Department of Perinatology, Kagawa Medical University, 17501 Ikenobe, Miki, Kagawa 761-0793, Japan
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Abstract |
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Key words: amniotic fluid/early second-trimester/fetal growth/hepatocyte growth factor/insulin-like growth factor-I
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Introduction |
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Concentrations of HGF in the amniotic fluid were highest between 20 and 29 weeks of gestation, and amnion from the second-trimester was shown to secrete 100-fold more HGF than that from the third-trimester (Horibe et al., 1995). There has been only one report on the concentration of HGF in human amniotic fluid at second-trimester, in relation to fetal birth weight (Kurauchi et al., 1995
). In that study, the concentration of amniotic HGF at second-trimester showed a significant inverse correlation with birth weight (r2 = 20%, P < 0.05). However, the number of observations (n = 20) reported in that study was very small, and the value of coefficient of determination was low. The aim of this study was to re-evaluate whether amniotic fluid HGF concentrations at second-trimester show a significant inverse correlation with birth weight, and to evaluate whether HGF concentrations in the early second-trimester amniotic fluid predict fetal growth at birth.
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Materials and methods |
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HGF was measured by an enzyme-linked immunosorbent assay (ELISA) kit (HGF Otsuka ELISA kit; Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan). The minimum detection limit of this assay for HGF was 0.3 ng/ml. The coefficients of intra-assay and inter-assay variation were 3.7 and 4.7% respectively.
IGF-I was measured by an immunoradiometric assay (IRMA) kit [IGF-I (Somatomedin-C) IRMA `Daiichi'; Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan]. The minimum detection limit of this assay for IGF-I was 0.03 ng/ml. The coefficients of intra-assay and inter-assay variation were 1.8 and 2.4% respectively.
All values were given as mean ± SD. Statistical analysis for comparison of gestational age at amniocentesis, birth age, birth weight, neonatal height, placental weight, and amniotic fluid HGF and IGF-I concentrations among the groups was performed using an analysis of variance and NewmanKeuls multiple comparison test. Statistical analysis for comparison of maternal age, and parity among the three groups was performed using a KruskalWallis one-way analysis of variance by ranks and multiple comparisons. The Spearman rank test was used to assess correlation between amniotic fluid HGF or IGF-I concentrations and birth weight, height, or placental weight. P < 0.05 was considered significant.
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Results |
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Discussion |
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The human placenta is one of the richest sources of HGF (Wolf et al., 1991), which was first sequenced from a human placenta cDNA library (Miyazawa et al., 1994
). Schmidt et al. (1995) and Uehara et al. (1995) demonstrated independently that HGF is essential for normal placentation in mice. Absence of either HGF or c-met seems to prevent the normal growth and development of the epithelially-derived labyrinthine trophoblast cells, leading to growth restriction and intrauterine death secondary to placental insufficiency (Somerset et al., 1997
). Moreover, it has been shown that amnion secretes a considerable amount of HGF into amniotic fluid, which suggests the importance of HGF in relation to fetal growth (Horibe et al., 1995
).
Before 20 weeks HGF concentrations in the amniotic fluid were relatively high, and they were significantly elevated between 20 and 29 weeks (Horibe et al., 1995). After 30 weeks, however, they dramatically decreased to concentrations lower than those before 20 weeks. These authors also demonstrated, by use of amnion organ culture, that HGF was released from amnion and the amount released from amnion during the second-trimester was considerably higher than that released from amnion of the third trimester. It was shown that amniotic fluid HGF concentrations at the second-trimester are negatively correlated with birth weight (Kurauchi et al., 1995
). However, the number of observations (n = 20) reported in their study was very small, and the value of coefficient of determination was low. In this study, there were no significant differences for amniotic fluid HGF concentrations among the three groups (SGA, AGA, and LGA infant groups), and there was also no correlation between amniotic fluid HGF concentrations and birth weight, height, or placental weight. The reason for this difference of the results between Kurauchi's (1995) and the current investigation is currently unclear. One possible explanation is that the concentration of HGF receptors in fetal and placental tissue in each group may be different for the determination of birth weight, height, and placental size. Another explanation is that the high HGF concentration in the second-trimester amniotic fluid may be simply a secondary reflection of local tissue events. As gestation advances, fetal urine makes an increasingly important contribution to the amniotic fluid. The low concentrations found for fetal and first neonatal urine samples indicate that fetal urine does not greatly contribute to the HGF concentration in amniotic fluid (Kurauchi et al., 1995
). The results of the present study suggest that HGF concentration in the early second-trimester amniotic fluid does not correlate with fetal growth at birth, and also does not correlate with placental size. A recent study (Aoki et al., 1998
) demonstrated that maternal serum HGF concentrations were decreased in pregnancies with SGA infants, whereas there was no significant difference for circulating HGF concentrations in cord blood between SGA and AGA infants (Aoki et al., 1998
). Further study is needed to clarify the role of high HGF concentrations in second-trimester amniotic fluid during pregnancy.
A negative correlation of growth factors with birth weight was earlier reported for umbilical cord IGF-I concentrations and explained by the elevated IGF-I binding proteins which inhibit the effects of IGF-I on tissue growth (Wang et al., 1991). Moreover, IGF-I binding protein, the concentration of which is high in amniotic fluid, inhibits the effect on IGF-I at a cellular level (Elgin et al., 1987
; Ritovos et al., 1988
). In this study, there were no significant differences for amniotic fluid IGF-I concentrations among the three groups (SGA, AGA, and LGA infant groups). There was also no correlation between amniotic fluid IGF-I concentrations and birth weight, height, or placental weight. Above mentioned studies on IGF-I and IGF-I binding protein (Elgin et al., 1987
; Ritovos et al., 1988
; Wang et al., 1991
) were all in-vitro studies, however, the results of this study were of an in-vivo investigation. Therefore, these differences in IGF-I effect on fetal growth may be due to the difference in experimental methods.
In conclusion, the difference of HGF concentrations in the early second-trimester amniotic fluid does not predict fetal growth and placental size at birth. The presence of extremely high HGF concentrations in amniotic fluid may be involved in maturation of the fetal lung (Itakura et al., 1997) or digestive tract (Okamura et al., 1998
), since these tissues become directly exposed through ingestion. Further study is needed to clarify the physiological role of amniotic fluid HGF as well as the origin of this factor.
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Notes |
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References |
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Submitted on March 16, 1999; accepted on July 1, 1999.