Current Practice in Obstetrics and Gynecology—1 Pankaj Desai
INDEX
×
Chapter Notes

Save Clear

Section 1
2Obstetrics

Current Concepts in the Prenatal Diagnosis of Neural Tube Defects1

Ashish Kumar Bhattacharjee
 
INTRODUCTION
A neural tube defect (NTD) is a birth defect, which involves the brain or spinal cord. The neural tube is the part of the fetus that becomes the spinal cord and brain. Neural tube defects (NTDs) including spinal malformations are the single most common congenital malformation encountered.1 The exact cause of this is unknown although it is said to be of multifactorial in origin. Several genetic, chromosomal and environmental factors are said to be responsible for this condition. The defect may be cranial involving the fetal skull and the brain or spinal involving the vertebrae and the spinal cord. Both cranial and spinal malformations may co-exist and hence these are also known as craniospinal defects. Primary spinal defects often lead to secondary cranial abnormalities. A child born with isolated spinal defect may eventually develop hydrocephalus thereby altering the prognosis as determined prenatally for the isolated spinal defect. While the cranial defects show uniformly poor prognosis, there is variation in the outcome of spinal defects. This depends on the type and the size of the defect and also on the facilities, resource and expertise available.2 Therefore, majority opts for termination of pregnancy after prenatal diagnosis considering the overall poor prognosis. The few who prefer to continue with the pregnancy end up having a severely handicapped child either physically or mentally or both, which unfortunately becomes a burden for the family in particular and society in general.4
 
INCIDENCE
The incidence of NTD varies from place to place and population to population. While it is very high in the UK, it is lowest in Japan. Currently, the highest reported incidence is in North China (3.7/1000 live births).2 The prevalence in the UK is 4 to 5/1000 births and that in the USA is about 1 to 2/1000 births.3,5,6 In general, it occurs in 1 in 500 to 600 births.1 The incidence of NTD in the UK increased 10-fold in mothers who had one previous affected child, 20-fold in mothers who had two previous affected children and 40-fold in mothers who had three previous affected children. Even though about 95% NTD babies are born to mothers who had not delivered an affected child before.3–5,7
The incidence of NTD from different parts of India has been reported to vary from 0.5 to 11 per 1000 births.8–10 In general, the incidence in northern states of Punjab, Haryana, Delhi, Rajasthan, UP and Bihar has been much higher (3.9–9.0/1000) compared to eastern, western and southern parts of the country (0.5–2.64/1000). However, Davangere in Karnataka showed high incidence of NTD.10,11 The reason for high prevalence of NTD in Punjab has been attributed to high incidences in Sikhs, which had remained high even in migrant Sikhs.12,13 However, it is not clear whether the high incidence of NTD in Sikhs is due to their sociocultural practices or genetic makeup. On the other hand, the high incidence of NTD in Davangere has been attributed to consanguinity. The prevalence of NTD in consanguineous couples was found to be 16.3–20.6/1000 compared to 5.9–8.4/1000 in couples without consanguinity.11 But this was not reported from Mysore14 and Madras (now Chennai).15 It would, therefore, be useful to collect prospective data from different areas of the country on a regular basis particularly since temporal variation in the prevalence of NTD has been reported from other parts of the world.16,17 The informative population could be of value in looking for genes responsible for NTD.
Anencephaly and encephalocele are associated with early spontaneous abortions. About 3% of all early spontaneous abortions show evidence of NTD. It has been shown that of all embryos with NTD at about 8 weeks, half aborts spontaneously, a quarter ends in stillbirths and only the remaining quarter is born alive.18 The actual incidence, therefore, in a population is expected to be higher than the quoted figures of this birth defect.
The birth prevalence of NTD has declined substantially over the past 60 years in the USA and the incidence reported is 3.6–4.6/10,000 live 5births.19 But population-based active surveillance programs that include prenatal diagnoses have reported NTD rates of 7.2–15.6/10,000 births (live born and stillbirths).20 In the UK, where MSAFP and ultrasound screening are more widespread, has recorded a 49–59% decline in the birth prevalence of anencephaly and a 32–38% decline in the birth prevalence of spina bifida attributable to elective termination of pregnancy following the diagnosis of the conditions.16
 
ANOMALIES
The three major NTD are anencephaly, encephalocele and spina bifida. The less common are iniencephaly and exencephaly. The lesion may be open or closed. While anencephaly is an open lesion, encephalocele is a close one. Spinal lesions may be both open (skin cover absent) and close (covered with skin). About 80% lesions were found to be open21,22 reported, 85% of the infants born with NTD who survived for 5 years had severe handicap, 10% were moderately handicapped and only 5% had no handicap. On an average, these children spent over six months in the hospital and had to undergo six operations during the first 5 years of their lives. Considering the scenario although most NTD are non-lethal anomalies (excepting for anencephaly where there is either stillbirth or the baby dies immediately after birth) are considered as lethal for all practical purpose.23
 
PATHOGENESIS
The pathogenesis of NTD remains unclear. However, the theory put forward is the failure of the rostral (directed towards the front end of the body) and caudal neuropores to close. This might explain the increased incidence of the defect to the cranial and caudal ends of the neural axis. The other theory proposes that the neural tube gets disrupted after its formation.24 The isolated NTD is considered to be polygenic multifactorial disorder.25 This means that several genes are involved for NTD. The role of genes in causation of NTD is supported by its increased risk of recurrence amongst first-degree relatives compared to the population. However, the genes responsible for NTD in humans have not yet been identified. Environmental factors also play an important role in causation of NTD.25 Other risk factors responsible for NTD are, family history of NTD, maternal hyperglycemia, hyperthermia, medications (like valproic acid, carbamazepine) and certain ethnic groups living in certain high-risk geographical areas.6
Maternal diabetes significantly increases the risk of congenital malformations in humans. Diabetic mothers have higher risk of NTD than the population in general.1 Even with good control of diabetes, the risk for neural tube and other birth defects is two to five times higher than normal if a mother has the disease. The risk could increase as diabetes and obesity, both of which can cause high blood sugar, make inroads into younger populations.26–29 These malformations arise at the beginning of organogenesis, during the first 8 weeks of gestation in human embryos. Diabetic embryopathy can affect any developing organ system, although defects of the neural tube and heart are among the most common. In studying neural tube defects (NTD) in a mouse model of diabetic embryopathy, it has been shown that expression of Pax-3, a gene that regulates neural tube closure, is significantly reduced in embryos of diabetic mice before the manifestation of morphological defects. The loss-of-function Pax-3 mutation causes the same kind of NTD as those caused by maternal diabetes (open NTD) in 100% of mutant embryos. This suggests that impaired expression of Pax-3 is sufficient to prevent normal formation of the neural tube. It has also been shown that the excess glucose surrounding the embryo, which is a consequence of maternal diabetes, is responsible for the adverse effects of diabetic pregnancy. Therefore, the mechanism which possibly explains the spectrum of malformations associated with diabetic embryopathy is that the embryo is exposed to excess glucose at critical times during induction of developmental control genes.30
A research report (Death Protein may cause NTD in babies of diabetic mothers, in FOCUS, 3/22/2002) which appeared in the March 15, 2002 issue of the journal Genes and Development provides a possible explanation for the increased incidence of NTD in diabetic mothers. A protein normally involved in programmed cell death may, as a consequence of high blood sugar, mistakenly tell cells of the nascent neural tube to die.
 
EMBRYOLOGY
The nervous system develops from the dorsal ectoderm. The lateral edges of the neural plate fold to form the neural groove. Fusion of the edges of the neural groove forms the neural tube. Fusion starts progressing both cranially and caudally. Both caudal and cranial ends of the tube remain temporarily open. The anterior neuropore closes by 25 days (20 somite stage) and the posterior neuropore closes at about 27 days (25 somite stage). 7Open NTDs have been suggested to result from defective primary neurulation (formation of neural plate), while defective secondary neurulation (closure and development of neural tube) gives rise to closed NTD. Neural tube is formed usually within 6 weeks from the last menstrual period (LMP).31–34
The neural tube defects occur because of a defect in the neurulation (formation of neural plate followed by its closure and development) process. Based on the presence or absence of exposed neural tissue NTD can be open or closed. While open NTD is probably as a result of primary neurulation, the closed ones are the results of secondary neurulation (canalization). Another possible explanation is that open NTD (spina bifida in particular) results from defects in either primary or secondary neurulation, depending on their site being cranial or caudal to the posterior neuropore (i.e., upper and lower spina bifida, respectively).33
 
PREVENTION
The exact etiology of NTD is not known. Several studies by individual workers and multicentric studies have shown the beneficial effect of folic acid in primary prevention of this defect. Folic acid supplementation during prepregnancy and early weeks of pregnancy (during organogenesis) has been shown to reduce the incidence of the condition in a given population. Women who have had a baby with a neural tube defect have a two to three percent chance of having another NTD affected pregnancy. Folic acid has been found to reduce greatly the risk of another NTD affected pregnancy in these women. The double blind randomized trial of Medical Research Council, Great Britain has shown that supplementation of 4 mg folic acid per day for at least one month prior to conception to 3 months postconception reduces the risk of recurrence of NTD by 70%.35 Its efficacy in the Indian population has also been demonstrated (unpublished ICMR Multicentric trial results). In 1992, a randomized controlled trial in Hungary reported the protective effect of folic acid-containing multivitamins against first occurrences of NTDs.36 However, a major study revealed that about 25 percent of NTD recurrences would not be helped with folic acid supplementation.37–39 Hence, more research is needed to better understand the biological mechanism by which folic acid prevents NTD and the causes of those cases that are not connected with folic acid consumption.
The mechanism of action of folic acid in preventing the occurrence of NTD has not been fully understood. Women who have given birth to an 8NTD child show marginally lower serum and red cell foliated levels, but the difference is not statistically significant.39 Many of these women have been found to have higher levels of serum homocysteine (and methionin) indicating a metabolic block in the folic acid pathway.40 It has been proposed that considerably larger amount of folic acid (ten times of daily requirement) is needed to overcome this metabolic block although no dose response data are available on the efficacy of folic acid. Folic acid found in foods is called folate and is present in a wide variety of foods like—peas, corn, dried beans, dark green leafy vegetables, white and whole wheat breads, beef liver and lean beef, bananas, fortified breakfast cereals and orange juice.
Joslin Study, a research focused on neural tube defects has shown that antioxidants may be critical in preventing birth defects in babies of women with diabetes.41
The secondary prevention is, probably, the only way to lower the incidence of this birth defect and lies in its antenatal detection and subsequent termination of pregnancy. However, the role of folic acid supplement has also been suggested in the prevention of both occurrence and recurrence of NTD.42 Fortunately, of all embryos with NTD detected at 8 weeks, only a quarter would be born alive.18
 
DIAGNOSTIC METHODS
The two modalities currently in use for screening and detection of NTD are ultrasonography (the biophysical method) and the biochemical method. Workers in this field have shown that a combination of the two methods ensures maximum detection rate and minimum false-positive rate. For the purpose of prenatal diagnosis, it is necessary to consider whether a defect is open or close as only the former can be diagnosed using biochemical tests. The latter group is best diagnosed using ultrasography by an expert in this field.
About 20% of fetuses with NTD have other congenital anomalies as reported by California Birth Defect Program.
 
Prenatal Diagnosis of NTD by Biochemical Tests
The secondary prevention of NTD is done by antenatal detection of the condition in the population and subsequent selective termination of pregnancy in diagnosed cases. This has become an important part of antenatal care in several countries. This would reduce the incidence of the birth defect. The aim of the antenatal screening by biochemical tests 9for open NTDs is to identify the group of patients who are at increased risk of having an affected child. Measurement of maternal serum alphafetoprotein (MSAFP) and measurement of AFP and acetyl-cholinesterase (AChE gel) in the amniotic fluid (AFAFP and AChE gel) are the available biochemical screening tests.
 
Maternal Serum Alphafetoprotein (MSAFP)
The alphafetoprotein (AFP) is a fetospecific glycoproterin of similar molecular weight of albumin (70,000 Daltons). The yolk sac and the fetal liver synthesize it. At about 17 weeks, AFP concentration in fetal serum is 30,000 times higher than in maternal serum and 150 times higher than that in amniotic fluid. The MSAFP increases during the second trimester by about 19% per week and reaches 50 times higher level of nonpregnant state at 30 weeks of gestation. Wald7 et al 1984 suggested that a gestational age of 16–18 weeks should be regarded as the best time for screening MSAFP for open NTDs. At this stage, about 3/4th of open NTDs have AFP levels of more than 97th percentile of normal.
The unit of expression of AFP is usually nanogram/ml (ng/ml) or IU/ml. However, much of the interlaboratory variations can be reduced by first finding a median value of that laboratory for that particular period of gestation and then expressing the AFP value as a multiple of the median obtained for normal singleton pregnancies for the period of gestation. A sample of minimum 50 normal singleton pregnancies should be studied and their AFP values at a particular period of gestation arranged in ascending order. The middle value or the average of two values gives the median. The AFP result, thereafter, is expressed as multiple of median (MoM).
There is no definite cut-off level between normal and abnormal MSAFP levels. The UK collaborative study (1977)21 has shown that using a cut off of 2.5 MoM at 16–18 weeks, 88% anecephalic pregnancies and 79% open NTD (69% of total NTD, including the close ones) were picked up. This also picked up 3.3% of normal pregnancies.
The MSAFP levels decrease with increasing maternal body weight. This may be due to more plasma volume of the heavier mothers diluting the quantity of AFP entering maternal circulation from the fetus.43 Although the benefits of weight adjustment for MSAFP values are small, but it is worth trying to reduce false-positive cases.
Women with insulin-dependent diabetes mellitus show low MSAFP levels (about 2/3 of that of normal pregnancies.6 This group of patients 10show increased incidence of NTD; and hence, a lower cut-off level for this group has been suggested by some workers.
Women carrying male fetuses tend to show significantly higher MSAFP levels than the ones carrying female fetuses. A study by Wald and Cuckle 19844 confirmed this.
the MSAFP levels in twin pregnancies are almost double that of singleton pregnancies. Monozygous twin pregnancies show even higher values than dizygous.44
Raised MSAFP levels were also detected amongst 6.8% of mothers who had high MSAFP values in their previous pregnancies. It is also important to note that about 90–95% of cases with confirmed elevated MSAFP are caused by conditions other than NTD. These may be underestimated gestational age, other congenital anomalies like ventral wall defects, intrauterine growth retardation, multiple gestation or fetal demise. A raised MSAFP is also considered a risk factor for preterm labor, pre-eclampsia, abruption placentae and low birth weight.
 
Amniotic Fluid AFP (AFAFP)
The AFP normally reaches amniotic fluid by excretion through fetal kidneys and gets recirculated by fetal oral ingestion and subsequent excretion. Conditions associated with leakage of serum or CSF from the fetus into the amniotic fluid raises the AFAFP. Other fetal conditions like congenital nephrosis, which increases fetal urinary excretion and conditions like duodenal atresia which interferes with fetal ingestion and digestion also raises AFAFP by interfering with its proper recirculation. The following cut-off levels for AFAFP were suggested by the UK collaborative study45—2.5 MoM at 13–15 weeks, 3.0 MoM at 16–18 weeks, 3.5 MoM at 19–21 weeks and 4.0 MoM at 22–24 weeks gestation. Positive results detected 98% of anencephaly and open NTDs and 0.79% unaffected pregnancies. Since the fetal serum AFP level is significantly higher in midpregnancy, a (fetal) blood-stained sample of amniotic fluid obtained at amniocentesis will abnormally raise the AFAFP level.16,46
 
Amniotic Fluid Acetylcholinesterase (AChE) Test
Cerebrospinal fluid (CSF) contains a high concentration of AchE. This substance, normally present in synapses, facilitates impulse transmission. Hence, the fetal conditions, which expose the CSF to the amniotic fluid, would raise the AChE level in the amniotic fluid. Smith et al 197947 11confirmed this in Oxford. A positive AChE gel test in amniotic fluid further reduces the false-positive rate of AFAFP test for detection of open NTD. It has also been shown that careful interpretation of AChE test (from the intensity of AChE band in the gel) can further distinguish fetal ventral wall defect from open NTD.48
Ultrasonography plays an important role in the biochemical screening process by precisely determining the gestational age at the time of screening for MSAFP (when accuracy of gestational age is doubtful) and by excluding multiple pregnancies where the MSAFP values are expected to be higher than the singleton ones. However, it has been shown that fetuses with spina bifida have smaller biparietal diameters for their gestational age.7 Therefore, a given concentration of AFP would mean a higher MoM when gestational age is adjusted at a lower level by the BPD finding. This would increase the detection rate of NTD but might influence the false-positive rate. However, a single dating scan prior to MSAFP test will sort out several fallacies in the interpretation of the result and detect some gross defects. A combination of both methods for screening should detect over 90% of NTD with no concomitant increase in the false-positive rate.49
 
Ultrasonography in Detection of NTD
Antenatal diagnosis of several fetal structural malformations is possible using ultrasonography. Since the days of Professor Ian Donald in late 1950s, the technology and expertise in this field have shown a tremendous improvement so much so that 3D or 4D ultrasound machines are now available. The improved quality of the image on the screen has enabled us to see more and more details of the structure and observe several normal variations of the same. The detection rates of even the minor and subtle defects have considerably increased. However, we must not, at any point of time, unnecessarily increase the anxiety of the mother by our overenthusiasm.
The incidence of NTD varies in different parts of the world. So depending on the prevalence of the condition on that locality, ultrasonography is either used alone as a screening tool or is used only in high-risk cases or in combination with the biochemical test for detection of NTD. Ultrasonography can detect both open and close NTDs. When used by experienced operators, prenatal sonography is sensitive and specific for the diagnoses of neural tube and ventral wall defects in a targeted at-risk population.50 The usual recommended time for doing 12this scan is around 18–20 weeks. However, early transvaginal scan at 12–14 weeks also detects several gross defects. A review of the multicentric data on ultrasongraphic diagnosis of NTD from 11 countries across Europe found 98% sensitivity for anencephaly and 75% sensitivity for spina bifida. A high prenatal detection rate for anencephaly was reported by all registers. There was a large variation in prenatal detection and termination rates for spina bifida between centers, reflecting differences both in policy and culture.51 The study revealed that, prenatal sonography is sensitive and specific for the diagnoses of neural tube defects.
 
Abdominal vs Transvaginal Probes
Many of the earliest studies of diagnostic ultrasound in Ob-Gyn involved transabdominal scanning with a 1.6 to 3.5 MHz transducer. While relatively comfortable for the patient and useful for imaging large fetuses, transabdominal transducer's low frequency had and continues to have a major limitation of decreased resolution. To address this concern, high-frequency transvaginal transducers, which operate at 5 or 7.5 MHz, were introduced during the late 1970s.
Modern transvaginal sonography represents a significant advance in diagnostic capability precisely because of the probe's proximity to the pelvic organs. Placement of the transducer in the vagina allows use of higher-frequency sound waves, which produce more precise images of smaller structures and permit diagnosis of many pathological conditions that previously could not be visualized.52–56
 
Three-dimensional (3D) Ultrasonography
Multiplanar views are generally more informative than rendered views for localizing boney defects of fetal spine. Prenatal diagnosis using 3D ultrasonography has been described. Both 2D and 3D were used separately to determine the extent of the vertebral defects in cases of spina bifida. Prenatal diagnosis was compared with postnatal analysis using radiograph and MRI. The accuracy of 3D ultrasonography in localizing the defects was found to be slightly better.57 Three-dimensional ultrasonography may improve characterization of spina bifida by adding diagnostic information that is complimentary to the initial 2D ultrasonography.13
 
Magnetic Resonance Imaging (MRI)
The MRI has been found to be useful in detecting very small spinal defects though it is not routinely used for prenatal diagnosis. In a reported case from Japan, where ultrasonography failed to comment whether the spinal defect was open or closed, MRI could detect a skin defect, which permitted prenatal diagnosis of open spina bifida.58 In prenatal intrauterine evaluation, combined use of multiple diagnostic tools is expected to have advantage over a single method.
 
FETAL SURVEY FOR NTD
For detection of any fetal structural abnormality, a thorough survey of the fetus is necessary. This might take only a few minutes for an expert; but at times, may not be possible due to an unfavourable position of the fetus, which restricts the view of certain parts of the fetus. Fortunately, fetus at this early stage of gestation keeps on moving and given some time might allow visualization of all parts of the fetus. If this does not happen, then asking the patient to come after some time or may be on another day will be the only option. The sonologist should have a checklist of the different structures to be observed during the procedure.
For the detection of NTD in particular, the survey starts at fetal skull. Whether it is present or not? The shape of the skull is observed and any defect looked for. The normal shape of a fetal skull is like an egg in the transverse plane. But this shape is lost in spina bifida and the anterior part of the frontal bone gets pinched up producing a typical lemon-shaped skull—the famous “lemon sign” well known in the ultrasound literature (Fig. 1.1). The contour of the skull is then carefully examined for any defect or any herniation of meninges or brain tissue.
Next, the intracranial structures are examined thoroughly. This is very important as it might give a clue to look for a small spinal defect, which might have been missed otherwise. For this purpose, the fetal brain is imaged in three different transverse planes. First, the transthalamic plane, the level at which fetal biparietal diameter (BPD) and head circumference (HC) are taken, moving slightly above (cranially) gives the transventricular view; and then moving further below (caudally) the first plane, the trancerebellar view is obtained. Examination of the cerebellum and the ventricles are most important in this regard. Cerebellum should maintain a right angle relation with the midline echo. Abnormalities in these structures (ventricles and cerebellum) usually suggest spinal defects.59–6414
zoom view
Fig. 1.1: Lemon sign
This should be followed by the examination of the spine throughout its length, starting at the level of neck till the end, both in longitudinal and transverse planes. The normal lumbosacral curve in the longitudinal section is looked for. Examination of the spine is not complete without having a transverse view throughout its entire length. The covering skin over the entire length of spine is carefully examined for any defect or herniation. Once a craniospianl abnormality is detected, special attention should be given to look for any other structural anomaly.62
 
Cranial Defects
 
Anencephaly
The CNS was the first to be investigated by ultrasound on a fetus in utero and anencephaly was the first congenital anomaly to be diagnosed by this technique.65 This is the commonest form of NTD characterized by absence of cranium and cerebral hemisphere. Anencephaly is considered to be the final stage of acrania, as a consequence of disruption of abnormal brain tissue unprotected by the skull.66 The reported incidence is 1 in 1000 births. Female fetuses are 4 times more affected than males. Family history of NTD and twins are considered risk factors.
Sonographic findings of anencephaly are obvious and the pick-up rate in experienced hand is up to 100%. The defect is reliably diagnosed by 10–14 weeks of gestation.55 Absence of cranial vault and the cerebral hemispheres 15are typical of anencephaly. The spine ends at the base of the skull and the vault is not seen. The orbits appear to protrude out from the base of the skull when the vault is absent. Polyhydramnios is usually associated with this condition due to the defective fetal swallowing. Other reported associated anomalies with this condition include renal anomalies, omphalocele, cleft lip-palate, diaphragmatic hernia, cardiovascular anomaly and gastrointestinal anomaly. Prognosis is uniformly fatal and termination of pregnancy should be advised whenever diagnosis is confirmed (Figs 1.2A to C).
zoom view
:
zoom view
:
16
zoom view
Figs 1.2A to C: Anencephaly
 
Encephalocele
This is a cranial defect (boney defect of the skull) through which meninges and CSF (meningocele) or meninges, CSF and brain tissue herniates (encephalocele).1 The incidence is relatively low and the reported figure is 1 in 2,000 to 1 in 10,000 births. It arises most often from the midline at the level of the occipital bone and less commonly from frontal and parietal bones (Figs 1.3A and B).
zoom view
Fig. 1.3A: Encephalocele with cervical meningomyelocele
17
zoom view
Fig. 1.3B: Encephalocele
The usual sonographic finding includes a mass (cystic or solid) usually at the back of the head. The mass when solid (containing brain tissue) covered by herniated meninges is easy to diagnose. The cystic mass (which is the herniated meninges alone without brain tissue) often needs to be differentiated from a cystic hygroma, which shows internal septations and a thick wall. Recognition of the boney defect is not always possible due to its small size. Encephalocele can also occur at the base of the skull protruding into the orbits, nasopharynx or oropharynx, but prenatal diagnosis of these conditions by ultrasonography is not possible. Ventriculomegaly and distortion of intracranial anatomy may be observed. Most encephaloceles are usually large enough to be diagnosed prenatally. Frontal encephaloceles are relatively difficult for ultrasound prenatal diagnosis.
Associated hydrocephalus has been reported in up to 80% of occipital meningocele, 65% of occipital encephalocele and 15% of frontal encephalocele.66 Spina bifida is presented in 7 to 15% of cases.68 The Meckel-Gruber syndrome, an autosomal recessive condition, is characterized by occipital encephalocele, cystic renal dysplasia and polydactyly of both feet and hands. It is also occasionally associated with Dandy-Walker malformation (cyst in the posterior cranial fossa), holoprocencephaly and agenesis of corpus callosum.6918
Prognosis depends on the herniation of brain tissue and associated findings. Infants with pure meningocele (herniation of only meninges) develop a normal intelligence in 60% cases following treatment. But a true encephalocele (containing brain tissue) carry a mortality rate of 40% and a high incidence of intelligence impairment.12,67,68 For all practical purpose, termination of pregnancy should be offered when diagnosed prenatally excepting for a small isolated defect of meningecele.
 
Iniencephaly
This is a rare malformation in which the defect of inion (occiput) is usually combined with a dysraphic defect of the cervical spine.68 The fetus adopts the “star gazing” position and the fixed hyperextension of the neck (a constant feature) is easily noted. The defect may be associated with an encephalocele or a closed spina bifida.
Foderaro et al (1987)69 reported a fetus with iniencephaly at 22 weeks of gestation with marked hyperextension of the head and a posterior fossa cyst.
Eighty-four percent of the infants with iniencephaly have been reported to have associated structural anomalies. These include various CNS and extra CNS defects (e.g. arthrogryposis, diaphragmatic hernia, omphalocele, facial cleft, cyclopia, clubfoot, CVS anomalies, etc). Polyhydramnios is often associated with this condition.70 Ramakrishnan 1991 reported a case report of iniencephaly with cyclopia, which is one of the rare cases in the literature.
The fetal head may be occasionally flattened and elongated (dolichocephaly). The cephalic index (CI), which is the ratio of biparietal to occipitofrontal diameter should be obtained. This normally ranges from 0.75 to 0.85. A low CI may be found in these cases due to hyperextended head. The prognosis is universally fatal and termination of pregnancy should be offered when prenatally diagnosed.
 
Exencephaly
This is characterized by complete or partial absence of the superior portion of the cranium with complete but abnormal development of the brain. It is also known as acrania. The incidence is much less than anencephaly. The pathogenesis of this condition may be similar to anencephaly and it could be just a precursor of the latter.66,71,72 The exposed brain tissue in the amniotic fluid undergoes trauma to produce abnormality.19
Sonographic findings include absence of cranial vault with floating brain tissue in the amniotic fluid. Associated anomalies include spinal defects, facial cleft and talipes.
Prognosis is universally fatal and termination of pregnancy is the only option.73
 
Spinal Defects
 
Spina Bifida
The spina bifida covers a range of vertebral and neural tube defects and results from the failure of the posterior vertebral arch to close (fuse). Fusion of the neural tube starts in the middle and precedes both cranially and caudally; and for some time, the tube remains open at both the ends. Mineralization of the spine starts at 8 weeks from three ossification centers for each vertebra. The ventral center forms the vertebral body and the dorsal-paired centers form the lateral and posterior parts of the vertebra. The dorsal centers appear first in the cervical spine and proceed toward the sacrum.32,74 This finding has been histologically confirmed. Filly et al (1987)75 described the morphology and maturation of the spine during the second trimester.
The defect can occur anywhere in the spine but is commonly noticed at the lumbosacral region. The primary defect is a dysraphic spine; and through this defect, the meninges, the CSF and the spinal cord protrude. If only the meninges protrude out, it is called meningocele; and when spinal tissue is also displaced out, the term is referred to as myelomeningocele or meningomyelocele. These two are also known as spina bifida aperta. The other type is spina bifida oculta where the defective vertebra is covered by normal soft tissue (including skin). This variety is difficult to diagnose prenatally; but, fortunately, it has a better prognosis particularly when a single vertebra is involved (Fig 1.4A).
The accuracy and sensitivity of detection of spina bifida by ultrasonography has continued to improve with the improvement of the technology of the ultrasound machines. Experience of sonologists and inclusion of biochemical tests into this field of prenatal diagnosis have been able to show the maximum sensitivity and specificity in the diagnosis of spina bifida. Roberts et al (1983)76 showed the improvement in the sensitivity and specificity to increase from 33% and 96 to 80% and 99% within a period of 3 years. Higher accuracy of diagnosis is observed in high-risk cases. The accuracy of referral centers (level III ultrasound) is close to 100%. However, in a retrospective multicentric study employing cranial signs, the sensitivity of ultrasound for diagnosis of spina bifida was 85%.5320
zoom view
Fig. 1.4A: Spinal defects
For the ultrasound diagnosis of spina bifida, the examination should start at the fetal head. The sensitivity of the cranial signs in identifying spina bifida exceeds 99%.49,62 The pinched up-front part of the head gives it a typical lemon shape—the “lemon sign”.53,61–63 This sign appears even before a small spinal defect is seen. Resolution of this sign occurs after 34 weeks.63 A low intraspinal pressure as observed in neonates, probably, gets transmitted to the fetal cranium deforming its shape when the cranial bones are soft in the early weeks. But as the fetal cranium becomes stronger with the progress of pregnancy, the sign disappears (Figs 1.4B and Figs 1.5A and B).63
zoom view
Fig. 1.4B: Spina bifida (lumbosacral region) meningomyelocele
21
zoom view
Fig. 1.5A: Lemon sign
zoom view
Fig. 1.5B: Spina bifida
The cerebral ventriculomegaly is often observed particularly of lateral ventricles. About 1/3rd of the fetuses with hydrocephalus have spina bifida and 3/4th of the spina bifida cases do have ventricular dilatation.63 22In one study, the sensitivity of picking up spina bifida when hydrcephalus was present, was 100%.64
The curved cerebellum associated with spina bifida has been described as “banana sign” (Fig. 1.6).60 This is actually due to the closure of the cisterna magna compressing the posterior fossa. Benacerraf et al noted obliteration of cisterna magna in 22 out of 23 cases between 16 to 27 weeks.60
The BPD measurement tends to be smaller compared to the abdominal circumference (AC) and femur length (FL) before 24 weeks.7 The cranial and intracranial findings are indirect findings to suggest a spina bifida.60,61
The usual spinal defects are found in lumbosacral region, the other common location being thoracolumbar. The sonographic appearance of spina bifida varies with the location, size and the type of spinal defect. First, a defective dysraphic vertebra or vertebrae are noted. This can be seen in both longitudinal and transverse view, but it is seen best in a transverse view particularly to pick up sigle vertebral involvement. In a normal spine the ventral and dorsal ossification centers (one ventral and two dorsal) form a “V”shaped acute angle throughout the entire length of the spine. The dysraphic vertebra shows wider angle forming a “U”or a saucer-shaped deformity, which becomes obvious when followed through its entire length. The longitudinal view is most useful in assessing the severity of the lesion.
zoom view
Fig. 1.6: Hydrocephalus with banana sign
23
The soft tissue finding associated with the dysraphic vertebra diagnoses the condition as meningocele (bulging meninges and CSF) or myelomeningocele (bulging meninges, CSF and spinal tissue). The prone position of the fetus favors easy diagnosis. Diagnosis is difficult if associated with oligohydramnios or when the defective part is close to the uterine wall or the placenta. Recently, 3 cases of spina bifida have been diagnosed using transvaginal scan (with 7.5 MHz annular array) using 2D and 3D techniques between 9 and 10 weeks.56 Early diagnosis of the condition is certainly helpful in the management.
It is important to describe the type and the size (extent and location) of the defect including any associated finding in order to discuss the prognosis with the concerned specialist and to counsel the parents. Multiple anomalies associated with NTD suggest chromosomal anomalies, although isolated NTD may also show abnormal karyotype.77 Hence, chromosome analysis of the fetus by amniocentesis should be done in suspected or high-risk cases. This is particularly important if the parents decide to continue with the pregnancy.
 
PROGNOSIS
The prognosis is best in spina bifida occulta. But this is mostly diagnosed after birth. About 20% infants with spina bifida die. The remaining 80% show substantial morbidity. Prognosis depends on: (i) location and extent of the spinal defect, (ii) open or closed defect, and (iii) presence or absence of hydrocephalus.60,78 It is also dependent on the expertise, the resources and the facilities available. Even with timely and best treatment, the physical and mental handicap of this group of children are very high.23 Various support groups are now available across the world to take care of this group of handicapped children. Based on 1988 cross-sectional data, the estimated lifetime cost of spina bifida is $ 258,000 per case.79 But the best option would be to reduce the incidence of these birth defects where the prognosis in general is poor. Therefore, early diagnosis and termination of pregnancy where needed is the option.
The study of changing prevalence of NTD in the North England during 1984–96 observed a significant reduction in birth prevalence with time. The proportion of NTD pregnancies terminated increased from 60.3% during 1984–90 to 78.6% during 1991–96, whereas the proportion of live births declined from 31.7 to 15%. The sensitivity of antenatal diagnosis was consistently high for anencephaly (98%) and increased significantly for spina bifida from 60% during 1984–90 to 85% during 1991–96 (p < 0.05). 24Ascertainment of all cases of NTD in the Northern Region revealed a two-fold reduction in birth prevalence between 1984–90 and 1991–96. This has resulted from improvements in the accuracy of antenatal detection of NTD-affected pregnancies with an increase in terminations of pregnancy.17,80
 
MANAGEMENT
Early detection of NTD may help parents to prepare emotionally. It may also help clinicians to offer intensive obstetric care and better prepare for the delivery and the care of the newborn. In a series of 208 patients aged 2–18 years with meningomyeloceles, no statistically significant difference was observed in motor or sensory level, or in the ambulatory function, between those delivered vaginally compared to those delivered by cesarean section (CS).81 In another retrospective population-based study of 160 fetuses with uncomplicated meningomyelocele, prelabor cesarean delivery resulted better motor function at 2 years age than vaginal delivery or CS after a period of labor.82 Follow-up to the age of 4 years in 85% of these cases continued to show a significantly better outcome compared to those delivered vaginally.
Management of infants born with NTD, where the pregnancies were decided to continue, is complicated and involves multidisciplinary team of experts. The team includes pediatrician, orthopedic surgeon, neurologist, physiotherapist, etc. Aggressive surgical and medical care is often necessary for severely affected cases. The treatment depends on the level and the severity of the defect. Infants with high defects with gross neurological deficits are not suitable for surgery. If good prognosis is expected, skin should be closed within 48 hours. Early physiotherapy is done for orthopedic abnormalities. Osteotomies, if required, are usually done within first few years of life. Shunting for hydrocephalus has been performed for a long time with varied results.
Immediate complications like meningitis occur at times. Mortality of these infants is around 10–15%. Another 10–15% suffer severe mental retardation. About 60% show normal IQ but have learning and attention deficit. Paralysis and incontinence of bladder are observed as late complications.31,78,83–85 Special schooling facilities and rehabilitative services are necessary for children with permanent disabilities.
 
CONCLUSION
Neural tube defects occur very early in pregnancy, probably, before the mother recognizes that she is pregnant. Therefore, the preventive aspect 25of NTD should be emphasized and the message should be sent to the general population since very little can be done to a handicapped child born with the defect. A fortified foodstuff with folic acid for the pregnant mothers is a good option towards prevention. Pregnant women should be offered both MSAFP and ultrasonographic tests for early detection of NTD. A repeat test may be performed in cases of doubt before embarking on amniocentesis because of the procedure-related risk (around 0.2–0.5%). There is no need for amniocentesis in patients with elevated MSAFP and normal ultrasonographic examinations.86 Amniocentesis, however, is useful particularly where fetal chromosomal abnormality is suspected. The biochemical tests are not to be considered as a substitute for fetal survey by ultrasound. The latter has the added advantage of diagnosing closed spinal defects as well as associated anomalies of other organ systems. This gives a total picture of the fetus to be able to draw a prognosis before counseling the parents. The high-resolution ultrasound particularly with 3D and 4D facilities should identify most detectable defects. The high recurrence risk of the condition and the increased incidence amongst the first-degree relatives establish the genetic origin of the condition. Hence, there is a need for setting up preconception clinics where the affected and anxious parents are counseled by experts for planning a future pregnancy. The potential benefits of early detection of NTD must, however, be weighed against the potential hazards of screening. The hazards include procedure-linked complications of amniocentesis (causing fetal damage or miscarriage) or the risks of elective termination of pregnancy. These also include the risk of elective abortion of normal pregnancies due to false-positive test results. But above all, the harmful psychological effect on parents with a positive test result is to be considered seriously. This is particularly important because a large majority of positive screening on low-risk pregnancies are false-positives and the expectant parents carrying normal fetuses, unnecessarily face mental trauma.
 
REFERENCES
  1. Main DM, Mennuti MT. Neural tube defects: Issues in prenatal diagnosis and counseling. Obstet Gynecol 1986; 67:1–15.
  1. Moore CA, Li S, Li Z, Hong SX, Gu HQ, Berry RJ et al. Elevated rates of severe NTD in high prevalence areas in northern China. Am J Med Gen 1997; 73: 113–118.
  1. Wald NJ, Cuckle HS. Biochemical detection of NTD and Down's syndrome. Turnbull AC, Chamberlain G (Eds): Obstetrics. Churchill Livingstone, Longman Group, UK Limited  UK:  1989.
  1. Wald NJ, Cuckle HS Open NTD. In Wald NJ (Ed): Antenatal and Neonatal Screening for Disease. Oxford University Press  Oxford:  1984;25–73.
  1. 26 Wald NJ, Cuckle HS 1984b. Neural tube defects: Screening for biochemical diagnosis. In Rodeck CH, Nicolaides KH (Eds): Prenatal diagnosis. Proceedings of the 11th Study Group of the Royal College of Obstetrics and Gynaecology, RCOG,  London,  214–219.
  1. Wald NJ et al. MSAFP and Diabetes mellitus. Brit J Ob and Gynaecol 1979;86:101–105.
  1. Wald NJ, Barker S, Cuckle HS, Brock DJH, Stirrat GM. Maternal serum AFP and spontaneous abortion. Brit J of Obstetrics and Gynaecology 1977;84:357–362.
  1. Verma IC. High incidence of NTD in northern India. Lancet 1978; I: 879.
  1. Sharma AK, Upreti M, Kamboj M, Mehra P, Das K, Misra A. et al. Incidence of NTD at Lucknow over a ten year period from 1982–91. Indian J Med Res 1994; 99: 223–226.
  1. Kulkarni ML, Mathew MA, Ramchandran B. High incidence of NTD in south India. Lancet 1987; I: 260.
  1. Kulkarni ML, Mathews MA, Reddy V. The range of NTD in southern India. Arch Dis Child 1989; 64: 201–204.
  1. Strevenson AC, Johnston HA, Stewart MJP, Golding DR. Malformations of structures developed from the neural tube. Bull WHO 1966; (Suppl 34): 25–34.
  1. Baird PA. Neural tube defects in the Sikhs. Amer J Med Genetics 1993; 16:49–56.
  1. Sharma PD. The incidence of major congenital malformations in Mysore. Indian J Pediatr 1970; 37: 618–619.
  1. Lakshminarayana P. Evaluation of genetic and environmental factors in Pregnancy loss and malformed fetus. Final Report DST No. SP/SO/B-38-91, Department of Science and Technology  New Delhi,  1998.
  1. Cuckle H, Wald N. The impact of screening for open neural tube defects in England and Wales. Prenatal Diagnosis 1987; 7: 91–99.
  1. Yen IH, Khoury MJ, Erickson D, James LM et al. The changing epidemiology of a NTD. Am J Dis Child 1992; 146: 857–861.
  1. Creasy MR, Albeman ED. Congenital malformations of the central nervous system in spontaneous abortions. J Med Genet 1976;13:9.
  1. Flood T, Brewster M, Harris J et al. Spina bifida incidence at birth in United States, 1983–1990. MMWR 1992; 41: 497–500.
  1. Crogan JD, Roberts HE, Edmonds LD et al. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis—United States, 1985–1994. MMWR 1995; 44(SS-4): 1–13.
  1. UK collaborative study on AFP measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Lancet 1977; 1:1323–1332.
  1. Wald NJ, Cuckle H, Boreham J et al. Small biparietal diameter of fetuses with spina bifida: Implications for antenatal screening. Brit Jr Obstet Gynaecol 1980; 87:219–221.
  1. Althouse R, Wald NJ. Survival and handicap in infants with spina bifida. Archives of Disease in Childhood 1980; 55:845–850.
  1. Nyberg DA, Mack LA. The spine and NTD. In Nyberg DA, Mahony BS, Pretorius DH (Eds): Diagnostic Ultrasound of Fetal Anomalies (Text and Atlas) 1990 Mosby yearbook. Inc.  ch 4 and 6 pp 67–82 and pp 146–202.
  1. Tolmie J. Neural tube defects and other congenital malformations of the central nervous system. In Rimoin DL, Connor JM, Pyeritz RE (Eds): Principles and Practice of Medical Genetics, 3rd edn. Churchill Livingstone  New York:  1996; 2145–2176.
  1. Mathra M Werler, Carol Louik, Samuel Shapiro, Allen A Mitchell. Prepregnant weight in relation to risk of neural tube defect. Jr of American Medical Association 1996;275:1089–1092.
  1. 27 Moore LL et al. A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology 2000;11(6): 689–94.
  1. Mills JL, Baker L, Knoeles HC et al. Malformations in infants of diabetic mothers occur before the 7th gestational week. Implications for treatment. Diabetes 1979;28: 292–293.
  1. Gary M Shaw, Ellen M et al. Risk of neural tube affected pregnancies among obese women. Jr of American Medical Association 1996;275:1093–1096.
  1. Lydie Pani, Melissa Horal, Mary R Loeken. Polymorphic susceptibility to the molecular causes of NTD during diabetic embryopathy (Brief genetic report). Diabetes; September 2002.
  1. Drolet BA. Cutaneous signs of neural tube dysraphism. Pediatr Clin North Am 2000; 47: 813–123.
  1. Sauerbrei E, Nguyen K, Nolan R et al. The fetal spine, normal development and ossification, optimal scan planes and abnormalities (abstract). J Ultrasound Med 1988; 7(10): 598.
  1. O'Rahilly R, Muller F. Neurulation in the normal human embryo. Neural tube defects. Ciba Foundation Symposium 181 1994; 70–89.
  1. Moore KL. The developing human, 4th edn. WB Saunders Co.  Philadelphia:  pp 364–401.
  1. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–137.
  1. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327:1832–5.
  1. Federal Register. “Folic acid; proposed rules.” pp 53254–53317. Thursday, October 14, 1993. Revised April 2001.
  1. Wald NJ, Hackshaw AK, Stone R, Sourial NA. Blood folic acid and Vitamin B12 in relation to neural tube defects. Br J Obstet Gynecol 1996; 103: 319–324.
  1. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet 2001; 358:2069–73.
  1. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, Finalelstein JD, Blom HJ, Thomas CMG et al. Maternal hyperhomocysteinemia: A risk factor for neural-tube defects? Metabolism 1994; 43: 1475–1480.
  1. A Scribe Newswire, Joslin Diabetes Center, Boston, and USA. March 26, 2003: Antioxidants May Prevent Birth Defects in Babies of Women With Diabetes.(Research focused on NTD).
  1. March of Dimes Birth Defects Foundation. Folic acid and the prevention of birth defects: A national survey of pre-pregnancy awareness and behavior among women of childbearing age, 1995–2002. Conducted by the Gallup Organization. March of Dimes Foundation,  White Plains, NY:  May 2002. Publication no. 31-1677-02.
  1. Wald N, Cuckle H, Boreham J, Terzian E, Redman C. The effect of maternal weight on MSAFP levels. Brit J of O&G 1981; 88: 1094–1096.
  1. Wald NJ, Cuckle HS, Peak S, Stirrat GM, Turnbull AC. MSAFP in relation to zygocity. BMJ 1979;1:455.
  1. UK collaborative study report on AFP in relation to NTD, second report, AFAFP measurement in antenatal diagnosis of anencephaly and open spina bifida in early pregnancy. Lancet 1979;ii: 651–662.
  1. Wald NJ, Cuckle HS. Neural tube defects: Screening and biochemical diagnosis. Prenatal Diagnosis 1983; 3: 219–241.
  1. Smith CJ, Kelleher PC, Belanger L, Dallaire L. Reactivity of amniotic fluid alpha fetoprotein with concanavalin A in diagnosis of NTD. BMJ 1979;I: 920–921.
  1. 28 Collaborative acetylcholinesterase study report 1881. Amniotic fluid acetylcholinesterase electrophoresis as a secondary test in the diagnosis of anencephaly and open NTD in early pregnancy. Lancet ii: 321–324.
  1. Watson WJ, Cheschier NC, Katz VL et al. The role of ultrasound in the evaluation of patients with elevated MSAFP: A review. Obstet Gynecol 1991; 78: 123–128.
  1. Lennon CA, Gray DL. Sensitivity and specificity of ultrasound for the detection of NTD and ventral wall defects in high risk population. Obstet Gynecol 1999 Oct; 94(4): 562–566.
  1. Boyd PA, Wellwsley DG, De Walle HE et al. Evaluation of the prenatal diagnosis of NTD by fetal ultrasonographic examination in different centres across Europe. J Med Screen 2000; 7(4): 169–74.
  1. Timor Tritsch IE, Monteagudo A. Transvaginal neurosonography: Standardization of the planes and sections by anatomic landmarks. Ultrasound Obstet Gynecol 1996; 8:42–50.
  1. Sebire NJ, Nobel PL, Thorpe-Beeston JG et al. Presence of the lemon sign in fetuses with spina bifida at the 10–14 weeks scan. Ultrasound Obstet Gynecol. 1997; 10: 403–407.
  1. Monteagudo A, Timor Tritsch I, Moomjy M. Nomogram of the lateral ventricles using transvaginal sonography. J Ultrasound Med 1993; 12:265–269.
  1. Johnson SP, Sebire NJ, Snijders RJM et al. Ultrasound screening for anencephaly at 10–14 weeks. Ultrasound Obstet Gynecol 1997; 9: 14–18.
  1. Blaas gestational week HGK, Eik-Nes SH, Isaksen CV. Detection of spina bifida before 10 gestational weeks using two and three D ultrasound. Ultrasound in Obstetrics and Gynaecology 2000;16(1): 25.
  1. Williams MA, Hickok DE, Zingheim RW et al. Elevated MSAFP levels and midtrimester placental abnormalities in relation to subsequent adverse pregnancy outcome. Am J Obstet Gynecol 1992; 167: 1032–103.
  1. Nakahara T, Uozumi T, Monden S et al. Prenatal diagnosis of open spina bifida by MRI. Brain Dev 1993 Jan-Feb; 15(1): 75–78.
  1. Babcock CJ, Chong BW, Salamat MS et al. Sonographic anatomy of developing cerebellum: Normal embryology can resemble pathology. AJR 1996; 166: 427–433.
  1. Benacerraf BR et al. Abnormal US appearance of the cerebellum (banana sign): Indirect sign of spina bifida. Radiology 1989; 171: 151–153.
  1. Furness ME, Barbary JE, Verco PW. Fetal head shape in spina bifida in the second trimester. JCU 1987; 15: 451–453.
  1. Nicholaides KH, Campbell S, Gabbe SG. Ultrasound screening for spina bifida: Cranial and cerebellar signs. Lancet 1986; 2:72–74.
  1. Nyberg DA, Mack LA, Hirsch J et al. Abnormalities of fetal cranial contour in sonographic detection of spina bifida: Evaluation of “lemon sign”. Radiology 1988; 167: 387–392.
  1. Nyberg DA, Mack LA, Hirsch J et al. Fetal hydrocephalus: Sonographic detection and clinical significance of associated anomalies. Radiology 1987; 163: 187–191.
  1. Campbell S, Johnstone FD, Holt EM. Anencephaly: Early ultrasonic diagnosis and active management. Lancet 1972; 2:1226.
  1. Timor Tritsch IE, Greencbaum E, Monteagudo A et al. Exencephaly-anencephaly sequence: Proof by ultrasound imaging and amniotic fluid cytology. J Mater Fetal Med 1996; 5:182–185.
  1. Guthkelch AN. Occipital cranium bifidum. Arch Dis Child 1970; 45: 104–109.
  1. Chervenak FA, Blakemore KJ, Mahoney MJ et al: Diagnosis and management of fetal cephalocele. Obstet Gynecol 1984; 64:86–90.
  1. 29 Foderaro AE, Abu-Yousef MM, Benda JA et al. Antenatal diagnosis of iniencephaly. J Clin Ultrasound 1987; 15: 550–554.
  1. David TJ, Nixon A. Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 1976; 13: 263–265.
  1. Cox GG, Rosenthall SJ, Holsapple JW. Exencephaly: Sonographic finding and radiologic-pathologic correlation. Radiology 1985; 755–756.
  1. Hendricks SK, Cyr DR, Nyberg DA et al. Exencephaly-Clinical and ultrasonic correlation to anencephaly. Obstet Gynecol 1988; 72: 898–901.
  1. Campbell S. Early prenatal diagnosis of NTD by ultrasound. Clin Obstet Gynecol 1977; 20:351–359.
  1. Cochlin DL. Ultrasound of fetal spine. Clin Radiol 1982; 33: 641–650.
  1. Filly RA, Simpson GF, Linkowski G: Fetal spine morphology and maturation during the second trimester. J Ultrasound Med 1987; 6: 631–636.
  1. Roberts CJ, Hibbard BM, Roberts EE et al. Diagnostic effectiveness of ultrasound in detection of neural tube defects. Lancet 1983; ii: 1068–1068.
  1. O'Reilly GC, Shields LE. Karyotyping for isolated NTD. Jr Rep Med 2000; 45: 950–952.
  1. Lober J. Results of treatment of myelomeningocele: An analysis of 524 unselected cases, with special reference to possible selection for treatment. Dev Med Child Neurol 1971; 13: 279–303.
  1. Waitzman NJ, Romano PS, Scheffler RM. Estimates of the economic costs of birth defects. Inquiry 1994; 31: 188–205.
  1. Rankin J, Glinianaia S, Brown R, Renwick M. The changing prevalence of neural tube defects: A population-based study in the north of England, 1984–96. Northern Congenital Abnormality Survey Steering Group. Ultrasound in Obstetrics and Gynecology 2000; 16(1):25.
  1. Cochrane D, Aronyk K, Sawatzky B et al. The effect of labor and delivery on spinal cord function and ambulation in patients with meningomyelocele. Child Nerv Syst 1991; 7: 312–315.
  1. Luthy DA, Wardinsky T, Shurtleff DB et al. Caesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991; 324: 662–666.
  1. Dias MS, Li V. Pediatric neurosurgical disease. Pediatr Clin North Am 1998; 45: 1539–1578.
  1. Sarawak JF. Spina bifida. Pediatr Clin North Am 1996; 43: 151–1158.
  1. Mapstone TB, Rekate HL, Nulsen FE et al. Relationship of CSF shunting and IQ in children with myelomeningocele: A retrospective analysis. Child's Brain 1984; 11: 112–118.
  1. Nadel AS, Green JK, Holmes LB et al. Absence of need for amniocentesis in patients with elevated MSAFP and normal ultrasonographic examinations. New Engl J Med 1990; 323: 557–561.