Prevention of congenital abnormalities by periconceptional multivitamin supplementation

Abstract

ceptional multivitamin supplementation on congenital abnormalities other than neural tube defects, which is the subject of this paper. Abstract Objective-:-To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities. Design-Randomised controlled trial of supplementation with multivitamins and elements. Setting-Hungarian family planning programme. Subjects-4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life. Interventions-A single tablet of a multivitamin including 0.8 mg of folic acid or elements supplement daily for at least one month before conception and at least two months after conception. Main outcome measures-Number of major and mild congenital abnormalities. Results-The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given elements and this difference cannot be explained totally by the significant reduction of neural tube defects. The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pJ'egnancies with known outcome in the vitamin group and 16.6/1000 in the group; relative risk 1.85 (95% confidence interval 1.02 to 3.38); difference, 7.6/1000. The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the group; relative risk 1.95 (1.23 to 3-09) ; difference, 13.6/1000. The rate of some congenital abnormalities was lower in the vitamin group than in the group but the differences for each group of abnormalities were not significant. Conclusions-Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities. Further studies are needed to differentiate the chance effect and vitamin dependent effect. Methods The Hungarian randomised controlled trial of periconceptional multivitamin supplementation was part of the Hungarian family planning programme, which was established on 1 February 1984. Couples who satisfy three criteria are eligible for participation in this programme: no delayed conception or infertility (that is, inability to conceive after more than 12 months of sexual activity without contraception); not currently pregnant; voluntary participation. In the first four years of the programme, there were two other criteria: age of the woman under 35 (older women were referred to the genetic counselling clinic) and no previous wanted pregnancy (induced abortion was not a reason for exclusion). The programme involves three main steps performed or supervised by qualified nurses: a check of reproductive health'; a three month preparation for conception including multivitamin or supplementation; and protection of early pregnancy .8 At the first visit eligible couples were informed about the purpose of multivitamin use and about the blind use of one of two kinds of tablets-that is, they were asked whether they agreed to be allocated to either group on the basis of a randomisation table. After this, the women were asked to sign a written informed consent and to stop taking other vitamins. The participants were advised to take a single tablet of either the vitamin, Elevit Pronatal (Roche), composed of 12 vitamins (vitamin A 6000 IV till the end of 1989 and 4000 IU in 1990-1, E-l 1.6 mg, E-2 1.8 mg, nicotinamide 19.0 mg, E-6 2.6 mg, calcium pantothenate 10 mg, biotin 0.2 mg, E-12 4.0 IJ.g, C 100 mg, D 500 IV, E 15 mg, folic acid 0.8 mg), four minerals (calcium 125 mg, phosphorous 125 mg, magnesium 100 mg, iron 60 mg), and three elements (copper 1 mg, manganese 1 mg, zinc 7.5 mg) or the trace element supplement (copper 1 mg, manganese 1 mg, zinc 7.5 mg, and vitamin C 7.5 mg) each day for one month before planned conception. At the second visit women were supplied with tablets for a further three months and were asked to attempt to conceive and to visit us again immediately after the first missed menstrual period. If the participant did not conceive within three months she was supplied with tablets for the next three months, a month at a time. The purpose of the third visit was the confirmation of pregnancy by a sensitive serum pregnancy test after the first missed menstrual period. Pregnancy was also confirmed by ultrasonography within two weeks. Further tablets were supplied until the 12th week of gestation. The fourth visit was a farewell meeting at the 12th week of pregnancy because after this the pregnant women were referred to other clinics for routine antenatal care. The compliance with the regimen of supplementation was verified verbally in discussion with the women; by evaluating the check marks on the form for the basal body Introduction