Case-control study of childhood leukaemia and cancer in Scotland: findings for neonatal intramuscular vitamin K.

Introduction

The issue of whether the prophylactic administration of intramuscular vitamin K to neonates increases the risk of childhood cancer continues to be of importance both clinically and in the public health arena. Prophylactic use of vitamin K to reduce the incidence of vitamin K deficiency bleeding has been weighed against the possible risk of developing a malignancy during childhood.[1] After the original observations from Bristol associating intramuscular doses with a raised risk of leukaemia[2] there has been a dearth of epidemiological evidence to support the original findings. Studies from Sweden,[3] Denmark,[4] the United States,[5] Germany,[6] and England have all failed to demonstrate any excess of childhood leukaemia or cancer in children who received intramuscular vitamin K. The findings of these investigations, however, remain inconclusive because of lack of power[5] or presumed rather than documented exposure to vitamin K.[3 4] The alternative use of medical notes is not ideal and the considerable difficulties of assessment of exposure are acknowledged.[6 7] Recording may be incomplete, and to compensate for this by imputing exposure according to the hospital policy at the time of birth will introduce misclassification as policy does not always equate with delivery of the drug.[7] To clarify the issue of vitamin K and fulfil the requirement for results from large well designed studies we conducted an analysis of data specifically collected on vitamin K.

Childhood cancer comprises a heterogeneous group of malignancies which are generally unique to childhood and clinically and pathologically distinct from adult cancers. The rarity of the disease can present difficulties for epidemiological research when the presence of small numbers necessitates the aggregation of biologically distinct diagnostic subgroups, therefore large studies are required to investigate putative risk factors. The Scottish case-control study of childhood leukaemia and other cancers was undertaken to identify risk factors for childhood cancer in the Scottish population.[8] One component was the collection of data from hospital maternity records to study obstetric and perinatal risk factors. Our paper presents the results of testing the specific hypothesis of an association between intramuscular vitamin K and childhood cancer for the diagnostic subgroups of leukaemias, acute lymphoblastic leukaemia, lymphomas, central nervous system turnouts, and other solid tumours.

Patients and methods

This population based case-control study defined cases as children (0-14 years) diagnosed with leukaemia and cancer during 1991-4 while they were living in Scotland, the childhood population of which at the 1991 census was 959 268. All diagnoses were pathologically confirmed and completeness of case ascertainment was optimised by cross checking with the Scottish Cancer Registration Scheme and the National Register of Childhood Tumours in Britain.[9] Controls matched on age (to within 1 month), sex, and health board of residence were randomly selected from all eligible children registered for primary care within each health board. An optimum of two controls per case were included and methodological details are published elsewhere.[8]

Mothers were approached and interviewed with consent from the consultant clinician or general practitioner. At interview mothers gave their signed permission for the researchers to abstract their medical notes. Medical records were seen from 76 hospitals and maternity units throughout Scotland relating to births from 1976 to 1994. For the small number of births in England and Wales (3.4%) records were obtained by post.

Abstraction of notes

Two trained researchers recorded information from obstetric, delivery, and neonatal records, including nursing notes, on to a highly structured standard form, specifically designed to collect data on vitamin K and validated in a previous study of childhood leukaemia and obstetric and perinatal risk factors.[7] The senior midwife abstracter (EF) ensured consistency and data quality through a programme of continual monitoring, coding checks, and duplicate abstractions. Demographic details of the mother were "collected at interview and additional data were obtained for a wide range of variables including method of delivery and admission to a special care …