Fundamental changes occur in maternal metabolism and physiology during pregnancy. Over 280 days the mother's weight increases on average by 12.5 kg. The main increase in weight occurs in the second half of pregnancy and is caused by the growth of the conceptus, the enlargement of maternal organs, maternal storage of fat and protein and an increase in maternal blood volume and interstitial fluid. An increase in the basal metabolic rate results in the need for increased energy intake. In addition throughout pregnancy maternal metabolism
Hypoglycaemia in Clinical Diabetes, 2nd Edition. Edited by B.M. Frier and M. Fisher © 2007 John Wiley & Sons, Ltd adapts to ensure an adequate supply of nutrients to the growing fetus and developing placenta. A normal pregnancy is characterised by major alterations of glucose homeostasis. Fasting glucose declines and, although the plasma glucose is elevated after an oral glucose tolerance test, the mean plasma glucose level is around 4 mmol/l during the third trimester of a normal non-diabetic pregnancy on a normal diet (Paretti et al., 2001).
Development of the placenta in the uterus during the first trimester of pregnancy occurs in a low oxygen environment when maternal blood supply is restricted. During this time fetal metabolism is heavily anaerobic, which may serve to protect the developing embryo from oxygen free radical-mediated teratogenesis. At the start of the second trimester, when organogenesis is complete, the maternal circulation develops to support fetal growth.
In the second and third trimester the development of insulin resistance leads to increased insulin secretion to avoid abnormal increases in glucose, free fatty acids and amino acids. In normal pregnancy insulin sensitivity is decreased by between 30 and 60%. Changing hormonal levels make a major contribution to insulin resistance. Human placental lactogen (HPL) has actions similar to growth hormone. It increases lipolysis with a rise in free fatty acids which are a steady source of energy for the mother and fetus during periods of starvation. Progesterone is also associated with insulin resistance. Maternal lipid stores increase during pregnancy and adipokines and cytokines may play a role in the development of increasing insulin resistance. The cytokine tumour necrosis factor-alpha (TNF-a) rises as the fat mass increases and can be related to insulin resistance. In pregnant women a decrease of adiponectin has been shown to relate to increasing insulin resistance in the third trimester. In women with type 1 diabetes the physiological development of insulin resistance during pregnancy poses challenges to the expectant mother who is attempting to maintain normoglycaemia.
Many other changes in physiology occur in pregnancy. The complex process of placental development is mostly complete by the end of the second trimester though the placenta continues to expand with the growing fetus. In the third trimester maternal metabolism switches from anabolism to catabolism, permitting an enhanced transfer of nutrients across the placenta to sustain rapid fetal growth. The placenta is an active organ in this process. In addition to synthesising various hormones the placenta regulates the transfer of maternal fuels to the fetus and facilitates maternal metabolic adaptation at different stages of pregnancy. Cells in contact with the maternal circulation and fetal circulation have a range of receptors, transporters and channels on both placental surfaces.
At term the placenta of the mother with diabetes shows a number of differences from those in women who do not have diabetes. These include changes in morphology, blood flow, transport and metabolism. This is important since transplacental transport of glucose is a facilitated process and net transfer is strongly dependent on the concentration gradient of glucose between the maternal and fetal blood. However, the correlation between various indices of glucose control - e.g. HbA1c and fetal growth - is poor, suggesting that factors other than maternal hyperglycaemia contribute to accelerated fetal growth (Penney et al., 2003b). Up-regulation of placental glucose transporters in type 1 diabetes may contribute to increased placental glucose transfer and stimulate fetal growth even if the mother has excellent glycaemic control. Transport of amino acids across the human placenta is an active process resulting in amino acid concentrations in the fetal circulation that are substantially higher than those in the maternal circulation.
Management strategies in women with type 1 diabetes need to take the metabolic adaptations of pregnancy into account. Although insulin resistance is the characteristic feature of the later stage of pregnancy, in the first trimester a modest increase in insulin sensitivity occurs. The Diabetes In Early Pregnancy study (DIEP) reported declining insulin requirements in the middle of the first trimester of pregnancy in women with type 1 diabetes (Jovanovic et al., 2001). Over-insulinisation at this stage may be an issue since women will be striving for optimal glycaemic control during the crucial period of organogenesis. Hyperemesis gravidarum may also contribute to an increased risk of hypoglycaemia.
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