, such as large maternal body habitus, fetal position, and lack of experience of the sonographer contribute to the difficulty of sonographic diagnosis [50,51].

Summary — Based upon review of existing data, the most sensitive approach to the prenatal diagnosis of NTDs is MSAFP screening followed (if the MSAFP is elevated) by a combination of ultrasound examination and amniocentesis [15]. Detection rates for NTDs are greater than 95 percent with rare false positives with both of these modalities. If one is certain of the diagnosis based upon the elevated MSAFP level and the ultrasound findings, an amniocentesis for confirmation may not be necessary. However, if there is any uncertainty about the diagnosis, or if the patient wishes to find out the karyotype (given the association with chromosomal abnormalities) an amniocentesis is warranted. The information may be particularly useful for diagnosis and estimating recurrence risk if there are associated anomalies.

We, and others, feel that a fetal karyotype should be obtained at the time of amniocentesis since this test adds no additional risk to the procedure, there is an elevated risk of chromosomal abnormalities with NTDs, and this information assists in accurate diagnosis of the current pregnancy and may be important for counseling regarding recurrence risks [30,52]. However, other authors have not recommended chromosome analysis in women under 35 years of age in the presence of a normal sonogram because of the cost and low risk of abnormality (0.3 to 0.6 percent) [53,54].

MANAGEMENT AND PROGNOSIS — The role of fetal surgery, route of delivery, pediatric management, and prognosis for children with these abnormalities are discussed separately. (See "Anencephaly and encephalocele" and see "Myelomeningocele").

Pregnancy complications — An elevated MSAFP level in the second trimester of pregnancy that cannot be explained (eg, presence of a fetal anomaly, maternal hepatocellular or ovarian tumor) is associated with an increased risk of subsequent fetal death. As an example, a case-control study of 612 women whose pregnancies ended in fetal death and 2501 women who gave birth to live infants reported that women with an MSAFP level 3.0 MoM had a 10-fold increase in risk of fetal death as compared to women who had a normal level and the risk remained high until term [55]. Elevated AFP levels were especially likely to be associated with fetal death in pregnancies complicated by hypertension.

In another series, a high MSAFP value was associated with the following adverse outcomes: neural tube defects (relative risk = 224), other major congenital defects (relative risk = 4.7), fetal deaths (relative risk = 8.1), neonatal death (relative risk = 4.7), low birth weight (relative risk = 4.0), newborn complications (relative risk = 3.6), oligohydramnios (relative risk = 3.4), abruptio placentae (relative risk = 3.0), and preeclampsia (relative risk = 2.3) [39].

The mechanism for poor pregnancy outcome in these cases may relate to defective placentation leading to higher than normal fetal to maternal AFP transport. Increased fetal surveillance has been suggested for these pregnancies, although the benefit of this intervention has not been demonstrated in controlled trials. (See "Pregnancy complications predicted by second trimester maternal serum screening").

SUMMARY AND RECOMMENDATIONS

Neural tube defects are the second most prevalent congenital anomaly in the United States, second only to cardiac malformations. Prenatal maternal serum screening programs for alpha fetoprotein (instituted in the 1970s and 1980s) combined with periconceptional folic acid supplementation and food fortification (instituted in the 1990s) have led to a decrease in the prevalence of neural tube defects where these interventions are practiced. (See "Incidence and epidemiology" above).
Occurrence of neural tube defects may be related to maternal folate deficiency (folate sensitive neural tube defects) or unrelated to maternal folate levels (chromosomal abnormalities, deformations, teratogens). (See "Etiology and risk factors" above).
We recommend maternal serum alpha-fetoprotein screening be offered to all pregnant women at 15 to 20 weeks of gestation (Grade 1B). It is an effective method for detecting neural tube defects and thus allows women the option of termination of an affected pregnancy or the opportunity to prepare for the birth of an affected child. (See "Screening" above).
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. A value above 2.0 to 2.5 MoM is designated an abnormal result.

A combination of ultrasound examination and amniocentesis (for acetylcholinesterase, alpha-fetoprotein, karyotype) should be performed in women with positive screen results. Detection rates for neural tube defects are greater than 95 percent with rare false positives with both of these modalities. (See "Prenatal diagnosis" above).
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