Amniotic IGF-I supplements improve gut growth but reduce circulating IGF-I in growth-restricted fetal sheep

Abstract

Insulin-like growth factor I (IGF-I) is an important regulator of fetal growth, and circulating concentrations are reduced in intrauterine growth-restricted (IUGR) fetuses. We investigated whether IGF-I administered into amniotic fluid could ameliorate IUGR in fetal sheep. Fetuses were assigned to control ( n = 9), IUGR+saline ( n = 12), or IUGR+IGF-I groups (daily intra-amniotic IGF-I injections of 20 μg, n = 13). IUGR was induced by placental embolization from 114 to 120 days. Treatment was from 120 to 130 days of gestation. Embolization produced asymmetrically IUGR fetuses with decreased body weight and lighter, thinner-walled guts. Fetal plasma and amniotic IGF-I levels were reduced. During treatment, fetal plasma, but not amniotic, IGF-I levels recovered in the saline group but remained depressed in the IGF-I-treated group. IGF-I treatment restored gut weight and wall thickness to control levels and increased the number of crypt mitoses. Fetal weight was similar to that of controls, but spleen, liver, and thymic weights were reduced by 30–37%, and placentome growth was altered. Amniotic fluid IGF-I supplementation may provide the basis of future therapeutic approaches to IUGR, but the systemic effects require further investigation.

Amniotic IGF-I supplementation of growth-restricted fetal sheep alters IGF-I and IGF receptor type 1 mRNA and protein levels in placental and fetal tissues

“…In the fetal rat, levels of expression of the IGFBPs increase with advancing gestation (Shoubridge et al 2001). Although IGF-I treatment enhanced gut growth in our study, morphological development of the small intestine appeared to be delayed with persistence of the apical endocytic complex (Bloomfield et al 2002a). The reduced mRNA levels of IGFBP-1, -2 and -3 in the gut that we report here may be consistent with delayed functional maturation.…”

“…However, there was no increase in fetal body weight or fetal growth rate. In contrast, fetal liver weight was actually 11% lower than that of saline-treated IUGR fetuses, and circulating concentrations of IGF-I were reduced by 30-40% (Bloomfield et al 2002a). This was despite the fact that amniotic fluid IGF-I levels were increased up to fivefold, and that 125 I-labelled IGF-I given into amniotic fluid is swallowed by the fetus and is taken up intact across the gut and into the portal venous system and thence into the systemic circulation (Bloomfield et al 2002b).…”

“…The experimental protocol for the animal studies has been reported previously in detail (Bloomfield et al 2002a). In brief, 29 ewes carrying singleton fetuses underwent surgery at 110 days of gestation (term 145 days) for implantation of chronic indwelling vascular and amniotic catheters.…”

“…Growth restriction was induced by uteroplacental embolisation using microspheres from 113 to 120 days of gestation, and growth-restricted fetuses were then treated with once daily intra-amniotic injections of 2 ml saline (n=9) or 20 µg human recombinant IGF-I (Pharmacia and Upjohn, Peapack, NJ, USA) mixed with 2 ml fresh amniotic fluid (n=11) for 10 days, from 120 to 130 days of gestation. We calculated that this dose would increase amniotic fluid IGF-I levels tenfold, but the actual increase was approximately fivefold (Bloomfield et al 2002a). Control fetuses were unembolised and untreated.…”

“…Insulin-like growth factor (IGF)-I is a major fetal growth factor in late gestation (Oliver et al 1999), is present in amniotic fluid (Merimee et al 1984), is nutritionally regulated (Oliver et al 1996) and circulating levels are correlated with birthweight (Verhaeghe et al 1993). We have recently reported the effects of chronic, 10-day supplementation of amniotic fluid with a low dose of IGF-I (20 µg/day) in late gestation growth-restricted fetal sheep (Bloomfield et al 2002a). We found a significant increase in gut weight, with histological evidence of increased gut growth and increased numbers of mitotic bodies in the intestinal crypts.…”