Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients and oxygen to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. Hormones play a central role in regulating fetal growth and development. They act as maturational and nutritional signals in utero and control tissue development and differentiation according to the prevailing environmental conditions in the fetus. The insulin-like growth factor (IGF) system, and IGF-I and IGF-II in particular, plays a critical role in fetal and placental growth throughout gestation. Disruption of the IGF1, IGF2 or IGF1R gene retards fetal growth, whereas disruption of IGF2R or overexpression of IGF2 enhances fetal growth. IGF-I stimulates fetal growth when nutrients are available, thereby ensuring that fetal growth is appropriate for the nutrient supply. The production of IGF-I is particularly sensitive to undernutrition. IGF-II plays a key role in placental growth and nutrient transfer. Several key hormone genes involved in embryonic and fetal growth are imprinted. Disruption of this imprinting causes disorders involving growth defects, such as Beckwith-Wiedemann syndrome, which is associated with fetal overgrowth, or Silver-Russell syndrome, which is associated with intrauterine growth retardation. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood. Given the high incidence of intrauterine growth retardation and the high risk of metabolic and cardiovascular complications in later life, further clinical and basic research is needed to develop accurate early diagnosis of aberrant fetal growth and novel therapeutic strategies.

1.
Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3–34.
2.
Hwa V, Oh Y, Rosenfeld RG: The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 1999;20:761–787.
3.
Schneider MR, Lahm H, Wu M, Hoeflich A, Wolf E: Transgenic mouse models for studying the functions of insulin-like growth factor-binding proteins. Faseb J 2000;14:629–640.
4.
Fowden AL: The insulin-like growth factors and feto-placental growth. Placenta 2003;24:803–812.
5.
Nayak NR, Giudice LC: Comparative biology of the IGF system in endometrium, decidua, and placenta, and clinical implications for foetal growth and implantation disorders. Placenta 2003;24:281–296.
6.
Gluckman PD, Pinal CS: Regulation of fetal growth by the somatotrophic axis. J Nutr 2003;133:1741S–1746S.
7.
Fowden AL, Forhead AJ: Endocrine mechanisms of intrauterine programming. Reproduction 2004;127:515–526.
8.
Baker J, Liu JP, Robertson EJ, Efstratiadis A: Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993;75:73–82.
9.
Butler AA, LeRoith D: Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology. Endocrinology 2001;142:1685–1688.
10.
Reik W, Constancia M, Fowden A, Anderson N, Dean W, Ferguson-Smith A, Tycko B, Sibley C: Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol 2003;547:35–44.
11.
Silha JV, Murphy LJ: Insights from insulin-like growth factor binding protein transgenic mice. Endocrinology 2002;143:3711–3714.
12.
Arends N, Johnston L, Hokken-Koelega A, van Duijn C, de Ridder M, Savage M, Clark A: Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 2002;87:2720–2724.
13.
Vaessen N, Janssen JA, Heutink P, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM: Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet 2002;359:1036–1037.
14.
Woods KA, Camacho-Hubner C, Savage MO, Clark AJ: Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996;335:1363–1367.
15.
Bonapace G, Concolino D, Formicola S, Strisciuglio P: A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Genet 2003;40:913–917.
16.
Walenkamp MJ, Karperien M, Pereira AM, Hilhorst-Hofstee Y, van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, van Duyvenvoorde HA, van Thiel SW, Sluimers CA, Bax JJ, de Laat JA, Breuning MB, Romijn JA, Wit JM: Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 2005;90:2855–2864.
17.
Jain S, Golde DW, Bailey R, Geffner ME: Insulin-like growth factor-I resistance. Endocr Rev 1998;19:625–646.
18.
Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD: IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211–2222.
19.
Domene HM, Bengolea SV, Martinez AS, Ropelato MG, Pennisi P, Scaglia P, Heinrich JJ, Jasper HG: Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004;350:570–577.
20.
Hitchins MP, Moore GE: Genomic imprinting in fetal growth and development. Expert Rev Mol Med 2002;2002:1–19.
21.
Reik W, Walter J: Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001;2:21–32.
22.
Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H, Audry G, Vazquez MP, Gicquel C: Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Ge net 2001;9:409–418.
23.
Young LE, Fernandes K, McEvoy TG, Butterwith SC, Gutierrez CG, Carolan C, Broadbent PJ, Robinson JJ, Wilmut I, Sinclair KD: Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet 2001;27:153–154.
24.
Fisher AM, Thomas NS, Cockwell A, Stecko O, Kerr B, Temple IK, Clayton P: Duplications of chromosome 11p15 of maternal origin result in a phenotype that includes growth retardation. Hum Genet 2002;111:290–296.
25.
Eggermann T, Meyer E, Obermann C, Heil I, Schuler H, Ranke MB, Eggermann K, Wollmann HA: Is maternal duplication of 11p15 associated with Silver-Russell syndrome? J Med Genet 2005;42:e26.
26.
Obermann C, Meyer E, Prager S, Tomiuk J, Wollmann HA, Eggermann T: Searching for genomic variants in IGF2 and CDKN1C in Silver-Russell syndrome patients. Mol Genet Metab 2004;82:246–250.
27.
Meyer E, Eggermann T, Wollmann HA: Analysis of genomic variants in the KCNQ1OT1 transcript in Silver-Russell syndrome patients. Mol Genet Metab 2005;84:376–377.
28.
Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y: Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 2005;37:1003–1007.
29.
Maher ER, Afnan M, Barratt CL: Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum Reprod 2003;18:2508–2511.
30.
Lucifero D, Chaillet JR, Trasler JM: Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology. Hum Reprod Update 2004;10:3–18.
31.
Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS: Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–737.
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