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Intrauterine Growth Restriction Still a Riddle

In this issue Anastasia Varvarigou extensively reviews the mechanisms leading to intrauterine growth restriction (IUGR) which is a potential risk factor for adult disease onset. In a substantial number of children the only information we have is that the child was born small for gestational age (SGA). 'As stated also by Varvarigou, a distinction should be made between infants born SGA who grow consistently on a low percentile and those who are small as a result of IUGR. Children born SGA are a non-homogeneous group. Etiology and diagnostic needs vary among subgroups. In view of the knowledge accumulated about immediate and future risk factors of these children born SGA it is important to study the etiology and to invest in long-term prevention programs. Current knowledge does not always enable us to identify in each child the etiological cause for IUGR. An intact maternal hormonal system is a prerequisite for a normal intrauterine growth pattern. But etiologies originating from the fetus, the placenta and the environment should also be taken into consideration. It is sometimes impossible to separate etiologies since systems interact and affect each other. As seen in the following example: Comparison of maternal and cord blood levels of vitamin A, folic acid and iron demonstrated no difference between mothers of IUGR children and those of normal children. At the same time, IUGR infants had a higher percentage of children with lower vitamin A, folic acid and iron levels than those born appropriate for gestational age (AGA). Mothers of IUGR infants had a higher level of ferritin than mothers giving birth to AGA children. Since infections induce an increase in ferritin blood levels it is possible that IUGR in these infants was secondary to intrauterine infection, lowering vitamin A, folic acid and iron blood levels. With the increased interest in mutations affecting growth, various mutations in the growth hormone (GH)-insulin-like growth factor (IGF) axis were discovered and their effects investigated, such as the human Arg59Ter insulin-like growth factor-I receptor (IGF1R) mutation and its implications for a gene dosage effect of human IGFJR. These changes may have an impact on human growth, organ function, and glucose metabolism. Few heterozygous mutations in IGF1R leading to IGF-I resistance and intrauterine and postnatal growth retardation have been described to date. In addition, it was recently reported that mutation within a kinase-conserved motif of the insulinlike growth factor-I receptor can also cause intrauterine and postnatal growth retardation. More explanations are needed to explain why different groups of children born SGA need a much higher dose of GH than those born AGA. Can epigenetic changes add an explanation not provided by mutations?