BRITISH MEDICAL JOURNAL
30 AUGUST 1975
activity may also cause them to adopt other means ofmaintaining
We recognize that the assessment of physical activity in this
study was subjective, but we made a special attempt to dis-
tinguish those men performing minimum and heavy activity.
Our findings suggest that if habitual heavy leisure activity is
associated with reduced morbidity from cqronary heart disease,
as reported by Morris et al.,8 the mechanism may be through
an associated lower level of coronary risk factors. Further study
is required to determine possible social, biological, or psycho-
logical differences that may exist among young and middle-aged
men who enjoy different levels of physical activity during their
We thank Gilbert MacKenzie, department of social and preventive
medicine, Queen's University, Belfast, and Julian McAirt, department
of statistics, Trinity College, Dublin, for their advice and help.
1Shapiro, S., et al., Journal of Chronic Diseases, 1965, 18, 527.
2Morris, J. N., et al., Lancet, 1966, 2, 553.
3Kannel, W. B., Sorlie, P., and McNamara, P., Coronary Heart Disease and
Physical Fitness, ed. D. A. Larsen and R. D. Malmborg, p. 256. Copen-
hagen, Munksgaard, 1971.
4Stamler, J., et al., Journal of Chronic Diseases, 1960, 11, 405.
5Paul, O., et al., Circulation, 1963, 28, 20.
6 Taylor, H. L. H., et al., Circulation, 1970, Suppl. 1, p. 211.
IKarvonen, M. J., et al., Circulation, 1970, Suppl. 1, p. 52.
8 Morris, J., et al., Lancet, 1973, 1, 333.
9Dahl, L. K., Ac
EnglandJournal of Medicine, 1958, 258, 1152.
10Holloszy, J. O., et al., American Journal of Cardiology, 1964, 14, 753.
11Mann, G. V., et al., American3Journal of Medicine, 1969, 12, 46.
12 Paffenbarger, R. S., et al., New England Journal of Medicine, 1970, 282,
13 Taylor, H. L., B'iskirk, E. R., and Remington, R. D., Federation Pro-
ceedings, 1973, 32, 1623.
14 Hickey, N., et al., Journal of the Irish Medical Association, 1971, 64, 155.
15Moriarty, J., Comnputer Bulletin, 1970, 14, 7.
16Goodman, L. A.,Journal of the American Statistical Association, 1964, 59,
Thalassaemia, Iron, and Pregnancy
U. M. HEGDE,
G. W. MARSH,
G. H. HART,
J. M. WHITE
British Medical3Journal, 1975, 3, 509-511
~-thalassaemia trait were followed during pregnancy.
The discriminant function, calculated from haemato-
logical indices, was of no value in diagnosing r-thalass-
aemia trait during pregnancy. Initially patients were
given iron supplements only if the serum iron and total
iron binding capacity levels indicated iron deficiency, but
bone marrow biopsies performed in the first 22 patients
at 32 weeks indicated deficient iron stores. These patients
were therefore given iron irrespective oftheir serum iron
level. All subsequent patients with r-thalassaemia were
also put on iron routinely at booking. Retrospectively the
patients were divided into two groups. Patients in
group 1 (18 patients) had received iron for less than 12
weeks, and their haemoglobin levels fell significantly
during pregnancy (P <0001). Haemoglobin levels in 16
patients who had received iron for more than 12 weeks
(group 2), however, did not fall significantly during
pregnancy (P <0 6). It is suggested (contrary to common
practice) that patients with
be given iron supplements during pregnancy. Serum
folate and vitamin B12 levels did not change significantly
in these patients and there was no increase in the inci-
dence of maternal or fetal complications.
of 35 pregnant women with
3-thalassaemia trait should
North Middlesex Hospital, London N.18
U. M. HEGDE, M.B., M.R.C.PATH., Senior Registrar in Haematology (Now
at Hammersmith Hospital, London W12 OHS)
S. KHUNDA, F.R.C.S., M.R.C.O.G., Registrar in Obstetrics and Gynaecology
(Now at Medical City, Baghdad, Iraq)
G. W. MARSH, M.D., M.R.C.PATH., Consultant Haematologist
G. H. HART, F.I.M.L.T., Chief Technician in Haematology
Royal Postgraduate Medical School and Hammersmith Hospital,
London W12 OHS
J. M. WHITE, M.D., M.R.C.PATH., Lecturer in Haematology and Honorary
Patients suffering from ,3-thalassaemiatrait have only mild, if
any, anaemia. But at times of stress, especially pregnancy, they
may develop moderate to severe anaemia. Generally doctors
have been reluctant to prescribe iron supplements in pregnancy,
though iron deficiency does occur in this condition.1 2 During a
study of the haematological values of 35 pregnant women with
F3-thalassaemia trait we found that at 32 weeks of pregnancy,
when bone marrow biopsies were performed in 22 women, 21
women were iron deficient; iron stores were absent and the
sideroblast count was less than 10%". Because of this finding all
subsequent patients suffering from r-thalassaemia trait were
given iron supplements from the time of booking. Retro-
spectively we examined the effect of adequate iron supplementa-
tion on the haemoglobin level.3
Patients and Methods
Thirty-five patients were studied. All came from a "high-risk" group
of Middle-eastern or Mediterranean origin.
diagnosed by the investigations described below.
described by Dacie and Lewis.' The haemoglobin A2 level was
quantified according to the method of Marengo-Rowe.4 Levels above
3-5 were considered diagnostic ofP-thalassaemiatrait. Haemoglobin
F was quantified by alkaline denaturation.5 Haematological indices
were measured at fortnightly intervals on a Coulter Model S counter.
The discriminant function (=mean cell volume-red blood count-
(haemoglobin x 5)-3 4) of England and Fraser" used to distinguish
3-thalassaemia trait from iron deficiency was calculated at antenatal
booking, at the 30th week, and in the first week post partum. Serum
iron and total iron binding capacity (T.I.B.C.) were measured each
month. Goldberg and Schwartz7 have reported increased folate
demands in women with
3-thalassaemia trait during pregnancy, so
serum folate and vitamin B12 levels were also measured each month.
Bone marrow biopsies were carried out at the 32nd week ofpregnancy.
The aspirations were studied for evidence of megaloblastic erythro-
poiesis, and cell morphology and reticulo-endothelial iron stores and
erythron iron were assessed independently by two people.
3-Thalassaemia trait was
In 35 women with the r-thalassaemia trait mean values at first ante-
natal presentation were haemoglobin 10 9 g/dl, mean cell volume
BRITISH MEDICAL JOURNAL
30 AUGUST 1975
65 fl, mean cell haemoglobin 29 pg, and Hb A2 4-2%. Serum iron and
T.I.B.C. levels showed wide variations. The variation was also great
when measured each month. At 32 weeks when bone marrow biopsies
were carried out on 22 patients 21 were found to have absent iron
stores and sideroblast counts of less than 10%. Only seven of these
patients had serum iron levels of less than 13-4 umol/l (75isg/1O0 ml),
and 10 had T.I.B.C. levels of over 89-5 tsmol/l (500 jig/100 ml),
measured at the time of bone marrow aspiration (see table). Because
we felt that serum iron and T.I.B.C. levels were not reliable indices
of incipient iron deficiency all subsequent patients were put on iron
supplements. The differences in the haemoglobin levels at antenatal
booking and third
received iron for less than 12 weeks (group 1) and those who had
received it for more than 12 weeks (group 2) are shown in fig. 1. The
mean initial haemoglobin values were similar in both groups-111
g/dl and 10-8 g/dl, respectively-but in group 1 this fell to a mean of
9-6 g/dl (P<0 001) while in group 2 there was no fall (10-7 g/dl;
P<0 6). One patient who had mild megaloblastic bone marrow
changes was excluded.
patients who had
FIG. 1-Effects of therapeutic iron on haemoglobin levels during pregnancy
in patients who had iron for less than 12 weeks (group 1) and in those who
had iron for more than 12 weeks (group 2). A=Haemoglobin at antenatal
booking. B =Lowest haemoglobin value in third trimester.
The values obtained for the discriminant function are shown in
fig. 2. Normally patients with iron deficiency anaemia have a positive
discriminant function and those withP-thalassaemia trait a negative
function. Nineteen of our patients (54%) at booking, however, and 30
(86o%) at the 30th week had a positive value, and on the fourth day
after delivery 28 patients (80%) still retained this positive value.
There was no significant change in serumB12 levels during preg-
nancy. The serum folate fell to subnormal levels in only one patient,
who showed mild megaloblastic change on bone marrow examination
at the 32nd week (this patient was excluded from analysis). There was
no increase in obstetric or fetal complications in either group com-
pared with normal women.
Our results confirm the view of England and Fraser6 that the
discriminant function has no validity in differentiating
FIG. 2-Distribution of discriminant function derived from mean
volume, red blood count, and haemoglobin concentration (discriminant
function=M.C.V.-R.B.C.-(HbX5)-34) in pregnancy and in the first
week after delivery.
thalassaemia minor from iron deficiency during pregnancy. It
was of interest that the discriminant function should retain its
positive value in 28 patients on the fourth day after delivery, by
which time the haemodilution that occurs in pregnancy should
normally have corrected.
Doctors are reluctant to give iron supplements to pregnant
women with ,-thalassaemia trait, but our results indicate that
if iron is given for an adequate period there is little change in
the mean haemoglobin level of these patients. These results
must be regarded as preliminary because of the nature of the
study. It was completely fortuitous that the beneficial effect of
iron on the haemoglobin level was discovered, and, obviously,
a larger double-blind trial is required before we can be certain
that iron treatment is valuable. Our results might also be
criticized because of the division of the groups on the basis of
whether iron was given for more than 12 weeks or not. Twelve
weeks was chosen since this is an acceptable period of time to
replete deficient body stores. Overall, however, we believe that
our data are sufficient to indicate that all women with
thalassaemia should be given iron. Moreover, serum iron and
T.I.B.C. values are of little value in assessing iron stores in
pregnancy in that there is no correlation between the stores and
The cause of the anaemia during pregnancy in these patients
has been widely discussed,'1
regards its management. Schuman et al.9 showed that the red
cell mass in pregnant women with thalassaemia trait increased
but not to the same extent as that in normal women. Haemo-
dilution alone, however, may not explain the degree of anaemia
that is sometimes seen. These authors9 also suggested that
hormonal influences could possibly alter the rates of globin
chain synthesis during pregnancy and that an increased rate of
y-chain synthesis could bind some of the excess a-chains,
8 but some confusion remains as
Serum Iron and Total Iron Binding Capacity Levels during Pregnancy in Women with
At antenatal booking
At bone marrow aspiration
Serurn a Iron (j±mol/l)
> 500 ,ug
(>89 5 ,imol)
Convession: SI to Traditional Units-1 pmol/l
BRITISH MEDICAL JOURNAL
30 AUGUST 1975
leading to less cell breakdown and more effective erythro-
poiesis. If so, an increase in normal erythropoiesis might lead to
a greater mobilization of available iron, and this, together with
the fetal demands, might lead to a negative iron balance and a
state of iron deficiency in the absence of iron supplements.
Early iron deficiency may be difficult to diagnose. The value
of measuring serum iron levels is limited when anaemia is
minimal or iron deficiency is incipient. The T.I.B.C. usually
increases with depletion of iron stores, but it also normally
increases in pregnancy and, therefore, a rising level may be
difficult to interpret. Absent iron stores are generally accepted
as a feature of iron deficiency. The absence of iron stores in
itself may not be of great importance and an increased ingestion
or absorption of food iron may be enough to satisfy iron require-
ments during a period of greater demand,'0such as pregnancy.
The number of sideroblasts in a bone marrow film is probably a
more accurate index and sideroblast counts of less than 10%
indicate iron deficient erythropoiesis. Of the 22 patients in
whom bone marrow examinations were done 21 showed this
feature. This finding apparently contradicts those of Schuman
et al., 9 but in most of their patients bone marrow examination
was carried out before the 28th week of pregnancy and they
make the point that their limited data on bone marrow haemo-
siderin after the 32nd week also suggested a diminution of iron
stores during pregnancy. Iron absorption is not increased in
3-thalassaemia trait," and Pakes et al."2 empha-
sized that these patients possess the same increased require-
ments for iron during pregnancy as do other women without
The serum folate and B,, levels were all normal except in one
patient, who had a low serum folate and showed mild megalo-
blastic change on bone marrow examination. These findings
imply that these patients tend to remain in positive balance for
vitamin B12 and folic acid, but they do not exclude increased
Hence, iron deficiency seems to be common in pregnant
women with f-thalassaemia trait, and these patients should be
given oral iron and physiological doses of folic acid throughout
pregnancy, as are other women without this defect.
We thank the consultant obstetricians, North Middlesex Hospital,
for help in studying these patients. We thank Miss C. Hollywell and
Miss S. Fairhurst for expert technical help.
Fleming, A. F., and Lynch, W., Journal of Obstetrics and Gynaecology of
the British Commonwealth, 1969, 76, 451.
2Wasi, P., Disthasongchan, P., and Na-Nakorn, S., Journal of Laboratory
and Clinical Medicine, 1968, 71, 85.
3Dacie, J. V., and Lewis, S. M., Practical Haematology, 4th edn. London,
4Marengo-Lowe, A. J., Journal of Clinical Pathology, 1965, 18, 790.
5 Singer, K., Chernoff, A. I., and Singer, L., Blood, 1951, 6, 413.
6 England, J. M., and Fraser, P. M., Lancet, 1973, 1, 449.
7Goldberg, M. A., and Schwartz, S. O., Blood, 1954, 9, 648.
8 Hegde, U. M., and Khunda, S., Journal of Obstetrics and Gynaecology of
the British Commonwealth, 1974, 81, 136.
9Schuman, J. E., et al., British Journal of Haematology, 1973, 25, 249.
10Isager, H., Scandinavian Journal of Haematology, 1974, no. 21 (Suppl.),
11Shahid, M. J., and Haydar, N. A., British3Journal of Haematology, 1967,
12Pakes, J. B., Copperberg, A. A., and Gelfand, M. M., AmericanJournal of
Obstetrics and Gynecology, 1970, 108, 1217.
Evaluation of Creatinine Phosphokinase in Screening
Patients for Malignant Hyperpyrexia
F. RICHARD ELLIS,
D. G. F. HARRIMAN
I. M. C. CLARKE,
British Medical Journal, 1975, 3, 511-513
Evidence is presented that serum creatinine phospho-
kinase (CPK) activity is of no direct value in screening
patients for susceptibility to malignant hyperpyrexia
and does not correlate with halothane-induced muscle
contracture or the presence ofmyopathy. Widely differing
CPK values were found at different times in the same
people. In most "malignant hyperpyrexia" families the
susceptible patients had either normal or inconsistently
raised CPK values.
Malignant Hyperpyrexia Investigation Unit, University of Leeds,
Leeds LS2 9LN
F. RICHARD ELLIS, PH.D., F.F.A. R.C.S., Senior Lecturer in Anaesthesia
I. M. C. CLARKE, M.B., F.F.A. R.C.S., Research Fellow
MARGARET MODGILL, M.B., F.F.A. R.C.S., Senior Registrar
S. CURRIE, M.D., M.R.C.P., Consultant Neurologist
D. G. F. HARRIMAN, M.D., F.R.C.S., Senior Lecturer in Neuropathology
The syndrome of malignant hyperpyrexia under anaesthesia,
characterized by a rapid rise of body temperature (greater than
2°C per hour), acidosis, hyperkalaemia, and usually muscle
rigidity, carries a 60-70% mortality.' The condition is inherited
as a Mendelian dominant and so screening all members of an
indexed family before anaesthesia is mandatory.
The association of myopathy with malignant hyperpyrexia23
led to the suggestion that serum creatinine phosphokinase
(CPK) levels may be consistently raised in susceptible patients.
malignant hyperpyrexia in relatives and yet some susceptible
patients have normal CPK levels.4
Muscle from susceptible patients was found to develop
contracture in vitro when exposed to certain known trigger
agents including halothane.5 The same muscle tissue when
investigated neuropathologically was also found to have structural
abnormalities consistent with myopathy.3 The discovery of
these abnormalities enabled us to offer a screening test for
malignant hyperpyrexia using muscle biopsy. When a family is
investigated the indexed patient is studied first because there are
other unrelated causes of hyperpyrexia under anaesthesia which
can mimic malignant hyperpyrexia. So far 10% of the indexed
patients referred to us for investigation have been found to have
normal muscle, and other causes of the hyperpyrexia have been
is now commonly used to indicate susceptibility to