Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7219.1223 (Published 06 November 1999) Cite this as: BMJ 1999;319:1223
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Dear Sir
In the randomised control trial of diabetic treatment in pregnant
women with diabetes, Nachem et al1, achieved better glycaemic control with
a four times daily regimen when compared with a standard two times daily
regimen. We have some concerns about the methods and analysis.
The authors compared baseline data between the two groups. Glycaemic
control was measured using Fructosamine, Capillary whole blood glucose and
HbA1c. We feel they could improve the study by stating baseline control
in the pregestational group. This would have demonstrated that the two
groups were comparable and the previous diabetic control had not
influenced the results.
We noted that the two groups were given different methods of insulin
administration. The four times daily regimen used pens, whilst the twice
daily used injections. Therefore we question, was the improvement in
control due to better compliance2 rather than the regimen used?
Another potential source of bias was the non-blind nature of the
study. We note the higher levels of insulin in the four times daily
group. This may reflect more aggressive monitoring and treatment by
clinicians. Blinding of the clinicians, whilst difficult to achieve,
would have ensured the same treatment for both groups.
Yours sincerely
Shikha Chattree
Hayden Ellis
Emma Poyner
Jonathan Smith
Anna Zoltowski
3rd Year Medical Students
Department of Epidemiology & Public Health,
University of Newcastle
References:
(1) Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four
times daily insulin dose regimens for diabetes in pregnancy: randomised
controlled trial. BMJ.1999;319:1223-1227
(2) Dunbar JM, Madden PM, Gleeson DT, Fiad TM, McKenna TJ. Premixed
insulin preparations in pen syringes maintain glycemic control and are
preferred by patients. Diabetes Care 1994;17:874-8
Words 197
Competing interests: No competing interests
Response to Nachum et al BMJ 6.11.99
Nachum and colleagues draw conclusions from their open study of
management of diabetes in pregnancy which are not justified by their data.
Firstly, They claim that the number of insulin injections per day explains
an apparently lower rate of neonatal morbidity. Previous work has clearly
demonstrated the importance of overall clinical approach and intensity of
diabetes care provided rather than the method of insulin administration
(1). In young people the change to a four times daily insulin regimen is
associated with an average deterioration of blood glucose control (2). It
is clearly the case that each person with diabetes should be managed in
the best and most practical manner for that individual. The number of
injections is but one consideration. Nachum and colleagues do not draw
attention to the considerable difference in average insulin dose between
the two groups (120 vs. 92 units per day in pre-existing diabetes group
and 65 vs. 43 units per day in the gestational diabetes group). Surely the
two groups should be labelled "intensive management" and "conventional
management"?
Secondly, the observation that neonatal hypoglycaemia rates were
lower in the intensively managed groups requires careful consideration.
The authors assume that the minimally better average blood glucose control
during pregnancy brought about the difference. However, in groups of women
with good control during pregnancy there is no relation between degree of
control and risk of neonatal hypoglycaemia but rather there is a clear
relationship with blood glucose levels during the final stages of labour
(3). Can Nachum and colleagues provide information on control during
labour? What were the characteristics of those women whose babies had
hypoglycaemia, and specifically what was the HbA1c during pregnancy
leading to neonatal hypoglycaemia compared to the rest?
As the study reported is large and prospective, answers to the above
questions will be important in allowing proper interpretation.
References
1. Marshall SM, Home PD, Taylor R, Alberti KDMM. Continuous
subcutaneous insulin infusion compared with injection therapy: A
randomised cross-over trial under usual diabetic clinic conditions. Diabet
Med 1987;4:521-5.
2. Mortensen HB, Villumsen J, Volund A, Petersen KE, Nerup J. The
relationship between insulin injection regimen and metabolic control in
young Danish type I diabetic patients. Diabet Med 1992;9:834-9.
3. Carron-Brown S, Kyne-Grzebalski D, Mwangi B, Taylor R. Effect of
managemnt policy upon 120 type 1 diabetic pregnancies: policy decisions in
practice. Diabet Med 1999;16:573-8.
Roy Taylor
Professor of Medicine and Metabolism
Royal Victoria Infirmary,
Newcastle upon Tyne NE2 2ES
roy.taylor@ncl.ac.uk
Competing interests: No competing interests
Editor- We read with interest the article by Nachum et al 1 and we
think some points regarding this insulin regime deserve comment.
Veciana M et al found that adjustment of insulin therapy using twice
daily insulin dose regimen in women with gestational diabetes according to
the result of the I hour post prandial blood glucose levels improved
glycaemic control and decreased the risk of neonatal hypoglycaemia,
macrosomia and Caesarean delivery2. The incidences of macrosomia and large
for gestational age were lower in this study compared to the study by
Nachum et al (9% vs 16% and 12% vs 26% respectively). The other end points
being comparable doubt arises about the compliance of two more injections
daily throughout pregnancy.
Human Insulin (HI) is immunogenic and a short course of HI therapy
induces insulin antibody (IA) in about 50% of women with gestational
diabetes and 92% Type 1 Diabetic patients3. Menon and colleagues reported
that placental transfer of insulin complexed with immunoglobulin was
associated with foetal macrosomia in mothers with near normal glycaemic
control during gestation4. In this study the antibody bound insulin
transferred to the foetus was proportional to the concentration of
antibody bound insulin increased in the mother. But if HI is used in
higher doses as done by Nachum et al1, the titre of IA will also be high
and consequently the percentage of insulin binding will be more and
associated adverse effects including macrosomia might increase. If these
IA remained positive the patients would be theoretically at risk of
developing insulin allergy or insulin resistance in case the
reintroduction of insulin is required.
The insulin lispro improves post prandial glucose control (which is
important for managing gestational diabetes), reduces hypoglycaemic
episodes and improves patient convenience compared with regular human
insulin. The duration of action of insulin lispro is shorter than regular
human insulin explaining its decreased immunogenicity and reduced
placental transfer. On the contrary regular Human insulin activity can
significantly overlap with basal insulin activity between meals and
especially at night causing excessive glucose excursions and
hypoglycaemia3.
Foetal pancreatic B cell development may be enhanced by minimal
elevations in plasma glucose and other fuels particularly insulinogenic
aminoacids. The ensuing foetal hyperinsulinaemia together with excess
nutrient supply may enhance foetal growth even if glycaemic control is
satisfactory in late gestation5.
In view of the above findings the maternal plasma aminoacid
concentration, the insulin antibody status in maternal serum and placental
transfer of insulin complexed with immunoglobulin would be quite useful as
they are well recognised causes of foetal macrosomia and large for
gestation infants. Moreover insulin lispro might be a better choice in
managing women with gestational diabetes because of its added advantages
mentioned earlier.
Thanking You
Yours truly
Dr Prabirkumar Bandyopadhyay
Senior SHO in General Medicine
Dr Saumitra Baksi
Visiting Specialist Registrar in General and Respiratory Medicine
St Mary's Hospital,
Newport,
Isle of Wight PO30 5TG
References
1 Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus
four times daily insulin dose regimens for diabetes in pregnancy:
randomised control trial. BMJ 1999; 319: 1223-7
2 Veciana M, Major CA, Morgan MA, Asrat T, Toohey JS, Lien JM et al. Post
prandial versus preprandial blood glucose monitoring in women with
gestational diabetes requiring insulin therapy. N Engl J Med 1995; 333:
1237-41
3 Balsells M, Corcoy R, Mauricio D, Morales J, Garcia- Patterson A,
Carreras G et al. Insulin antibody response to a short course of human
insulin therapy in women with gestational diabetes. Diabetes Care 1997;
20: 1172-75
4 Menon RK, Cohen RM, Sperling MA, Cutfield WS, Mimouni F, Khoury JC.
Transplacental passage of insulin in pregnant women with Insulin dependant
diabetes mellitus: its role in foetal macrosomia. N Engl J Med 1990; 323:
309-15
5 Butte NF, Hsu HW, Thotathuchery M, Wong WW, Khoury J, Reeds P. Protein
metabolism in insulin treated gestational diabetes. Diabetes Care 1999;
22: 806-11
Competing interests: No competing interests
..is continuous administration of insuline subcutaneously
by a small pump - plus survey by a specialised department - at least for
pregnant German women with IQ over 99.
Competing interests: No competing interests
Confirmation of theory
This paper was presented at our monthly journal club at the QE2
hospital, Welwyn Garden City, Hertfordshire, England. All members of the
Diabetes Care Team were present from the Diabetes Specialist Nurses, down
to the Consultant!
The paper was received with great interest particularly as there is little
evidence base for what is already common practice in the management of the
pregnant diabetic ladies, ie.intensive insulin therapy.
During the critical analysis of the paper it was recognised that some
of the data lacked clarity, for example, details of mean blood sugars
;information should have been clearer as to whether these were the mean
blood sugars for the whole pregnancy or only at time of delivery. It would
also have been of interest to know whether the identified cases of
hypertension were treated or untreated as this may have been particularly
relevant to the identified outcomes.
OVERALL, VERY INTERESTING READING, AND CERTAINLY AN INDICATION THAT
FURTHER, LARGER SCALE STUDIES OF THIS SORT ARE INDEED NEEDED TO INFLUENCE
AND IMPROVE PRACTICE.
Competing interests: No competing interests