INTRODUCTION — Open neural tube defects (NTDs) are relatively common congenital anomalies that develop when a portion of the neural tube fails to close normally during the third and fourth weeks after conception (the fifth and sixth weeks of gestation). The resulting defect may involve the vertebrae, spinal cord, cranium, and/or brain. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications", section on 'Embryology of the neural tube'.)

Two key advances related to open NTDs have occurred in recent decades:

●Folic acid fortification of commonly consumed foods (eg, bread, flour, cornmeal, rice, pasta) and administration of folic acid supplements have been shown to prevent occurrence/recurrence of most open NTDs.

●Maternal serum and sonographic screening programs have led to identification of most affected pregnancies, allowing parents to make decisions about pregnancy management.

This topic will review prenatal screening and diagnosis of open NTDs, parental counseling, and pregnancy management. Folic acid supplementation for prevention of open NTDs is discussed separately. (See "Folic acid supplementation in pregnancy".)

Pediatric management and prognosis for children with open NTDs are discussed separately. (See "Myelomeningocele (spina bifida): Management and outcome" and "Primary (congenital) encephalocele" and "Anencephaly".)

TYPES OF NEURAL TUBE DEFECTS — NTDs may be open or closed. Open NTDs (defect is only covered by a membrane or, rarely, nothing at all) comprise 80 percent of NTDs; the most common open NTDs are myelomeningocele (spina bifida), meningocele, myelocele, encephalocele, and anencephaly. Open NTDs of the spine can be associated with cerebral ventriculomegaly.

●(See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications".)

●(See "Primary (congenital) encephalocele".)

●(See "Anencephaly".)

Examples of closed NTDs (defect is covered by skin) include lipomyelomeningocele and lipomeningocele. Although covered with skin, closed NTDs may be associated with a tuft of hair, dimple, birthmark, lump, or other skin abnormality at the site of the defect, as well as cerebral ventriculomegaly. Closed NTDs will not be discussed further in this topic, but are reviewed separately. (See "Closed spinal dysraphism: Pathogenesis and types".)

PREVALENCE — The prevalence of open NTDs worldwide is highly variable. In a 2016 systematic review, NTD prevalence medians were: Eastern Mediterranean (21.9 per 10,000 births), Southeast Asia (15.8 per 10,000 births), Africa (11.7 per 10,000 births), Americas (11.5 per 10,000 births), Europe (9.0 per 10,000 births), and Western Pacific (6.9 per 10,000 births) [1]. In the United States, the prevalence was 5.5 per 10,000 live births from 2009 to 2011 [2].

These differences may reflect differences in genetic predisposition as well as environmental factors/application of interventions. Periconceptional folic acid supplementation, food fortification with folic acid, and prenatal screening for open NTDs combined with access to pregnancy termination (83 percent of anencephaly and 63 percent of spina bifida affected pregnancies are terminated [3]) have led to a dramatic decrease in the prevalence of open NTDs at birth where these interventions are applied. (See "Folic acid supplementation in pregnancy", section on 'Evidence of efficacy'.)

Differences in prevalence may also reflect differences in surveillance systems. Prevalence should include all NTD phenotypes and all pregnancy outcomes (live births, stillbirths, and terminations of pregnancy for fetal anomalies) to avoid underestimation [4].

ETIOLOGY — NTDs may result from an underlying abnormality of one or more of the pathways necessary to achieve neural tube closure or from a genetic variant or environmental insult that disrupts the closure process even when the underlying machinery is intact [5].

RISK FACTORS

Folate deficiency — Most isolated NTDs appear to be caused by folate deficiency ("folate sensitive" NTDs), likely in combination with genetic or other environmental risk factors [6].

Folate deficiency may be related to inadequate oral intake, inadequate intestinal absorption, use of folic acid antagonists, or genetic factors causing abnormal folate metabolism. Some folic acid antagonists that have been linked to an increased risk of NTDs include valproic acid, carbamazepine, and methotrexate [7-9]. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of AEDs on the fetus and neonate'.)

Several lines of evidence support the hypothesis of a link between folate and NTDs:

●Randomized trials have consistently shown that folic acid supplementation markedly reduces the incidence of NTDs. (See "Folic acid supplementation in pregnancy", section on 'Evidence of efficacy'.)

●Administration of specific folic acid antagonists increases the risk of NTDs [10].

●Serum and red cell folate concentrations are lower in women carrying a child with an NTD or who had a previous pregnancy with an NTD than in women with unaffected pregnancies [11-13].

●Methylenetetrahydrofolate reductase (MTHFR) is one of the enzymes that regulate the intracellular folate pool for synthesis and methylation of DNA. A common genetic polymorphism (677C->T) reduces its catalytic activity. Both heterozygous CT and homozygous TT genotypes are associated with a low tissue concentration of folate and a "dose" responsive increase in risk of NTDs. In a systematic review, compared with normal controls (CC), the odds of the CT and TT genotypes in patients with NTDs were 1.2 and 1.9, respectively [14]. Mothers with NTD progeny were also more likely to carry the CT and TT genotypes than CC controls (odds ratio [OR] 1.1 and 2.0, respectively).

Genetic factors — Although no specific genes have been identified, genetic factors have been implicated in the pathogenesis of NTDs because NTDs are highly concordant in monozygotic twins as compared with dizygotic twins [15], recur within families (1/20 recurrence risk with one previous affected pregnancy and 1/10 recurrence risk with two affected pregnancies) [16], and are more common in females than in males [17].

Syndromes — Syndromes that may be associated with NTDs include Meckel-Gruber, Roberts, Jarcho-Levin, HARD (hydrocephalus, agyria, and retinal dysplasia), trisomy 13 or 18, and triploidy. Limb-body wall complex, cloacal exstrophy, and OEIS complex (omphalocele, exstrophy of the cloaca, imperforate anus, and spine abnormalities) are also associated with NTDs.

Amniotic bands — Amniotic bands can physically disrupt normal neural tube development, resulting in NTDs. (See "Amniotic band sequence".)

Fever/hyperthermia — Elevation of maternal core temperature from a febrile illness or other source (eg, hot tub, sauna) in the first trimester may be associated with an increased risk of congenital anomalies, especially NTDs, or miscarriage [18,19]. In a 2014 meta-analysis of 46 case-control and cohort studies of the effect of antepartum maternal fever on offspring, maternal fever was associated with increased risks of NTDs (OR 2.90, 95% CI 2.22-3.79, nine studies), congenital heart disease (OR 1.54, 95% CI 1.37-1.74, seven studies), and oral clefts (OR 1.94, 95% CI 1.35-2.79, five studies), but miscarriage rates were not increased [20]. The authors hypothesized that patients may have been recruited too late in pregnancy to identify those with early pregnancy losses given that animal studies and individual studies support an association [19,21].

Carefully performed prospective studies are needed as the studies in this meta-analysis had several limitations. For example, fever was ascertained by maternal self-report in all but one study and included episodes of fever from up to three months before conception. The degree and duration of fever were not consistently reported or accurately determined, and it is known from animal studies that the consequences of hyperthermia depend upon the extent of temperature elevation, its duration, and the stage of development in which it occurs [19,22]. Importantly, fever usually occurs as a response to infection, which necessitates distinguishing the effects of fever from those of an underlying infection and/or its treatment.

The association between hyperthermia and NTDs appears to be weaker for mothers who report consuming the recommended amount of folic acid (≥400 mcg per day: OR 1.8, 95% CI 0.8-4.0) than for mothers with low folic acid intake (<400 mcg per day: OR 4.2, 95% CI 2.2-8.2) [23].

Antipyretic use also seems to attenuate the risks associated with fever exposure [20]. The National Birth Defects Prevention Study (NBDPS) observed that maternal fever from a cold or the flu during early pregnancy was associated with an increased risk for selected birth defects [24] and, among women with infection-related fever, single-agent use of acetaminophen was associated with a statistically significant reduction in NTDs, as well as cleft lip/palate and gastroschisis [25]. The reduction in birth defects should be confirmed in other studies before acetaminophen is recommended to febrile women only for this purpose. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Acetaminophen'.)

Pregestational diabetes — Poorly controlled pregestational diabetes mellitus, inclusive of type 2 diabetes, has been associated with NTDs (table 1) [26-29]. Good periconceptional glucose control is the key factor for prevention of NTDs and other anomalies in these pregnancies, but folic acid also plays a role. A particular challenge is the increased frequency of type 2 diabetes that is unrecognized by the patient before she is screened during pregnancy. (See "Folic acid supplementation in pregnancy", section on 'Preexisting diabetes'.)

Obesity — Obese women have almost a twofold increase in risk of NTDs. This is particularly a concern because of the limitations of fetal imaging as a woman's body mass index increases [30]. Increased supplementation with folate does not appear to decrease the recurrence or occurrence rate related to obesity. (See "Obesity in pregnancy: Complications and maternal management", section on 'Congenital anomalies'.)

Other possible risk factors

●Pesticide exposure – Studies evaluating maternal pesticide exposure have not demonstrated an association between maternal pesticide exposure and NTDs [31]. Studies also have not demonstrated an association between paternal pesticide exposures; however, they do note a weak association when there is a combined maternal and paternal exposure [32].

●Nitrosatable drugs and clomiphene – Associations between use of nitrosatable drugs (eg, metformin, albuterol, paroxetine) and NTDs have been reported [33]. The potential for bias and lack of information about underlying health disorders leading to use of nitrosatable drugs preclude drawing strong conclusions from these studies.

In a meta-analysis, periconceptional exposure to clomiphene citrate was not associated with a clear increase in risk of NTDs (pooled OR 1.21, 95% CI 0.88-1.66 [34]). The inability to assess the independent effects of subfertility precludes drawing strong conclusions from available studies.

●Surveillance data from Botswana have suggested a potential association between maternal dolutegravir use at the time of conception and NTDs in the infant, but the absolute risk remains small [35,36]. In the United States, the NTD prevalence in HIV-exposed pregnancies from 2013 to 2017 was similar to that in the general population [37]. (See "HIV and women", section on 'Individuals of childbearing potential'.)

●A variety of dietary factors other than folate deficiency have been associated with NTDs, but require further study [38].

PRENATAL SCREENING AND DIAGNOSIS

Burden of disease — NTDs result in substantial morbidity and mortality: Anencephaly is almost always lethal in utero or within hours or days of birth; encephalocele is often lethal or results in severe neurologic and cognitive deficits; spina bifida can cause varying degrees of neurologic impairment, depending upon the level of the lesion, and can impair cognitive function, depending upon the presence and degree of associated ventriculomegaly or associated genetic syndrome.

●(See "Anencephaly".)

●(See "Primary (congenital) encephalocele".)

●(See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications".)

Rationale for prenatal screening — Screening and early diagnosis of affected pregnancies allows couples the option of pregnancy termination or an opportunity to prepare for the birth of an affected child. Prenatal detection of an NTD can also inform decisions about the optimal time, route, and site of delivery. (See 'Postdiagnostic fetal evaluation' below.)

Fetal surgery for NTDs has been evaluated in a large randomized trial and is available in certain centers. However, not all fetuses with NTDs are eligible and a balance of benefits and risks, both fetal and maternal, is integral to consideration of this approach. (See 'Consider fetal surgery for myelomeningocele' below.)

Candidates for screening — All pregnant women should be offered screening for NTDs as universal screening identifies the majority of affected pregnancies [39,40] (see 'Screening tests' below). Selective screening based on risk factors performs poorly since 90 to 95 percent of cases occur in pregnancies without any risk factors [41].

In the United States, universal screening is supported by the American College of Obstetricians and Gynecologists (ACOG) [42] and the American College of Medical Genetics and Genomics (ACMG) [43]. These organizations emphasize the need to provide adequate counseling and follow-up services, expertise in high-resolution ultrasound and detection of fetal anomalies, capability for amniocentesis for further fetal evaluation (if needed), and reliable standardized laboratories.

Additional benefits and risks of screening — Screening for NTDs may lead to detection of fetal abnormalities other than NTDs [44,45]. For example, sonographic screening for NTDs may detect other congenital anomalies.

Maternal serum screening may lead to detection of fetuses with congenital nephrosis, some types of abdominal wall defects, and some tumors associated with elevated alpha-fetoprotein levels. (See 'Results and factors affecting interpretation' below.)

The risks of screening include the anxiety associated with positive results and complications associated with postscreening interventions such as invasive procedures, if performed.

Screening tests — The two approaches to NTD screening are ultrasound examination and measurement of maternal serum alpha-fetoprotein (MSAFP).

Choice of test — We suggest ultrasound screening for NTDs as long as high-quality second-trimester fetal ultrasound is available because it appears to detect more NTDs than MSAFP alone [46]. (See 'NTD detection rate' below and 'Ultrasound examination' below.)

When ultrasound screening is performed to detect NTDs, we believe MSAFP screening is not required. However, if optimal images of the fetal spine or intracranial anatomy are not obtained (eg, fetal position or maternal obesity), MSAFP should be performed to improve detection of NTDs.

ACOG states that high-quality, second-trimester fetal anatomy ultrasonography is an appropriate screening test for NTDs where routinely performed for fetal anatomic survey at 18 to 22 weeks [42].

Ultrasound examination — Open NTDs involve the spine, and often the cerebral ventricles and cranium. The diagnostic findings on ultrasound examination are reviewed separately (including multiple graphic images). (See "Neural tube defects: Prenatal sonographic diagnosis".)

Timing — If two ultrasound examinations are planned as part of routine prenatal care in the first half of pregnancy, experts generally suggest performing the first study transvaginally at 12 to 14 weeks of gestation and the second examination transabdominally at 18 to 20 weeks of gestation. If one ultrasound examination is planned, the optimal timing is at 18 to 20 weeks of gestation. This allows for good visualization of anatomy and is sufficiently early to allow completion of prenatal diagnostic procedures (eg, amniocentesis for chromosomal microarray, additional imaging studies) at a gestational age below the limit of viability, the threshold where pregnancy termination is often prohibited. If pregnancy termination is desired, clinicians should be aware of the laws in their state and nearby regions regulating the upper gestational age for termination of pregnancy.

NTD detection rate — First-trimester studies at 12 to 14 weeks of gestation using transvaginal ultrasound generally have reported detection rates >90 percent for anencephaly and 80 percent for encephalocele but lower rates for spina bifida (44 percent). A review of second-trimester ultrasound examination in a high-risk population reported 92 to 95 percent detection of spina bifida and 100 percent detection of anencephaly [47]. Thus, second-trimester ultrasound examination needs to be performed if the first-trimester examination is normal.

Detection of NTDs on ultrasound examination depends in part upon the size and location of the defect, the position of the fetus, the volume of amniotic fluid, maternal habitus (maternal obesity decreases detection rates [30]), and the skill and equipment of the sonographer/sonologist.

Alpha-fetoprotein

Biology — Alpha-fetoprotein is a fetal-specific globulin, synthesized by the fetal yolk sac, gastrointestinal tract, and liver. The function of alpha-fetoprotein is unknown. It may be involved in immunoregulation or may function as an intravascular transport protein.

Alpha-fetoprotein can be measured in maternal serum (MSAFP), amniotic fluid, and fetal plasma. The MSAFP concentration is much lower than that in amniotic fluid or fetal plasma. It rises in early pregnancy, peaks between 28 and 32 weeks of gestation, and then falls. Increasing fetoplacental permeability and advancing gestation may explain the rise in MSAFP that occurs when amniotic fluid and fetal serum concentrations are declining.

AFP is secreted by the fetal kidney into the urine and then excreted into the amniotic fluid. The concentration of amniotic fluid alpha-fetoprotein (AFAFP) is highest early in pregnancy, peaks between 12 and 14 weeks of gestation, then declines until it becomes undetectable at term. AFAFP levels may be measured to aid in the diagnosis of NTDs. (See 'Follow-up of screen positive MSAFP results' below.)

The concentration of fetal plasma alpha-fetoprotein peaks between 10 and 13 weeks of gestation, then declines exponentially from 14 to 32 weeks, and falls even more dramatically near term [48]. The fall in alpha-fetoprotein can be explained by both decreased fetal synthesis and a dilution effect due to increasing fetal blood volume. There is no clinical role for measurement of alpha-fetoprotein in fetal plasma.

Results and factors affecting interpretation — Results are expressed as multiples of the median (MoM) for each gestational week because these values are easy to derive, stable, and allow for interlaboratory variation. A value ≥2.0 or 2.5 MoM is considered an abnormal result, depending upon the laboratory's preference for balancing the detection and false-positive rates in their population.

Many factors influence the correct interpretation of MSAFP results:

●Gestational age – Knowledge of accurate gestational age is critical to interpretation of MSAFP. An incorrect gestational age will falsely raise or lower the reported MoM, since it is based upon gestational age. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)

●Maternal weight – Maternal weight affects MSAFP screening because of dilution of alpha-fetoprotein in the larger blood volume of heavier women. Correction for maternal weight increases the detection rate for NTDs [49]. Maternal weight should be measured and reported to the MSAFP laboratory on the day of testing.

●Diabetes mellitus – The prevalence of NTDs is higher in women with pregestational diabetes mellitus. The MSAFP level for women with type 1 diabetes is 15 percent lower than in nondiabetic women. For these reasons, there is a lower threshold MSAFP value (eg, approximately 1.5 MoM) to obtain the same sensitivity of detection of NTDs as in nondiabetic women. MSAFP levels for women with type 2 diabetes are also lower, although the data in this setting are more limited [50]. The presence of maternal diabetes should always be noted on the MSAFP laboratory requisition.

●Fetal anomalies – Non-NTD fetal defects can be associated with an elevated MSAFP. There is direct correlation between the degree of MSAFP elevation and the frequency of anomalies. In one study, the risk was 3 percent at a level of 2.5 MoMs and 40 percent at a level >7.0 MoMs [51].

Abdominal wall defects are commonly associated with elevated MSAFP levels. One representative series reported MSAFP was raised in 89 percent of fetuses with omphalocele and in 100 percent of fetuses with gastroschisis [52]. Fetal congenital nephrosis, teratomas, benign obstructive uropathy, and fetal anemia can also be associated with elevated MSAFP levels. (See "Congenital and infantile nephrotic syndrome" and "Gastroschisis" and "Omphalocele: Prenatal diagnosis and pregnancy management".)

●Multiple gestation – The concentration of MSAFP is proportional to the number of fetuses; thus, the upper limit for a twin pregnancy is twice (eg, 4 to 5 MoMs) that of a singleton gestation. Multiple gestations are also at slightly increased risk for NTDs.

●Race – The MSAFP level is 10 to 20 percent higher in Black women. Thus, an adjustment based upon race should be made by the laboratory when calculating MSAFP results. The risk of NTDs in the pregnancies of Black women is approximately half that for White women; some laboratories use a higher cutoff in Black women (2.5 MoMs versus 2.0 MoMs in White women) to keep the risk for those women with positive results similar [53]. However, this would reduce both detection and false-positive rates.

●Fetal viability – Fetal death raises the MSAFP value. This is not of diagnostic concern except in cases of multiple gestation with death of one fetus. MSAFP results are not interpretable in this situation.

Timing of blood test — Serum screening (MSAFP) is performed ideally at 16 to 18 weeks of gestation but can be performed as early as 15 weeks or as late as 20 weeks [43]. First-trimester serum screening is not recommended because of low sensitivity [54-58].

NTD detection rate — ACMG reported the detection rate for anencephaly is ≥95 percent at 2.0 or 2.5 MoMs [53]. For open spina bifida, the detection rate at 2.0 MoMs is 75 to 90 percent versus 65 to 80 percent at 2.5 MoMs, with false-positive rates of 2 to 5 percent and 1 to 3 percent, respectively.

A 2009 meta-analysis of effectiveness of prenatal serum biomarker screening for NTDs reported overall sensitivity and specificity of 75.1 and 97.7 percent, respectively, and a false-positive rate of 2.2 percent and false-negative rate of 24.9 percent (22 studies, n = 684,112 women) [40].

Follow-up of screen positive MSAFP results — An ultrasound examination is performed to further assess whether an NTD or another anomaly associated with elevated MSAFP levels is present, as well as to confirm gestational age, fetal viability, and number of fetuses. All of these factors can affect interpretation of MSAFP results. (See 'Ultrasound examination' above and 'Results and factors affecting interpretation' above.)

Routinely performing amniotic fluid tests to detect NTDs is not cost-effective if ultrasound shows an NTD or ventral wall defect given the accuracy of high-resolution ultrasound examination [59,60]. If ultrasound findings are uncertain or show an apparently normal fetus after a screen-positive MSAFP result, genetic counseling and further evaluation via amniocentesis are usually indicated.

AFAFP and amniotic fluid acetylcholinesterase (AChE) are the primary biochemical tests performed on amniotic fluid for detection of NTDs. AChE is an enzyme contained in blood cells, muscle, and nerve tissue. An elevation of both AFAFP and AChE values suggests a fetal NTD with 96 percent accuracy; false-positive rates of 0.08 and 0.14 percent have been reported [61,62]. Blood contamination of the amniotic fluid sample is responsible for one-half of false-positive AChE results.

An unexplained elevated MSAFP may be a marker for pregnancies at increased risk of some complications (eg, early fetal demise, fetal growth restriction, preeclampsia); however, the predictive value of MSAFP alone is low, and there is no evidence that more intensive fetal and maternal monitoring in otherwise normal pregnancies will improve outcome [63].

PARENTAL COUNSELING AND REFERRALS — After sonographic diagnosis of an NTD, parents are faced with the choice of preparing for the birth of an affected child or pregnancy termination. Additional fetal evaluation to detect associated anatomic or chromosomal abnormalities; referral to a spina bifida clinic to discuss possible fetal interventions, postnatal management, and prognosis; and facilitating a connection with other parents of affected children to discuss what to expect for their child and family can help them make this decision. (See "Myelomeningocele (spina bifida): Management and outcome", section on 'Prenatal counseling and choice of management'.)

Prolonged exposure of neural tissue to neurotoxic amniotic fluid, microtrauma at the level of the exposed neural elements, and continuous leakage of cerebrospinal fluid may result in progressive development of fetal hydrocephalus and loss of nerve function. Postnatally, this can result in musculoskeletal weakness and bowel and genitourinary dysfunction. In utero determination of the upper anatomic level of the spinal defect (L1, L2, L3, L4, L5, S1) and fetal motor activity allow some prediction of postnatal motor dysfunction; however, motor function will be accurately predicted by imaging in only 25 percent of infants, approximately 20 percent will perform one or more levels better than predicted, and approximately 50 percent will perform one or more levels worse than predicted [64]. This is because ultrasound assessment of lesion level is not always accurate [65], and more importantly, NTD is a heterogeneous group of conditions with outcomes depending on several factors in addition to lesion level, such as whether a sac is present, the role of a teratogenic agent and that agent's other effects (increased NTD with high body mass index, high glycemic levels with diabetes, etc), and whether there is an underlying genetic etiology (not necessarily syndromic but detectable by sequencing).

POSTDIAGNOSTIC FETAL EVALUATION

Screen for associated anomalies — A complete fetal anatomic survey should be performed to look for associated anomalies, which occurred in 20 percent of the cases in one large series [66]. Oral clefts and malformations in the musculoskeletal, renal, and cardiovascular systems were the most common associated anomalies.

Offer chromosomal microarray — Fetuses with NTDs are at increased risk of chromosomal abnormalities, especially if other anomalies are present [67-73]. As an example, a study evaluating the frequency of karyotype abnormalities in 200 fetuses with NTDs reported the overall frequency of chromosomal abnormalities was 6.5 percent, but was 2.4 percent in those with a referral diagnosis of isolated NTD and 27 percent in those with an NTD plus associated anomalies [67].

Fetal genetic testing is appropriate if this information will affect pregnancy management. Although many NTDs are associated with genetic abnormalities that would be detected by a conventional G-banded karyotype, microarray has become the preferred genetic test when structural abnormalities are identified given the additional yield of pathogenic subchromosomal copy number variations. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

If prenatal findings will not impact pregnancy or newborn management, postnatal genetic testing can be performed for diagnostic evaluation and recurrence risk counseling.

Role of gene sequencing — We suggest prenatal sequencing only in collaboration with a prenatal diagnostic program with expertise in genomic testing and interpretation of genomic data. Gene sequencing, and in particular exome sequencing, is increasingly being utilized in prenatal clinics. Two large studies indicate that the presence of a structural anomaly confers an approximate 6 to 10 percent risk of a pathogenic variant in the fetus's gene sequence [74,75]. Prenatal clinical exome sequencing, such as is used in the neonatal care unit and pediatric setting, is likely to become available.

Interpretation of the results requires close collaboration between the imaging provider, laboratory, and geneticist. Variants of unknown significance remain a diagnostic challenge, especially in the prenatal setting, where time to results is critical and a detailed phenotype is impeded by the in utero status.

Consider fetal magnetic resonance imaging — Magnetic resonance imaging (MRI) is not performed routinely but may be done in selected cases, such as to confirm uncertain ultrasound findings and exclude/detect central nervous system and other abnormalities when this information will affect pregnancy management. In particular, confirming the absence of additional major structural anomalies is one of the key factors in determining whether the second-trimester fetus is an appropriate candidate for in utero fetal surgery. (See 'Consider fetal surgery for myelomeningocele' below.)

MRI is also sometimes performed to better define the level of the NTD, although this does not correlate well with postnatal motor function) [76]. (See 'Parental counseling and referrals' above.)

In a study that evaluated the role of MRI in 19 fetuses with ultrasound findings suspicious for NTDs and in whom the ultrasound examination was deemed to be inadequate, fetal MRI correctly ruled out the ultrasound diagnosis of cephalocele in one fetus with oligohydramnios and documented an NTD in the other 18 fetuses [77]. Fetal MRI also detected new findings unsuspected at ultrasound that changed the ultrasound diagnosis in 3 of the 19 cases and detected previously occult findings that caused a minor change in the classification of the anomaly in 5 of the 19 cases. MRI did not influence the ultrasound diagnosis in the other 11 of 19 fetuses.

PREGNANCY MANAGEMENT

Consider fetal surgery for myelomeningocele — Fetal surgery for myelomeningocele can arrest leakage of spinal fluid from the back and might, therefore, prevent or reverse herniation of the hindbrain (Chiari II malformation) and hydrocephalus and their sequelae. It is a complex procedure that should be performed at a fetal surgery center with the requisite expertise [78]. Several such specialized centers exist across North America and Europe [79].

This option should be discussed with the patient when there is an isolated myelomeningocele in an otherwise uncomplicated singleton pregnancy with a normal microarray and no additional major structural anomalies [80]. It is generally performed between 19 and 26 weeks of gestation. Risks include preterm birth, chorioamnionitis, chorion-amnion separation, spontaneous membrane rupture (PROM), oligohydramnios, placental abruption, pulmonary edema, maternal bleeding, maternal transfusion, increased incidence of uterine thinning/dehiscence of the uterine scar during current and subsequent pregnancies, and need for cesarean delivery with all future deliveries.

●Types of fetal procedures and complications

•Risk for uterine rupture – Many centers perform the procedure via hysterotomy, which increases the risk of uterine rupture. Investigational work in minimally invasive in utero repairs is ongoing, with approaches including water-tight sealants for adherence of patches, fetoscopic repairs, and the use of umbilical cord grafts. Minimally invasive second-trimester fetoscopic repair through two or three uterine ports rather than hysterotomy allows patients to give birth vaginally, does not appear to increase the risk of uterine rupture or dehiscence, and results in similar offspring outcomes at 12 months of age [81].

In a 2019 systematic review, the frequency of maternal complications after 779 open repairs and 268 fetoscopic repairs ranged from 11.5 to 12.5 percent, and the only four uterine ruptures occurred after open repair [82]. The number of patients who underwent a trial of labor was not reported. In this study, PROM, chorionic membrane separation, preterm labor, and preterm delivery were not considered to be maternal complications.

A subsequent study of 52 pregnancies that underwent an open repair in a previous pregnancy and were over 20 weeks of gestation in the subsequent pregnancy reported uterine rupture in five (9.6 percent) at a median gestational age of 33 weeks (range 26.0 to 36.8 weeks); two of the five cases resulted in fetal death [83]. Nine women (17.3 percent) had uterine dehiscence at cesarean delivery. Additional maternal complications at delivery included one woman with placenta previa, one woman with placenta accreta, and four women requiring transfusion. (See "Myelomeningocele (spina bifida): Management and outcome", section on 'Fetal surgery'.)

•Other risks – Minimally invasive fetoscopic repair appears to cause less maternal hemodynamic change than open fetal surgery, which is important since the hemodynamic stability of the fetus depends on the hemodynamic stability of the mother [84,85]. Fetal bradycardia during surgery also appears to be related to excessive uterine manipulation and umbilical cord compression, which are more common during open compared with minimally invasive fetal surgery. (See "Myelomeningocele (spina bifida): Management and outcome", section on 'Fetal surgery'.)

●Delivery after repair – Given a lack of data showing harm, patients and providers may reasonably consider a trial of labor after fetoscopic (not open) repair. The impact of induction on maternal risks following fetoscopic NTD repair has not been separately considered.

A prudent approach in women undergoing a trial of labor is to manage labor similarly to that in women undergoing a trial of labor after a previous cesarean delivery. If a cesarean delivery is planned, it should be scheduled for 39+0 weeks. (See "Trial of labor after cesarean birth: Intrapartum management".)

All women who undergo an open repair should also undergo an early term (37+0 to 38+6 weeks) or late preterm (34+0 to 36+6 weeks) scheduled cesarean delivery because of the high risk of rupture, especially during labor. The timing of delivery within this range depends upon patient specific factors. For example, if the patient is having worrisome uterine activity, we would deliver earlier rather than later.

●Postnatal outcome – Fetal surgery appears to decrease the need for postnatal shunting and improve motor development and function [86-92]. Postnatal outcome is discussed in more detail separately. (See "Myelomeningocele (spina bifida): Management and outcome", section on 'Fetal surgery'.)

Fetal surveillance

●Serial ultrasound examinations to assess the size of the fetal head, appearance of associated Chiari malformation, the size of the ventricles, and the size of the NTD can inform delivery planning of potentially viable neonates [93]. The optimum frequency is unclear, but monthly examinations until delivery are reasonable.

While marked ventriculomegaly is not common with NTD, when the biparietal diameter is >99 percent, then a vaginal delivery would be contraindicated and discussion of a classical cesarean is appropriate.

●For fetuses who underwent in utero repair of the NTD, follow-up imaging (ultrasound, magnetic resonance imaging) is guided by the protocol of the center that performed the procedure.

●Because fetuses with major congenital anomalies appear to be at increased risk of stillbirth [94], some clinicians, including the authors, monitor pregnancies with NTDs with nonstress tests or biophysical profiles in the third trimester. No evidence is available to support or refute the value of this approach. (See "Overview of antepartum fetal assessment".)

Delivery

Myelomeningocele

Preparation — For infants with a prenatal diagnosis of myelomeningocele, delivery should occur at a center with a level III or above neonatal intensive care unit, pediatric neurosurgery services, and other personnel experienced in the neonatal management of these infants. Ideally, latex-free gloves and equipment are used during delivery and subsequent care of the infant because individuals with myelomeningocele are at risk for developing life-threatening latex allergy later in life [95,96].

Timing — Term delivery is preferable to minimize prematurity-related morbidity. If in utero surgery with transfundal surgical repair of the NTD was performed, early term or late preterm cesarean delivery is indicated because of the increased risk of uterine rupture during labor. In our practice, this is often determined by whether the woman is experiencing late preterm ongoing contractions.

Route — Fetuses presenting in the breech position are typically delivered by cesarean. No randomized trials have been performed to determine the risks and benefits of labor and vaginal delivery for cephalic-presenting infants in the absence of standard indications for cesarean delivery. Although the first retrospective study to evaluate motor outcome by route of delivery reported a benefit from prelabor cesarean delivery [97], the body of data from subsequent observational studies has not confirmed this association.

●In a 2019 meta-analysis of nine studies (one prospective and eight retrospective cohort studies, n = 672 women) comparing vaginal and cesarean delivery in women who did not undergo fetal repair of NTDs, the motor-anatomic level in offspring was similar for both groups (mean difference -0.10, 95% CI -0.58 to 0.38), and the vaginal delivery group was less likely to require a shunt or have sac disruption (odds ratio [OR] 0.37, 95% CI 0.14-0.95 and OR 0.46, 95% CI 0.23-0.90, respectively) [98]. Prelabor cesarean was associated with a nonstatistically significant trend toward improved ambulation in toddlers compared with exposure to labor (ie, vaginal delivery or intrapartum cesarean [ambulation, independent or with assistance, at age two years with prelabor cesarean: OR 2.13, 95% CI 0.35-13.12]).

●In a subsequent retrospective study including nearly 2000 nonsyndromic, liveborn neonates with spina bifida, cesarean delivery was not associated with a significant reduction in risk of infant death (cesarean versus vaginal delivery: hazard ratio [HR] for death before 29 days 0.77, 95% CI 0.49-1.21 and HR for death before 365 days 0.93, 95% CI 0.63-1.38, respectively) [99].

In the absence of data establishing a benefit of prelabor cesarean delivery for fetuses with myelomeningocele, we believe vaginal delivery is reasonable if the head is near normal size, the meningocele is unlikely to cause dystocia, and there are no obstetric indications for cesarean. Cesarean delivery is indicated in cases in which the head circumference (HC) is increased and vaginal delivery is thought not to be possible because of dystocia. The cutoff for determining when a cesarean delivery is indicated will vary with gestational age at delivery, the absolute and relative HC, and the size of the maternal pelvis. We believe that abdominal delivery to avoid cephalopelvic disproportion is reasonable when the HC is >40 cm or the biparietal diameter is ≥12 cm. Pelvimetry is unlikely to be of benefit and is generally not used in this setting.

Anencephaly — Most anencephalic fetuses are stillborn or die shortly after birth, but some infants have been reported to survive as long as 28 days [100,101]. Given this poor prognosis, most pregnancies are terminated or induced shortly after diagnosis; cesarean delivery would only be performed for maternal indications [102,103].

In ongoing pregnancies, preterm labor and delivery may occur from uterine overdistention due to polyhydramnios or the pregnancy may extend postterm because absence of fetal brain precludes normal pathways in the fetus' initiation of labor [104]. Anencephalic infants are not good candidates for organ donation. (See "Anencephaly", section on 'Management'.)

Encephalocele — No data are available on outcomes with vaginal versus cesarean delivery. The mode of delivery should take into account the postnatal prognosis. For viable infants, vaginal delivery may be safe if the lesion is relatively small and appears unlikely to cause dystocia or become traumatized, whereas cesarean delivery is prudent if the encephalocele is large. These are subjective clinical judgments based on discussion among the obstetric providers, parents, neonatologists, and pediatric neurosurgeons.

RECURRENCE RISK

●The risk of recurrence for isolated NTDs is approximately 2 to 4 percent with one affected sibling [105-109]. With two affected siblings, the risk is approximately 10 percent [110].

●The risk of NTD according to family history is shown in the table (table 2). The risk of recurrence appears to be higher in countries such as Ireland where the occurrence (prevalence) of NTDs is high [111]. Recurrence is likely related to a multifactorial inheritance pattern, including genetic and environmental risk factors.

●The recurrence risk for anencephaly is estimated at 2 to 5 percent [112].

●Isolated encephaloceles are not familial; however, encephaloceles may be part of specific genetic syndromes if there are associated anomalies; the inheritance pattern is autosomal recessive in these cases. As an example, the risk of recurrence for an encephalocele with Meckel-Gruber syndrome (posterior encephalocele, cleft palate, and polydactyly) is 25 percent in cases with known autosomal recessive inheritance.

PREVENTION — Supplemental folic acid is a safe and effective treatment for prevention of NTDs. Doses and administration are described in detail separately. (See "Folic acid supplementation in pregnancy".)

Testing for MTHFR polymorphisms is not recommended as routine folic acid supplementation at 0.4 mg/day will adequately increase red cell and serum folate concentrations whether or not the woman has a polymorphism. (See "Folic acid supplementation in pregnancy", section on 'Other populations (obesity, MTHFR polymorphism)'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal screening and diagnosis" and "Society guideline links: Congenital malformations of the central nervous system".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Spina bifida (myelomeningocele) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Open neural tube defects (NTDs) are those in which the defect is only covered by a membrane or, rarely, nothing at all. Open NTDs comprise 80 percent of NTDs; the most common open NTDs are myelomeningocele (spina bifida), meningocele, encephalocele, and anencephaly. (See 'Types of neural tube defects' above.)

●Most isolated open NTDs appear to be caused by folate deficiency, likely in combination with genetic or other environmental risk factors. (See 'Folate deficiency' above.)

●Open NTDs have also been associated with some fetal syndromes, amniotic band sequence, hyperthermia in early pregnancy, pregestational diabetes (including type 2), and obesity. (See 'Risk factors' above.)

●All pregnant women should be offered screening for open NTDs. Screening and early diagnosis of affected pregnancies allow couples the option of pregnancy termination or an opportunity to prepare for the birth of an affected child. Fetal surgery may be an option in some cases. (See 'Candidates for screening' above and 'Rationale for prenatal screening' above.)

●We perform ultrasound screening for NTDs (ideally at 18 to 20 weeks) because it appears to detect more open NTDs than maternal serum alpha-fetoprotein (MSAFP) screening. If optimal images of the fetal spine or intracranial anatomy are not obtained (eg, fetal position or maternal obesity) or high quality ultrasound examination is unavailable, MSAFP screening should be offered. (See 'Choice of test' above and 'Ultrasound examination' above.)

●For MSAFP screening, the American College of Medical Genetics and Genomics reports the detection rate for anencephaly is ≥95 percent at 2.0 or 2.5 multiples of the median (MoMs). For open spina bifida, the detection rate at 2.0 MoMs is 75 to 90 percent versus 65 to 80 percent at 2.5 MoMs, with false-positive rates of 2 to 5 percent and 1 to 3 percent, respectively. (See 'NTD detection rate' above.)

●In women with an elevated MSAFP, an ultrasound examination is performed to further assess whether an open NTD or another anomaly associated with elevated MSAFP levels is present, as well as to confirm gestational age, fetal viability, and number of fetuses. (See 'Follow-up of screen positive MSAFP results' above.)

●In a high-risk population, ultrasound examination has been reported to detect 92 to 95 percent of spina bifida and 100 percent of anencephaly. Detection of NTDs on ultrasound examination depends upon the size and location of the defect, the position of the fetus, the volume of amniotic fluid, maternal habitus (maternal obesity decreases detection rates), and the skill and equipment of the sonographer/sonologist. (See 'Ultrasound examination' above.)

●When an NTD is detected on ultrasound examination, the obstetric provider should (see 'Postdiagnostic fetal evaluation' above and 'Parental counseling and referrals' above):

•Document for presence or absence of associated fetal abnormalities, including magnetic resonance imaging when needed to confirm uncertain ultrasound findings or better define the level of the open NTD, and to exclude/detect central nervous system abnormalities when this information will affect pregnancy management.

•Offer microarray because of the increased incidence of chromosomal abnormalities. Gene sequencing remains investigational.

•Discuss reproductive options: pregnancy termination or continuation.

•Refer parents to a spina bifida clinic to discuss postnatal management, possible interventions, and prognosis. Also facilitate a connection with other parents of affected children.

•Discuss possible referral for fetal surgery for myelomeningocele, which is performed in highly selected cases (euploid fetuses between 19 and 26 weeks of gestation without additional abnormalities) in a few specialized centers. (See 'Consider fetal surgery for myelomeningocele' above.)

●Serial ultrasound examinations are performed to assess the size of the fetal head, appearance of associated Chiari malformation, and the size of the ventricles. This information can inform delivery planning if marked head enlargement is present. The optimum frequency is unclear, but monthly examinations until delivery are reasonable. We also obtain nonstress tests in the third trimester. (See 'Fetal surveillance' above.)

●Delivery should occur at term at a center with a level III or above neonatal intensive care unit, pediatric neurosurgery services, and other personnel experienced in the neonatal management of these infants. Ideally, latex-free gloves and equipment are used during delivery and subsequent care of the infant. (See 'Myelomeningocele' above.)

●Because no study has definitively shown advantages of cesarean delivery for fetuses with myelomeningocele, we believe vaginal delivery is reasonable if the head is near normal size, the meningocele is unlikely to cause dystocia, and there are no obstetric indications for cesarean. Cesarean delivery is indicated in cases in which the head circumference (HC) is increased and vaginal delivery is thought not to be possible because of dystocia. The cutoff for determining when a cesarean delivery is indicated will vary with gestational age at delivery, the absolute and relative HC and the size of the maternal pelvis. Abdominal delivery to avoid cephalopelvic disproportion is reasonable when the HC is >40 cm or the biparietal diameter is ≥12 cm. (See 'Myelomeningocele' above.)

●The risk of recurrent open NTDs according to family history is illustrated in the table (table 2). (See 'Recurrence risk' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Lauri Hochberg, MD, and Joanne Stone, MD, who contributed to an earlier version of this topic review.