Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Early Postnatal Growth and Foetal Programming
- Carol Anne Walshaw, Jenny M Owens (27 November 2003)
-
Metformin crosses the placenta: a modulator for fetal insulin resistance?
- William M Hague, Peter M. Davoren, H. David McIntyre, Ross Norris, Xiao Xiaonian, Bruce Charles (4 December 2003)
|
|
|||
|
Carol Anne Walshaw, GP Oakworth Medical Centre, 3 Lidget Mill, Oakworth, Keighley, BD22 7HN, Jenny M Owens
Send response to journal:
|
Editor 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 metabolic syndrome. 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 performed). 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 Jenny M Owens
1 Prentice A M. Intrauterine factors, adiposity, and hyperinsulinaemia. BMJ 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 Geneva 1994. 5 Fomon S J et al. Acta Paediatr Scand 64: 172-181, 1975 Competing interests: None declared |
|||
|
|
|||
|
William M Hague, Senior consultant physician in obstetric medicine University of Adelaide, Women's and Children's Hospital, North Adelaide, South Australia 5006, Peter M. Davoren, H. David McIntyre, Ross Norris, Xiao Xiaonian, Bruce Charles
Send response to journal:
|
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 |
|||