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Elevated Umbilical Cord Ghrelin Concentrations in Small for Gestational Age Neonates

Endocrinology and Diabetes Unit (A.C.K.W., J.-P.C.), Special Care Nursery (J.F., R.W., P.C.), British Columbia’s Children’s Hospital, Vancouver, British Columbia, Canada V6H 3V4; and Endocrine Division, Lilly Research Laboratories, Eli Lilly & Co. Corporate Center (M.H.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Dr. Jean-Pierre Chanoine, Endocrinology and Diabetes Unit, Room K4-212, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, British Columbia, Canada V6H 3V4. E-mail: jchanoine{at}cw.bc.ca.

	Abstract

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Ghrelin has orexigenic effects. It is present in umbilical cord plasma in full-term neonates, raising the prospect that ghrelin plays a role in fetal and neonatal energy balance. We measured ghrelin in small (SGA), appropriate (AGA), and large (LGA) for gestational age neonates and evaluated whether ghrelin levels are modulated by neonatal insulin and glucose concentrations. Plasma concentrations of ghrelin, insulin, and glucose were measured in cord blood sampled at birth in 123 SGA, AGA, and LGA neonates (gestational age, 24–41 wk) born to mothers with and without diabetes. Ghrelin was detected in samples from all infants. Its concentration was 40% higher in SGA neonates (mean ± SD, 2436 ± 657 pg/ml) compared with AGA (1738 ± 380) and LGA (1723 ± 269) neonates. There was a positive correlation between ghrelin and gestational age in AGA/LGA (r = 0.23; P < 0.05) and a negative correlation in SGA (r = -0.67; P < 0.005) neonates. Therefore, the difference in ghrelin between SGA and AGA/LGA neonates decreases with advancing gestational age. Birth weight z-score, maternal hypertension, and glucose concentrations were significant determinants of ghrelin concentrations. In conclusion, SGA neonates present with higher umbilical cord ghrelin plasma concentrations than AGA/LGA neonates. Ghrelin may play a physiological role in fetal adaptation to intrauterine malnutrition.

	Introduction

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GHRELIN IS A 28-amino acid peptide secreted by the fundus of the stomach (1, 2, 3, 4, 5), the hypothalamus (1), and the placenta (6) in rats and humans. Ghrelin stimulates GH secretion and has orexigenic effects when injected in the hypothalamus or iv (7, 8, 9). In animals it also increases adiposity by decreasing fat utilization (10).

In adult humans, plasma ghrelin increases before each of the three main meals and decreases to a nadir 90 min after the meal, suggesting that it plays a physiological role in meal initiation (11). Ghrelin is closely associated with glucose metabolism and body mass. Broglio et al. (12) demonstrated that ghrelin induces hyperglycemia and decreases plasma insulin concentrations. Conversely, hyperglycemia (13, 14) and insulin (in the absence of hypoglycemia) (15) decrease plasma ghrelin. Fasting ghrelin concentrations are increased with anorexia nervosa (3, 16) and decreased with obesity (17), suggesting that in these conditions ghrelin does not play a causative role, but may change as part of an adaptive response. In contrast, markedly increased plasma ghrelin concentrations were observed in patients with Prader-Willi syndrome, a genetic condition characterized by insatiable appetite and massive obesity (18), suggesting that ghrelin overproduction may be responsible for the food-seeking behavior in these patients.

We recently demonstrated the presence of immunoreactive ghrelin in umbilical cord plasma samples in a large cohort of full-term Caucasian newborns, raising the prospect that ghrelin may play a role in fetal and neonatal energy balance (19).

The goal of the present study was 1) to compare ghrelin concentrations in premature and full-term infants born small (SGA), appropriate (AGA), and large (LGA) for gestational age; and 2) to evaluate whether ghrelin levels were modulated by neonatal insulin and glucose levels.

	Subjects and Methods

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Subjects

Plasma concentrations of ghrelin, insulin, and glucose were determined in cord blood sampled at birth in 123 newborns (64 males and 59 females) born at Children’s and Women’s Health Center of British Columbia over a 4-month period. The ethics committee of the University of British Columbia approved the study, and written informed consent was obtained from all mothers before cord blood sampling.

Demographic data

The following information was obtained from the medical record: maternal age, gestational age (calculated according to the date of the last menstrual period or, if unknown, to ultrasound dating), antenatal steroid administration (im injection of 12 mg betamethasone once a day for 2 d in mothers at risk of preterm delivery between 23–33 wk), presence of maternal diabetes [requiring insulin or treated with dietary measures only, according to WHO criteria (20)] or hypertension (blood pressure >140/90 mm Hg). Prematurity was defined as a gestational age less than 37 wk.

Neonatal anthropometric characteristics

Weight, length, and head circumference were recorded at birth by the attending nurse. SGA and LGA were defined as a birth weight below the 10th and above the 90th percentile for gestational age, respectively (21).

Cord blood

Venous cord blood was collected in EDTA tubes and kept at 4 C for 1–24 h before centrifugation. For ghrelin determination, aprotinin (10,000 KI/ml Trasylol, Bayer. Inc., Toronto, Canada), a protease inhibitor. was added in a 1:20 ratio to the plasma aliquot. All samples were stored at -80 C until analysis. All measurements were performed in the same assay, without extraction.

Immunoreactive ghrelin concentrations were measured in duplicate using a commercial RIA (Linco Research, Inc., St. Charles, MO). The antibody used in the assay is a rabbit polyclonal antibody against full-length octanoylated human ghrelin. Intra- and interassay coefficients of variation were 3.3% and 17.8% (for ghrelin concentrations of 1500 pg/ml), respectively. In our study EDTA cord blood samples were stored at 4 C for up to 24 h before being centrifuged, reflecting the 24 h service of a delivery room. To test the stability of ghrelin in the conditions of our study, blood EDTA (n = 4) samples were kept 2–8 and 8–24 h at 4 C before centrifugation and analysis. Ghrelin levels were 109 ± 10% and 108 ± 6%, respectively, of the values obtained when the samples were centrifuged within 2 h of delivery. Insulin was determined by ELISA using a two-site immunoassay with two monoclonal antibodies (Linco Research, Inc.). Intra- and interassay coefficients of variation were 6.0% and 10.3%, respectively. Glucose was measured using a coupled glucose oxidase/peroxidase reaction by reflectance spectrophotometry (Ortho Diagnostics, Rochester, NY).

Statistical analysis

Except when otherwise noted, values are expressed as the mean ± SD. Using multiple regression analysis, we examined the association between total ghrelin concentrations and gestational age, birth weight z-score [(birth weight - the mean of the population)/SD of the population], cord plasma insulin and glucose concentrations, maternal hypertension, gender, maternal age, maternal diabetes status, and prenatal administration of steroids (SPSS version 11.0, SPSS, Inc., Chicago, IL). Cord ghrelin plasma concentrations in SGA, AGA, and LGA neonates were compared by one-way ANOVA with post hoc test using the Bonferroni method. The relationship between ghrelin concentrations and birth weight z-score (Fig. 1), gestational age (Fig. 2) and glucose concentrations in SGA and AGA/LGA neonates was estimated using the Spearman coefficient (r). P < 0.05 was taken as significant.

View larger version (25K): [in this window] [in a new window]   FIG. 1. Relationship between cord ghrelin concentrations and birth weight z-score (n = 123; r = -0.34; P < 0.0001). Conversion factors (metric units to Systeme International units) for ghrelin: pg/ml x 0.296 = pmol/liter.

View larger version (23K): [in this window] [in a new window]   FIG. 2. Relationship between cord ghrelin concentrations and gestational age in SGA (n = 20; r = -0.68; P = 0.001) and AGA/LGA (n = 103; r = 0.22; P = 0.025). Conversion factors (metric units to Systeme International units) for ghrelin: pg/ml x 0.296 = pmol/liter.

	Results

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Figure 2 shows the relationship between ghrelin concentrations and gestational age. Visual inspection of the data suggests that this relationship was different in SGA and AGA/LGA neonates. There was a positive (r = 0.23; P < 0.05) and a negative (r = -0.67; P < 0.005) correlation between ghrelin and gestational age in AGA/LGA and SGA neonates, respectively. Overall, ghrelin concentrations were 40% higher in SGA neonates compared with those in AGA and LGA neonates (P < 0.0001, by ANOVA; Table 1), but the difference decreased with increasing gestational age (Fig. 2). The characteristics of the four premature, SGA neonates with the highest ghrelin concentrations were as follows: 1) pregnancy-induced hypertension, prenatal steroids, absent end-systolic umbilical artery flow, oligohydramnios, antiphospholipid syndrome, cesarean section, and male gender (ghrelin, 3236 pg/ml); 2) prolonged rupture of membranes, chorioamnionitis, oligohydramnios, steroids, spontaneous vaginal delivery (SVD), and female gender (ghrelin, 3286 pg/ml); 3) twin, SVD, and male gender (ghrelin, 3306 pg/ml); and 4) pregnancy-induced hypertension, substance-abusing mother (cocaine, amphetamine), SVD, and male gender (ghrelin, 4114 pg/ml).

	Discussion

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The results of our study show that umbilical cord concentrations of ghrelin were inversely related to birth weight z-score. In addition, ghrelin concentrations were higher in SGA compared with AGA/LGA neonates, and the difference decreased with advancing gestational age.

The source(s) of circulating ghrelin in the fetus remains unclear. Circulating ghrelin could conceivably originate from the placenta (6), the stomach (1, 2, 3, 4, 5), or other tissues, such as the pancreas or lung (22), that are known to synthesize ghrelin during early fetal life. In humans, ghrelin mRNA is detected throughout pregnancy, but ghrelin peptide is only detected during the first trimester (6), suggesting that it might not be a significant source of circulating ghrelin for the fetus after 25 wk gestation. In addition, whether locally produced ghrelin remains in the placenta or is secreted into the maternal or fetal circulation is presently unknown. The human stomach could serve as the main source of circulating ghrelin in the fetus as it does in the adult, but it is conceivable that other tissues could contribute to the fetal pool of ghrelin. For instance, significant synthesis of ghrelin has been demonstrated in the fetal, but not the adult, human pancreas (23).

The existence of an inverse relationship between cord ghrelin concentrations and birth weight z-score is intriguing and goes against the intuitive concept of a positive role for ghrelin in energy balance (2). However, a similar inverse relationship has been repeatedly observed in adults, where patients with anorexia nervosa and obesity have higher and lower ghrelin concentrations, respectively, than controls (3, 16, 17). Insulin resistance and hyperinsulinism, commonly reported in obese subjects, have been proposed to explain part of this relationship (24, 25, 26, 27). In our neonates, the cause of the inverse relationship is unclear. It is possible that as yet undetermined factors associated with lower birth weight could explain this relationship.

We also observed an inverse relationship between ghrelin and gestational age in SGA neonates. The more premature the SGA neonate, the higher the ghrelin concentrations. The cause of this difference is unknown. We hypothesize that SGA neonates born prematurely may be more severely affected than SGA neonates reaching term and that confounding metabolic factors associated with prematurity in these neonates may account for these differences.

In the present study ghrelin concentrations were significantly correlated with birth weight z-score, but were not affected by gender. This contrasts with our previous report, where we observed a significant negative correlation between ghrelin and birth weight in girls from Caucasian (but not Asian, our unpublished results) girls (19). The populations of infants investigated in the two studies are, however, very different. In the first study (19), we focused on healthy Caucasian, AGA, full-term neonates, and 80% of the birth weights were between 3100–4100 g. In the present study a more diverse group of premature and full-term, SGA and AGA/LGA, Caucasian and Asian neonates from mothers with or without diabetes is considered, and it is therefore not surprising that gender may not be found as a significant determinant of ghrelin concentrations.

Ghrelin concentrations were inversely related to glucose concentrations, but were independent from insulin concentrations and the existence of maternal diabetes. These data are consistent with animal and human studies showing that hyperglycemia (13) and insulin-induced hypoglycemia (28) markedly decreases and increases, respectively, ghrelin concentrations. Although the relationship between ghrelin and glucose was modest, it should be noted that the range of glucose concentrations observed in cord blood was relatively narrow (median, 4.7; 25th percentile, 3.9; 75th percentile, 5.6 mmol/liter), suggesting good control of the mothers with diabetes. Our results suggest that ghrelin regulation by glucose is already present at birth and raise the possibility that extreme variations in maternal glucose metabolism, such as in poorly controlled diabetes, might affect fetal ghrelin metabolism. The potential implications of this observation are presently unknown.

The potential role of ghrelin in the neonate remain poorly understood. A simple hypothesis is that higher ghrelin concentrations would stimulate appetite and result in higher nutritional intake by the neonate. Although prospective data are presently not available, this hypothesis is consistent with the recent findings by Iniguez et al. (29). They observed a significantly smaller glucose-induced drop in ghrelin concentrations in 1-yr-old infants born SGA who had experienced catch-up growth compared with those who had not, and proposed that higher postprandial ghrelin concentrations may have resulted in greater weight gain early in life.

In conclusion, ghrelin is present in umbilical cord plasma in human neonates, especially in SGA neonates. Ghrelin may play a physiological role in fetal adaptation to intrauterine malnutrition.

	Acknowledgments

 
Our thanks go to the nurses of the delivery suite at Children’s and Women’s Health Center of British Columbia for their help in collecting cord blood samples, and to David Young for expert statistical help.

	Footnotes

 
Abbreviations: AGA, Appropriate for gestational age; LGA, large for gestational age; SGA, small for gestational age; SVD, spontaneous vaginal delivery.

Received February 19, 2003.

Accepted May 29, 2003.

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