Clinical manifestations

Presentation and course

There are three forms of anencephaly: holoanencephaly (total), meroanencephaly (partial), and craniorachischisis.

Although anencephaly is often an isolated, nonsyndromic anomaly, it not uncommonly manifests with other major anomalies (eg, cleft face, cleft palate, congenital heart defects). The eyes of anencephalics are normally formed; the apparent bulging of the eyes is a result of the absence of the frontal portion of the cranial vault. Cerebellum, brain stem, and spinal cord are generally intact.

Anencephaly most commonly involves singleton births, but it can occur with multiple births (eg, involving one or both of a set of twins) or, rarely, may involve one or both of a set of conjoined twins.

The "area cerebrovasculosa" of anencephalic fetuses is an irregular vascular proliferation resembling an angioma, within which are scattered primitive neuroglial tissue elements and disorganized neuroepithelial tissue. It typically appears as a bilaterally symmetrical cystic mass covering the anterior and middle cranial fossae, which is walled with glial tissue, partially lined with ependyma, and filled with abnormally vascular choroid plexus (92; 17; 150). The highly vascular covering of the cyst and the overlying squamous epithelium are in continuity with hairy skin at the margins of the lesion. The posterior cranial fossa contains a variable quantity of medulla oblongata that has no connection with the cystic mass. The degree of hindbrain development is associated with heterotopic glial tissue in the spinal subarachnoid space of some anencephalic fetuses (16; 17).

Liveborn infants with anencephaly generally die quickly, but some may live for days, weeks, or rarely, months. In an exceptional situation in 1995, an anencephalic infant, "Baby K," was kept alive on assisted ventilation by order of the Fourth Circuit Court of Appeals, a ruling that caused considerable professional duress (90; 266). To date, the longest survival of an unsupported infant has been 28 months (89). The prenatal ultrasound image published in this case suggested that more brain tissue was present than usual. Surprisingly, affected infants can have seemingly purposeful movements, startle myoclonus, increased tone and deep tendon reflexes, normal cardiovascular status, and regular respiratory patterns. They may have difficulty maintaining a normal body temperature and become hypothermic. Some infants with anencephaly make crying sounds and can swallow. Such lifelike activities create anxiety for caregivers. For these reasons, practitioners are cautioned in the use of careful and precise language as they counsel families, focusing on the specifics of prognosis rather than abstract generalities (345).

Because of the severity of impairment and frequency of early death, many workers discuss the option of termination of pregnancy with families (139). Some have suggested that organs of anencephalic infants might be used for transplantation; however, a significant proportion of these organs are often hypoplastic or malformed (176; 273; 206; 178). A medical task force on anencephaly reviewed the medical, social, legal, and ethical issues regarding anencephaly and recognized various complicating factors, including the difficulty in documenting brain death in affected infants (204). In 1995, the ethics council of the American Medical Association announced its support for procuring organs for transplantation from anencephalic infants; subsequent controversy caused the council to withdraw its opinion (342). This issue remains unresolved (245).

Prognosis and complications

Approximately 65% of fetuses with anencephaly die in utero (204). Most liveborn infants with anencephaly die within minutes to hours of delivery, and nearly all die in the first week, though a few long-term survivors have been reported. In a review of 26 patients, the survival time ranged from 10 minutes to eight days (234). Cases carried to term may be complicated by stillbirth, polyhydramnios (sometimes severe), caesarean delivery, shoulder dystocia, and possible obstetrical hemorrhage (94). In twin pregnancies discordant for anencephaly, the risk for premature delivery and low birth weight of the nonaffected twin is elevated, requiring increased monitoring and possible intervention (174; 184). In one small series, an increased risk for neural tube defect was observed among siblings of patients with lipomyelomeningocele (279).

Clinical vignette

This female infant was born at 39 weeks to a 22-year-old gravida 1 mother who suffered from cervical carcinoma. The prenatal course was unremarkable, and the mother gave no history of drug or alcohol use or smoking. The infant was delivered by cesarean section because of a breech presentation and given Apgar scores of 6 at one minute and 9 at five minutes. Moro-like reflexes and grasping could be elicited, but the infant manifested occasional seizure activity and choking. With increasing periodic apnea and bradycardia, she expired at 23 hours.

Biological basis

Etiology and pathogenesis

Anencephaly is etiologically heterogeneous (142; 175) but is thought to involve an interaction of genetic and environmental factors.

At present, known risk factors account for less than one half of cases (02). Multiple etiologic factors have been implicated, but most have not been confirmed or are found only in isolated cases. Implicated factors include maternal exposure to certain drugs (eg, aminopterin, salicylates, clomiphene, and gonadotropins), infections (ie, influenza), nitrite-cured meats, blighted potatoes, and hard water. Difficulties in maternal glucose control (ie, diabetes), hyperinsulinemia, obesity, and intake of simple sugars have been associated with increased risk of neural tube defect and may act by affecting gene expression in the developing embryo (292; 269; 252). Periconceptional maternal cannabis use is associated with the development of anencephaly (330; 259). Maternal hyperthermia, treatment of seizures in pregnant mothers with valproic acid, and the fungal product fumonisin are recognized causes of neural tube defects. One study identified an association of acute conditions (eg, maternal fever) and more chronic ones (eg, as migraine headaches) with neural tube defects (205). In another study, the greatest attributable risk for anencephaly was Hispanic ethnicity (02).

Genetic factors. A genetic basis for some cases of anencephaly seems likely, but it has been difficult to ascertain because the condition appears to be multigenic with complex gene-environment interactions (124). A genetic contribution has been suggested by the association with other conditions having a recognized genetic basis, such as anal stenosis, anterior sacral meningocele, and Meckel syndrome (88). A genetic basis is also suggested by the identification of numerous mutations whose function causes neural tube defects in mice (62; 124) and the occurrence of familial cases with a 10-fold increased risk among siblings (33). Familial cases can be striking, with recurrence of three to six affected infants per mother. Demenais and colleagues suggested that familial cases may involve monogenic inheritance with environmental influences (85), whereas Kalter and Warkany suggested that a genetic model would most likely involve multigenic inheritance (161; 162). Current thinking supports a multifactorial etiology (62; 124).

Analysis of sex ratios show a predominance of female anencephalics, and many twins (usually discordant) have been reported. The increased incidence of anencephaly among twins does not appear to be related to mode of conception (ie, natural vs. artificial) (19). Interestingly, this female predominance is more pronounced in those exhibiting localized cranial lesions than those with schisis involving the upper vertebral column (78).

A small percentage of individuals with anencephaly has an abnormal karyotype. In one study, 2% of affected fetuses had karyotype abnormalities, most often trisomy 18 or trisomy 13 (282). Two cases of anencephaly associated with partial duplication of 2p have been reported, suggesting that genes on the short arm of chromosome 2 could be important to CNS development (315).

A homozygous mutation in FOXN1, a member of the forkhead (or Fox) gene family, has been discovered in a human fetus with absent thymus, abnormal skin, anencephaly, and spina bifida (08). This finding suggests that the gene may be involved in neurulation in humans.

The presence of genetic factors is also supported by the observation that some 30% of defects are not prevented by folic acid supplements alone (23). It is possible that obesity (as quantified by basal metabolic index) influences the body distribution of folate (320). The relationship of red blood cell folate levels and obesity appears to vary by basal metabolic index but requires further study (187).

Mouse models. Mutant mouse models of neural tube defects provide insight into the mechanisms that result in neural tube defects (132; 134; 133; 135; 131; 331). Most of the (more than 50) single-gene mutations that cause neural tube defects in mice also cause lethal embryonic syndromes in which exencephaly is a nonspecific feature. Multigenic causes, such as those present in the curly tail mutant mouse or the SELH/Bc mouse strain, produce nonsyndromic neural tube defects; 15% to 20% of the offspring of curly tail mutant mice have spina bifida, whereas a similar percentage of the offspring of SELH/Bc mice have exencephaly (134; 331). "Spina bifida occulta" (ie, a dorsal gap in the vertebral arches overlying an intact neural tube) is genetically and developmentally unrelated to exencephaly or "spina bifida" (aperta). Almost all genetic forms of exencephaly or spina bifida aperta are caused by a failure of neural fold elevation (134). In addition, mutations causing neural tube defects affect distinct rostrocaudal zones along the neural folds though heterogeneous mechanisms; depending on which zone is affected, failure of neural fold elevation may variously produce "split face," exencephaly, rachischisis, or spina bifida (134).

At the tissue level, failure of elevation may be caused by various processes (134):

At the biochemical and cellular level, different mutants act through or affect different cellular processes (134):

The neural tube defect preventative effect of maternal dietary supplementation is also heterogeneous, reflecting underlying differences in biochemical deficiencies and cellular processes, as the following examples illustrate.

Mouse mutants in folate pathway genes rarely result in neural tube defects. Folr1-null mouse embryos die by the tenth day of gestation with no neural tube closure, but if they are treated with folinic acid, most homozygotes live to the eighteenth day of gestation and 30% have exencephaly (among other defects of face, body wall, jaw, eyes, and limbs). Folr1 codes for folate receptor alpha, which suggests that a deficiency of folate entering the cells contributes to failure of cranial neural tube closure.

The curly tail (ct) mutant mouse has been studied for more than 70 years and is now the best understood mouse model of neural tube defect pathogenesis (280; 331). Expressions of ct gene mutations in curly tail mice include prenatal death, spina bifida, and various degrees of kinky or curly tail. Failure of closure of the spinal neural tube in curly tail mutant mice results in spina bifida, which is caused by a tissue-specific defect of cell proliferation in the tail bud of the E9.5 (ie, embryonic day 9.5) embryo. This cell proliferation defect results in a growth imbalance in the caudal region, leading to delayed neuropore closure and spina bifida, or tail defects. In addition to the principal ct gene on mouse chromosome 4, the curly tail phenotype is influenced by several modifier genes and by environmental factors, illustrating a very clear, but complex, gene-environment interaction (331). Neural tube defects in curly tail mice are "resistant" to correction by folic acid supplementation (as is the case in 30% of human neural tube defects), but they can be prevented by supplementation with myo-inositol (331). Curly tail mice also exhibit enhanced susceptibility to the teratogenic effect of vitamin A given on day 8 of gestation, but if vitamin A is administered on day 9, the occurrence of neural tube defects is decreased rather than increased (281).

Similarly, human neural tube defects, including nonsyndromic anencephaly or spina bifida, may also reflect heterogeneous multigenic defects and complex gene-environment interactions that affect the developmental mechanisms responsible for elevation of the neural folds.

Embryology. The pathogenesis of anencephaly remains unclear. Two major schools exist: one holding that the primary mechanism is nonclosure of the rostral neural folds, and the other that cranial mesenchyme is primarily defective (190; 214). Most workers favor nonclosure of the neural tube as the primary mechanism, as evidenced by the widespread popularity of the term "neural tube defect" to designate anencephaly, encephalocele, and myelomeningocele. A third possibility is that a closed neural tube reopens, but supporting evidence is weakest in this area.

In human embryos, primary neurulation (closure of the neural folds) takes place between stage 8 and stage 12 (see Table 1). Anencephaly and other neural tube defects occur when development is abnormal, although the exact mechanism of closure remains unknown. The Hedgehog signaling pathway has been implicated in neural tube closure because increased Sonic Hedgehog signaling is associated with the appearance of exencephaly (215). Embryonic metabolism also appears to be important because studies using mass spectrometry have identified abnormalities in glucose metabolism during neural tube closure (352).

Some investigators have postulated that the variations of anencephaly and other neural tube defects can be explained by multiple sites of closure of the neural tube (329; 121; 304). Others counter that “accessory loci” for closure exist in human embryos but are highly variable and do not follow a constant pattern (239). Research progress is intermittent and capricious because affected embryos are rare and die at very early ages (ie, 5 to 6.5 weeks) (216). Two anencephalic embryos, stages 13 and 22, are extreme exceptions to this, having intact neural crest derivatives (240). This observation suggests that the process responsible for anencephaly began after the initiation of crest cell migration or that crest cells survived the pathogenetic event.

Table 1. Normal and Abnormal Events of Primary Neurulation

An understanding of these stages is important for counseling parents. Anencephaly can be said to have a "termination point" (ie, a time after which the anomaly cannot occur); therefore, exposures or other maternal events that occur after the critical periods for anencephaly can be ruled out as causative factors.

Exencephaly, the superior extrusion of a relatively large, bulbous portion of cerebral tissue beyond the calvaria, is a forerunner of anencephaly (350; 214). This has been demonstrated experimentally and by prenatal ultrasonography in fetuses prior to spontaneous degeneration of brain tissue. Holoprosencephaly is rarely associated with anencephaly (177; 296) and may involve aberrant morphogenesis of prechordal and paraxial developmental fields (297). The genetics of neural tube defects and midline craniofacial malformations is becoming understood, as illustrated by studies of the tuft mouse mutant (111).

Pathological findings in the central nervous system depend on the gestational age and extent of the lesion. Rudimentary cerebral hemispheres can be found in 50% of anencephalic newborns, and complete absence can be found in the remainder. Absence of the cerebellum and brainstem has also been reported (332). These infants usually manifest a connective tissue mass adherent to the dura mater. Their cerebral tissue is soft and infiltrated with blood, and scattered islands of neural cells and choroid plexus can often be identified. As a result of this appearance, the term "area cerebrovasculosa" is often applied to the anencephalic brain. This vascular finding is a reactive change to the exposure of neural tissue to amniotic fluid.

Examination of the brainstem reveals variability in the preservation of nuclei and absence of the pyramidal tract. The eyes often bulge dramatically. They may also appear normal but lack central connections to the brain, ending blindly posterior to the optic foramina. Other pathological changes of the eyes include absence or reduction in axis cylinders and colobomata of the optic disc. The spinal cord may show reduced white matter in some tracts, absence of Clarke column, and a lower termination of the conus medullaris.

Cranial bones are highly abnormal (108; 214): calvarial bones are displaced, rudimentary, or absent; the zygomatic bones may be rotated abnormally; the sphenoid is hypoplastic in the cranial base; and petrous ridges are malpositioned. The maxillae, palatine bones, and vomer may be normal, although the mandible is large and prognathic. Temporal and occipital bones may also be malformed (12). An understanding of this bony anatomy has proven especially helpful in certain forensic situations involving found human remains of anencephalic infants (93).

Additional malformations of other systems are common. One study found that liveborn anencephalics had 12% additional malformations of other systems, but if there was an associated spina bifida or encephalocele, the prevalence was 88% (273). Anomalies of extraocular muscles have been observed in a large percentage of affected fetuses (250). Endocrine system anomalies are present in anencephalic infants with absence or hypoplasia of the pituitary gland and nearly universal hypoplasia of the adrenal glands (198). Diaphragmatic malformations (eg, hernia or eventration), abdominal wall defects, and other thoracic cage abnormalities are common (176; 206). Frequently, the lungs and heart are hypoplastic. One study demonstrated various degrees of intestinal aganglionosis in anencephaly (195). Anthropometric studies have shown an increased growth of the arms in anencephaly (217). A proximodistal gradient existed with the upper arm being increased by 24%, the forearm by 16%, and the hand by 2%. This is a variable finding, for Barr has observed normal arm length in anencephaly (Barr, personal communication 1997). Other anomalies of the limbs are found, but no one abnormality stands out, except perhaps talipes equinovarus. One detailed anatomic study identified several anomalies of skeletal muscles in a single fetus (06). A sternalis muscle is present in up to 50% of anencephalics but is unusual in the general population (1% to 4%).

Research directions. Important avenues for research include studies of genes controlling folate metabolism (83; 27), screens for human homologs to genes that cause anencephaly in laboratory animals (306), and maternal or sex-influenced genetic effects (80). Mutations in planar cell polarity genes (responsible for maintaining epithelial orientation during neural tube closure) have been identified in mice with neural tube defects and may be functional in humans as well (82; 160). The regulatory effects of bone morphogenetic protein and Sonic hedgehog have been implicated in neural tube bending and may play a role in pathogenesis (63), as may maladjustment of microRNAs in the mitogen-activated protein kinase signaling pathway (362).

Epidemiology

Of congenital defects, only cardiac defects are more common than neural tube defects. Over the past 50 years, the prevalence of anencephaly has averaged about 1 per 1000 deliveries, but wide variations exist geographically and by race (61). Worldwide, the annual number of new cases is estimated to be at least 300,000 (194).

Effect of pregnancy termination

Reported neural tube defect birth prevalence figures do not include the large number of anencephalic embryos and fetuses that undergo spontaneous abortions and may not include therapeutic terminations (25; 103; 180; 247). In fact, reports of the declining birth prevalence of neural tube defects may be influenced significantly by pregnancy termination (314). An estimated 83% of pregnancies complicated by anencephaly and 63% of cases with spina bifida undergo termination (156). The termination rate in France is estimated at 97% (319). Data from these cases may not be available in the form of death certificates or other formal documentation. These points are borne out by a study in Japan, wherein an extensive review of over 311,000 deliveries and terminations in cases of myelomeningocele and anencephaly disclosed a birth prevalence of 0.8 to 0.9 per 1000 deliveries (2014 and 2015 data) (168). Pregnancies involving anencephaly were terminated in 80%, an indication of the potential magnitude of data that may be lost if only live births are reported.

Spatial and temporal variation in birth prevalence

Birth prevalence may also fluctuate over time and among different cultures. British Columbia, for example, has experienced a decline in the occurrence of neural tube defects (but also an increase in the severity of lesions) and a striking decrease in recurrence from 2.3% to 0.2% (52). The birth prevalence in Ireland (where terminations were illegal) dropped 4-fold from 1980 (4.7 per 1000 births) to 1994 (1.2 per 1000 births) (201). This resembles the prevalence for Germany (1.2 per 1000 births), a country that has lagged in folate fortification (138). By contrast, a decrease in birth prevalence in northern England is attributed to improved prenatal diagnosis and intervention (255).

An increased birth prevalence of anencephaly has been noted among Hispanics in south Texas. Hispanics have a birth prevalence three times higher than non-Hispanics (34), though no difference exists between Hispanics born in Mexico and Hispanics born in Texas (35). This difference in birth prevalence has also been noted in California, where Hispanic women were 45% more likely to have an anencephalic conceptus than white women (107) and elsewhere in the United States (24).

Problems of study comparability

Although international and national distributions of neural tube defect occurrence have often been used to generate etiological hypotheses concerning neural tube defects (eg, potato blight, tea consumption, and zinc deficiency), few of these studies have been conducted with scientific rigor, and most have imprecise estimates due to small sample sizes (22). Moreover, comparability is compromised by nonuniformity in the duration and diligence of case ascertainment, the lack of a standardized nomenclature and classification, inconsistency in the placement of the gestational boundary between late fetal deaths and spontaneous abortions, and differences in the choice of the denominator (22). Findings are often compared from studies conducted at different times without considering secular trends and using studies that have varying thoroughness of case ascertainment, all inherently assuming that the differences reflect true spatial or temporal variations rather than variations in the quality of ascertainment. Consequently, geographic patterns of neural tube defects may be attributable to variations in the validity of studies used to describe these patterns (22).

High-frequency clusters

In a cluster of neural tube defects in central Washington state, mostly anencephaly, the rate was four times the national average (48). In this study, no significant differences were found between cases and controls. The area is largely rural, so an effect of pesticides and other agricultural materials might be postulated. However, an epidemiological study from California did not identify an association between pesticide exposure and neural tube defects (354).

Mortality statistics

Death certificate reports of anencephaly may be imprecise or inaccurate (291). The diagnosis of anencephaly on death certificates relies on the expertise and experience of the individual completing the document. Fetuses dying by natural means or pregnancy termination before 20 weeks elicit no death certificate. By one estimate, over one third of anencephalic fetuses may not be included in published frequencies, which, for this reason, are low (341).

Risk factors

The etiology of neural tube defects is complex, with both genetic (polygenic or oligogenic) and environmental factors having important contributions (62).

Dietary folate. Dietary folate intake is the strongest known and best documented risk factor for neural tube defects (171).

Observational studies. The prevalence of anencephaly has increased during periods of poor maternal nutrition (eg, the Great Depression and wartime famines), and it has dropped with global socioeconomic development (210).

In 1964, British obstetrician Brian Hibbard (1926–2021) suggested an association between fetal neural tube defects and maternal deficiency or defective metabolism of folates (140; 171). In 1976, Richard Smithells (1924–2002) and colleagues at the University of Leeds demonstrated that women with megaloblastic anemia during pregnancy have a high frequency of neural tube defects in their offspring (300). In 1980, Smithells and colleagues reported a nonrandomized trial of multivitamin supplementation among women who had previously given birth to one or more infants affected with neural tube defects (301): there was a 5% recurrence rate for the nonsupplemented group compared with a 0.6% recurrence rate for the supplemented group.

Additional observational studies and nonrandomized clinical trials were published during the 1980s and 1990s and documented the protective effects of higher folic acid intake or of vitamin supplements containing folic acid during the periconceptional period (ie, from 1 month before pregnancy through the first trimester) among women who had not previously had a pregnancy affected by a neural tube defect (ie, occurrence studies) and among women who had a previous pregnancy affected by a neural tube defect (ie, recurrence studies) (171). These studies showed a wide range of estimated efficacy in the occurrence of neural tube defects with folic acid supplementation, but the summary efficacy estimate across the various studies indicated an overall 50% reduction in risk of neural tube defects (335).

Randomized controlled trials. The strongest evidence in support of periconceptional folic acid supplementation comes from two large, randomized trials published in the early 1990s (212; 73; 68; 70; 69; 335; 75; 171). The Medical Research Council (MRC) study under the direction of Sir Nicholas Wald (b 1944) at St. Bartholomew’s Hospital Medical College in London was a multicenter, multinational, randomized, double-blind, controlled, recurrence prevention trial conducted in 33 centers in seven countries (212; 335). The MRC study found a 72% reduction in recurrence of neural tube defects with 4 mg of folic acid daily over the period from before conception and during the first trimester among women with a previous neural tube defect–associated pregnancy (212; 335). The Hungarian study, conducted by Andrew Czeizel (1935–2015) of the National Institute of Hygiene in Budapest, was a randomized, double-blind, controlled, occurrence prevention study with periconceptional supplementation with multivitamins, including 0.8 mg of folic acid (73; 75; 69; 337). Among approximately 5000 women with confirmed pregnancy and an “informative offspring,” maternal periconceptional folic acid supplementation produced a significant decrease in the first occurrence of neural tube defects compared to a placebo-like (ie, trace element) control group.

A meta-analysis of data from these trials and a previous small (underpowered and not statistically significant) trial by Laurence and colleagues collectively indicated that periconceptual folate administration reduces both the occurrence and recurrence risks of neural tube defects by at least 70% (172; 212; 335). Subsequent studies have generally supported these findings and suggest that periconceptional multivitamin supplementation can significantly reduce the occurrence of other congenital abnormalities in addition to neural tube defects (166; 68; 70; 74).

Governmental recommendations and health policy. Data from the randomized controlled trials have been used to establish (1) governmental recommendations concerning folic acid intake and (2) health policy concerning vitamin fortification of foodstuffs (143; 171). In 1991, the U.S. Centers for Disease Control and Prevention (CDC) published a review of the evidence for the prevention of recurrent neural tube defects and recommended 4 mg of folic acid for women who had previously had an infant or fetus with a neural tube defect (47). In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant should consume 0.4 mg (4000 mg) of folic acid daily (44; 65). Because naturally occurring folate is less readily absorbed than synthetic folic acid, in 1998, the Institute of Medicine recommended that women of childbearing age consume 0.4 mg daily from dietary supplements or fortified foods for the primary prevention of neural tube defects (149).

Potential strategies for increasing folate levels among women are (1) dietary modification, (2) folic acid supplementation, and (3) food fortification (44; 338; 71; 202; 171). Despite various education campaigns, the estimated dietary folate intake for U.S. women averages only 0.2 mg daily, and it was considered impractical to have women systematically increase their intake of folate-rich foods (eg, fruits, leafy green vegetables, and grains) sufficiently to raise daily folate intake to 0.4 mg daily (43). Folic acid supplementation can also be effective, but vitamins are consistently used by less than a third of women of childbearing age, and the remainder do not consider taking vitamin supplements until after they discover that they are pregnant (202). Unfortunately, neural tube defects develop in the fourth week post-conception, ie, before a pregnancy is confirmed. Furthermore, about half of pregnancies are unplanned (125; 117), but even women who plan their pregnancies are poorly compliant with folate supplementation (59; 278; 344; 202). Therefore, an approach relying on supplementation will not prevent most of the folate-preventable cases of neural tube defects. Food fortification, in contrast, can cost-effectively increase folate levels across the population without requiring a change in behavior (261; 337).

Food fortification. In 1996, the U.S. Food and Drug Administration (FDA) selected flour, corn meal, pasta, and rice for mandatory folic acid fortification beginning in January 1998 at a level of 140 mg per 100 g of cereal grain product (114; 116; 113; 115; 171). This was estimated to result in an average adult consumption of approximately 100 mg of folic acid daily from fortified cereal grain products, effectively ensuring that about half of women of reproductive age would receive the recommended 0.4 mg daily from all sources (114; 116; 261). This level of fortification—considered the best possible accommodation between concerns for the fortification of the target population of women of childbearing age and the safety of the much larger no-target population—was expected to prevent many but not all neural tube defects that might be prevented by sufficient maternal folic acid intake. Folic acid fortification was limited to relatively low levels because of a fear that folic acid would correct the hematological abnormality in patients with vitamin B12 deficiency, potentially delaying diagnosis, and allowing progression of central and peripheral nervous system manifestations of vitamin B12 deficiency (260). Many have challenged the logic and ethics of this rationale and the resulting national fortification decisions (339), but levels of fortification remain modest. As a result, dietary modification and folic acid supplementation continue to be necessary and appropriate modes of intervention.

Since 1996, folic acid fortification has produced a significant improvement in population folate status in the United States (153; 173; 143; 337; 99; 196; 253; 45; 248; 171). In 1999, data from the Framingham Offspring Cohort showed that fortification of enriched grain products with folic acid was associated with a substantial improvement in the folate status of the population (153; 253). Similar results were demonstrated in populations enrolled in large managed care plans (173) and in representative samples of women participating in the National Health and Nutrition Examination Survey (NHANES) (41; 248).

By 2001, findings using birth certificate data for live births in 45 states and in the District of Columbia between 1990 and 1999 suggested that a decline of approximately 20% in the prevalence of neural tube defects at birth followed fortification of the U.S. food supply with folic acid (143). A later analysis by the CDC suggested a 27% decline in the average annual proportion of pregnancies affected by neural tube defects after fortification (ie, 1999–2000 compared with 1995–1996) (45a).

Folic acid supplementation has been successful in reducing the prevalence of defects in Hispanic and non-Hispanic white patients but not necessarily in black patients (Medical Task Force on Anencephaly 2000; 308; 118; 346). The fortification of corn masa flour, a food used in Hispanic food preparation, could be useful in further reducing neural tube defects in Hispanics (127; 213).

Similar improvements have been observed in other countries that have adopted this strategy (257; 337; 39; 84; 274). For example, a decrease of 31% has been noted in Chile (39), and a notable decrease has also been observed in Brazil following mandatory supplementation of flour (274). In Canada, the prevalence of neural tube defects decreased by 46% from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full fortification period (84).

Folic acid is also successful in preventing recurrent neural tube defects (336; 256; 308).

Mechanism of folate action in preventing neural tube defects. The physiological effects of folic acid on embryological development are complex and incompletely understood. There is general agreement among several observational studies that folate deficiency, hyperhomocysteinaemia, and homozygosity for the methylenetetrahydrofolate reductase thermolabile variant are probable risk factors for placenta-mediated diseases, such as preeclampsia, spontaneous abortion, and placental abruption (258).

For example, an association between deficiencies in folate level and increased pregnancy loss has been suggested (258), but agreement on this issue is not universal (312). The idea that folic acid supplementation reduces the prevalence of neural tube defects by inducing miscarriage in affected fetuses has been proposed (144; 145; 144; 72) and challenged (29; 126; 277; 258; 20). Available data in humans have not resolved the debate, but studies using mouse models do not support the proposed action of folic acid in encouraging the in utero demise of affected fetuses (ie, "terathanasia") (62). Incidentally, the word "terathanasia" has been introduced and promulgated but is a misnomer; the correct term should be “teratothanasia” (120).

Antifolates: substances that interfere with folate metabolism. A diet rich in folate may lower the risk of neural tube defects, whereas conversely, food substances, toxins, and pharmaceuticals that interfere with folate metabolism may result in an increased risk (181; 37).

Tea catechins. Compounds called catechins in tea have antifolate properties and, for this reason, have been evaluated as potential risk factors for neural tube defects (Lucock and Roach 2005; 222; 221; 224; 223; 226; 05; 271; 272; 270; 303; 13; 294; 268; 267; 351; 358; 357; 307; 363; 327; 353).

The ester bond containing tea polyphenols epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) are potent and specific inhibitors of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (224; 225; 272; 268) and can also downregulate DHFR expression (270). Their slow-binding inhibition of DHFR is thought to be due to formation of a slow dissociation ternary complex by the reaction of nicotinamide adenine dinucleotide phosphate (NADPH) with the enzyme-inhibitor complex (224; 225). Catechins contained in green tea also apparently inhibit the cellular uptake of folic acid (05).

The anti-inflammatory and anti-cancer properties of EGCG are mediated by folate cycle disruption, adenosine release, and NF-kappaB suppression (224; 225; 2007; 2008; 271; 351). EGCG inhibits the growth of a human colon carcinoma cell line in a concentration- and time-dependent manner (224; 225). Rescue experiments using leucovorin and hypoxanthine-thymine medium indicated that EGCG can disturb folate metabolism within cells (224). In addition, EGCG increased the uptake of tritiated thymidine and showed synergy with 5-fluorouracil, whereas its inhibitory action was strengthened after treatment with hypoxanthine, which indicates that EGCG decreases the cellular production of nucleotides, disturbing both DNA and RNA synthesis (224; 225). In addition to its effects on nucleotide biosynthesis, it is linked to a decrease in cellular methylation as a result of folic acid deprivation, and it causes adenosine to be released from the cells because it disrupts purine metabolism (224; 225).

Antiviral activities of EGCG with different modes of action have been demonstrated on diverse families of viruses, including interfering with the replication cycle of DNA viruses (307). Most of these in vitro studies demonstrated antiviral properties within the range of physiological concentrations of EGCG. In contrast, the minimum inhibitory concentrations against bacteria are generally 10- to 100-fold higher than those needed to demonstrate antiviral properties (307).

Nevertheless, EGCG affects the folic acid metabolism of bacteria and fungi by inhibiting the cytoplasmic enzyme DHFR (222; 303; 307). EGCG acts as a bisubstrate inhibitor on bacterial DHFR, with the ability of EGCG to bind to the enzyme both on substrate (DHF) and cofactor (NADPH) sites (303). The catechin EGCG, one of the main constituents of green tea, showed strong antibiotic activity that was attributable to its antifolate activity, which was synergistic with the nonclassical antifolate compound, trimethoprim, and attenuated by including leucovorin in the growth medium (222). Moreover, the tea polyphenol epigallocatechin-3-gallate inhibits ergosterol synthesis by disturbing folic acid metabolism in Candida albicans (221).

Some studies have suggested that higher tea intake during the periconceptional period was associated with an increased risk of neural tube defects (358; 357), but data at present are inconsistent and insufficient to either strongly support or exclude this possibility.

In a human pilot study, green tea extracts lowered serum folates in rats at very high dietary concentrations but did not affect plasma folates (13).

In a health study of pregnant women with singleton pregnancies in Japan, the serum folate levels of the participants with high consumption of green tea or oolong tea were significantly lower than those of others after adjusting for confounding variables, including dietary folate intake and use of folic acid supplements or multivitamins (294).

In a study from China utilizing a population-based surveillance system in northern China during the period 2002 to 2007, 631 neural tube defect cases and 857 controls were included (358). Compared with women who did not drink tea during the periconceptional period, women who drank tea daily had a 3-fold increased risk of having a neural tube defect–affected pregnancy (odds ratio = 3.1; 95% CI = 1.4–7.0). The elevated risk associated with daily tea drinking remained after adjusting for maternal age, educational level, occupation, and periconceptional folic acid supplementation. The association was present for major subtypes of neural tube defects (ie, anencephaly, encephalocele, and spina bifida).

In a subsequent study using data collected in the Slone Epidemiology Center Birth Defects Study from 1976 to 2010, there was no significant overall increased risk for daily tea intake. However, for 1998 and onward, there was a suggestion of a modest increase for those who drank more than 3 cups a day, although this did not reach statistical significance (OR 1.92; 95% CI 0.84–4.38). Among women with total folic acid intake greater than 400 μg, consumption of 3 cups or more of tea per day was associated with an increased risk of spina bifida during the period 1976 to 1988 (OR 2.04; 95% CI 0.69–7.66) and in later periods (OR, 3.13; 95% CI, 0.87–11.33), but none of these were statistically significant.

A systematic review and meta-analysis found that tea consumption in the periconceptional period does not significantly increase the prevalence of neural tube defects (353). Seven articles with nine studies collectively comprised 2834 cases and 19,924 participants. Tea consumption during the periconceptional period did not significantly increase neural tube defect prevalence (OR 1.37; 95% CI 0.96–1.95), a finding that was consistent for three subtypes of neural tube defects: anencephaly (OR 1.36; 95% CI 0.84–2.20), spina bifida (OR 1.51; 95% CI 0.84–2.72), and encephalocele (OR 0.99; 95% CI 0.46–2.15). Furthermore, no dose-response association between tea consumption and the risk of neural tube defects was evident.

Pharmaceuticals. Exposure to folic acid antagonists or "antifolates" (ie, carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim, methotrexate, aminopterin) increases the risk for neural tube defects (137). Women taking antiepileptic drugs are at an increased risk of having offspring with neural tube defects, which is at least partly due to the antifolate properties of many anticonvulsants (109). Folic acid supplementation does reduce, but does not eliminate, the risk of neural tube defects in women taking these drugs (118).

Folate-receptor autoantibodies. A small case-controlled study of women from Brooklyn, New York, found that serum from women with a pregnancy complicated by a neural tube defect contained autoantibodies that bind to folate receptors that can block the cellular uptake of folate (263). However, the presence and titer of maternal folate-receptor autoantibodies in stored frozen blood samples were not significantly associated with a neural tube defect–affected pregnancy in an Irish population (211). A separate smaller case-controlled study using fresh samples produced similar results. A subsequent population-based cohort study utilizing samples obtained from the California Birth Defects Monitoring Program found that high concentrations of IgG or IgM antibodies to folate receptors or folate binding proteins in midgestational serum samples were significantly associated with neural tube defects (30). Therefore, high concentrations of IgG or IgM antibodies to folate receptors or folate-binding proteins are risk factors for neural tube defects.

Folate-resistant neural tube defects. Recurrence of neural tube defects despite high-dose folic acid supplementation suggests that a proportion of neural tube defect cases are "resistant" to folic acid, or at least are not amenable to folate supplementation, and presumably occur by other (possibly genetic) mechanisms (40). Heterogeneity in the etiology of neural tube defects has also been suggested in animal studies, particularly mouse models.

Inositol isomers. Inositol metabolism is associated with neural tube defects, but the mechanisms are not clear (134; 133; 135; 331; 62; 40; 364; 91; 151).

Inositol isomers (particularly myo- and chiro-inositol) can prevent folate-resistant neural tube defects in the curly tail mutant mouse model, suggesting that some cases of human neural tube defects might also benefit from inositol supplementation (40; 91). Specific isoforms of protein kinase C are essential for the prevention of folate-resistant neural tube defects by inositol; specifically, there is an absolute dependence on the activity of PKCbeta and gamma for the prevention of neural tube defects by inositol and partial dependence on PKCzeta (60).

Pregnant women carrying fetuses with neural tube defects have lower concentrations of inositol in their blood than pregnant women not carrying fetuses with neural tube defects (40). Moreover, in pilot studies, periconceptional combination therapy with folic acid and inositol produced normal live births, despite a high recurrence risk for neural tube defects (40). Inositol may be used prophylactically in humans in conjunction with folate supplementation (64; 321).

Valproic acid embryopathy. Valproic acid has been linked to neural tube defects in humans and in various animal models (323; 219; 220; 235; 128; 276; 242; 04; 67; 243; 302; 237; 79; 81; 244; 154; 325; 324; 100; 186; 318; 03; 147; 326; 287; 288; 286; 249; 305). In humans, valproic acid is associated with a 1% to 2% birth prevalence of neural tube defects when taken during the first trimester of pregnancy. A high frequency of neural tube defects following maternal exposure has been demonstrated in mammals (particularly mice) as well as in birds and amphibians (235; 326).

Mouse models. In mouse models, maternal valproic acid treatment reduced the number of live fetuses per litter, impaired fetal growth, and increased the frequency of major malformations, including, most prominently, exencephaly (04).

Maternal valproic acid treatment produced gross metabolic changes in embryos, likely caused by a multiplicity of mechanisms, including the following:

By comparing the effects of maternal exposure to valproic acid and various enantiomers, structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function, branching on carbon atom 2 with two chains containing three carbon atoms each for maximum teratogenic activity (220). Because pharmacokinetic studies demonstrated that the various enantiomers reached the embryo to the same degree, the intrinsic teratogenic activity of the enantiomers differ. Therefore, stereoselective interaction between valproic acid and a chiral structure within the embryo is involved in the mechanism of teratogenicity. In contrast, the anticonvulsant activity of valproic acid and related compounds do not have this property, offering the possibility for development of novel antiepileptic agents with low teratogenic potency.

The peak concentrations of valproic acid, not total dose provided (ie, as indicated by the area under the concentration/time curves), correlated with the teratogenicity of this compound (218).

The valproic acid embryopathy was more common in some mouse strains, indicating that genetic factors moderate the effect of valproic acid (242; 67; 237). In particular, a gene for ribonucleotide reductase subunit R1 conferred sensitivity to valproic acid–induced neural tube defects in mice that specifically targets and disrupts neural tube closure between the prosencephalon and mesencephalon region (future fore/midbrain; neural tube closure site II) (67). Valproic acid also deregulates genes involved in the cell cycle and apoptosis pathways of neural tube cells (237; 324) and upregulates various transcription factors, including Stat3 (signal transducer and activator of transcription 3), a transcription factor that is activated via tyrosine phosphorylation, as well as other transcription factors associated with cell survival and anti-apoptotic mechanisms (287; 288; 286).

Pretreatment with some additional chemicals was demonstrated to be protective against valproic acid–induced neural tube defects in embryos in some mouse models, including folic acid (79), folinic acid (323), vitamin E (04), pantothenic acid (276; 79), and sildenafil (which prolongs nitric oxide signaling) (318). Folic acid and pantothenic acid protect mouse embryos from valproic acid–induced neural tube defects by independent, but not mutually exclusive, mechanisms, both of which may be mediated by the prevention of valproic acid–induced alterations in specific proteins involved in neurulation (79). In addition, spirulina (a biomass of cyanobacteria with purported strong antioxidant effects) is reported to be protective against valproic acid–induced neural tube defects in mice.

In other mouse or chicken models, folate derivatives were not protective against valproic acid–induced neural tube defects (128; 326). Whether this reflects differences in genetic susceptibility alone or a precise sensitivity window is not clear. Strain-dependent susceptibility has been repeatedly demonstrated (128; 243; 302; 305). In another mouse model, prolonged dosing of folic acid was associated with sustained elevation of plasma levels (ie, above control levels) and acceleration of neural tube closure (243). Maintenance of elevated levels was necessary to provide protection against valproic acid–induced neural tube defect development, suggesting that plasma folic acid and B12 must be maintained at high levels throughout organogenesis to protect embryos against valproic acid–induced neural tube defects. Enhanced susceptibility of folate-binding protein-2 (Folbp2) knockout mice to in utero valproic acid exposure was demonstrated for only some dietary folate regimens, indicating "a relatively frail relationship" between that genotype and valproic acid–induced neural tube defects (302).

Other drugs and chemical substances may act synergistically to increase the frequency of neural tube defects in offspring of mice exposed to valproic acid, including methotrexate (96), trimethoprim (97), ethanol (95), and homocysteine (244).

Cell culture models. In cell culture models, exposure to valproic acid significantly increased homologous recombination events and intracellular reactive oxygen species (ROS) levels, and the latter were attenuated by preincubation with polyethylene glycol-conjugated (PEG)-catalase (81). Valproic acid may produce detrimental DNA damage through ROS-mediated double-strand breaks in DNA (81; 324). Although these can be repaired through homologous recombination, the process is error prone; consequently, detrimental genetic changes may occur. Because the developing embryo requires tight regulation of gene expression to develop properly, loss or dysfunction of genes involved in embryonic development through aberrant homologous recombination may ultimately cause neural tube defects.

The valproic acid–induced gene expression response in cultured cells indicates that approximately 30% of the approximately 200 genes known from genetic mouse models to be associated with neural tube defects were altered in embryos of mothers exposed to valproic acid (154). Altered gene expression was demonstrated for other known effects of valproic acid [ie, histone deacetylase inhibition, G(1)-phase cell cycle arrest, induction of apoptosis]. Therefore, combined deregulation of multiple genes is a possible mechanism of valproic acid teratogenicity.

Other risk factors. Overarching reviews of the epidemiology of neural tube defects suggest that a host of interactions, including gene-gene and gene-environment, as well as maternal genetic effects, probably affect the risk of neural tube defects (208; 262).

Obesity and gestational diabetes. In a study conducted in the United States, women at highest risk were young, unmarried, obese smokers who ate few fruits and vegetables and had a low level of education (42). Obesity and gestational diabetes remain risk factors even when adjustments are made for the effects of maternal age, education, ethnicity, vitamin use, and tobacco and alcohol use (09). A lack of periconceptional folic acid is associated with an increased risk for birth defects in women with diabetes mellitus (66).

Women who have undergone gastric bypass are at special risk, perhaps because obesity is a risk factor but also because folates and other vitamins are absorbed less completely following this procedure (209). Clearly, ongoing surveillance is necessary (18).

Parental age. An inverse association was observed between the age of the pregnant women and the occurrence of anencephaly in the Arkhangelskaja Oblast in Russia and in Norway (247). A meta-analysis of neural tube defects and maternal age found that advanced maternal age (ie, greater than 40 years) is also associated with an increased risk for spina bifida and, to a lesser extent, anencephaly, whereas mothers 19 years old or younger have a higher risk of having a child with spina bifida (333).

Paternal age does not appear to be a factor (11).

Occupational and environmental exposures. Further efforts are needed to assess various occupational and environmental exposures, particularly organic solvents, pesticides, and other chemicals used in agriculture, nitrates, heavy metals (eg, mercury), ionizing radiation, byproducts of water purification, and hazardous waste (285; 241; 170; 265). One paper found that paternal exposure to organic solvents is associated with an increased risk for neural tube defects (182). Another found a positive association between maternal exposure to chlorinated solvents in early pregnancy and neural tube defects (86).

Maternal stress. Maternal stress, arising from challenging life events, has been associated with a 2.4-fold increase in risk for women who did not take folate supplements and a 1.4-fold increase in women who did (36).

Although the birth prevalence of anencephaly averages about 1 in 2000 live births, the recurrence risk is 100 times higher (about 1 in 20). Recurrence is higher for syndromic forms than isolated ones (56; 57). Many preventive efforts, therefore, have been directed toward pregnant women who have had a previous child with anencephaly or other neural tube defect.

Socioeconomic status. In the Texas–Mexico border region, an area recognized for an elevated incidence of neural tube defects, women living in poverty are at increased risk for having a baby with craniorachischisis (157).

Women employed in industry or agriculture have a 6.5-fold higher risk of having an anencephalic baby than business or professional women (21). A study identified no association between maternal alcohol consumption and anencephaly (183).

Other potential risk factors. Other risk factors, including low serum B12, high serum homocysteine, diarrhea, stress, fumonisins (environmental toxins produced by Fusarium molds that grow on agricultural commodities in the field or during storage), high nitrate or nitrite intake, and obesity, play a role in the risk for Hispanics living on the Texas–Mexico border (310).

A 2018 study demonstrated an association between a low-carbohydrate diet and anencephaly or spina bifida (87); women with a carbohydrate-restricted diet were 30% more likely to have a baby with one of these defects. A follow-up study confirmed this association, indicating that the increased risk was not due to low folic acid intake (293).

Excess homocysteine may play an independent role in the development of neural tube defects (106; 310).

Prevention

Neural tube defects are amenable to different prevention approaches. Anencephaly, specifically, is amenable to both primary and secondary prevention, whereas less severe forms of neural tube defects are also amenable to tertiary prevention.

Primary prevention. Primary prevention, which aims to prevent neural tube defects before they ever occur for a given woman, can be addressed by increasing periconceptional folate levels through (1) dietary modification, (2) folic acid supplementation, and (3) food fortification. Food fortification has been proven to be the most important and effective approach as it requires no change in behaviors. Moreover, because many women become aware of their pregnancies after the critical period has already begun, food fortification provides a safer background level of folate levels without requiring any active intervention or behavior change. Efforts are underway to monitor the use and efficacy of natural and exogenous forms of folic acid, with the goal of making both available worldwide (232; 233).

The use of both supplemental vitamins and fortified foods (ie, cereals) could contribute significantly to the reduction in neural tube defects (229; 230; 28; 143; 105; 196; 348). However, physicians do not always understand the timing or dosage of folate administration (01).

Several trials worldwide have demonstrated the benefit of folic acid supplementation before and during early pregnancy in reducing the prevalence of first-time neural tube defects by as much as 70%. All women contemplating pregnancy should supplement their diet with 0.4 mg folic acid daily (339; Centers for Disease Control and Prevention 1996; 110), but, at present, only 15% to 25% of folic acid–preventable neural tube defects are being prevented globally (361). Increased intake of additional micronutrients, including betaine (trimethyl glycine), iron, and various vitamins [ie, A (including retinol), B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), C, and E], may also decrease the risk of neural tube defects (53). Women aged 18 to 24 (of all educational levels) are least aware of the need for supplementation (49; 254).

Fortification of foodstuffs alone is insufficient as many women do not maintain protective folic acid levels, a situation further compounded by pregnancy, especially if there is hyperemesis gravidarum; its effects can, for example, be impacted adversely by dieting (50). The need for fortification is ongoing as women seem to be inconsistent in taking folic acid supplements during their childbearing years (46; 167), and making recommendations alone appears to be insufficient for prevention (309). Governing bodies are sometimes slow to develop policies as well (231).

Harmful effects of folic acid supplementation have not been identified (334).

Secondary prevention. Secondary prevention, which aims to reduce the impact of neural tube defects that have already occurred, is accomplished by (1) detecting neural tube defects as soon as possible with prenatal screening and (2) encouraging personal strategies to prevent recurrence with subsequent pregnancies (eg, folate supplementation). Maternal serum and sonographic screening programs can identify most affected pregnancies, allowing parents to make decisions about pregnancy management.

Women who have a neural tube defect or a child with a neural tube defect should take 5 mg of folic acid daily (256).

Tertiary prevention. Tertiary prevention, which aims to lessen the impact of an ongoing illness or injury that has lasting effects, applies only to milder forms of neural tube defects and does not apply to anencephaly.

Differential diagnosis

Confusing conditions

Most infants with anencephaly are easily diagnosed. Whenever cerebral remnants are visible through a defect in calvaria and skin, the diagnosis can be made; however, confusion may still result because infants with extreme microcephaly (ie, atelencephaly or aprosencephaly), microcephaly with an encephalocele covered by thin, nearly transparent fetal skin, or craniocerebral damage resulting from amniotic bands can be mistakenly diagnosed as anencephalic (159).

Iniencephaly. Iniencephaly is a rare, complex, and lethal form of neural tube defect that involves the occiput and inion, producing a characteristic extreme retroflexion of the neck.

Iniencephaly is more common among female infants. The cranium is closed and covered in skin (unlike anencephaly). The neck is severely retroflexed with an upward-looking face. The neck is short or may appear to be missing (due to fusion of cervical and thoracic vertebrae). The spine is usually closed but may be open in the cervical and thoracic regions. Variable features may include hydrocephalus, an occipital encephalocele, and a myelomeningocele or a meningocele.

Iniencephaly may be difficult to diagnose antenatally by ultrasound as it can be confused with other defects involving the brain and spine (eg, anencephaly or craniorachischisis, especially with neck retroflexion). Even postnatally, iniencephaly can be confused with craniorachischisis with spinal retroflexion.

Iniencephaly is a lethal condition. Iniencephaly is often (84%) associated with other findings, including certain chromosomal abnormalities (ie, trisomy 13, trisomy 18, and monosomy X) and other unrelated birth defects (eg, micrognathia, cleft lip and palate, cardiovascular disorders, diaphragmatic hernias, and gastrointestinal malformations).

The aprosencephaly/atelencephaly spectrum. In vertebrates, the forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary brain vesicles during the early development of the nervous system, listed from rostral to caudal. In humans, these divisions are evident by 5 weeks in utero. At the five-vesicle stage, at 8 weeks in utero, the forebrain separates into the diencephalon (thalamus, hypothalamus, subthalamus, and epithalamus) and the telencephalon, which develops into the cerebrum (cerebral cortex, underlying white matter, and basal ganglia).

The aprosencephaly/atelencephaly spectrum includes rare CNS malformations characterized by varying degrees of absence or dysplasia of the derivatives of the prosencephalon (ie, telencephalon and diencephalon), with an intact cranial vault: atelencephaly, in which only the telencephalon is affected, is the less severe form, whereas both the telencephalon and diencephalon are involved in aprosencephaly.

As summarized by Pasquier and colleagues, the aprosencephaly/atelencephaly spectrum

Hence, aprosencephaly is the absence of the forebrain and its derivative structures, atelencephaly is the absence of the telencephalon (leaving only a rudimentary medial diencephalic structure), and holoprosencephaly is a failure of cleavage of the telencephalon so that the embryonic forebrain fails to divide into two lobes. During embryonic development, aprosencephaly is thought to occur after the optic vesicles form but before the cerebral vesicles appear (129). Atelencephaly and aprosencephaly differ from anencephaly in that the cranial vault is covered with skin, cerebral damage probably occurring by means of an encephaloclastic process after closure of the neural tube (298). Aprosencephaly/atelencephaly spectrum disorders are exceedingly rare, with approximately only 20 cases reported.

The amniotic band syndrome. Amniotic band syndrome occurs when the lining of the amniotic sac is damaged during pregnancy. This creates fibrous strands of tissue in which the fetus gets tangled. These strands, called amniotic bands, may wrap around and attach to different parts of the developing body, including the head, causing damage from constriction, distortion, and avulsion or amputation. The signs and symptoms vary greatly depending on the areas of the body involved and may include cleft lip or palate, acalvaria, encephalocele, exencephaly, anencephaly, and even acephaly (169; 148; 38; 328; 152; 122; 360; 54; 58; 264; 104; 199; 165; 322; 76; 77; 283; 359; 356).

Diagnostic workup

Of CNS anomalies diagnosed prenatally, nearly half are neural tube defects (189). Prenatal diagnosis is primarily accomplished by imaging and the finding of an elevated alpha-fetoprotein through screening. When used alone, imaging appears to be more successful in diagnosing neural tube defects than alpha-fetoprotein screening (228). Substantive differences in screening policies still exist worldwide (26). Although these two tests have been generally successful, a significant number of cases are still missed (347).

Ultrasonography. First trimester ultrasonographic diagnosis of anencephaly is possible at routine nuchal translucency examination, as early as 8 to 10 weeks, permitting further workup or termination of pregnancy when desired (158; 185; 163; 295). Anencephaly can be reliably diagnosed at the routine 10- to 14-week ultrasound scan, provided a specific search is made for the sonographic features for this condition (158). First trimester ultrasonography by an expert sonographer with appropriate training, together with the application of a standardized protocol, are essential for a high detection rate of neural tube defects during a scan performed at 11 and 14 weeks (193).

In the first trimester, the pathognomonic feature on ultrasound is acrania, with variably evident disruption or distortion of the developing brain, whereas in the second trimester, the absence of most of the brain is evident in addition to acrania (158). Because ossification of the fetal cranium is not completed until the eleventh week of pregnancy, fetal acrania can only be diagnosed after the eleventh week of pregnancy (158; 112; 07; 313). Between the eleventh and fourteenth weeks of pregnancy, most of the ossification points are found in lateral parts of frontal and parietal bones, whereas calvarium ossification is not yet visible in the mid-sagittal cross-section (313). Therefore, an incorrect diagnosis may occur if the U.S. imagining covers only a sagittal cross-section of the fetal cranium.

A high percentage (89%) of fetuses with acrania have echogenic amniotic fluid; hence, it is used as a supportive marker of fetal acrania in the first trimester (31). The presence of abundant but abnormal brain tissue, observed on ultrasonography, is helpful in distinguishing isolated acrania from more common anencephaly (188).

The main diagnostic 2D-ultrasound features of anencephaly may be characterized by (1) findings of acrania; (2) increased amniotic fluid echogenicity; and (3) the appearance in coronal images of a "Mickey Mouse face" (or a “Mickey-Mouse bi-lobular face") or a “frog face” or “frog eyes” sign (227; 55; 98; 193).

Twin pregnancies. In twin pregnancies, discordant amniotic fluid echotexture may be the first sign of the "acrania-exencephaly-anencephaly sequence" (193).

The "acrania–exencephaly–anencephaly sequence" for secondary anencephaly. Acrania itself can potentially transform into a secondary form of anencephaly (ie, as distinct from primary anencephaly due to failure of closure of the neural tube) through the so-called "acrania–exencephaly–anencephaly sequence" (343; 197; Calcifi and Sepulveda 2003; 123; 14; 193). Cerebral tissue that is not protected by the meninges, cranial bones, and skin may be gradually destroyed due to exposure to the harmful effect of amniotic fluid (eg, increased urea concentration in the amniotic fluid) and mechanical injuries (eg, friction with the uterine wall, placenta, and fetal limbs). Thus, acrania may lead to exencephaly—a lethal disorder of the fetal brain characterized by the absence of the calvarium and various degrees of remaining fetal brain tissue—and then ultimately to secondary anencephaly (Calcifi and Sepulveda 2003; 14).

In cases of the acrania–exencephaly–anencephaly sequence, first trimester ultrasound shows a normal amount of brain tissue visible in the frontal plane of the fetus, resembling the rounded ears of Mickey Mouse—the “Mickey Mouse sign” or “Mickey Mouse face"—a sign typical for exencephaly. In the second trimester, a significant amount of brain tissue disappears, which manifests itself on ultrasonography as the “frog face” or “frog eyes” sign due to a lack of recognizable brain tissue above the fetal orbits—a sign typical for anencephaly (227; 55; 98).

Destroyed brain tissue suspended in small fragments in the amniotic fluid significantly increases the echogenicity of the amniotic fluid in such cases (197; Calcifi and Sepulveda 2003; 123).

In a series of five cases in the acrania–exencephaly–anencephaly sequence, cerebral structures were found on ultrasonography to be enclosed by a thin, inertial rippled membrane with a smooth outer contour (313). A thin anechoic space corresponding to CSF was observed between this membrane and underlying brain structures—the “beret sign." In three cases diagnosed with exencephaly, (1) the calvarium was absent; (2) brain structures had an irregular appearance with an unequal outer contour and remained motionless; and (3) amniotic fluid was anechoic. In two cases diagnosed with anencephaly, (1) the calvarium, meninges, and brain structures were missing and (2) the “frog eyes” sign and slightly echogenic amniotic fluid were visible.

Three-dimensional ultrasonography. Three-dimensional ultrasonography, particularly with the HDlive rendering method, may confirm or further elucidate diagnoses made by 2-dimensional techniques (136; 193; 311; 313). The HDlive rendering method can generate amazingly realistic images of the human fetus from sonographic data using an advanced virtual illumination model and skin rendering techniques with the latest generation of beam-forming technology, speckle reduction algorithms, and compound resolution imaging technologies.

Fetal MRI. Fetal MRI has also been used with success (289; 32) and may be especially helpful in cases where prenatal ultrasound diagnosis is inconclusive (290).

Alpha-fetoprotein. In general, amniotic fluid alpha-fetoprotein is reliable as a screening test for anencephaly at and after 14 weeks. Maternal serum alpha-fetoprotein is most reliable at 16 weeks to 18 weeks. Elevations in maternal serum alpha-fetoprotein occur at the fetal-maternal interface and, therefore, amniotic fluid alpha-fetoprotein is not uniformly elevated in anencephaly. The finding must be evaluated carefully and supplemented with imaging studies, as other factors also result in elevated maternal serum alpha-fetoprotein (eg, gestational age, number of fetuses, maternal weight, race, presence of diabetes, or placental abnormality) (317). The combination of elevated maternal serum alpha-fetoprotein and low estriol appears to be especially predictive of anencephaly (355).

The marginal benefit of alpha-fetoprotein in addition to imaging may be quite low. Consequently, routine measurement of amniotic fluid alpha-fetoprotein during amniocentesis may not be warranted in centers with expertise in targeted ultrasonographic imaging, although medicolegal concerns may preclude substantive change in practice (299).

Postnatal diagnosis of anencephaly. The postnatal diagnosis of anencephaly is made by physical examination. No tests are necessary.

In rare cases, radiography may help further elucidate cranial anomalies. For example, a case of anencephaly with sirenomelia and renal agenesis was diagnosed by prenatal ultrasound, confirmed by postnatal radiography, and diagnosed as axial mesodermal dysplasia syndrome (316). Autopsy may also be helpful in identifying anomalies not discernible by imaging (51; 164).

Management

Management is limited, as most liveborn anencephalics die soon after birth. The median survival time was 55 minutes in one study, although survival of 10 weeks has been reported (251). Comfort care for the affected infant, and parental, and even staff, counseling is necessary (234).

The ethics of transplanting organs from anencephalic infants has long been debated without resolution (204; 200; 245; 207). Families should be counseled regarding this possibility (155), or the opportunity to donate tissue for research. Formal procedures have been established for this purpose (275; 10). Treatment of patients with other neural tube defects is, of course, highly diverse (119). Regardless of the nature of the defect, careful perinatal counseling is indicated (236).

Special considerations

Pregnancy

Pregnancy in mothers carrying anencephalic fetuses is complicated by polyhydramnios, shoulder dystocia, and an increased fetal death rate (234). In cases of discordant monoamniotic twin pregnancy, the anencephalic twin may pose a risk to the survival of the healthy co-twin. In such cases, selective termination has been performed (284). Parents will be expected to sustain considerable grief over the loss of one twin, and benefit from compassionate perinatal palliative care (203).

Anesthesia

Anencephaly is a lethal disorder, and affected individuals are highly unlikely to undergo procedures that would require anesthesia.