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Department of Pediatrics (R.C., S.R., F.B., J.M.L.), Department of Nuclear Medicine (F.B.d.C.), Department of Biochemistry and Molecular Biology (O.D., E.M.), and Department of Obstetrics and Gynecology (P.G., P.D.), University Hospital, Angers 49000, France
Address all correspondence and requests for reprints to: Dr. Régis Coutant, Department of Pediatrics, University Hospital, 4 Rue Larrey, 49000 Angers, France. E-mail: recoutant{at}chu-angers.fr
Abstract
The control of fetal growth depends on multiple hormones, including both IGF-I and placental GH (PGH) in the mother, and IGF-I rather than pituitary GH (pitGH) in the fetus. Leptin, which is produced by adipocytes and syncitiotrophoblast cells, has also been thought to influence fetal growth by an as yet unknown mechanism. This study assessed the relationships between the GH-IGF-I axis in mothers and newborns, and maternal smoking, neonate gender, and maternal and fetal leptin. We collected blood in 87 mothers at the onset of labor and cord blood immediately after birth in their 87 healthy full-term newborns. GH concentrations were log10 transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor).
PGH was lower in the 30 smoking mothers, as compared with the 57 nonsmoking mothers [18.2 (11.5; 28.6) vs. 27.0 (15.1; 48.2) µg/liter, P < 0.01]. Cord blood IGF-I was lower in neonates from smoking mothers (90 ± 44 vs. 135 ± 65 µg/liter, mean ± SD, P < 0.01), consistent with their lower birth weight percentile (P < 0.01).
A gender effect was observed for PGH, which was higher when the newborn was female, and for newborn pitGH and newborn leptin, which were, respectively, lower and higher in females, even after adjustment for birth weight and maternal smoking category (P < 0.05 for all comparisons).
Multiple regression analyses identified maternal leptin as a negative predictor of PGH (P < 0.05) and newborn leptin as a positive predictor of newborn IGF-I (P < 0.05).
Maternal smoking is associated to decreased maternal PGH and cord blood IGF-I concentrations. A sexual dimorphism for PGH, newborn pitGH, and newborn leptin exists at the time of birth, but its physiological significance remains to be studied. The relationships between maternal leptin and PGH and between cord blood leptin and IGF-I are consistent with the hypothesis that leptin could contribute to the control of fetal growth.
PLACENTAL GH (PGH) plays a crucial role in fetal development: it progressively becomes the major form of GH in the maternal circulation, has metabolic activities comparable to those of pituitary GH (1, 2, 3) and is an important regulator of maternal IGF-I (4, 5). As PGH and maternal IGF-I do not cross the placenta, their effects on fetal growth are presumably mediated by effects on placental metabolism and substrate supply to the fetus (4, 5, 6). Maternal smoking during pregnancy is a well known cause of low birth weight (7). It has been associated to decreased biochemical markers of placental function, such as maternal levels of human CG (8), but its effects on PGH and maternal IGF-I have not been reported.
Limited data concerning the regulation of PGH production have been published. PGH is negatively modulated by maternal glucose (9, 10, 11) and is not controlled by placental GH-RH (12). Metabolic and hormonal factors that are known to control pituitary GH (pitGH) production may be involved in the control of PGH secretion. Leptin, which is secreted by adipocytes (13) and syncitiotrophoblast cells (14), was found to have complex relationships with pitGH (15, 16, 17, 18, 19, 20, 21) and IGF-I secretion (22, 23, 24, 25, 26, 27) in animals as well as in humans. Maternal circulating leptin levels increase with advancing gestation (28, 29), and leptin receptors are localized at the apical membrane of the syncytiotrophoblast cells, suggesting that maternal leptin could affect placental metabolism (30). We thus hypothesized that maternal circulating leptin may interact with the placental GH-maternal IGF-I axis to control substrate supply to the fetus.
In the fetus, IGF-I is one of the major hormonal determinants of growth (31), and it is influenced by nutrients delivered via placenta rather than by fetal pitGH (32). Fetal leptin has also emerged as a potential factor controlling fetal growth because cord blood leptin levels were found to increase with fetal body weight (33, 34, 35, 36, 37). We thus studied interactions of cord blood leptin with cord blood pitGH and IGF-I.
In a total of 87 term pregnancies, both in smoking mothers (n = 30) and nonsmoking mothers (n = 57), we performed two sets of measurements. At the onset of the labor, we measured GH (PGH and pitGH), IGF-I, IGFBP3, leptin, C-peptide, glucose, FFAs and ketones in the maternal blood. Immediately after birth, we measured pitGH and the same growth factors and metabolites in cord blood as in maternal blood. Our first aim was to determine whether maternal smoking and neonate gender affect these factors. Our second aim was to study the relationships between leptin and the GH-IGF-1 axis in both mother and neonate.
Subjects and Methods
Subjects
This study was carried out in the Department of Gynecology and Obstetrics of the Angers University Hospital and was approved by the ethics committee of the University of Angers. Blood was obtained with informed consent of the parents.
Mothers
Over a 1-yr period, 87 healthy mothers who gave birth to single healthy newborns were included in the study. Mothers responded to an interviewer-administered questionnaire indicating whether they had smoked during pregnancy or not, and if so, the daily number of cigarettes smoked. Thirty smoking and 57 nonsmoking mothers were studied. Smoking mothers reported a cigarette consumption of 3–40 cigarettes per day. The mothers did not have preeclampsia, diabetes, or hypertension and denied the use of any illegal substance. Subjects with complications during pregnancy or labor were excluded. Maternal weight before pregnancy was reported by mothers, and final weight and height were recorded the day of birth.
Newborns
Thirty full-term infants delivered by mothers who smoked during pregnancy and 57 full-term infants whose mothers were nonsmokers were studied. All neonates were born with normal labor after an uneventful pregnancy. No medications were used during labor, and the amniotic fluid was clear in all pregnancies. All neonates were healthy, had no signs of fetal distress, and had Apgar scores of 8 or more at 1 and 5 min. Newborn gestational age (37–42 wk) was determined using ultrasonographic criteria from early ultrasound scan. Body weight and length were recorded. The percentile for birth weight was calculated, according to the standard French growth curves of Leroy (38). Fourteen neonates were considered as small for gestational age (birth weight less than the 10th percentile), 70 as appropriate for gestational age (birth weight between the 10th and 90th percentiles), and 3 as large for gestational age (birth weight more than the 90th percentile).
Blood sampling
Maternal blood was obtained from a cannulated vein at the onset of labor (cervical dilatation < 3 cm) because advanced labor may alter placental hormone production (1, 11, 39). To verify whether PGH measured at the onset of labor is an accurate reflection of the PGH produced at the end of pregnancy, a subset of 10 pregnant women had blood drawn twice: first, during a clinic visit between 35 and 40 wk of gestation before the onset of the labor; then, at the onset of labor. In this subset, we found that PGH concentration did not differ between the paired specimens. We also measured PGH in another cohort of 20 pregnant nonsmoking women between 35 and 40 wk of gestation before the onset of labor: PGH was 29.0 (14.5; 58.2) µg/liter, not significantly different from the values we found in nonsmoking mothers at the onset of labor. In all mothers, the time between the last meal and blood collection was recorded and was 6–12 h.
Venous cord blood was drawn immediately after birth after double clamping of the umbilical cord.
Measurements
Serum leptin was measured by a specific RIA (Mediagnost, Tübingen, Germany). Sensitivity was 0.04 µg/liter, and the intra and interassay coefficients of variation were 5% and 7.6%, respectively. Serum placental GH was measured by IRMA (Biocode, Liège, Belgium) using recombinant placental GH standards developed by Hennen’s group (40). Pituitary GH exhibited a 0.001% cross-reactivity in the placental GH assay. The sensitivity was 0.2 µg/liter. Intra and interassay precision were 5.1% and 5.5%, respectively, at a level of 20 µg/liter. Serum pitGH was measured by IRMA (Immunotech/Beckman Coulter, Inc., Villepinte, France), calibrated against the first International Reference Preparation (66/217). Sensitivity was 0.05 µg/liter, and the intraassay and interassay coefficients of variation were 1.5% and 14.03%, respectively. There was no cross-reactivity of PGH. The pitGH results are expressed in International Reference Preparation 66/217 U, for which 2 µU = 1 ng. Serum total IGF-I measurements were performed by IRMA after acid-ethanol extraction, and serum IGFBP3 measurements by IRMA (Immunotech/Beckman Coulter, Villepinte, France). The intra and interassay variations were 5.7% and 8.6% for IGF-I, and 4.8% and 6.4% for IGFBP3, respectively. Serum C-peptide was measured by RIA (CIS-Bio International, Gif sur Yvette, France). Plasma glucose was measured with a Hitachi 917 analyzer (Roche-Diagnostics Co., Meylan, France). Plasma FFAs and ketones (3 hydroxybutyrate and acetoacetate) were measured using enzymatic methods (Wako Chemical, Richmond, VA) on a Cobas Mira analyzer (Roche-Diagnostics Co., Meylan, France).
Statistical analysis
Given the non-Gaussian distribution of body mass index, serum leptin, GH, C-peptide, plasma FFA, and ketones in the study population, we used the log10 transformed variables to normalize their distribution, and results are presented as the geometric means (-1, +1 tolerance factor). All other data are presented as means ± SD. We used t test to compare anthropometric, hormonal and metabolic measurements, and Pearson’s test for univariate correlations. To assess the relationships between leptin and the GH-IGF-I axis, simple correlation analyses between maternal and cord blood leptin and the growth factors in mothers and newborns (i.e. PGH, fetal pitGH, maternal and fetal IGF-I) were first performed. Then, the growth factors that were significantly related to maternal or cord blood leptin in simple correlation analyses were used as dependent variables in multiple regression analysis: all significant variables correlated to these growth factors in univariate correlations, as well as their interactions, were tested in a backward multiple regression strategy. This allowed us to appraise the effect of leptin independently of other influential variables on the GH-IGF-I axis in mothers and newborns. The IGF-I/IGFBP-3 molar ratio was calculated as a potential indicator of the amount of unbound and biologically active IGF-I (41). The following molecular masses were used in the calculation: IGF-I, 7.5 kDa; and IGFBP-3, 29 kDa. Significance was defined as P < 0.05. All analyses were two-tailed and performed with the SPSS, Inc. (Chicago, IL) 9.0.1 statistical package.
Results
Effect of maternal smoking
The auxological and biological
characteristics of mothers and newborns
are summarized in Table 1
and Table 2.
Maternal characteristics were similar between smoking and nonsmoking
mothers. By contrast, birth weight, birth length, and placental weight
were significantly lower in neonates from mothers who smoked during
pregnancy. As a consequence of the proportionally lower birth weight
and height, body mass index was not different between the two neonate
groups. Placental GH and the maternal IGF-I/IGFBP-3 molar ratio were
lower in mothers who smoked during pregnancy [18.2 (11.5; 28.6)
vs. 27.0 (15.1; 48.2) µg/liter, P < 0.01,
and 0.35 ± 0.07 vs. 0.40 ± 0.10,
P < 0.05, respectively]. Cord blood IGF-I and the
IGF-I/IGFBP-3 molar ratio were lower in neonates from mothers who
smoked during pregnancy (90 ± 44 vs. 135 ± 65
µg/liter, P < 0.01, and 0.29 ± 0.11
vs. 0.37 ± 0.17, P < 0.05,
respectively). Other measured hormones and metabolites did not differ
according to maternal smoking category.
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The auxological characteristics of mothers and newborns were
similar for males and females, except for maternal age, which was
younger in female neonates (27.0 ± 4.3 vs. 29.5
± 4.8 yr, P < 0.05). In maternal blood, PGH was
higher when the newborn was female [27.1 (15.2; 48.1) vs.
20.6 (12.0; 35.2) µg/liter, P < 0.05], even after
adjustment for gestational age, birth weight, and maternal smoking
category (Fig. 1). There was no
difference in maternal serum IGF-I according to neonate gender
(476 ± 138 vs. 422 ± 141 µg/liter, female
vs. male newborns, P = 0.10). In cord blood,
serum leptin was higher in females than in males [7.7 (3.8; 15.8)
vs. 4.1 (1.5; 11.2) µg/liter, P < 0.01],
serum pitGH was lower in females [12.6 (6.9; 23.0) vs.
16.7 ± (9.4; 29.8) µg/liter, P < 0.05], and
serum IGFBP-3 was higher in females [1589 ± 923 vs.
1173 ± 277 µg/liter, P < 0.05]. Other
hormones and metabolites did not differ according to neonate
gender.
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Birth weight percentile was positively correlated with newborn IGF-I (r = +0.54, P < 0.001), newborn leptin (r = +0.37, P < 0.001), newborn C-peptide (r = +0.26, P < 0.05), maternal PGH (r = +0.22, P < 0.05), maternal IGF-I (r = +0.23, P < 0.05), placental weight (r = +0.49, P < 0.001), gestational age (r = +0.27, P < 0.05), and maternal final BMI (r = +0.26, P < 0.05), and negatively with maternal smoking category (r = -0.32, P < 0.01; no = 0, yes = 1) in univariate correlations.
To examine the relationships between maternal or cord blood leptin and
growth factors (PGH, maternal IGF-I, newborn pitGH, newborn IGF-I),
simple correlations were first performed: PGH was negatively correlated
with maternal leptin and cord blood IGF-I was positively correlated
with cord blood leptin (Table 3).
Maternal IGF-I and cord blood pitGH were not related to maternal or
cord blood leptin.
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) were entered in a multiple regression
analysis: maternal leptin was still an independent negative predictor
of PGH (ß = -0.19, P < 0.05), as was maternal
smoking category (no = 0, yes = 1; ß = -0.12,
P < 0.05), whereas placental weight (ß =
+0.0012, P < 0.001), maternal IGF-I (ß =
+0.00036, P < 0.05) and neonate gender (M = 0,
F = 1; ß = +0.08, P = 0.07) were
independent positive predictors (multiple R = 0.66,
P < 0.0001). Similarly, in multiple regression analysis, cord blood leptin was still an independent positive predictor of cord blood IGF-I (ß = +32.1, P < 0.05), as was birth weight percentile (ß = +0.98, P < 0.001), whereas maternal smoking category was an independent negative predictor (ß =-26.8, P < 0.05) (multiple R = 0.59, P < 0.0001).
Discussion
This study demonstrated that maternal smoking was associated with reduced PGH and a lower maternal IGF-I/IGFBP-3 molar ratio. These alterations likely impaired substrate supply to the fetus and contributed to a reduction in cord blood IGF-I, IGF-I/IGFBP-3 molar ratio, and birth weight in comparison with newborns of nonsmoking mothers. We also observed a gender effect on maternal PGH and cord blood pituitary GH, which were respectively higher and lower when the neonate was female. Last, we found a negative relationship between maternal leptin and PGH and a positive relationship between cord blood leptin and IGF-I, both of which persisted in multiple regression analyses. These observations support the hypothesis that maternal and fetal serum leptin could interact with growth factors and contribute to the control of fetal growth.
We observed a significant decrease in serum PGH in mothers who smoked during pregnancy. Although maternal smoking category was correlated to placental weight, and placental weight to serum PGH, both maternal smoking and placental weight were independent predictors of serum PGH in multiple regression analysis. This suggests a direct effect of smoking on PGH production, independent of its effect on placental weight. Despite the positive relationship between PGH and maternal serum IGF-I in the whole cohort of mothers, which was consistent with the stimulatory effect of GH on IGF-I production (1, 2, 3), the decrease in serum IGF-I observed in the smoking mothers was nonsignificant. However, the IGF-I/IGFBP-3 molar ratio, which is believed to reflect the circulating unbound form of IGF-I (41), was significantly reduced in these mothers. The bioavailability of IGF-I may be further controlled by placental IGFBP-3 proteolysis (42). As the ability of the IGFBP-3 assay to discriminate between intact and fragmented IGFBP-3 has not been evaluated (43), only direct measurement of free IGF-I and placental protease activities will clearly establish an alteration in biologically active IGF-I in smoking mothers: future research is needed to better clarify this point.
We found no difference in cord blood pitGH and a significant reduction in IGF-I and the IGF-I/IGFBP-3 molar ratio in the newborns of smoking mothers, consistent with their lower birth weight. Our findings are in accordance with the known role of IGF-I in fetal growth (31, 32), and they contrast with the increased cord blood IGF-I levels previously described at birth in neonates born to mothers who smoked during pregnancy (44), although we cannot explain these discrepancies. Maternal smoking has also been shown to have a significant negative effect that is independent of obesity on leptin concentrations in preterm newborns, and a borderline significant effect (P = 0.07) in full-term newborns (37). We did not find any difference in cord blood leptin according to the mothers’ smoking category in full-term newborns, whereas body mass index was similar in both groups of neonates. This indicator of adiposity was significantly related to cord blood leptin, as previously described (33, 34, 35, 36, 37), but we could not confirm an independent effect of maternal smoking on cord blood leptin.
We observed a sexual dimorphism in the maternal PGH concentration that was higher when the neonate was female. This neonate gender effect on PGH has been recently reported throughout pregnancy (45), although its physiological meaning is unknown. In cord blood, leptin and pitGH were respectively higher and lower in female newborns, whereas gestational age, birth weight, body mass index, and cord blood IGF-I were similar between the sexes. The sexual dimorphism in cord blood leptin has already been described in several studies (35, 36), but it has not been reported for pitGH. However, gender differences in the pitGH-IGF-I axis have been found in adolescents and adults, suggesting a role for gonadal steroids in these differences (46, 47). Testosterone and dihydrotestosterone, which strongly stimulate pitGH secretion (47), are significantly higher in the serum of males than females during the first day of life (48). These androgens may explain the gender difference in pitGH concentration in cord blood, as they have been thought to explain the gender difference in leptin concentration (25). Overall, our data suggest that a gender effect on several hormones produced by the feto-placental unit is operative in early life: the determinants and significance of these differences remain to be studied.
It has been shown that more than 98% of the leptin produced by the normal placenta is released in the maternal circulation, and less than 2% in the fetal circulation (49). In our study, maternal leptin was related to maternal BMI and not to placental weight. Similarly, cord blood leptin was related to newborn BMI and birth weight, and not to placental weight. These relationships suggest that fat mass in mother and newborn is the main determinant of maternal and cord blood leptin, respectively.
Maternal leptin was an independent negative predictor of PGH. This is in line with the negative association between serum leptin and pitGH found in prepubertal children (18, 19), postmenopausal women (20), and elderly subjects (21), although the mechanism by which leptin and GH are inversely related has not been determined. Leptin may inhibit GH secretion, GH may inhibit leptin secretion, or they may be independently regulated covariables. In humans, GH administration has been shown to acutely increase and chronically decrease serum leptin as a consequence of the reduction of fat mass (21). The effect of leptin administration on pitGH has not yet been investigated in humans. In animals, it corrected the fasting-induced alteration of GH secretion (16). According to the hypothesis that leptin mediates endocrine adaptive responses to fasting (15), a starvation-induced fall in maternal serum leptin could stimulate PGH production to maintain substrate supply to the fetus.
In agreement with previous studies, we found positive correlations between birth weight and cord blood C-peptide, IGF-I, and leptin (33, 34, 35, 36, 37, 50). In our study, cord blood leptin was a significant independent positive predictor of serum IGF-I, even after adjustment for birth weight percentile. Similar association between serum leptin and IGF-I has been described in anorexia nervosa (24), and in healthy 50- to 80-yr-old lean subjects (26). It was not found in one study in newborns (50), however, possibly because the population studied was different from ours. In that study, 33% of the population were large-for-gestational-age newborns, and small-for-gestational-age newborns were excluded. Our cohort, on the other hand, comprised 80% newborns who were appropriate for gestational age and 15% who were small for gestational age (see Subjects and Methods). IGF-I administration in humans has been shown to decrease serum leptin (27). Leptin administration in one obese child with leptin gene mutation tended to increase serum IGF-I despite the decrease in fat mass (51). According to the hypothetic role of leptin in energy balance, leptin might signal sufficient energy stores in the fetus to promote IGF-I secretion and fetal growth.
In conclusion, our study demonstrates that maternal smoking, neonate gender, and maternal circulating leptin are related with maternal PGH concentration. The associations between maternal leptin and PGH and between cord blood leptin and cord blood IGF-I are consistent with the hypothesis that leptin could be part of the mechanisms linking maternal and fetal storage of energy and fetal growth.
Acknowledgments
We acknowledge with gratitude the contribution of the nursing staff of the delivery room of Angers University Hospital.
Footnotes
Abbreviations: PGH, Placental GH; pitGH, pituitary GH.
Received February 1, 2001.
Accepted July 11, 2001.
References
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