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  Oct 20, 2018

Intrauterine growth restriction: pathophysiology

Intrauterine growth retardation (IUGR) is a condition in which the baby fails to grow properly in the mother’s womb. While there are various causes, they can be placed under three headings in all: fetal, maternal, and placental causes. The fact remains that IUGR is mostly multifactorial.

Fetal causes mostly relate to defects in fetal genetics or metabolism, or excessive fetal number. Maternal causes have to do with maternal uterine anomalies, medical conditions, and demographic or social characteristics of the mother. Placental causes are related to defects in placenta formation and function.

Basis of IUGR

Both placental and maternal causes act chiefly to reduce blood flow across the placenta, and thus prevent the effective and adequate transfer of blood gases and food from the mother to the fetus.

The reduced availability of oxygen and nutrition during fetal development causes the fetus to change its genetic mode of expression by various molecular changes, called epigenetic changes. This dictates its response to food supply throughout its life (the ‘thrifty phenotype’ hypothesis).

IUGR in preeclampsia

In pregnancies with preeclampsia, a hypertensive condition associated with IUGR in many cases, there is a marked release of many hormones and other molecules which inhibit the proper development of blood vessels and activate the blood clotting system in an inappropriate way.

These eventually result in abnormal development of the placental blood vessels, with the failure of the maternal spiral arterioles in the uterine wall to convert into the normal low-pressure placental circulation with a high blood flow. This is designed to provide plenty of nutrition to the baby. In its absence, the baby is likely to suffer from IUGR.

Nutritional deficiency in IUGR

In addition, various fetal changes occur leading to reduced stores of fat and glycogen in liver and muscles. Glycogen is a storage form of starch in the human body which can be broken down to simpler sugars for energy needs. Deficiency of glycogen stores in turn results in hypoglycemia, or low glucose levels, in the newborn period, while the baby is adjusting to its cutoff from placental nutrition.

Babies with IUGR has little fat stored under the skin, and this is noticeable in the appearance of the pinched ‘old-looking’ face, the prominent rib cage, and easily pinched skin folds. The low store of fat means that other sources of energy are also not available.

These changes also lead to the baby’s being unable to burn fat and create sugar from the byproducts, a process called gluconeogenesis. Glucose cannot be produced as required in the baby’s body. Stress hormones like epinephrine, and glucose-enhancing hormones such as glucagon, are low. Insulin receptors become more sensitive to glucose levels.

Hormonal disruption in IUGR

The growth of a baby in the womb is seriously dependent on several hormones, including insulin, thyroid hormones, adrenal and pituitary hormones.

Insulin promotes cell division, and increases the use of glucose by the body cells. It inhibits the breakdown of protein for energy and so encourages its use for body building. Insulin secretion in the baby is a signal that enough food is available for growth. Lack of insulin is thus a growth inhibitor, and the baby starts to show signs of IUGR.

Another factor is the insulin-like growth factor (IGF)-1, which increases in concentration as the glucose supply goes up. It promotes cell multiplication and encourages glucose or amino acid transfer across the placenta. It is necessary for proper brain development and thus its deficiency in the baby results in IUGR with poor growth of central nervous system neural networks.

Deficiency of thyroid hormones in the baby during its life in the womb causes poor uptake of oxygen, decreased burning of glucose, and so lack of energy for growth and other body functions. The normal secretion of IGF-1 is also dependent upon thyroid hormone levels.

Glucocorticoid hormones are the classical stress hormones, and are important in the development of many organs in the growing baby. They influence the storage of glycogen in various tissues, the production of glucose as needed by the body for extra fuel, the burning of fatty acids for energy and to start off glucose manufacture. In addition, they trigger lung maturation in the baby at term by inducing the production and secretion of lung surfactant.

These are molecules which reduce the surface tension in the lung alveoli and so keep them open even during respiration. Glucocorticoids also help with the proper development of the gastrointestinal tract, the production of adult hemoglobin rather than fetal hemoglobin, which is the predominant form during the baby’s life in the womb, and the maturation of important glands such as the thymus, liver and kidney.

The pregnancy-associated plasma protein-A (PAPP-A) is a placental hormone, and it enters the mother’s blood to enhance IGF action. When it is low in early pregnancy, it signals that the chances of IUGR are high.

Hypoxia in IUGR

In addition to this, the chronic reduction in oxygen supply from the dysfunctional placenta leads to chronic hypoxia, which stimulates the baby to produce the hormone erythropoietin. This in turn stimulates red cell production. Eventually the red cell count is so high that polycythemia results.

These babies often tolerate the uterine contractions of labor poorly as they are already surviving on very little oxygen. This leads to perinatal asphyxia, or hypoxic changes in the baby during the process of labor and birth, which may even result in stillbirth.

Other issues

Other problems in IUGR babies include low blood calcium levels, as a result of decreased oxygen levels. The baby cannot burn enough fat and sugar to maintain a normal body temperature because of the low energy stores, and is therefore at risk of hypothermia.

Other contributors to this condition include immature thermoregulation mechanisms (which normally keep the body temperature normal), low stress hormone levels, loss of water through the skin, hypoglycemia, and the lack of an insulating layer of fat below the skin. The IUGR baby may have bleeding into the lungs because of the effects of various combinations of the above factors on lung and vascular development.

Such babies also generally show poor immune system development. In fetal causes of IUGR, the low growth may be due to genetic abnormalities, metabolic defects which prevent the proper functioning of various systems, or the presence of infections in intrauterine life which destroy fetal cells and so restrict growth and development.