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Levels of Leptin in Maternal Serum, Amniotic Fluid, and Arterial and Venous Cord Blood: Relation to Neonatal and Placental Weight

Evangelisches Krankenhaus (C.S.), D-35398 Giessen; Children’s Hospital, Justus Liebig University (W.K., P.E., W.R., J.D., S.H., W.F.B.), D-35385 Giessen; and Lilly Germany (A.A., W.F.B.), D-61350 Bad Homburg, Germany

Address all correspondence and requests for reprints to: W. Kiess, MD Children’s Hospital, Justus Liebig University, Feulgenstrasse 12, D-35385 Giessen, Germany.

	Abstract

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The mechanisms by which maternal and fetal weight are regulated during pregnancy are poorly understood. The ob protein, termed leptin, is produced by adipocytes. It is involved in the regulation of body weight by suppressing appetite and stimulating energy expenditure both in humans and rodents. In this study we examined whether leptin concentrations in the mother and the newborn correlate with birth weight, placental weight, and maternal weight at term. Leptin concentrations were measured in amniotic fluid, venous and arterial cord blood, and maternal serum at birth (n = 27) using a specific RIA employing human recombinant leptin for tracer and standard preparation. Gestational age was 38–42 weeks, maternal age was 21–42 yr, mean maternal weight at birth was 80.0 ± 10.8 kg, and mean body mass index before pregnancy was 23.4 ± 2.8 kg/m². The newborns’ mean weight was 3450 ± 580 g, and mean placental weight was 616 ± 120 g. Serum leptin levels from nonpregnant women ranged between 1.7–18.4 ng/mL, median 5.5 ng/ml (n = 30). Mean leptin concentration in maternal serum at birth was 20.0 ± 13.2 ng/mL and was higher (P < 0.002) than in arterial cord blood (9.7 ± 9.4 ng/mL) and venous cord blood (8.9 ± 8.6 ng/mL). Mean amniotic fluid leptin concentration was 3.6 ± 2.8 ng/mL. Placental weight correlated inversely with leptin levels in maternal serum at birth (r = -0.49, P < 0.01). In addition, leptin concentrations in venous cord blood correlated significantly with the levels in arterial cord blood (r = 0.98, P < 0.0001), and leptin levels in cord blood correlated positively with birth weight (r = 0.57, P = 0.03) and placental weight (r = 0.50, P < 0.01). In contrast, there was no correlation between maternal serum leptin levels and birth weight. Thus, leptin levels are high in the fetus and in the mother at term. We hypothesize that high leptin levels could represent an important feed-back modulator of substrate supply and subsequently for adipose tissue status during late gestation.

	Introduction

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BODY WEIGHT increase during pregnancy is caused by sodium and water retention with the consequence of increased extracellular fluid volume and by an increase in body fat tissue mass both in the mother, and in particular during the third trimester, in the fetus. The mechanisms by which maternal and fetal weight and fat mass are regulated during pregnancy and particularly during third trimester are poorly understood (1). Hormonal factors such as insulin and the insulin-like growth factors (IGFs) (1), genetic predisposition and chromosomal aberrations (2), and environmental factors such as health, nutrition, infections, and toxic substances such as alcohol and nicotine are all of importance for weight gain both of the fetus and the mother (1, 3). Failure to increase fat mass during pregnancy causes increased neonatal and maternal morbidity (1, 2, 3).

The ob protein, termed leptin, is produced by adipocytes. It is involved in the regulation of body weight through suppressing appetite and stimulating energy expenditure in humans and/or in rodents (4, 5, 6, 7). Leptin administration in the ob/ob mouse results in weight loss by reduction of food intake and increased energy expenditure (8, 9). In contrast, ob gene expression and leptin levels are increased in human obesity and in various animal models of obesity (5, 6, 7, 10, 11, 12). It has been postulated that leptin acts through specific receptors in the brain (13, 14, 15, 24). It is feasible that leptin production by adipose tissue is under neuroendocrine control (15, 16).

No information is available in respect to leptin levels during gestation and at term. In addition, no data exists about potential roles for leptin during gestation. In fact, during late pregnancy, leptin could be one of the links between the neuroendocrine system and the adipose tissue, which expands during pregnancy. Therefore, we examined whether leptin was present in human arterial and venous cord blood and amniotic fluid at birth. In addition, we measured leptin in maternal serum at term and examined whether there were correlations between leptin concentrations and birth weight, placental weight, and maternal weight and body mass index (BMI).

	Patients and Methods

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Patients

Twenty-seven healthy mothers who gave birth to healthy newborns at the Department of Gynecology and Obstetrics of the Evangelisches Krankenhaus Giessen, Germany, were included in the study. All pregnancies were without complications. Informed consent was obtained from all mothers. Approval of the study protocol by the Ethical Committee of the University of Giessen had been sought before the start of the study. Clinical and auxological data (Table 1) were obtained by one investigator (C.S.) and recorded using a standardized data sheet. Amniotic fluid was gained after amniotomy when amniotomy had been mandatory for clinical reasons. 30 healthy normally menstruating women (age 20–35 yr, BMI 20–28 kg/m²) served as controls and donated venous blood for leptin measurements.

Maternal blood was obtained from a cannulated vein directly after birth. Venous and arterial cord blood was drawn immediately after birth from the umbilical blood vessels by one investigator (C.S.). Sera were obtained by centrifugation at 4 C, immediately frozen, and stored at -20 C until further analysis.

Leptin measurement

Leptin was measured by a specific RIA that has been described in detail elsewhere (Blum W. F., Englaro P.; submitted for publication). In brief, recombinant human leptin (a gift from Dr. Heiman, Eli Lilly Research Laboratories, Indianapolis, IN) was used for the generation of antiserum in rabbits and for the preparation of tracer by the chloramine-T method (12) and of standards. The assay buffer was composed of 0.05 mol/L sodium phosphate, pH 7.4, 0.1 mol/L NaCl, 0.1% (vol/vol) gelatin from teleost fish (Sigma Chemicals, Munich, Germany), 0.1% (vol/vol) Triton X100 (Serva, Heidelberg, Germany), and 0.05% (vol/vol) NaN₃. The assay volume was 0.3 mL. After incubation at room temperature overnight, bound and unbound tracer were separated by a second antibody technique (17, 18). Maximal tracer binding was 37–45% and half-maximal binding occurred at 0.9 µg/L unlabeled leptin. Excellent parallelism was obtained with serial dilutions of human serum, and spiking experiments with 0.1 ng/tube yielded a recovery of 97 ± 2.1%. Sensitivity was 0.03 µg/L, and the intra- and interassay coefficients of variation were 0.8% and 8.5%, respectively.

Statistical analysis

Statistical analysis was performed using the Prism program (Prism, version 2.0, GraphPad Software, San Diego, CA). Data with Gaussian distribution were correlated by linear regression. Nonparametric data were compared by the Mann-Whitney U test and parametric data by two-tailed t test. In case of multiple tests, P values were corrected according to Bonferoni. A P value of <0.05 was considered statistically significant.

	Results

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Clinical and auxological data of newborns and mothers

All newborns (16 female, 11 male) and mothers were healthy and did not require special medical attention after birth. The clinical data are presented in Table 1. Placental weight and birth weight correlated significantly (r = 0.71, P < 0.0001, y = 3.45x + 1323).

Leptin levels in maternal serum, cord blood, and amniotic fluid

Leptin concentrations were distributed log normal. Mean leptin concentrations in maternal serum at birth were significantly higher than those found in nonpregnant serum from healthy women (n = 30): 20.0 ± 13.2 ng/mL vs. 5.5 ± 2.8 ng/mL (P < 0.001). In arterial cord blood leptin concentration was similar as but slightly higher than in venous cord blood (9.7 ± 9.4 ng/mL vs. 8.9 ± 8.7 ng/mL). When a paired analysis (Wilcoxon test) was performed, this difference was found to be significant (P = 0.006). A significant positive relation was found between arterial and venous cord blood (r = 0.98, P < 0.0001) (Fig. 1). In addition, maternal leptin serum levels were significantly higher than cord blood levels (ANOVA, P < 0.003) and did not correlate with leptin concentrations in either arterial or venous cord blood. Mean amniotic fluid leptin concentration was 3.7 ± 0.8 ng/mL (Table 2) and correlated with maternal serum levels of leptin (r = 0.76, P < 0.001) (Fig. 2). There was a constant ratio of approximately 4:1 between the values of maternal and amniotic fluid concentrations. Amniotic fluid levels did not correlate with venous or arterial cord blood leptin levels. There was no significant sex difference between leptin levels in cord blood or amniotic fluid (data not shown).

View larger version (17K): [in this window] [in a new window]   Figure 1. Correlation between leptin serum concentration (nanograms per milliliter) in umbilical vein and leptin serum concentration in umbilical artery in 27 healthy newborns (r = 0.98, P < 0.00001, y = 0.91x + 0.03).

View larger version (17K): [in this window] [in a new window]   Figure 2. Correlation between leptin concentration (nanograms per milliliter) in maternal serum and amniotic fluid from 27 healthy mothers at term (r = 0.76, P < 0.001, y = 3.55x + 7.1).

There was a significant correlation between leptin levels in umbilical vein and birth weight of the neonates (r = 0.57, P < 0.03) (Fig. 3). An analogous relation was found between leptin levels in umbilical artery and birth weight (r = 0.54, P < 0.03). Maternal BMI at the beginning of pregnancy and at term or maternal weight did not correlate with leptin levels in maternal serum at term. Placental weight correlated inversely with leptin levels in maternal serum at birth (r = -0.49, P < 0.01) (Fig. 4A) and leptin levels in amniotic fluid (r = -0.70, P = 0.003) (Fig. 4B). In contrast, leptin levels in arterial and venous cord blood were positively correlated with placental weight [r = 0.50, P < 0.01 (Fig. 4C) and r = 0.49, P < 0.02, respectively]. When stepwise regression analysis and ANOVA was used to determine whether placental weight or birth weight contributed more to the relation between leptin levels and auxological data, both the influence of placental weight and of birth weight remained independent from one another. A similar and independent contribution of placental weight and birth weight in respect to leptin concentrations was suggested by comparable P values in the ANOVA (P < 0.0001) for both placental weight and birth weight. There was no relation between leptin levels and pH of arterial cord blood or APGAR score at term or 5 or 10 min after delivery (data not shown). There was no sex difference of leptin levels in cord blood or amniotic fluid.

View larger version (16K): [in this window] [in a new window]   Figure 3. Relation between leptin serum concentration (nanograms per milliliter) in umbilical vein and birth weight (g) in 27 healthy newborns (r = 0.57, P < 0.01, y = 0.008x - 1.7).

View larger version (15K): [in this window] [in a new window]   Figure 4. Correlation between leptin concentrations (nanograms per milliliter) and placental weight (g) in 27 healthy newborns. A, Leptin concentration in maternal serum vs. placental weight (r = -0.49, P < 0.01, y = -0.054x + 53.0). B, Negative correlation between leptin concentration in amniotic fluid and placental weight (r = -0.70, P = 0.003, y = -0.011x + 10.2). C, Positive correlation between leptin serum concentration in umbilical artery and placental weight (r = 0.50, P < 0.01, y = 0.031x - 0.9).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

In contrast, BMI at delivery and maternal weight did not correlate with leptin levels in maternal serum. This might suggest that during gestation or at least at birth the regulation of leptin levels differs from that in nonpregnant females in which leptin levels are highly correlated with BMI and fat mass (7, 19). Alternatively and most likely, the fact that there is a poor correlation between BMI or weight and maternal leptin serum concentrations at birth may simply reflect the inability to directly measure fat mass. Lastly, a general increase in fat mass in all subjects towards the end of pregnancy might mask the original differences in fat mass and subsequently leptin levels in these subjects.

At this point it is unclear what specific regulators of leptin levels might be effective during gestation and at term. These data might simply reflect the poor correlation of BMI and weight measurements with fat tissue expansion during pregnancy. In fact, extracellular fluid expansion takes place during pregnancy and might override changes in fat mass. Unfortunately, no objective technique to assess fat mass was available to be applied in this study. Possibly, high levels of leptin might lead to uncoupling of feeding behavior and might represent a relative unresponsiveness of leptin receptors during gestation.

Hormonal regulation of leptin levels in the fetus and neonate might be different from the endocrine modulation of leptin levels seen throughout adult life; whereas insulin and glucocorticoids (15, 20, 21) are thought to modulate leptin levels throughout adult life, this might not be entirely relevant for the fetus and neonate. There was no sex difference of leptin levels in cord blood at term. This is in contrast to the situation in the adult where consistently higher levels of leptin are found in serum from females than from males (7, 22, 23). One possible explanation for the absence of a gender difference of leptin levels at birth might be that the percent body fat of a neonate is not gender specific. In general, leptin levels in pregnant women (7) and at term (this study) approximate those found in obese humans.

The relatively high leptin concentrations in amniotic fluid and the negative correlation of maternal leptin levels and placental weight may point to a putative role for leptin as an important regulator of maternal and placental weight. The positive correlation between cord blood leptin levels and birth weight might point toward a role for leptin as a regulator of fetal weight and growth.

The high leptin levels in arterial and venous cord blood suggest that the fetus and/or the placenta express the ob gene product at term. It is possible that high levels of leptin provide a signal of satiety around birth. A subsequent sudden fall in leptin levels after delivery may then provide a major stimulus for appetite and feeding. In fact, low levels of leptin have been measured in newborn serum during the first days of life (W.F. Blum, P. Englaro, unpublished observations).

	Acknowledgments

 
We thank the mothers who participated in the study. We also express our sincere gratitude to the midwives, nurses, and colleagues who participated in the care of mothers and newborns.

Received October 15, 1996.

Revised January 17, 1997.

Accepted January 27, 1997.

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				J. Matsuda, I. Yokota, Y. Tsuruo, T. Murakami, K. Ishimura, K. Shima, and Y. Kuroda Developmental Changes in Long-Form Leptin Receptor Expression and Localization in Rat Brain Endocrinology, November 1, 1999; 140(11): 5233 - 5238. [Abstract] [Full Text]

				A. Meisser, P. Cameo, D. Islami, A. Campana, and P. Bischof Effects of interleukin-6 (IL-6) on cytotrophoblastic cells Mol. Hum. Reprod., November 1, 1999; 5(11): 1055 - 1058. [Abstract] [Full Text] [PDF]

				D. Chardonnens, P. Cameo, M.L. Aubert, F.P. Pralong, D. Islami, A. Campana, R.C. Gaillard, and P. Bischof Modulation of human cytotrophoblastic leptin secretion by interleukin-1{alpha} and 17{beta}-oestradiol and its effect on HCG secretion Mol. Hum. Reprod., November 1, 1999; 5(11): 1077 - 1082. [Abstract] [Full Text] [PDF]

				J. Dötsch, K.-D. Nüsken, I. Knerr, M. Kirschbaum, R. Repp, and W. Rascher Leptin and Neuropeptide Y Gene Expression in Human Placenta: Ontogeny and Evidence for Similarities to Hypothalamic Regulation J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2755 - 2758. [Abstract] [Full Text]