R. W. Smithells

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

Abstract Objectives To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects. Design Retrospective cohort study of births monitored by birth defect registries. Setting 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review. Main outcome measures Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable). Results The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects. Conclusions Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

Maternal nutrition in early pregnancy.

1. Mean daily nutrient intakes of 195 women in the first trimester of pregnancy were assessed by weighed dietary records. 2. In comparsion with recommended intakes for non-pregnant women aged 18-55 years (Department of Health and Social Security, 1969), more than two-thirds of the subjects were having insufficient energy, iron and cholecalciferol. Unsatisfactory intakes of other nutrients were not uncommon. In relation to recommended intakes for the second trimester (Department of Health and Social Security, 1969), all mothers were having insufficient cholecalciferol and more than 80% of mothers had unsatisfactory intakes of energy and Fe. 3. Intakes appreciably lower than those recommended were associated with the following factors: social classes III, IV and V; maternal age under 20 years; smoking ten or more cigarettes daily; vomiting on more than 3 d/week.

The effect of periconceptional supplementation on blood vitamin concentrations in women at recurrence risk for neural tube defect.

1. We measured erythrocyte folic acid and riboflavin, serum folic acid and leucocyte vitamin C in women at high risk for neural tube defect (NTD) recurrence who were receiving periconceptional vitamin supplementation, before they received extra vitamins, after 28 d of supplementation and at the 8th week of pregnancy. Blood vitamin concentrations in unsupplemented high-risk women were also compared with the values found in unsupplemented low-risk women. 2. Vitamin supplementation with Pregnavite Forte F (Bencard) raised the mean values for all vitamins measured by the 8th week of pregnancy. Mean erythrocyte folic acid rose from 250 to 478 ng/ml; plasma folic acid from 8.4 to 26.1 ng/ml; leucocyte vitamin C from 1.82 to 3.21 micrograms/ml blood; erythrocyte riboflavin (glutathione reductase (EC 1.6.4.2) activation ratio) from 1.08 to 1.04. All women receiving supplements had increased their serum and erythrocyte folic acid levels above the highest values found in women in an earlier study, who subsequently gave birth to children with NTD. Not all women, however, increased their leucocyte ascorbic acid or erythrocyte riboflavin levels above the highest values. 3. When vitamin concentrations in unsupplemented high-risk women compared with levels in unsupplemented women at low risk for NTD, no significant differences were found in the mean values. However, a significantly higher proportion of high-risk compared with low-risk women had erythrocyte folic acid and leucocyte vitamin C values on or below the 5th percentile of the adult normal range. 4. The effectiveness of Pregnavite Forte E (Bencard) for increasing maternal vitamin reserves is discussed with a view to preventing NTD and the possibility of identifying groups at risk for NTD because of low blood vitamin levels is considered.

Temporal relations between maternal rubella and congenital defects

The Time relations between maternal rubella infection in pregnancy and the presence and type of defects in the children were determined from the records of 422 children with confirmed congenital rubella, registered in the National Congenital Rubella Surveillance Programme. In the 106 children born after laboratory-proven maternal infection, no defects were recorded following infection after the 17th week of pregnancy, but in the remaining 316 children defects followed infection reported to be as late as 33 weeks. The striking difference underlines the importance of serological investigation of pregnant women who present with a rash or a history of contact with rubella. With proven infection later than the 16th week the risk of fetal damage seems to be very small. Of 148 children followed up to school age, 40 (27%) attended normal schools.

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.

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.

Vitamin A, pregnancy, and oral contraceptives.

It has been shown that women receiving oral contraceptives have increased levels of serum vitamin A. High vitamin A levels may constitute a teratogenic hazard and it has been suggested that women who conceive soon after discontinuing oral contraceptive therapy may be especially at risk to this hazard. We have confirmed a significant increase in vitamin A levels in women taking oral contraceptives. During early pregnancy there is no significant difference in vitamin A levels between women who have recently been taking oral contraceptives and those who have not. We have been unable to show that either taking oral contraceptives shortly before pregnancy or a high vitamin A level during the first trimester of pregnancy, comparable to that of a woman taking oral contraceptives, has any detrimental effect on the outcome of pregnancy. It seems unlikely that women who conceive soon after discontinuing oral contraception run any teratogenic risk from increased vitamin A levels.

Uptake and Utilization of DL-5-[methyl-14C] Tetrahydropteroylmonoglutamate by Cultured Cytotrophoblasts Associated with Neural Tube Defects

Abstract 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]tetrahydrop-teroylmonoglutamate ([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.

Maternal vitamin nutrition and malformations of the neural tube

I N T R O D U C T I O N . N U T R I T I O N A L D E F I C I E N C Y A N D N T D . . ANIMAL S T U D I E S . STUDIES I N MAN . P E R I C O N C E P T I O N A L V I T A M I N I N T A K E A N D NTD . . MULTI-VITAMIN I N T E R V E N T I O N S T U D I E S . . RETROSPECTIVE S T U D I E S OF VITAMIN I N T A K E . . P E R I C O N C E P T I O N A L VITAMIN INTERVENTION S T U D I E S I N PROGRESS . M I C R O N U T R I E N T M E T A B O L I S M A N D N T D . . C O N C L U S I O N S . R E F E R E N C E S . . 33 34 34 35 36 36 40 41 42 44 45

Leucocyte ascorbic acid and pregnancy

1. Leucocyte ascorbic acid concentrations have been measured in 1147 females during early pregnancy and in smaller numbers of women before conception, throughout pregnancy and at 6 months post partum. 2. The leucocyte concentration in the 1st trimester was found to be affected by season, social class and smoking. Selecting individuals by extremes of social class, season and smoking produced two small populations with almost separate ascorbic acid distributions and mean concentrations of 21.7 and 45.1 microgram/10(8) leucocytes. 3. Early pregnancy had little effect on leucocyte ascorbic acid concentrations but values decreased in the second trimester. However, this was associated with a leucocytosis so that the total leucocyte ascorbic acid content of blood was unchanged. 4. Low ascorbic acid concentrations during the 1st trimester were not associated with subsequent spontaneous abortions, still-births or neonatal deaths, but there was an increased frequency of low values in women who gave birth to infants smaller than 3250 g. 5. The adequacy of ascorbic acid reserves in early pregnancy is discussed.