Apparent prevention of neural tube defects by periconceptional vitamin supplementation. 1981.

An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of periconceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1(0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.

Investigation of folate intake and metabolism in women who have had two pregnancies complicated by neural tube defects.

OBJECT: To investigate folate intake and blood levels of folic acid and vitamin C in women with and without a history of two NTD-affected pregnancies and to measure the increase in serum folate following ingestion of orange juice. SUBJECTS: Sixteen women with a history of two NTD-affected infants and 16 controls with no such history, none of whom were either pregnant or taking vitamin supplements. The orange juice loading test was carried out on eight matched pairs. MAIN OUTCOME MEASURES: Dietary intake of folate was assessed by questionnaire and blood levels of folate and vitamin C were measured. RESULTS: There was no evidence of decreased intake of folate in subjects who had had two NTD-affected pregnancies. In controls, both serum and red cell folate showed significant correlation with dietary folate, while in subjects there was no such correlation. Subjects also had smaller increases in serum folate following an oral load than controls, although the differences were not significant. CONCLUSION: Women who have had two NTD-affected pregnancies may have defective folate metabolism. Further investigations on short term utilisation of ingested food folates in these women are required.

Investigation of factors influencing folate status in women who have had a neural tube defect-affected infant.

OBJECTIVE: To investigate folate intake and blood levels of vitamins in women with and without a history of neural tube defect (NTD)-affected infant and to explore the relation between red cell and serum folate in those women. SUBJECTS: Twenty-nine women with a history of NTD-affected infant, who had taken periconceptional vitamin supplements one year or more prior to the study and twenty-nine controls with no such history. MAIN OUTCOME MEASURES: Dietary intake of folate was assessed by questionnaire and blood levels of folate, vitamin B12 and vitamin C were measured. RESULTS: Neither dietary intake of folate nor any of the blood vitamins measured were lower in the women with a history of NTD infant. The majority of women who had received periconceptional vitamin supplementation subsequently had adequate folate intakes and red blood cell folates greater than 160 micrograms/l. Smokers had lower plasma Vitamin C levels than nonsmokers. Multiple regression analysis suggested that the relation between red blood cell (RBC) and serum folate may differ between women with and without a history of NTD. CONCLUSIONS: Women with a history of NTD-affected infants may have different folate metabolism from those who have not.

Uptake and utilization of DL-5-[methyl-14C] tetrahydropteroylmonoglutamate by cultured cytotrophoblasts associated with neural tube defects.

A significant advance in the primary prevention of neural tube defects (NTD) is the recent finding that the periconceptional supplementation with folate has a 72% preventive effect against recurrence of NTD. However, failure of folate supplements to prevent all recurrences supports the multifactorial causation hypothesis, with inherited components exerting their influence, possibly through defects of storage, transport, or metabolism of folate. We have assessed the kinetics of DL-5-[methyl-14C]tetrahydropteroylmonoglutamate ([14C]MTHF) uptake and incorporation into the nucleic acid and protein pools by NTD-associated and control trophoblasts cultured in a medium lacking thymidine and other DNA precursors. We report a significant initial "lag" in the rate of incorporation of 14C label into the nucleic acid pool in NTD-associated trophoblasts. This we attribute to a defect in the de novo pathway of folate metabolism and its associated pathways, including the pathway for methionine synthesis, although the rate of incorporation of 14C label into the protein pool was not significantly different from that of the control cells. We discuss the possible pathways involved in the transfer of the label from the methyl group of [14C]MTHF to the nucleic acid pool, and argue that a slightly (but significantly) reduced rate of uptake into the NTD-associated cells is a reflection of the lag in incorporation into the nucleic acid pool. It is concluded that in the absence of thymidine, most of the NTD-associated trophoblasts require a longer period than controls to adjust to utilization of [14C]MTHF for synthesis of DNA, a period that could be crucial for completion of neural tube embryogenesis. We suggest that these findings could offer a way to a marker for risk of NTD.

Delayed detection of congenital hearing loss in high risk infants.

OBJECTIVE: To examine the methods used to investigate children at high risk of congenital hearing impairment, and to see whether the introduction of evoked response audiometry has reduced the mean age at which hearing loss is identified. DESIGN: Clinicians who notified children to the national congenital rubella surveillance programme were asked retrospectively to complete a questionnaire examining the methods used to identify hearing impairment and the age at testing in two consecutive five year cohorts. The presence or absence of hearing loss was confirmed by obtaining the results of audiometric evaluations and, whenever possible, a recent pure tone audiogram. SETTING: The United Kingdom. PATIENTS: Children notified to the national congenital rubella surveillance programme and born in 1978-87 in whom IgM specific for rubella was detected shortly after birth. MAIN OUTCOME MEASURES: The age at which hearing loss was identified and the degree of loss in decibels at 250, 500, 1000, 2000, and 4000 Hz measured by pure tone audiometry. RESULTS: 61 (52%) Of 117 children born in 1978-82 had a hearing impairment of 40 dB or greater in both ears. The mean loss was 93 dB. In the following five years 75 (47%) of 159 children had impaired hearing, their mean loss being 96 dB. The age at which the hearing loss was confirmed decreased from 11.6 to 9.8 months as a result of earlier auditory evoked response testing. Nevertheless, only eight (13%) of the children with hearing impairment born in 1978-82 and 16 (21%) of those born in 1983-7 had these tests performed in the first six months of life. CONCLUSIONS: Unacceptable delays in identifying hearing loss occurred in this high risk group because of failure to arrange auditory evoked response testing in early infancy. Evoked response audiometry is sensitive and specific and should be undertaken within the first few months of life for all infants known to be at risk of sensorineural hearing loss.

Multiple abnormalities in a child with partial duplications of 10p and 13q from a 3:1 segregation of a maternal t(10;13) translocation.

Partial duplications of 10p and 13q in association with partial deletions of other chromosome segments have been variously reported. We describe here a female child with multiple congenital abnormalities and combined partial duplications of 10p and 13q resulting from a 3:1 segregation of a maternal t(10;13)(p13;q22). In comparing the phenotypic features of the two chromosome imbalances, the expression of features typical of partial duplication 10p appeared more pronounced.

Onset and severity of hearing loss due to congenital rubella infection.

Of 111 children born in 1978-82 with congenital rubella infection, confirmed by the detection of rubella specific IgM shortly after birth, 68 were reported to be hearing impaired when notified to the National Congenital Rubella Surveillance Programme (NCRSP). The average age at which the diagnosis of hearing impairment was confirmed was 11.6 months. Recent audiograms showed a hearing loss that was usually uniform across all frequencies, equal in both ears and severe, averaging 93 dB across the range 250-4000 Hz. Despite the early diagnosis of congenital rubella and the known risk of deafness, only eight of 57 infants had been tested for auditory evoked responses in the first 6 months of life; all eight had severe hearing loss. Evidence of progressive hearing loss was found in only one of the 57 children. Definitive hearing tests (as distinct from screening tests) were frequently delayed until after the first birthday. Newborn babies identified as being at high risk of congenital deafness should have a full audiological assessment in early infancy.