Neural Tube
The neural tube, the early structure that develops into the brain and spinal cord, develops and closes very early in pregnancy – by the 6th week. Failure of this complex process to occur correctly results in one or more neural tube defects (NTDs).
Folic acid supplementation has dramatically reduced the incidences of NTDs but has not eliminated them; NTDs are caused by numerous factors, such as genetics, medication, nutritional deficiencies, and environmental causes. Research is underway to determine additional, specific causes of NTDs and what additional preventative steps may be taken to further reduce risk.
Until then, the widely-held recommendation still stands: the best way to prevent NTDs based on current knowledge is to supplement with folic acid before pregnancy and at least through the first trimester – but ideally the entire pregnancy.
Women should not take any supplements during pregnancy without speaking to their HCP first, and should refer all questions they have regarding the prevention of NTDs to their HCP.
Background
This article overlaps with Folic Acid – Nutrition Section.
The neural tube is the embryonic structure that eventually forms the brain and spinal cord. Its development begins very early in pregnancy, with neural tube closure occurring before some women even realize they are pregnant. If this process does not occur correctly, it can result in one or more neural tube defects (NTDs).
In the United States, NTDs affect 3,000 pregnancies every year, and 700 to 900 pregnancies in the United Kingdom. Globally, it is estimated that approximately 300,000 babies are born each year with an NTD.
The link between folate (natural form of folic acid) deficiency and NTDs was suspected as early as 1964:
Folate plays a very specific role early in pregnancy; fetal growth causes an increase in the total number of rapidly dividing cells, which requires folate. These cells help to create, form, and close the neural tube.
Supplementation of folic acid only works to prevent NTDs before and during the first few weeks of pregnancy.
Docosahexaenoic acid (DHA), an omega-3 fatty acid, may also play a role in neural development as the mother’s DHA levels have been observed to be significantly increased right before neural tube closure. Further, DHA is a major structural fat in the human brain and eyes, representing about 97% of all omega-3 fats in the brain and 93% of all omega-3 fats in the retina.
Neural Tube Development
Neurulation is the process of forming the neural tube, which becomes the brain, spinal cord, and retina, among other structures.
At the beginning of the 5th week of pregnancy, ectoderm (outermost layer of the embryo) thickens to create the neural plate. Note: In embryology, the neural plate, neural groove and the neural tube all refer to the “same” thing, but at different times.
The neural plate rises and caves in to form the neural folds (the first sign of brain development), which creates a neural groove in the middle. At this point, all three main divisions of the brain can be identified. These folds move toward each other, fuse together (creating a tube), then “zip up” in two directions to form and close.
Closure of the neural tube normally begins around 22 days after conception (about 5 weeks, 1 day of pregnancy with a 28-day cycle) and is completed within 4 to 6 days.
By six weeks of pregnancy, the neural tube is [normally] completely closed.
When the neural tube is initially formed, it is hollow with two open holes at each end, called neuropores. The neuropore near the future “head” of the embryo is closed around day 25 after fertilization, while the neuropore near the future lower back completes closure around day 28. It is the closure failure of the “lower back” neuropore that causes spina bifida (“split spine”), which leaves part of the spinal cord exposed.
The neuropore toward the head of the embryo only takes a few hours to close. Failure of this neuropore to close results in a lethal condition called anencephaly, where the baby does not develop parts of the brain and skull.
The failure of the neural tube to close over the entire body is called craniorachischisis, which is the most severe neural tube defect. Babies with this condition have both spinal bifida and anencephaly.
Potential Causes of NTDs/Risk Factors
As described above, the process of neurulation is very complex, involves numerous cell processes, and when disrupted, results in one or more neural tube defects. Due to this complexity, most defects are considered to have more than one cause, such as genetics, nutrition, medications, environmental toxins, etc.
The vast majority of NTDs results from failure of the neural folds to elevate and fuse. In other cases, the folds may have come together, but the fusion process was not completed.
Genetics are believed to play a role in most NTDs. The recurrence risk for siblings of a baby born with an NTD is approximately 50-fold compared to the general population.
A lack of folic acid in the diet can increase the risk for NTDs:
It is possible that compromised DNA synthesis (which occurs in dividing cells) produced by a deficiency in folate (or B12) may increase the embryo's sensitivity to other factors that play a role in NTDs.
It is estimated that folic acid helps prevent up to 70% of NTDs. Folic acid supplementation does not prevent all NTDs because they have more than once cause that folic acid likely has no effect on. Therefore, despite folic acid awareness, NTDs continue to be a leading cause of disease and mortality worldwide.
Low maternal vitamin B12 levels may also significantly increase the risk of NTDs, and evidence of the necessity of B12 is getting stronger.
Vitamin B12 and folate have a strong relationship, and B12 helps maintain folate metabolism. Since folic acid does not prevent all NTDs, it is hypothesized that supplementation of B12 as well as folic acid could reduce risk even further, but this has not yet been formally studied. This may also be critical for those who have a genetic mutation in which they cannot metabolize folate.
Women should not take folic acid or B12 supplementation without talking to their HCP first.
Obesity may be another risk factor. A study published in July 2021 indicated that pregnant women who are considered obese appear to be at significantly higher risk of NTDs, while no significant difference was found in overweight and underweight pregnant women.
Hyperthermia (prolonged heat exposure – opposite of hypothermia) is a strong NTD-causing teratogen in rodents. Further, reports of NTDs following episodes of high fever in pregnant women or extreme sauna usage in early pregnancy suggest it is possible this may also occur in humans.
There are also additional environmental factors assessed to be associated with NTDs, such as various chemicals, certain medications, pollutants, and infections.
Valproic acid, an anticonvulsant medication, causes NTDs in 1% to 2% of pregnancies if taken in early pregnancy, when the neural folds are fusing.
Actions
Women should not take any supplements during pregnancy without speaking to their HCP first, and should refer all questions they have regarding the prevention of NTDs to their HCP.
The worldwide recommendation of folic acid supplementation ranges from 400 to 1,000 micrograms (mcg)/day for all women planning to have a baby and those currently pregnant, and 4,000 to 5,000 mcg/day (4 to 5 milligrams) for women who have had a baby with an NTD, or are at high risk for having a baby with an NTD (read Folic Acid for more information).
Resources
Embryonic Development of the Neural Tube (LifeMap Sciences)
Embryology of Neural Tube Development (American Journal of Medical Genetics)
Neural System Development (UNSW Australia/Embryology; Dr. Mark Hill)