Sheila Sheppard

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%).

Further experience of vitamin supplementation for prevention of neural tube defect recurrences

In accordance with a previous protocol, a second cohort of 254 mothers with a history of previous neural tube defect (NTD) births was before a subsequent conception and continued until the time of the second missed menstrual period. There were 2 NTD recurrences (0.9% of 234 infants/fetuses examined), which is significantly fewer than the 11 NTD recurrences (5.1% of 215 infants/fetuses examined) born to 219 unsupplemented (US) mothers in the same centres over the same period. When the data for the two cohorts were combined, the overall recurrence rates were 0.7% for 454 fully supplemented (FS) mothers and 4.7% for 519 US mothers. The recurrence rates after 1 previous NTD were 0.5% for FS and 4.2% for US mothers: after 2 or more previous NTDs, 2.3% for FS and 9.6% for US. There were no recurrences among the offspring of a further 114 mothers whose duration of supplementation fell short of the full regimen (partially supplemented, PS).

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.

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.

PARITY OF WOMEN CONTRACTING RUBELLA IN PREGNANCY: Implications with Respect to Rubella Vaccination

Data from the National Congenital Rubella Surveillance Programme showed that 44% of children with congenital rubella reported to the programme were born to primiparae. This high proportion is thought to be due to the fact that there was a two-fold increase in the rate of abortion for rubella in pregnancy for women with two or more children. This higher incidence of congenital rubella in firstborns emphasises the need for rubella vaccination prior to a womans first pregnancy.

Richard Worthington Smithells, 1924–2002

Richard (Dick) Smithells, MRCS LRCP, MB BS Lond, DCH, MRCP Edin, MRCP Lond, FRCP Edin, FRCP Lond, MD Lond, FRCOG (ad eundem) was born in London, was educated at Bedales and Rugby Schools, and studied medicine at St. Thomas’s Hospital Medical School. His first post after graduation was as House Surgeon to the Orthopaedic and Plastic Surgery Departments. Of this he later wrote in his journal: ‘Children are born with club feet; they break their legs; babies have cleft lips and palates. My pediatric career was about to begin.’ A second house post was followed by two years’ National Service with the Royal Army Medical Corps in Germany, where his duties included responsibility for families. During this time he gained a Diploma in Child Health. On leaving the army he held Pediatric Registrar posts at Bradford Children’s Hospital and at three hospitals in Leeds: the General Infirmary, St. James’s, and Seacroft. After this he moved to London to become a Senior Registrar at Guy’s Hospital. In 1959, he was appointed Lecturer in Pediatrics and Child Health at the University of Liverpool and Honorary Consultant and was based at Alder Hey Children’s Hospital, the largest acute care children’s hospital in the country. There he was asked by Professor John Hay, the head of his department, to start a genetic counseling clinic and to introduce developmental testing of babies. He was also instrumental in establishing the Liverpool Congenital Anomalies Registry, which in later years became one of the founding members of the European Registry of Congenital Abnormalities and Twins (EUROCAT). The registry soon witnessed a curious ‘epidemic’ of limb defects in newborn babies, later recognized as the effects of maternal treatment with the drug thalidomide. This led to Dick’s lifelong association with the victims of this teratogen, fighting for their care and proper support and compensation. It was there, too, that together with Bryan and Elizabeth Hibbard of the Department of Obstetrics he published a seminal paper linking maternal folic acid deficiency with neural tube defects (Hibbaerd and Smithells, 1965). In 1965, Dick was appointed Professor and Head of the Department of Pediatrics and Child Health in the University of Leeds, thereby continuing a family connection with that university. His father was a chemistry graduate, and his grandfather had held the Chair of Organic Chemistry, and his great uncle the Chair of Chemistry. During his tenure at Leeds he established the first genetic counseling clinic in Yorkshire, and his principal research interest was in the prevention of congenital abnormalities. He established a departmental laboratory to investigate the possible link between maternal nutrition and birth defects. This culminated in the study of periconceptional folate supplementation in women who had previously had a child with a neural tube defect, which was to change antenatal care forever. The history of folic acid and its role in the prevention of neural tube defects undertaken by Dick and his team is the subject of a companion paper by Chris Schorah, and the sequelae, which still continue today, are the subject of this special edition of Birth Defects Research A. In addition, Dick headed the Northern Registry of the National Congenital Rubella Surveillance Programme. This was a long-term study designed to monitor the incidence of congenital rubella in the years following the introduction of a vaccination program for schoolgirls, by noting any changes when the vaccinated patients reached child-bearing age. A clear fall in cases and in the number of rubella-related terminations of pregnancy was observed. Dick also investigated the effects of Bendectin (Debendox in the United Kingdom). There were suspicions that this antinausea drug might be teratogenic. Dick studied the occurrence of birth defects in the offspring of women who took the drug during pregnancy and found no evidence of teratogenesis.

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.

TERATOGENICITY TESTING IN HUMANS: A METHOD DEMONSTRATING SAFETY OF BENDECTIN

We investigated the incidence of birth defects in the offspring of women who took Bendectin during pregnancy. Copies of all prescriptions issued for Bendectin in two Cities, Leeds and Liverpool, over periods of 12 and 14 months, respectively, were scanned and a record initiated for each patient. Birth notifications were later searched for matching with indexed patients. Births were traced for 2,298 patients and the incidence of major defects compared with those in the relevant populations. We found no evidence to suggest that Bendectin is teratogenic in humans.