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Intrauterine factors, adiposity, and hyperinsulinaemia

BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7420.880 (Published 16 October 2003) Cite this as: BMJ 2003;327:880

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Metformin crosses the placenta: a modulator for fetal insulin resistance?

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
diabetes.

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
placental transfer(5).

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.

References:

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
1961;16:509-520.

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
Livingstone, 1975:205-220.

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
2003;326(7392):762.

7. Charles BG, Jacobsen NW, Ravenscroft PJ. Rapid liquid-chromatographic
determination of metformin in plasma and urine. Clin Chem 1981;27(3):434-
6.

Competing interests:
None declared

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

04 December 2003
William M Hague
Senior consultant physician in obstetric medicine
Peter M. Davoren, H. David McIntyre, Ross Norris, Xiao Xiaonian, Bruce Charles
University of Adelaide, Women's and Children's Hospital, North Adelaide, South Australia 5006