Etiology of NTDs and Pregnancies at Increased Risk for NTDs

What causes NTDs and who is at increased risk?

The majority of NTDs are the result of multifactorial inheritance, meaning the combined effect of genetic and environmental factors. Poverty, famine, wars, seasonal variations and dietary preferences have contributed to our recognition that poor quality diets are an important environmental contributor.

One type of genetic factor that has been implicated in multifactorial NTDs is the genetic variants in enzymes used in the homocysteine metabolism cycle, e. g. ^{5 10} methylene tetrahydrofolate reductase (MTHFR). There are considerable population variations in the frequency of the enzyme variants, so their importance as a contributor differs among ethnic groups. In this situation, folic acid supplementation helps improve enzyme function.

Most babies born with an NTD are born to couples with no specific pregnancy, health or genetic concerns.

Family members with close relatives with an NTD are at increased risk for an NTD-affected pregnancy, and this risk is influenced by the population rate of NTDs. Couples with a previous child with an NTD have a 2% to 5% risk for another affected pregnancy, depending on the baseline population risk. Siblings and second degree relatives of an NTD-affected child have a 1% to 2% risk, and third degree relatives have a 0.5% to 1% risk for an affected pregnancy. Among individuals with an NTD, the risk for an NTD-affected pregnancy is 4%, independent of the underlying population risk.

A minority of NTDs result from underlying teratogenic exposures, maternal health problems, genetic disorders, syndromes and chromosomal abnormalities. The proportion due to these causes appears to be increasing as NTDs due to nutritional causes decline, and it is now 20% to 30% of all NTDs. Unfortunately, most of the NTDs due to underlying disorders are not preventable with folic acid.

Teratogenic exposures associated with an increased risk for NTDs include excessive maternal alcohol consumption, antineo-plastic agents, maternal hyperthermia and maternal use of valproic acid, carbamazepine and other anticonvulsants.

Poorly controlled maternal diabetes mellitus is associated with a two to three fold increased risk of all congenital anomalies, including a 1% risk for NTDs. ⁴⁴ Maintaining preconceptional and first trimester diabetic control can substantially reduce but not eliminate this increased risk.

Maternal epilepsy is associated with a 1% to 2% risk for offspring with NTDs and an overall two to three fold increased risk for congenital anomalies in the offspring. This risk is considered to be due to anticonvulsant use, in particular valproic acid and carbamazepine. Genetic factors leading to epilepsy may also predispose offspring to having NTDs.

Independent of quality of diet, women with obesity have an increased risk over the background risk for NTD-affected pregnancy. ⁴⁵-⁴⁷

Low maternal vitamin B12 status has been identified as an independent risk factor for NTDs. ⁴⁸ Maternal disorders leading to B12 deficiency, including pernicious anemia, malabsorption disorders such as celiac sprue, and inflammatory bowel disease, create an increased risk for NTDs. Women who have cultural and dietary preferences that exclude red meat and other sources of vitamin B12 have an increased risk for NTDs not correctable with high dose folic acid.

A number of single gene disorders and syndromes are associated with NTDs. 49 Many of these disorders and the anomalies they cause are not preventable with folic acid. All chromosome disorders, such as Down syndrome and trisomy 13 and 18, are associated with an increased risk of NTDs. Folic acid neither prevents the NTDs nor prevents the chromosome abnormalities.

It is important to determine the underlying etiology of the NTD. The overall prognosis and medical management of an affected individual is altered according to the underlying diagnosis. Additionally, the risk for the parents and other family members of having further children affected with NTDs is dependent on the etiology. In some cases, treatment of maternal health concerns can substantially reduce the risk of another affected pregnancy.

How much folic acid is recommended for women whose pregnancy is at increased risk for NTDs?

Research has demonstrated that among women with a previous NTD-affected pregnancy 4.0 mg per day of folic acid taken in the periconceptional period reduces the recurrence risk by 72%. ⁵⁰

Studies of women with epilepsy who are using carbamazepine and valproic acid suggest that they may benefit from periconceptional use of 4.0 mg folic acid per day. However, the concern remains that these medications are teratogens acting directly on the developing neural tube. The physician may wish to reduce the dosages of anticonvulsants, change to other anti-convulsants or reduce the number of anticonvulsants taken for seizure control, in addition to prescribing high dose folic acid supplements.

Women with diabetes reduce their risk for NTDs by ensuring optimal glycemic control in the periconceptional period. High dose folic acid supplementation may or may not provide added benefit compared with the usual dosage of 0.4 mg folic acid daily.

It is not known whether women with obesity can decrease their risk of NTDs by taking folic acid.

My patient took folic acid as recommended and still had a child with an NTD. What advice should she be given? What about her next pregnancy?

Referral to a medical genetics clinic is recommended for further evaluation prior to a subsequent pregnancy and for counselling regarding prenatal testing. It is recommended that women not use high dose folic acid continuously for a prolonged period of time, because it may contribute to zinc deficiency. Rather, when not planning a pregnancy, a patient who has had a child with an NTD should be advised to take 1.0 mg folic acid daily in a multivitamin-multimineral supplement. When pregnancy planning begins, 4.0 mg folic acid daily should be prescribed, in conjunction with a daily multivitamin. Vitamin B12 status should be evaluated before initiation of this treatment. At the end of the first trimester of pregnancy, the patient should return to the usual dosage of folic acid in pregnancy.

Recurrence of NTDs resulting from genetic, syndromic and chromosomal causes does not appear to be influenced by high dose folic acid supplementation. The evidence for this is anecdotal, coming from case series of NTDs and not from rigorous, controlled intervention trials.

My patient had one child with an NTD, was taking high dose folic acid, and had another child with an NTD - what next?

Unfortunately, some recurrent NTDs are not preventable with high dose folic acid supplementation. In these situations, it is far more likely that there is an underlying disorder causing the NTD. Further investigations are warranted, and the patient should be referred to a medical genetics clinic for evaluation. The baby should be evaluated for underlying disorders and the mother reassessed for possible underlying medical conditions. Mutation testing for MTHFR and enzymes of the homocysteine-methionine metabolism pathway as well as assessment of micronutrients, including vitamin B12 and red cell and serum folate, need to be considered.

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