Periconceptional Supplementation Research Articles

Long term effects of periconceptional multivitamin supplements for prevention of neural tube defects: a seven to 10 year follow up.

Periconceptional supplementation with Pregnavite Forte F was offered to women who presented consecutively to the Oxford genetic counselling service in the early 1980s who had previously had one or more pregnancies complicated by a neural tube defect. The first 100 children born alive to these women are the subject of this study. Birth weight, gestation, and congenital abnormalities were recorded. At age 2-5 years all 96 children remaining in the United Kingdom were assessed clinically and developmentally and behavioural information was obtained by questionnaire. At age 7-10 years, follow up of 91 children by telephone and postal questionnaire yielded further information about growth, general health, vision, hearing, and educational and behavioural status. Entry criteria excluded single mothers but the social class distribution of the sample was otherwise representative of the Oxfordshire population. There were no recurrences of neural tube defects. One child had radiological evidence of spina bifida occulta affecting only the fifth lumbar vertebra. One had an autosomal recessive disorder. Eight had random minor congenital anomalies. Birth weight for gestational age was significantly greater than for the local population and at age 7-10 years the girls were considerably taller than expected. Health, auditory, visual, and developmental status were no different from the general population. None of the children had special educational needs. None showed a major behaviour disorder but worries, fussiness, and fearfulness were highly significantly over represented.

Periconceptional vitamin supplementation and neural tube defects; evidence from a case-control study in Western Australia and a review of recent publications.

The aim was to assess the association of neural tube defects with periconceptional vitamin supplementation. This was a matched, population based case-control study. Western Australia, 1982-1984. Mothers of 77 cases (93% of those eligible) with isolated neural tube defects, mothers of 77 matched control infants with defects other than neural tube defects (control group I), and mothers of 154 liveborn, matched, control infants with no birth defects (control group II) participated in the study. Information was collected by interview and self administered questionnaire. Crude and adjusted odds ratios (and their 95% confidence intervals) showed a small but non-significant protective effect of folate supplementation in comparisons with both control groups. The adjusted ratios for the three months before pregnancy were 0.69 (0.06, 8.53) with control group I, and 0.11 (0.01, 1.33) with control group II. In the first six weeks of pregnancy, the adjusted odds ratios were 0.70 (0.32, 1.52) with control group I and 0.74 (0.29, 1.88) with control group II. The odds ratios for vitamin supplementation of any kind were all very close to or greater than one, and all confidence intervals embraced unity. These data do not provide evidence of an association between periconceptional vitamin supplementation and neural tube defects, although a protective effect of folate supplementation cannot be excluded with confidence, due to the low power of the study. Of three other observational studies of vitamins and neural tube defects, two have shown an association. While further studies of this kind may be of value, evidence must now be sought from randomised controlled trials.

Periconceptional supplementation with folic acid: Does it prevent neural tube defects?

There has been considerable controversy in recent years concerning the benefit of periconceptional vitamin supplementation in the prevention of neural tube defects. Recent reports of a successful randomized clinical trial have prompted official recommendations for folic acid supplementation in women with a history of an affected pregnancy. Periconceptional supplementation of low-risk women remains controversial.

Neural tube defects: Are neurulation and canalization forms causally distinct?

Neural tube defects (NTD) may be separated according to the overall location and probable embryological origin into 2 groups: upper or neurulation defects, and lower or canalization defects. Evidence as to whether these 2 forms are causally related or distinct was sought from 2 sources. Families with more than one NTD individual were studied to examine whether there was concordance within sibships for these 2 types of lesion. Seven of the 38 sibships were discordant (18%). Eight of the 10 cases of NTD that had arisen despite maternal periconceptional vitamin supplementation were neurulation defects and 2 were canalization defects. Both observations suggest that upper and lower types of NTD are causally related, and offer no support for the suggestion that they are distinct.

Towards the prevention of neural tube defects

The value of maternal periconceptional vitamin supplementation in preventing the conception of fetuses with neural tube defects has yet to be assessed in a properly designed study. Avoidance of the birth of affected infants continues to rest on second-trimester maternal serum alphafetoprotein screening. The performance of screening programmes in achieving this objective is reviewed.

Ethics of a Randomized Trial of Periconceptual Vitamins

To the Editor.— We would like to comment on the article by Mulinare et al. 1 In Hungary, we are also trying to test the efficacy of periconceptional multivitamin supplementation 2 in the reduction of first occurrences of neural tube defects. 3 At the first visit, women seeking family planning are informed about the purpose of multivitamin use. Those who agree are asked to sign a form of consent and instructed to take capsules for 1 month before planned conception and for 3 months after the last menstrual period. Study.— In a double-blind study, a single capsule of vitamins and minerals (Elevit Pronatal) or placebo is taken each day. The composition of the capsule of vitamins and minerals is as follows: vitamin A, 6000 IU; thiamine hydrochloride (vitamin B 1 ), 1.6 mg; riboflavin (vitamin B 2 ), 1.8 mg; niacinamide (nicotinamide), 19.0 mg; pyridoxine hydrochloride (vitamin B 6 ), 2.6 mg; calcium

Ethics of a Randomized Trial of Periconceptual Vitamins

To the Editor.— Mulinare and colleagues 1 reported an association between periconceptional use of multivitamins by women and subsequent reduced risk of neural tube defects among their infants. Dr Holmes, 2 in an accompanying editorial, interpreted this study as finding no protective effect of vitamins among black women, then speculated that genetic differences between whites and blacks may result in a greater responsiveness of whites to periconceptional vitamin supplements. Dr Holme's speculation is based on a failure to recognize the large type II error associated with small sample sizes and a faith in genetic determinism with no supporting data. Any inferences regarding blacks in this study are hazardous because only 28 blacks were included among the cases reported in Table 2 of the article and only 2 of these reported vitamin use. If the true odds ratio among black women was similar to that found among white women (0.4), then

Neural tube defect recurrence after 'partial' vitamin supplementation.

A total of 227 mothers enrolled for periconceptional multivitamin supplementation because of previous neural tube defect (NTD) births took vitamins for less than the recommended minimum period (at least 28 days before conception until two menstrual periods have been missed). Of 213 examined infants/fetuses born to these partially supplemented mothers, two had NTD, one of whom followed four previous NTDs. The observed NTD recurrence rate is similar to that observed in fully supplemented mothers. A further 14 mothers started supplements before the second missed period but after the normal time of neural tube closure. Three of their offspring had NTD. The significance of this apparently high recurrence rate is discussed.

Prevention and avoidance of congenital malformations.

Many congenital abnormalities do not have either a Mendelian pattern of inheritance or an identifiable chromosome abnormality and are described as 'multifactorial' as it is assumed they are determined by several genes, each with added effects and modified to a greater or lesser extent by environmental factors. They include spina bifida and anencephaly, cleft lip or cleft palate or both, congenital heart defect and congenital dislocation of the hip, and they constitute a major community health problem. Developments in genetics, biochemistry and cytogenetics have presented new approaches to the prevention and avoidance of congenital abnormalities. The approaches available for the avoidance of congenital malformations include the avoidance of harmful environmental factors, the screening of the newborn and early treatment, genetic counselling and antenatal monitoring with selective termination. The prevention of neural-tube defects in 'high risk' mothers can be achieved by periconceptional vitamin supplementation. In Northern Ireland, of 438 fully supplemented women, only 4 (0.98%) infants or fetuses among 407 infants and fetuses examined had a neural-tube defect, whereas of 356 unsupplemented women, 16 (4.7%) infants or fetuses among 337 infants or fetuses examined had a neural-tube defect.

Orofacial clefts in Czechoslovakia. Incidence, genetics and prevention of cleft lip and palate over a 19-year period.

The precise value of incidence was calculated based on the sample of 3,660 probands with orofacial clefts born in Bohemia between 1964-1982, as all cases born in this region and time were registered. For non-syndromic cases, the incidence of cleft lip was 0.4396 per 1,000 live birth, 0.7684 for cleft lip and palate and 0.6024 for isolated cleft palate. The sample of 4,950 of our older probands born between 1886-1963 was added and the whole sample of 8,250 individuals was evaluated with respect to sex-ratio, laterality, clinical severity, seasonal incidence and age of parents. The risk of recurrence and value of heritability were calculated as well. Based on these evaluations, a four-threshold multifactorial model for cleft lip and palate was suggested and also confirmed by our results of primary prevention of orofacial clefts using periconceptional supplementation with vitamins and folic acid.

Periconceptional vitamin supplementation and the prevention of neural tube defects in south-east England and Northern Ireland.

A comparison has been made of the effectiveness of periconceptional vitamin supplementation for the prevention of recurrence of neural tube defects (NTD) in south-east England and Northern Ireland. These areas represent the extremes of birth prevalence of NTD (low and high respectively) within the United Kingdom. Vitamin therapy resulted in a slightly less than two-fold reduction in the recurrence risk in south-east England and a greater than three-fold reduction in Northern Ireland, when compared with unsupplemented women at the same risk from the two areas. It is probable that one of the recurrences in each area did not involve the multifactorial form of NTD and, if these are excluded, then the reduction in recurrence risk with vitamin supplementation is 2.4 times in south-east England and 5.4 times in Northern Ireland. Either way, beneficial effects of supplementation are apparent in both areas but are more marked in the high prevalence area. The implications of this for the future are discussed. Two other important findings were that all but one of the recurrences of NTD with full supplementation occurred in male fetuses, and there was a higher than expected occurrence of isolated hydrocephalus in infants or fetuses following full supplementation.

TOENAIL ZINC (Zn) IN MOTHERS OF PROGENY WITH NEURAL TUBE DEFECTS (NTDS)

Diet-induced Zn deficiency in pregnant rats is known to cause cong. malfs. in 90-100% of their progeny, some 3% having spina bifida(SB).Mothers of children with SB have been reported to have high concentrations of hair Zn. Recent UK claims suggest vitamin A/folic acid periconceptional supplementation dramatically reduces the rate of recurrence of NTDs in women at risk.Because animal data have established a consistent relation between low plasma vitamin A and Zn deficiency, we studied the Zn status of women with a NTD fetus.Toenail clippings obtained mostly between 18-24 wks gestation provides a valuable retrospective assessment of maternal Zn status in the months prior to & around the periconceptional period.Zn analyses of toenails were performed by neutron activation analysis on 35 patients.21 controls (7 matched normal pregnancies, 14 normal females & males) had a normal range for Zn of 79.6-125 ppm.10 mothers with NTD fetuses, 2 with omphalocele, & 2 with with exogenous Zn intake were analyzed. High Zn values were found in 2 with SB fetuses (181;144), 1 with anencephaly (Anen.)(213), & 2 with Zn intake (208.4;290.8).Lowest value of all 35 was 1 with anen.(62.3).2 with SB+other malfs., 2 with Anen, 1 with lone SB all had normal Zn.In Zn deficiency both decreased and paradoxical increased Zn values have been found in hair.The consonance of our findings of high (3) or low(1) toenail Zn values among 10 mothers with NTD fetuses, suggests an abnormality in Zn metabolism in some women who bear children with NTDs.

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.

Apparent Prevention of Neural Tube Defects by Periconceptional Vitamin Supplementation

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.

Apparent prevention of neural tube defects by periconceptional vitamin supplementation.

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 per conceptional 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.

POSSIBLE PREVENTION OF NEURAL-TUBE DEFECTS BY PERICONCEPTIONAL VITAMIN SUPPLEMENTATION

Women who had previously given birth to one or more infants with a neural-tube defect (NTD) were recruited into a trial of periconceptional multivitamin supplementation. 1 of 178 infants/fetuses of fully supplemented mothers (0·6%) had an NTD, compared with 13 of 260 infants/fetuses of unsupplemented mothers (5·0%).