FILAS DE RESISTENCIAcreada no solo por un “artista” sino ser ejecutado por todo

The primary method for screening for NTDs is testing for the presence of alpha- fetoprotein (AFP) in maternal serum. AFP is the principal fetal plasma protein early in gestation and remains so until the fetal liver matures and albumin becomes the primary plasma protein.103 Amniotic fluid AFP (see below) passes through the placental barrier into the maternal circulation and levels are measurable early in the first trimester. When a fetus has an open neural tube lesion, high concentrations of AFP build up in amniotic fluid subsequently leading to increased maternal serum concentrations.103, 104

Maternal serum AFP (MSAFP) levels rise through the first and second trimesters of gestation in unaffected pregnancies, so gestational age must be considered when interpreting results.104 MSAFP for prenatal screening purposes should be performed between the 15th and 20th weeks of gestation and results should be expressed in multiples of the median (MoM) for gestational age.103 A result of 2.5 MoM in single gestations and 4.5 MoM in twin gestations is considered elevated enough to perform additional diagnostic testing.103 Sensitivity of MSAFP screening has been determined in a number of trials, but depends on the NTD under evaluation. When used to evaluate anencephaly, MSAFP has a reported sensitivity between

88 and 92 percent depending on the underlying risk in the population.105, 106 Sensitivity to MSAFP testing for spina bifida is lower, but depending upon the type of lesion involved, it is still between 64 and 76 percent.105, 106

Because of the possibility of overlap of MSAFP level in affected and unaffected NTD cases at different gestational ages, elevated MSAFP should not be considered diagnostic.104 However, elevated MSAFP levels have been shown to be highly predictive of NTDs in a number of trials. In a series of studies by Drugan et al, MSAFP levels of 2.5 to 2.9 MoM are associated with NTDs 3.4 percent of the time, while defects occurred 40.3% of the time with a MoM of greater than 7. 107, 108 Other studies indicate that level of MSAFP greater than 5 MoM can be associated with ultrasound confirmed defects as much as 71 percent of the time109, while levels greater than 8 MoM are most commonly associated with large structural defects and/or fetal death prior to 20 weeks of gestation.110

The UK Collaborative AFP Study, the first major study to determine the parameters of association between AFP and NTDs, produced detection rates for anencephaly of 98.2 percent and open spina bifida of 97.6 percent.111 False positives do occur when fetal blood contaminates the sample. Fetal blood contains 100 to 200 times the AFP per milliliter that amniotic fluid does at a given gestational age, and will thus give false results.104 The

diagnostic cut off for AFP varies by gestational age between 2.5 at 13-15 completed weeks to 4.0 for 22-24 completed weeks.104

2. Amniocentesis

Amniocentesis is the collection of amniotic fluid from the amniotic sac of a developing fetus through an abdominal needle aspiration.112 This screening procedure is normally

performed between the 15th and 20th week of gestation to aide in the determination of fetal karyotyping.113 Although the procedure is extremely accurate in the screening and diagnosis of certain genetic disorders and NTDs, it is not without risk. Tabor et al conducted a

randomized controlled trial and found that the risk of spontaneous abortion after

amniocentesis was approximately 1 percent.114 Roper et al found a similar cumulative fetal loss rate of 1.2 percent, but the rate was variable dependent upon the gestational age at amniocentesis.115 When the amniocentesis was performed before 14 weeks, the fetal loss rate was 1.0 percent, while the rate increased to 3.1 percent after 18 weeks of gestation. As these rates are generally higher than some of the observed rates of the genetic disorders and NTDs that amniocentesis is meant to detect, less invasive and less risky tests are preferred in populations at low risk for the underlying defect.

Amniocentesis can also be used to detect the presence of acetylcholinesterase enzymes (AChE) in the amniotic fluid. While non-specific cholinesterase enzymes are present in the amniotic fluid, AChE are normally only found in the cerebrospinal fluid and within red blood cell membranes.104 When an open NTD occurs, AChE can be detected in the amniotic

fluid.116 Between the 13th and 24th weeks of gestation, a group of confirmed open NTDs with a high amniotic fluid AFP (>99.6 percentile) had a positive amniotic fluid AChE in 99.5 percent of cases.117 The Second Report of the Collaborative AChE Study recommended that the best policy for use of the AChE test was in the analysis of amniotic fluid samples with AFP results greater than 2.0 MoM.118 This approach was predicted to yield a true positive rate for open spina bifida of 96 percent and a false positive rate of 0.14 percent.104, 118

3. Ultrasonography

Ultrasonography is considered the primary diagnostic technique for prenatal

identification of NTDs. This technology, first utilized in 1958, has been demonstrated to provide accurate diagnostic information for gestational age and fetal anomalies.119-122 Prenatal ultrasonography is a complex technology which uses sound waves to produce images of the developing fetus.113 These images of the developing fetus allow the direct visualization of anencephaly and cephaloceles. 45, 103, 123 Anencephaly was the first

malformation to be diagnosed by ultrasound.124 Campbell et al determined that ultrasound could be used between the 14th and 15th week of gestation to determine a diagnosis of anencephaly.123, 125 Accuracy of diagnosis of anencephaly by prenatal ultrasound has been shown to approach 100 percent.105, 126, 127

In the case of spina bifida, direct visualization is often difficult, thus indirect visualization methods have been devised.45 Infants with spina bifida who undergo ultrasound at 24 weeks of gestation frequently have a bilateral, concave, frontal contour of the cranium (the lemon sign) and cerebellar hemispheres with anterior curves with loss of the cisterna magna (the banana sign).45 One of the first studies to confirm the utility of ultrasonography in spina bifida affected pregnancies was that of Nicolaides et al.128 The authors retrospectively analyzed the ultrasounds of 70 fetuses between 16 and 24 weeks of gestation that were diagnosed with open spina bifida lesions. Their work confirmed the use of indirect signs, such as the “lemon” sign and the “banana” sign in the diagnosis of NTDs.45 Van den Hof et al were able to detect 98 percent of spina bifida cases in a cohort of 1561 high risk mothers, however, rates of 55 to 60 percent detection have been reported by others.105, 129

While the diagnostic ability of ultrasound for spina bifida may not approach that of anencephaly, when combined with other maternal screening approaches, diagnostic ability is improved. Nadel et al showed that the use of ultrasound in mothers with elevated MSAFP decreased the need for amniocentesis to confirm the diagnosis of a NTD.130 Lennon et al examined a group of 2257 patients at high risk for an open NTD either because of a family history of NTDs or a positive MSAFP.131 2053 patients were given an ultrasound with 55 NTDs occurring in this cohort. All of the NTDs in this cohort were detected prenatally. The sensitivity and specificity of ultrasound in the identification of NTDs was 97 and 100 percent respectively. The positive predictive value was 100 percent and the negative predictive value was 99.9 percent.

4. Current UK Guidelines For NTD Screening

The Royal College of Obstetricians and Gynecologists and the National Institute for Clinical Excellence have proposed routine antenatal care for pregnant women.132 Women should be scheduled for between seven and ten antenatal appointments for uncomplicated pregnancies. Ultrasound testing is recommended for all pregnant women between the 10th and 13th week of pregnancy to determine gestational age, detect multiple pregnancies, and improve the performance of screening procedures for Down’s syndrome and other anomalies. In addition, women should be offered an additional ultrasound scan between week 18 and 20 to detect congenital anomalies. The Guideline recommends standard screening for Down’s syndrome between 11 and 20 weeks of gestation through the performance of nuchal translucency as well as several combined tests. The recommendations are as follows: 1) Gestational age from 11 to 14 weeks - Nuchal translucency (NT) or the combined test (NT,

hCG and PAPP-A); 2) Gestational age from 14 to 20 weeks - the triple test (hCG, AFP and uE3) or the quadruple test (hCG, AFP, uE3, inhibin A); 3) Gestational age from 11 to 14 weeks and14 to 20 weeks - the integrated test (NT, PAPP-A + hCG, AFP, uE3, inhibin A) or the serum-integrated test (PAPP-A + hCG, AFP, uE3, inhibin A). The “Triple”,

“Quadruple”, “Integrated” and “Serum-integrated” tests all incorporate tests for alpha- fetoprotein thus also serving as a screening tool for NTDs.

Nuchal translucency (NT) testing may have some utility in the detection of NTDs. NT testing is conducted using a transvaginal ultrasound device to measure the normal

subcutaneous space between the skin and the cervical spine in the fetus early (12th to 14th week) in pregnancy. A space less than 3 mm has been associated with increased risk for Down’s syndrome, 18, 13 and triploidy and Turner syndrome.133 As this screening

ultrasound occurs much earlier than diagnostic ultrasounds for other abnormalities (NTDs for example), researchers have assessed if these early ultrasound can be used to identify other abnormalities. McAuliffe and colleagues determined that while NT can identify some serious structural abnormalities (i.e. anencephaly), the 18 to 20 week ultrasound should remain the gold standard.134