| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Clinical Biochemistry, Soroka University Medical Center and Temple University, Philadelphia, Pennsylvania; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Address reprint requests to: Arnon Wiznitzer, MD Soroka University Medical Center Department of Obstetrics and Gynecology P.O. 151 Beer-Sheva Israel
 |
Abstract |
|---|
Top
 Abstract Material and MethodsResultsDiscussionReferences |
|---|
Methods: Serum samples were collected from maternal veins and umbilical arteries of 52 consecutive, term, LGA neonates of nondiabetic mothers. Maternal and neonatal serum samples were analyzed for levels of leptin, insulin-like growth factor-I, and insulin by specific radioimmunoassays. Multiple regression analysis was used to determine independent risk factors for fetal macrosomia.
Results: The independent risk factor significantly associated with fetal macrosomia was umbilical cord leptin concentration (P < .01, ß = 0.59). There was a statistically significant correlation between umbilical cord leptin and insulin-like growth factor-I levels and birth weight (r = 0.51, P < .01; r = 0.37, P < .01; respectively). The correlation between umbilical cord insulin levels and birth weight was not statistically significant (r = 0.06, P = .63), nor was that between maternal body mass index and birth weight (r = 0.09, P = .50).
Conclusion: Our data showed that umbilical cord leptin concentration was an independent risk factor for fetal macrosomia.
Although growth is a fundamental characteristic of fetal life and well-being, the relationship between growth-promoting factors and fetal growth is understood poorly. In the prenatal period, growth hormone (GH) does not influence fetal growth greatly. Infants with congenital GH deficiencies and defects in GH-receptor genes have only mild growth restriction at birth.1,2 Insulin, however, is believed to have an important growth-promoting function in utero.3,4 In some women whose diabetes is well controlled, and in whom fetal insulin levels are presumably normal, fetal size is excessive nevertheless. Therefore, other factors might explain abnormal fetal growth. Our group and other investigators have found that insulin-like growth factors and their binding proteins have important effects on fetal growth.5–7
In 1994, the obesity gene (ob/ob) was cloned and its gene product identified.8 Leptin, the gene product, is a 167-amino-acid peptide produced and released exclusively from adipose tissue. Expression and secretion of leptin are correlated highly with body fat mass and adipocyte size.9 Most leptin effects are believed to be mediated through specific counteraction of neuropeptide Y in the hypothalamus, regulating appetite, food intake, and metabolic activity. Some peripheral actions of leptin also were recently investigated, one of which was the regulation of insulin secretion by direct action on pancreatic ß-islet cells10; therefore, positive interaction between leptin and insulin was established.11,12 We tested the hypothesis that fetal overgrowth is related to high leptin levels; therefore, our aim was to measure the serum levels of leptin, insulin-like growth factor-I, and insulin in cases of fetal macrosomia and analyze them for independent risk factors.
|
Material and Methods |
|---|
|
Top
AbstractMaterial and MethodsResultsDiscussionReferences |
|---|
Gestational age was based on last menstrual period, first-trimester ultrasound examination, and early physical examination. Diabetes mellitus was excluded by normal glucose challenge test or oral glucose tolerance test when indicated and between 24 and 28 weeks’ gestation. Pregnancy-induced hypertension was excluded using established criteria.13 Newborns were defined as LGA when birth weight was above the 90th percentile of the growth curve in our institution.14
Umbilical arterial blood and maternal peripheral venous blood were collected within minutes of birth and centrifuged. Serum was stored at -70C until assayed. Standard neonatal measurements were taken. After separation of the placenta and removal of the attached blood clots, the placenta was weighed separately. Maternal body mass index (BMI) was obtained from the chart on admission to the delivery room using standard tables, and was defined as weight (in kilograms) divided by height (in meters squared).
Total leptin concentrations in serum were measured by radioimmunoassay using commercially available iodine-125-labeled human leptin radioimmunoassay kit (Linco Research Co, St. Charles, MO). Analyses were done in duplicate. Sensitivity was less than 0.4 ng/mL, intra-assay coefficient of variation was less than 5.2%, and interassay coefficient of variation was 8.7%. A standard curve was generated with human leptin and fitted with an interactive nonlinear curve-fitting program. Levels of insulin-like growth factor-I were measured in plasma using a radioimmunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). Sensitivity was 0.1 ng/mL, interassay coefficient of variation was 2.4%, and intra-assay coefficient of variation was 5.2%. Plasma levels of insulin were measured by specific radioimmunoassay kit (Linco Research Co, St. Louis, MO). Sensitivity was 2 mU/mL, interassay coefficient of variation was 3.5%, and intra-assay coefficient of variation was 4.4%. The study protocol was approved by the institutional review board of Soroka University Medical Center, and informed consent was given by all participants before inclusion.
Statistical analysis was done with Statistica for Windows release 5.0 software (StatSoft, Inc. Tulsa, OK). Results are reported as mean ± standard deviation (SD). The Student t test was used for comparison of continuous variables. Correlations between the variables were evaluated using Pearson correlation coefficients. For multivariate stepwise regression analysis in the first stage, birth weight was used as a dependent variable and the model was tested using only hormonal variables. In the second stage, all variables were included in the model to predict neonatal birth weight adjusted to significant variables. P < .05 was considered statistically significant.
|
Results |
|---|
|
Top
AbstractMaterial and MethodsResultsDiscussionReferences |
|---|
. The mean birth weight was 4124 ± 319 g. The mean maternal BMI at term was 31.6 ± 6.1 kg/m2. Table 2 gives the levels of leptin, insulin-like growth factor-I, and insulin in maternal and cord blood. Serum leptin was detectable in the cord blood of all 52 neonates. There was a direct correlation between cord serum leptin concentrations and birth weight (P = .01) (Figure 1A), but there was no correlation between maternal serum leptin concentrations and birth weight (Figure 1B). There also was no statistically significant correlation between neonatal birth weight and maternal BMI at delivery (P = .05; r = 0.09) (Figure 2).
|
|
|
|
A significant positive correlation was found between umbilical cord insulin-like growth factor-I levels and birth weight (P < .01; r = 0.37) (Figure 3A) but not between maternal serum insulin-like growth factor-I levels and birth weight (Figure 3B). The correlations between insulin levels and birth weight in umbilical cord (Figure 4A) or maternal serum (Figure 4B) were not significant (P = .63; r = .06).
|
|
). There was no statistically significant correlation between placental weight and leptin concentration in maternal or fetal compartments. We calculated the correlation between insulin-like growth factor-I and insulin levels and placental weight and found the same negative results.
|
|
Discussion |
|---|
|
Top
AbstractMaterial and MethodsResultsDiscussionReferences |
|---|
Neonatal fat mass is the morphometric measure that explains great variance in circulating leptin concentration in the fetal compartment. Clapp and Kiess18 found a strong relationship between neonatal fat mass and birth weight, coupled with a weak relationship between neonatal fat mass and neonatal fat-free mass. They suggested that the relationship between birth weight and cord blood leptin is primarily caused by the large contribution that fat mass makes to variability in birth weight. We did not measure skin-fold thickness of the neonates; however, the mean birth weight of the neonates in our study was almost 4200 g with some more than 4500 g, so we assume they were overweight and likely obese neonates.
A strong positive correlation between umbilical cord leptin levels and birth weight suggests that leptin is synthesized by fetal tissue; however, studies recently found expression of leptin messenger and leptin immunoreactive proteins in placental tissue.12,19 Those studies raise the possibility of placental contribution to the increased leptin levels. The placenta does not appear to be a major source of fetal leptin, at least in normal pregnancies. In our study, leptin concentrations were measured in umbilical arteries to evaluate the fetal compartment. Although Marchini et al20 did not find a significant difference in leptin concentrations between arterial and venous cord blood, another study21 found significantly higher concentrations of leptin in the umbilical artery than in the vein. No correlation was found between maternal and cord leptin concentrations, which is consistent with a noncommunicatory two-compartment model of fetoplacental leptin regulation. Our data support the latter model.
Most clinical studies of leptin’s role in causing obesity have indicated an association between obesity and high levels of leptin messenger RNA. Conclusions based on those observations are incomplete and miss some regulatory effect. Besides the regulation associated with adipose tissue differentiation, leptin gene expression seems to be tightly controlled by hormonal factors. A prime candidate for such regulation is insulin. There is evidence in the literature that mothers with insulin-dependent diabetes mellitus gave birth to infants with significantly higher levels of leptin and insulin compared with normal mothers.11,12,22 The correlation between leptin and insulin suggests that maternal hyperglycemia might cause fetal hyperleptinemia by insulin overproduction in the fetus. We did not find a correlation between insulin and leptin levels in fetal and maternal compartments of those normal pregnancies. All women had glucose tolerance tests between 24 and 28 weeks’ gestation, and the results were within the normal range. Therefore, no diabetic women were included in our study. Women received non–glucose-containing solutions during labor and delivery. Consistent with some reports11,23 and contrary to others,24 we found no significant sex-specific differences in cord leptin concentrations, indicating that infant gender did not affect cord leptin concentrations.
Plasma leptin levels are correlated highly with size of adipose tissue mass. Those data provide evidence that leptin is related highly to fetal nutritional status. Although we found a positive trend in the correlation between maternal BMI at delivery and umbilical cord leptin concentrations, it was not statistically significant. Leptin, which has a molecular weight of 16,000 Dalton, probably does not cross the placenta. Hartmann et al25 did not find a correlation between maternal prepregnancy BMI and umbilical cord serum concentrations of leptin. They concluded that umbilical cord serum leptin concentrations might indicate the amount of adipose tissue in infants rather than the degree of adiposity in mothers. Schubring et al26 found significant correlation between maternal BMI and serum leptin levels at 6–8 weeks’ gestation. Those correlation coefficients decreased with increasing gestational age, and at birth only a poor correlation persisted. Recently, Sivan et al27 showed changes in leptin levels that did not correlate with changes in weight or BMI. Leptin levels decreased rapidly in the immediate postpartum period, despite fairly constant maternal BMI. Those findings show that maternal BMI does not regulate fetal weight. Fetal leptin levels appear to greatly affect regulation of growth potential. However, the precise mechanism by which leptin regulates fetal growth remains undetermined.
|
Footnotes |
|---|
Received February 11, 2000. Received in revised form May 23, 2000. Accepted June 15, 2000.
|
References |
|---|
|
Top
AbstractMaterial and MethodsResultsDiscussionReferences |
|---|
2. Savage MO, Blum WF, Ranke MB, Postel-Vinay MC, Cotterill AM, Hall K, et al. Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrin Metab 1993;77:1465–71.[Abstract]
3. Schwartz R, Gruppuso PA, Petzold K, Brambilla D, Hiilesmaa V, Teramo KA. Hyperinsulinemia and macrosomia in the fetus of the diabetic mother. Diabetes Care 1994;17:640–8.[Abstract]
4. Simmons D. Interrelation between umbilical cord sex hormones, sex hormone-binding globulin, insulin-like growth factor I, and insulin in neonates from normal pregnancies and pregnancies complicated by diabetes. J Clin Endocrinol Metab 1995;18:611–7.
5. Le Roith D. Insulin-like growth factors. N Engl J Med 1997;336: 633–40.
6. Reece EA, Wiznitzer A, Le E, Homko CJ, Behrman H, Spencer EM. The relationship between human fetal growth and fetal blood level of insulin-like growth factor I and II, their binding proteins, and receptors. Obstet Gynecol 1994;84:888–95.
7. Wiznitzer A, Reece EA, Homko C, Furman B, Mazor M, Levy J. Insulin-like growth factors, their binding proteins and fetal macrosomia in offspring of nondiabetic pregnant women. Am J Perinatol 1998;15:23–8.[Medline]
8. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32.[Medline]
9. Considine RV, Sinha M, Heiman ML, Kriaugiunas A, Stephens TW, Nyce MR, et al. Serum immuno-reactive leptin concentration in normal-weight and obese humans. N Engl J Med 1996;334:292–5.
10. Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic b-cells. Diabetes 1997;46:1087–93.[Abstract]
11. Shekhawat PS, Garland JS, Shivpuri C, Mick GJ, Sasidharan P, Pelz CJ, et al. Neonatal cord blood leptin: Its relationship to birth weight, body mass index, maternal diabetes, and steroids. Pediatr Res 1998;43:338–43.[Medline]
12. Lepercq J, Cauzac M, Lahlou N, Timsit J, Girard J, Auwerx J, et al. Overexpression of placental leptin in diabetic pregnancy: A critical role for insulin. Diabetes 1998;47:847–50.[Abstract]
13. Davey D, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158:892–8.[Medline]
14. Leiberman JR, Fraser D, Weitzman S, Glezerman M. Birth weight curves in southern Israel population. Isr J Med Sci 1993;29:198–203.[Medline]
15. Sivan E, Lin WM, Homko CJ, Reece EA, Boden G. Leptin is present in human cord blood. Diabetes 1997;46:917–9.[Abstract]
16. Tamura T, Goldenberg RL, Johnston KE, Cliver SP. Serum leptin concentrations during pregnancy and their relationship to fetal growth. Obstet Gynecol 1998;91:389–95.[Abstract]
17. Harigaya A, Nagashima K, Nako Y, Morikawa A. Relationship between concentration of serum leptin and fetal growth. J Clin Endocrinol Metab 1997;82:3281–4.
18. Clapp JF 3rd, Kiess W. Cord blood leptin reflects fetal fat mass. J Soc Gynecol Invest 1998;5:300–3.[Medline]
19. Henson MC, Swan KF, O’Neil JS. Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term. Obstet Gynecol 1998;92:1020–8.[Abstract]
20. Marchini G, Fried G, Ostlund E, Hagenas L. Plasma leptin in infants: Relationship to birth weight and weight loss. Pediatrics 1998;101:429–32.
21. Schubring C, Kiess W, Englaro P, Rascher W, Dotsch J, Hanitsch S, et al. Levels of leptin in maternal serum, amniotic fluid, and arterial and venous cord blood: Relationship to neonatal and placental weight. J Clin Endocrinol Metab 1997;82:1480–3.
22. Maffei M, Volpe L, Di Cianni G, Bertacca A, Ferdeghini M, Murru S, et al. Plasma leptin levels in newborns from normal and diabetic mothers. Horm Metab Res 1998;30:575–80.[Medline]
23. McCarthy JF, Misra DN, Roberts JM. Maternal plasma leptin is increased in preeclampsia and positively correlated with fetal cord concentrations. Am J Obstet Gynecol 1999;180:731–6.[Medline]
24. Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M, et al. Serum leptin concentration in cord blood: Relationship to birth weight and gender. J Clin Endocrinol Metab 1997;82:1642–4.
25. Hartmann BW, Wagenbichler P, Soregi G. Maternal and umbilical-cord serum leptin concentrations in normal, full-term pregnancies. N Engl J Med 1997;337:863.
26. Schubring C, Englaro P, Siebel T, Blum WF, Demirakca T, Kratzsch J, et al. Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: Relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels. Horm Res 1998;50:276–83.[Medline]
27. Sivan E, Whittaker PG, Sinha D, Homko C, Lin M, Reece EA, et al. Leptin in human pregnancy: The relationship with gestational hormones. Am J Obstet Gynecol 1998;179:1128–32.[Medline]
This article has been cited by other articles:
|
|
 |
|
  E. Johannsson, T. Henriksen, and P. O. Iversen Increase in matrix metalloproteinases from endothelial cells exposed to umbilical cord plasma from high birth weight newborns Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1563 - R1568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-M. Alexe, G. Syridou, and E. Th. Petridou Determinants of Early Life Leptin Levels and Later Life Degenerative Outcomes Clin. Med. Res., December 1, 2006; 4(4): 326 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Basbug, I. S. Serin, B. Ozcelik, M. Kula, E. M. Basbug, and A. Tutus Correlation of Elevated Leptin Levels in Amniotic Fluid and Maternal Serum in Neural Tube Defects Obstet. Gynecol., March 1, 2003; 101(3): 523 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Yajnik, H. G. Lubree, S. S. Rege, S. S. Naik, J. A. Deshpande, S. S. Deshpande, C. V. Joglekar, and J. S. Yudkin Adiposity and Hyperinsulinemia in Indians Are Present at Birth J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5575 - 5580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Takahashi, Y. Yokoyama, I. Kawabata, S. Iwasa, and T. Tamaya Leptin as an Acute Stress-Related Hormone in the Fetoplacental Circulation Obstet. Gynecol., October 1, 2002; 100(4): 655 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.S. Muhlhausler, C.T. Roberts, J.R. McFarlane, K.G. Kauter, and I.C. McMillen Fetal Leptin Is a Signal of Fat Mass Independent of Maternal Nutrition in Ewes Fed at or above Maintenance Energy Requirements Biol Reprod, August 1, 2002; 67(2): 493 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Reis, D. D'Antona, and F. Petraglia Predictive Value of Hormone Measurements in Maternal and Fetal Complications of Pregnancy Endocr. Rev., April 1, 2002; 23(2): 230 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K G Tantisira and S T Weiss Complex interactions in complex traits: obesity and asthma Thorax, September 1, 2001; 56(90002): ii64 - 74. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Laml, O. Preyer, I. Schulz-Lobmeyr, E. Ruecklinger, B. W. Hartmann, and P. Wagenbichler Umbilical Venous Leptin Concentration and Gender in Newborns Reproductive Sciences, April 1, 2001; 8(2): 94 - 97. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
