Intrauterine factors, adiposity, and hyperinsulinaemiaBMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7420.880 (Published 16 October 2003) Cite this as: BMJ 2003;327:880
All rapid responses
Your editorial “Intrauterine factors, adiposity and
hyperinsulinaemia(1)” highlighted the hyperinsulinaemia in the cord blood
of Indian babies when compared with British babies(2), and raised the
question of how best to address the issue of regulation of fetal growth,
in such as way as to reduce the current pandemic of obesity and type 2
One potential response to this important issue might be to modulate
the fetal hyperinsulinaemia in utero with an insulin-sensitising agent
such as metformin.
Data on the passage of metformin across the placenta are few and
contradictory. A radio-labelled study in rodents suggested that metformin
does not cross the placenta(3), while a spectrophotometric assay found
metformin in the amniotic fluid but not in cord blood in samples from two
women(4). A more recent study suggested that metformin does not affect
human placental glucose uptake or transport, but that its size argued for
We therefore performed a study to establish whether orally ingested
metformin does cross the placenta into the human fetus. Blood was drawn
on several occasions (n=19) from 7 women who were being treated with
metformin during pregnancy as part of a clinical trial(6). The median
daily dose was 2000 mg (range 1500-3000 mg), and the median time after
dosing 270 minutes (range 100-720 minutes). Cord blood was taken at
delivery from the babies of these 7 women and also from a further 16
babies whose mothers had been taking metformin during pregnancy, but who
had not been sampled during pregnancy: the median time after dosing was
600 minutes (range 210-20160 minutes).
Plasma metformin concentrations were measured in duplicate, using
reverse phase, high performance liquid chromatography: Within-day and
between-day precision (CV) for the assay of plasma containing 2 µg/mL (1.2
x 10^-5 mol) of metformin hydrochloride was 3.6% and 3.9%, respectively.
The lower limit of quantitation is 0.05 µg/mL (3.0 x 10^-7 mol.L^-1
metformin)as metformin hydrochloride(7). Results are shown in the table.
metformin concentration: median (range) Pregnant women 1.05 (0.06-2.93) µg/mL Cord blood 0.63 (0.08-2.55) µg/mL
The median difference in metformin concentration between maternal and
cord blood was 0.54 µg/mL (95% confidence interval 0.19-0.93) (one-sided
Mann-Whitney: P=0.0027). We concluded that significant amounts of
metformin can cross the human placenta.
Transplacental passage of metformin therefore offers the possibility
of modulating the intra-uterine development of insulin resistance in the
human fetus/neonate. It will clearly be important to follow up in the
long term the offspring of women taking part in ongoing randomised trials
of metformin in pregnancy, such as the MiG study(6), to determine the
impact of such interventions. There may of course be different effects in
different ethnic populations.
1. Prentice AM. Intrauterine factors, adiposity, and
hyperinsulinaemia. BMJ 2003;327(7420):880-881.
2. Yajnik CS, Lubree HG, Rege SS, Naik SS, Deshpande JA, Deshpande SS, et
al. Adiposity and hyperinsulinemia in Indians are present at birth. J Clin
Endocrinol Metab 2002;87(12):5575-80.
3. Cohen Y. Le passage transplacentaire des medicaments. Therapie
4. Stowers J, Sutherland H. The use of sulphonylureas biguanides and
insulin in pregnancy. In: Sutherland H and Stowers J, editors.
Carbohydrate metabolism in pregnancy and the newborn. Edinburgh: Churchill
5. Elliott B, Langer O, Schuessling F. Human placental glucose uptake and
transport are not altered by the oral antihyperglycemic agent metformin.
American Journal of Obstetrics & Gynecology 1997;176(3):527-530.
6. Hague WM, Davoren PM, Oliver J, Rowan J. Contraindications to use of
metformin. Metformin may be useful in gestational diabetes. BMJ
7. Charles BG, Jacobsen NW, Ravenscroft PJ. Rapid liquid-chromatographic
determination of metformin in plasma and urine. Clin Chem 1981;27(3):434-
Competing interests: metformin concentration: median (range)Pregnant women 1.05 (0.06-2.93) µg/mLCord blood 0.63 (0.08-2.55) µg/mL
Prentice discusses foetal programming and the predicted global
epidemic of obesity driven type 2 diabetes.1 The disharmony between (low)
foetal growth and (high) adult weight predicts pathology. Improved
availability of nutrition in adulthood will inevitably mean that “thin-
fat” babies will be exposed to an increased risk of developing the
Barker has asked “can the adverse effects of increasing energy
intakes be offset by improved fetal and infant nutrition?”2 Maternal
constraint limits intrauterine growth but the early postnatal period is
important, increased weight gain during the first year is associated with
lower adult risk.2 The foetal growth period extends beyond birth,
continuing over several weeks or months3; maternal constraint has been
removed so growth should be rapid.
Our interest in this area was stimulated when we realised that many
young babies were gaining weight much too slowly over the first few
months. This problem was more obvious in breastfed babies, many of whom
were having prolonged feeds, often from only one breast and an irregular
feeding pattern. A change to regular feeds, both breasts (10 minutes each
side) at each feed results in a tremendous improvement in weight gain.
Some babies gain 1lb (454g) or even more a week. Bottle-fed babies also
benefit from a regular feeding pattern. However although babies still grow
very well the ability to gain weight quite so quickly seems to be lost in
many after the age of 6-8 weeks.
This clinical experience is supported by evidence from studies
showing that both breast4 and bottle-fed5 babies exhibit the ability to
gain weight more quickly than expected over the first 6-8 weeks. (Advice
to breastfeeding mothers has changed since the breastfeeding studies were
With regard to the development of type 2 diabetes Prentice asks “so
how should we try to intervene to limit the damage”.
We suggest that rapid postnatal growth, promoted by appropriate
feeding patterns would act to improve adult outcomes.
Carol A Walshaw
Oakworth Medical Centre,
3 Lidget Mill,
Jenny M Owens
Oakworth Medical Centre,
3 Lidget Mill,
1 Prentice A M. Intrauterine factors, adiposity, and
2003;327:880-1 (18th October.)
2 British Medical Bulletin 2001;60. ISBN 0-19-922484-6
3 Karlsberg J et al. Acta Paediatr Scand (Suppl)356:26-37, 1989
4 An Evaluation of Infant Growth. WHO Working Group on Infant Growth.WHO
5 Fomon S J et al. Acta Paediatr Scand 64: 172-181, 1975
Competing interests: No competing interests