PRENATAL DIAGNOSIS Prenat Diagn (2009) Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2250 REVIEW Prenatal screening and diagnosis of neural tube defects Martin Cameron and Paul Moran* Fetal Medicine Department, Leazes Wing, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, UK This review article discusses prenatal screening and diagnosis of neural tube defects (NTD). High detection rates occur in countries operating ultrasound screening programmes because classical two-dimensional ultrasound cranial signs (lemon shaped head, banana cerebellum, ventriculomegaly) are important diagnostic clues to the presence of spina bifida. Careful evaluation of both the spine and a search for other abnormalities is warranted. Important prognostic information for spina bifida relates to the lesion level, with a ���watershed��� between L3 and L4 marking a very high chance of being wheelchair bound with the higher lesions. Three-dimensional ultrasound using multiplanar views can achieve diagnostic accuracy within one vertebral body in around 80% of patients. There are high rates of pregnancy termination for spina bifida in many European countries, but the use of new imagining techniques allow better prediction of outcome, and consequently a refinement of prenatal counselling. Copyright ��� 2009 John Wiley & Sons, Ltd. KEY WORDS: prenatal screening 3D ultrasound 4D ultrasound Neural tube defects spina bifida meningocele myelomeningocele anencephaly encephalocele INTRODUCTION Neural tube defects (NTD) range from the lethal (anen- cephaly) to the potentially asymptomatic (some closed spina bifida). Spina bifida outcomes appear to be highly variable and difficult to predict. This is in part not only due to the genuine heterogenicity of the condi- tion but also due to image interpretation and a lack of prospective outcome data (Boyd et al., 2008). We review prenatal screening options for NTD, and the role of two-dimensional (2D) and three-dimensional (3D) ultra- sound techniques in achieving diagnosis with prognostic prediction. PRENATAL SCREENING FOR NTD Risk assessment prior to biochemical and/or ultrasonic screening The average incidence of NTD is 1 : 1000 births, but this masks a marked geographical variation between countries with the highest rates of NTD (e.g. UK and USA), and the lowest (e.g. Japan) (Davis and Young, 1991 Ehara et al., 1998 Pilu, 2008). Risks increase to 2 to 3% if one pregnancy has been affected, to 10% if two pregnancies have been affected. Other indepen- dent risk factors are valproic acid, folic acid antago- nists (methotrexate and aminopterin), vitamin A, mater- nal diabetes, maternal obesity, hyperthermia and folate deficiency (Padmanabhan 2006 Shaer et al., 2007 Ras- mussen et al., 2008). However, 90% of children with NTD are born to women with no identifiable risk factors. *Correspondence to: Paul Moran, Fetal Medicine Department, Leazes Wing, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, UK. E-mail: paul.moran@nuth.nhs.uk Two approaches have been used for NTD screening in low-risk populations: biochemical testing of mater- nal blood for alpha-fetoprotein (AFP) or the use of traditional 2D ultrasound. Some screening programmes combine the two techniques. Biochemical screening For over 30 years, maternal serum AFP has been used as a screening test for open NTD. AFP is a glycoprotein, secreted by the fetal yolk sac and liver. Fetal serum concentrations are 150 to 200 times that of amniotic fluid (Habib, 1977). Amniotic fluid levels of AFP and acetylcholinesterase were historically used to diagnose NTDs, but have been superseded by fetal ultrasound. Open NTD increase AFP in both amniotic fluid and maternal blood. As closed NTD (10% of lesions) do not increase AFP, biochemical screening is not effective. The maternal serum level of AFP varies with gestation, so needs to be expressed as multiples of the median (MoM). Using 2.5 MoM as screen positive in single- ton pregnancies, the detection rate for anencephaly is expected to be 95% and for open NTD between 65 and 80%. False-positive rates should lie between 1 and 3% (Bradley et al., 2005). A raised serum AFP is not diag- nostic for open NTD as it can be associated with other abnormalities including gastroschisis, omphalocele, con- genital nephrosis and fetal demise. Many now question the benefit of amniotic fluid biochemical markers where there is access to high-quality ultrasound (Kooper et al., 2007). Ultrasound screening Traditional 2D ultrasound has largely superseded mater- nal AFP as a screening tool. Boyd et al. (2008) recently Copyright ��� 2009 John Wiley & Sons, Ltd. Received: 25 July 2008 Revised: 2 February 2009 Accepted: 2 February 2009

M. CAMERON AND P. MORAN surveyed the national screening policies current in 2004 for 18 European countries. There was a formal national ultrasound screening policy for structural anomalies in 14 of the 18 European countries, with 3 of 18 having no official policy but regularly performing an 18- to 22- week anomaly scan. The overall prenatal detection rate for NTD was 88%, (range 25���94%). Detection rates were highest in those countries with standards deter- mined by a national screening policy. Gestational age and type of NTD greatly influences detection rates. First trimester studies typically quote detection rates of 90% for anencephaly and encephalo- cele (80%), but lower rates for spina bifida (44%) (Whit- low et al., 1999 Taipale et al., 2003). Second trimester scanning improves the detection of spina bifida, typi- cally to 92���95% (Grandjean et al., 1999 Smith and Hau, 1999). An important principle is that, in diagnosing an NTD a careful evaluation of the whole fetus should be performed because associated malformations are found in around 20% (Stoll et al., 2007). IMAGING TECHNIQUES FOR DIAGNOSING NTD 2D ultrasound Anencephaly Failure of closure of the rostral neuropore causes failed cranial vault development and the condition of exen- cephaly, the precursor of anencephaly. Ossification of the skull vault is not always apparent until 12 weeks��� gestation and anencephaly should not be diagnosed before this time (Russell et al., 2007). This should be an easy diagnosis to make. First trimester ultra- sound findings include absent calvarium, reduced crown- rump length, exposed neural tissue with a lobulated appearance (exencephaly), or absent neural tissue, and a loss of the normal head contour with the orbits mark- ing the upper limit of the fetal face in the coronal plane (Figure 1). By the second or third trimester there may be associated polyhydramnios from impaired fetal swallowing. Cephalocele To confirm the diagnosis, it is necessary to visual- ize the bony skull defect through which the meningeal sac alone (meningocele) or sac plus cerebral tissue (encephalocele) herniated (Figure 2). This communica- tion between external mass and intracranial cavity differ- entiates cephaloceles from other lesions such as lipomas or teratomas. Seventy-five percent arise from a defect in the occipital bone, with remainder roughly equal between parietal and frontal bones. Associated find- ings including cerebral ventriculomegaly, microcephaly, Dandy���Walker malformation, agenesis of the corpus callosum, facial clefts and cardiac defects. Spina bifida Detection rates by routine ultrasound screening should approach 100% for open spina bifida due to the presence of the easily recognizable cranial signs the ���lemon��� and ���banana��� signs (Nicolaides et al., 1986) (Figures 3 and 4). The lemon sign describes the shape of the skull in transverse plane caused by the concavity of the parietal bones. It is gestation dependent has been described as early as 13 weeks (Blaas et al., 2000), and in 98% before 24 weeks but in only 13% after 24 weeks (Van den Hof et al., 1990). Its resolution is thought to be due to further ossification and strengthening of the bony calvarium, increasing intracranial pressure or both. The lemon sign is not specific for open NTD (Ball et al., 1993) with up to 1% of normal fetuses displaying a mild concavity of Figure 1���Two-dimensional Ultrasound of anencephaly Copyright ��� 2009 John Wiley & Sons, Ltd. Prenat Diagn (2009) DOI: 10.1002/pd