Neural Tube Defects: Definitions, Key Clinical Findings and Management
WHAT IS IT?
Approximately 3 to 4 weeks after fertilization, the neural plate folds, creating the neural tube. There are multiple factors, environmental as well a genetic, that go in to ensuring a full closure. When this process is not fully completed, neural tube defects (NTD) result. Folic acid supplementation decreases the risk for failed closure. ACOG recommends that folic acid, 400 micrograms, should be offered to all women “capable of becoming pregnant” starting at least 1 month before pregnancy (see ‘Related ObG Topics’ for more on folic acid recommendations).
Types and Definitions
Cranial
Anencephaly
Failure of cephalic fusion
Abnormal clinical findings: Brain | Skull | Skin
Exencephaly
Failure of scalp/skull formation
Abnormal clinical findings: Exteriorization of brain
Encephalocele
Complete failure of skull formation
Abnormal clinical findings: Brain extrusion
Iniencephaly
Failure of cervical/upper thoracic vertebrae closure
Abnormal clinical findings: Exposure of cord and meninges
Lumbosacral most common
Meningocele
Abnormal clinical findings: Exposure of meninges
Spina Bifida Occulta
Vertebral defect without spinal cord or meningeal exposure
Complex – Severe
Holorachischisis
Entire spinal cord exposed
Craniorachischisis
Anencephaly and additional NTD (usually affecting cervical-thoracic region)
KEY POINTS:
Clinical Findings
75% of infants with myelomeningocele survive to early adulthood with modern therapies
CNS
Ventriculomegaly (hydrocephalus)
Can be treated with ventriculoperitoneal shunt placement
Placement often in first year of life, with many requiring revisions
Arnold–Chiari malformation (herniation of the cerebellar tonsils and distal medulla oblongata into the foramen magnum / spinal canal
Risk of severe neurologic morbidity or mortality
Intellectual delay
Intelligence dependent on level/type of the NTD, Arnold-Chiari malformation, hydrocephalus
Ambulation
Ability to walk dependent on level of NTD
L4 level or lower have better function
Bladder function
Myelomeningocele commonly associated with neurogenic bladder
Not related to vertebral defect level
May result in chronic renal dysfunction, with related morbidity and mortality
Bowel function
Most patients with open (no skin covering) NTDs will have bowel dysfunction and fecal incontinence
Note: Approximately 30% of individuals with NTD will have severe, life-threatening latex allergy
Screening and Diagnosis
Elevated MSAFP
Screening test only
Differential diagnosis
Incorrect dating | Multiple Gestation | Fetal demise
≥2.5 MoM (15 to 20 weeks): Detection rates as follows (1to 3% false positive rate)
Anencephaly: >95%
Open NTD: 65% to 80%
Increased risk for adverse events like IUGR and fetal demise
According to the ACOG guideline, with modern ultrasound and recommendation for universal second trimester anatomy exam, MSAFP screening “is less important”
ACMG released an updated guideline on open neural tube defects that includes the role of MSAFP in prenatal care that includes the following points
Since quality ultrasound and prenatal care are not uniform, there is still a role for MSAFP screening
Follow up recommendations for elevated MSAFP are consistent with management guidelines below
It is important to consider a priori risk for NTD that may be elevated due to factors such as
Personal or family history of NTD use | Diabetes | Medications (e.g., valproate)
Ultrasound
2D ultrasound can be considered diagnostic
3D ultrasound not superior for diagnosis but may provide further anatomic detail
Optimal timing: 18 to 22 weeks, but earlier if indicated due to high risk or abnormal MSAFP
First-trimester
NTD can be diagnosed in the first trimester but less sensitive and should not replace standard second trimester ultrasound
Fetal MRI
To be used in conjunction with ultrasonography as indicated, particularly for diagnostic confirmation
MRI should not be used for
Routine NTD screening following ultrasound diagnosis
Primary NTD screening modality
Amniocentesis
Specifically for NTD Diagnosis
Reserve for acetylcholinesterase measurement if closed vs open NTD is inconclusive on ultrasound
ACOG recommends amniocentesis using microarray in the setting of fetal anomalies
Antepartum and Intrapartum Management
Refer to MFM unit with additional multidisciplinary support including genetics, pediatric neurosurgical and neonatology expertise
Outcomes likely superior if delivery occurs in high-risk, tertiary centers
Offer detailed sonography including fetal echocardiography
Individualize counseling
Increased antenatal fetal surveillance is not recommended
Delivery
Plan for term delivery but individualize (e.g., increasing hydrocephalus)
Cesarean section for breech presentation
ACOG states “Because it is not clear whether or how significantly the neurologic outcome is affected by the method of delivery in these infants, decisions about the timing and route of delivery should be made individually in consultation with personnel with experience and knowledge of NTDs”
Fetal Surgery
ACOG recommends that “utero repair is an option for women who meet appropriate criteria… only in an established fetal therapy center”
Benefits
Management of Myelomeningocele Study (MOMS) RCT
Participants
19w0d to 25w6d
Upper border T1-S1 with Arnold–Chiari malformation
12-month follow-up
Results
158 patients
Lower incidence of composite outcome of fetal or neonatal death or need for shunt placement
68% vs 98% | RR, 0.70; 97.7% CI, 0.58 to 0.84
Lower incidence of hindbrain herniation
64% vs 96% | RR, 0.67; 95% CI, 0.56 to 0.81
Higher level of function, two or more levels better than expected, including ambulation without devices or orthotics
No difference in cognitive test scores
Maternal and neonatal risks
Planned cesarean required due to uterine rupture risk
Preterm birth
<35 weeks: 50%
<30 weeks: 11%
Other risks include
PROM | Oligohydramnios | Dehiscence | Transfusion
Endoscopic repair has been reported and may improve outcomes
NICHD Study Update: Does Prenatal Surgery of Myelomeningocele Improve Motor Development Beyond 2 Years Follow-Up?
BACKGROUND AND PURPOSE:
The initial report of the NICHD prenatal myelomeningocele study demonstrated improvement in the following
Decreased hindbrain herniation and consequent need for shunting and improved distal neurologic function
Long-term outcomes have confirmed shunting benefit but data on neurologic and motor function outcomes were lacking
Farmer et al. (Am J Obstet Gynecol., 2018) report the 30-month outcomes for the entire cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele
METHODS:
Follow-up analyses of NICHD sponsored Management of Myelomeningocele Study
Women had been randomly assigned to undergo
Standard postnatal repair
Prenatal repair at <26 weeks gestation
Primary outcome of the study was a composite of mental development and motor function outcome at 30 days
Secondary outcomes
Independent ambulation and the Bayley Sales of Infant Development (2nd edition)
Effects and Subgroups
Fetal leg movements
Ventricle size
Presence of hindbrain herniation
Gender
Location of the myelomeningocele lesion
Within the prenatal surgery group only, these and other baseline parameters were evaluated as predictors of 30-month motor and cognitive outcomes
Researchers also assessed if the presence or absence of a shunt at 1 year was associated with 30-month motor outcomes
RESULTS:
Data from 183 subjects were analyzed
Prenatal repair improved the primary outcome
Composite score of mental development and motor function was 199.4 ± 80.5 vs 166.7 ± 76.7 (P=.004)
Prenatal surgery resulted in improvements in the secondary outcomes of
Independent ambulation (44.8% vs 23.9%, P=.004)
Self-care score (20.8 vs 19.0, P=.006)
Mean Bayley Scales of Infant Development, psychomotor development index (17.3% vs 15.1%, P=.03)
Prenatal surgery did not affect cognitive development at 30 months
Boys demonstrated slightly better improvement in functional level and psychomotor development index
Independent ambulation was associated with
Patients receiving prenatal surgery
The presence of in utero ankle, knee, and hip movement
Absence of a sac over the lesion and a myelomeningocele lesion ≤L3
Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement
CONCLUSION:
The full cohort data of 30-month cognitive development and motor function supported previous findings
Prenatal surgery of myelomeningocele improved motor function, mental development, independent ambulation, self care score
Indicators of independent ambulation were identified including presence of in utero joint movement and absence of sac over the lesion and a lesion ≤L3.
Future research should focus on longer-term follow up to school age
This study did not use fetoscopic methods, which also awaits further research
Primary benefit of fetoscopy would be to avoid requirement for cesarean section
The ACOG / SMFM Committee Opinion states
Open maternal–fetal surgery for myelomeningocele repair has been demonstrated to improve a number of important pediatric outcomes at the expense of procedure-associated maternal and fetal risks.
Women with pregnancies complicated by fetal myelomeningocele who meet established criteria for in utero repair should be counseled in nondirective fashion regarding all management options, including the possibility of open maternal–fetal surgery.
Interested candidates for fetal myelomeningocele repair should be referred for further assessment and consultation to a fetal therapy center that offers this intervention and possesses the expertise, multi-disciplinary team, services, and facilities to provide detailed information regarding maternal–fetal surgery and the intensive care required for patients who choose to undergo open maternal–fetal surgery.
ACOG guidance provides the latest update on neural tube defects (NTDs) including recommendations related to screening, management and delivery. The USPSTF has reaffirmed its recommendation that folic acid supplementation prevents NTDs in offspring. Evidence of potential harms to mother or infant is no greater than small.
PROFESSIONAL RECOMMENDATIONS
USPSTF
All women who are planning or capable of pregnancy should take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid
Approximately 50% of pregnancies in the US are unplanned so it is best to already be on folic acid prior to pregnancy
ACMG
Daily folic acid intake of 400 µg (0.4 mg) is recommended in all women of child-bearing age
If planning pregnancy, start at least 4 weeks prior to planned conception
Women at High risk: 4,000 µg (4 mg) of daily folic acid supplementation at least 12 weeks prior to conception
Then continue with 400 µg (0.4 mg) after 12 weeks gestation
Note: ACMG highlights that folic acid supplementation reduces risk but not entirely prevent NTDs even among women who are fully compliant
ACOG, CDC, AAFP, AAP, Health and Medicine Division of the National Academies (formerly the Institute of Medicine), US Public Health Service, American Academy of Neurology
Women who are capable of becoming pregnant should take at least 0.4 mg (400 µg) of folic acid daily
ACOG, CDC, and several other organizations
Women with a history of neural tube defects, or has a partner with an NTD or a partner who has had a child with an NTD or other high-risk factors take 4 mg (4000 μg) of folic acid daily
Note: While USPSTF focuses on prevention of NTD, other organizations also stress the prevention of other birth defects such as heart defects, urinary tract anomalies and oral facial clefts
High risk factors include the following
Patient has a previously NTD-affected pregnancy
Patient herself is affected
Patient with a first- or second-degree relative with a NTD
NOTE: Folic acid may not prevent NTDs in diabetic pregnancies, especially if not well controlled | Likewise regarding obesity and antiepileptic medications may also be folate-resistant
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