Use of randomisation in the Medical Research Council's clinical trial of streptomycin in pulmonary tuberculosis in the 1940sBMJ 1998; 317 doi: https://doi.org/10.1136/bmj.317.7167.1220 (Published 31 October 1998) Cite this as: BMJ 1998;317:1220
All rapid responses
Editor - In 1936 G.W.Theobald, an obstetrician at St. Mary Abbots
Hospital in London, studied the effect of calcium, vitamin A and vitamin C
on toxaemia. According to his report1, "an equal number of blue and white
beads (presumably 50 plus 50) were placed in a box. Each woman accepted
for the experiment was asked to draw a bead from the box. Those who drew
blue beads were placed in Group A and those who drew white beads were
placed in Group B. The beads drawn out were placed in a separate
container. The patients in group A were requested to take daily ... while
those in group B served as controls." True randomisation of individuals
was thus apparently used.
We are informed that the two randomisation groups were similar with
respect to numbers of women older than 30, primigravidae below 20, as well
as primigravidae older than 30 (9 v. 11, 2 v. 2, and 2 v. 2,
respectively). Further, "symptoms were recorded by independent antenatal
officers who had no knowledge as to which patients were receiving the
additional substances", although Theobald himself "saw every patient … and
confirmed the findings". He also considered that incorporating methylene
blue in the preparation could be expedient to assess patient compliance.
Women with symptoms of toxaemia tended to be less frequent in the
treatment group. E.S. Pearson did the statistical analysis and "expressed
the opinion that the difference in incidence of complications between the
two groups is very unlikely to have arisen by chance" (no statistics were
provided, however, and reconstructing the tests would require a post hoc
selection among several different outcome measures provided in the
tables). Theobald himself stated that "it therefore seems logical to
assume that the difference ... must, if not due to chance, be attributed
to the substances given".
We cannot know how rigorously he performed the randomisation. The
method was vulnerable to pressures from patients or others to take a new
bead until the patient ended in the preferable group, which would be
difficult to check if each attempt were not numbered (this problem was
avoided in the streptomycin trial which used numbered, sealed envelopes
and where the patients who ended in the control group were not informed
that they were part of the trial2,3). The most serious potential flaw,
however, follows from Theobald's statement that the small number of
participants was "due to the fact that only a small proportion of the
patients booked sufficiently early and attended the hospital antenatal
clinic throughout their pregnancies"1. Does this mean that a substantial
proportion of the women were enrolled and later excluded? If he truly had
understood the underlying ideas of randomisation, however, he would try to
avoid these problems.
London was certainly focus of controlled trials during those years.
From March 1938 to the end of 1939 the People's League of Health (PLH)
undertook their trial4,5,6,7, which is still likely to be the largest
properly controlled trial of a dietary supplement in pregnancy ever
published. Apart from the size, the PLH trial had many similarities to
Theobald's trial. More than 5000 pregnant women from 10 London hospitals
were alternately allocated to receive no supplement or a supplement which
provided calcium and vitamins A and D, but at other doses than in
Theobald's trial and with other vitamins and minerals added as well. It is
interesting that, after the publication of the preliminary report4,5, the
PLH trial was criticised in very general terms by R.B. Fisher in these
columns8; this may have contributed to the PLH trial's bad reputation7
which in many ways was undeserved, as the trial was an enormous
achievement and, as far as we can judge afterwards, had strong
Theobald foreshadowed the PLH trial by stating that "experiments
conducted on these lines would show to what degree, if any, the different
protective substances are associated with toxaemia symptoms" and that he
published the results "in the hope that further experiments on a larger
scale will be conducted elsewhere"1. Of particular note is the fact that
W.C.W.Nixon of St Mary Abbots Hospital was medical secretary to the PHL
committee1. The PHL investigators team must certainly have been aware of
Theobald's trial, and in retrospect it is a pity that they did not use his
idea of implementing true randomisation; one can only speculate why this
Despite the fact that it was ahead of its time, Theobald's trial is
remarkably little cited. Might it be because of the potential flaws
mentioned above? Or were there other serious problems which could justify
its dismissal from various reviews? Or has it simply been forgotten?
Sjúrður F Olsen Senior Epidemiologist
Danish Epidemiology Science Centre, Statens Serum Institut
5 Artillerivej, DK-2300 Copenhagen C, DENMARK
1 Theobald GW. Effect of calcium and vitamin A and D on incidence of
pregnancy toxaemia. Lancet 1937; ii: 1397-1399.
2 Medical Research Council. Streptomycin treatment of pulmonary
tuberculosis. BMJ 1948; ii: 769-82.
3 Yoshioka A. Use of randomisation in the Medical Research Council's
clinical trial of streptomycin in pulmonary tuberculosis in the 1940s. BMJ
4 People's League of Health. Nutrition of expectant and nursing
mothers. British Medical Journal 1942; ii: 77-78.
5 People's League of Health. Nutrition of expectant and nursing
mothers. Interim report. Lancet 1942; ii: 10-11.
6 People's League of Health. The nutrition of expectant and nursing
mothers in relation to maternal and infant mortality and morbidity.
Journal of Obstetrics and Gynaecology of the British Empire 1946; 53: 498-
7 Olsen SF, Secher NJ. A possible preventive effect of low-dose fish
oil on early delivery and pre-eclampsia: indications from a 50-year old
controlled trial. Br J Nutrittion 1990; 64: 599-609.
8 Fisher RB. Dietetics in pregnancy. British Medical Journal 1943;
Competing interests: No competing interests