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Obstetrics & Gynecology 2000;96:342-345
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Differences in Umbilical Venous and Arterial Leptin Levels by Mode of Delivery

NOBUYUKI YOSHIMITSU, MD, TSUTOMU DOUCHI, MD, MASAKI KAMIO, MD and YUKIHIRO NAGATA, MD

From the Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.

Address reprint requests to: Nobuyuki Yoshimitsu, MD Department of Obstetrics and Gynecology Kagoshima University 8-35-1 Sakuragaoka Kagoshima 890-8520 Japan


   Abstract
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Abstract
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 Results
 Discussion
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Objective: To investigate the differences in umbilical venous and arterial leptin levels by mode of delivery.

Methods: Subjects were 30 mothers who had elective cesarean deliveries and 34 mothers who had vaginal deliveries. Umbilical venous and arterial leptin levels were measured immediately after delivery. Maternal age, neonatal gender, neonatal birth weight, placental weight, and gestational duration were recorded. Inter- and intragroup comparisons were made in umbilical venous and arterial leptin levels and obstetric variables. Significant determinants of differences in umbilical venous and arterial leptin levels were investigated.

Results: Umbilical venous and arterial leptin levels were higher in the vaginal delivery group (n = 34) than in the cesarean group (n = 30) (P < .01). In the vaginal delivery group, umbilical venous leptin levels were significantly higher than arterial leptin levels (P < .001). These differences were still significant after adjustment for neonatal gender, neonatal birth weight, and placental weight. However, in the cesarean group, leptin levels did not differ between umbilical vein and artery.

Conclusion: Placental leptin release is augumented during advanced labor.

Serum leptin is a circulating hormone that is expressed abundantly in adipose tissue. Leptin plays an important role in the regulation of energy homeostasis and in the neuroendocrine and reproductive systems. Reports indicate that leptin is produced in the placenta and released into fetal and maternal circulation.1–4 Some hormones, including fetal serum sex steroid and glucocorticoid, and lipid levels increase under stress during advanced labor.5–7 These findings suggest that fetal leptin levels may differ between vaginal and elective cesarean deliveries or between umbilical vein and artery.

The purpose of this study was to investigate the differences in umbilical venous and arterial leptin levels by mode of delivery.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
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Sixty-five women who underwent cesarean deliveries and 125 women who delivered vaginally at term gestation at the Department of Obstetrics and Gynecology, Kagoshima University, between April and October 1998 were considered for the study. Exclusion criteria were severe preeclampsia (n = 3), diabetes mellitus (n = 4), multiple pregnancy (n = 2), and placental dysfunction syndrome (n = 5). Emergency cesarean cases such as those involving fetal distress (n = 29) also were excluded from the study. Vaginal delivery patients (n = 83) who experienced active labor for less than 10 hours were excluded, as were neonates with congenital anomalies (n = 3) (some cases were excluded for multiple reasons). The remaining 30 women (mean age ± standard deviation [SD], 30.3 ± 3.8 years) who underwent elective cesarean deliveries and 34 women (27.4 ± 4.5 years) who delivered vaginally were enrolled. Indications for elective cesarean included breech presentation (n = 5), previous cesarean (n = 24), and cephalopelvic disproportion (n = 1). Thus, all subjects were deemed to have had uncomplicated pregnancies. Demographic variables included maternal age, weight before pregnancy, height, body mass index (BMI) before pregnancy, weight gain during pregnancy, and parity. Obstetric variables included neonatal birth weight, gestational duration, duration of active labor in vaginal delivery group, placental weight, and neonatal gender. Body mass index was calculated as weight (kg) divided by height squared (m2).

Umbilical cord blood samples were obtained from the umbilical vein and artery immediately after delivery. Blood samples were separated by centrifugation. The specimens were then stored at -80C until analysis. Measurements of serum leptin levels were made with a commercially available radioimmunoassay kit based on a polyclonal antiserum raised against full-length recombinant human leptin (Linco, St. Charles, MO). The day-to-day variation was monitored by repeated analysis of two quality-control samples provided by the manufacturer, and the interassay coefficients of variation were 3.4 and 6.9% when control samples containing 2.9 and 13.8 ng/mL, respectively, were used.

Informed written consent was obtained in accordance with institutional guidelines. The study also was conducted in accordance with the provisions of the Declaration of Helsinki.

Intergroup and intragroup comparisons were made in umbilical venous and arterial leptin levels and obstetric variables with the use of paired or unpaired Student t test, as appropriate. The {chi}2 test also was used to assess group differences for categoric variables such as neonatal gender distribution. Significant determinant factors of the differences in umbilical venous and arterial leptin levels were investigated with the use of univariate and multiple regression analysis. On regression analysis, dependent variables were umbilical venous leptin levels, arterial leptin levels, or venous-arterial leptin level differences. Independent variables were neonatal gender, neonatal birth weight, placental weight, and mode of delivery. The strength of correlation was shown by standardized regression coefficient. This is a coefficient similar to Pearson correlation coefficient. Mode of delivery and neonatal gender were nominal variables, so we registered cesarean delivery or male neonate as 1, and vaginal delivery or female neonate as 2. Statistical analyses were performed with a Statview IV statistical package (Abacus Concepts, Berkeley, CA). P < .05 was considered statistically significant. To detect the difference of 1.0 (SD = 1.3) between cesarean and vaginal delivery with {alpha} = 0.05 and ß = 0.20, 30 subjects in each group were required.


   Results
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Abstract
 Materials and Methods
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Discussion
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Table 1Go presents the obstetric variables of the two groups. Maternal age in the cesarean group (n = 30) was significantly higher than that in the vaginal delivery group (n = 34) (P < .01). Gestational duration and neonatal birth weight were significantly higher in the vaginal delivery group than in the cesarean group (P < .001 and P < .05, respectively), whereas parity was significantly higher in the cesarean group (P < .001). However, no significant differences were observed in maternal weight before pregnancy, height, BMI before pregnancy, weight gain during pregnancy, neonatal gender distribution, or placental weight between the two groups.


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  		Table 1. Demographic and Obstetric Variables
 
Table 2Go presents the differences in umbilical venous and arterial leptin levels. In all neonates (n = 64), both umbilical venous and arterial leptin levels in the vaginal delivery group (n = 34) were higher than in the cesarean group (n = 30) (P < .01). Umbilical venous leptin levels were significantly higher than arterial leptin levels in the vaginal delivery group (P < .001). No significant differences in venous and arterial leptin levels were observed in the cesarean group (n = 30). Furthermore, we attempted to compare the umbilical leptin levels between the two groups divided by neonatal gender, which is known to influence leptin levels in fetal circulation.2,8,9 In female neonates (n = 32), both umbilical venous and arterial leptin levels in the vaginal delivery group (n = 16) were higher than in the cesarean group (n = 16) (P < .01). Umbilical venous leptin levels were higher than arterial leptin levels (P < .01) in the vaginal delivery group (n = 16). No significant differences in venous and arterial leptin levels were observed in the cesarean group (n = 16).


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  		Table 2. Differences in Umbilical Venous and Arterial Leptin Levels
 
On univariate regression analysis, mode of delivery was positively correlated with venous leptin levels, arterial leptin levels, and the differences in venous and arterial leptin levels (standardized regression coefficient = .426, P < .01; .406, P < .01; and .396, P < .01; respectively). Neonatal birth weight was positively correlated with venous leptin levels, arterial leptin levels, and the differences in venous and arterial leptin levels (standardized regression coefficient = .380, P < .01; .375, P < .01; and .264, P < .05; respectively). However, neonatal gender and placental weight were not correlated with leptin levels. After adjustment for neonatal gender, neonatal birth weight, and placental weight on multiple regression analysis, mode of delivery was still correlated with venous leptin levels, arterial leptin levels, and the differences in venous and arterial leptin levels (standardized regression coefficient = .334, P < .01; .310, P < .01; and .371, P < .01; respectively).


   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
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In the present study, we found that both umbilical venous and arterial leptin levels in the vaginal delivery group were respectively higher than in the cesarean group. In addition, umbilical venous leptin levels were higher than arterial leptin levels in the vaginal delivery group. These differences were still significant after adjustment for neonatal birth weight, neonatal gender, and placental weight, which are known to influence leptin levels in fetal circulation.2,8,9 However, in cesarean patients, no significant differences were observed in umbilical venous and arterial leptin levels. These findings suggest that placental leptin release is augumented during advanced labor. Although several reports2,9–11 documented that umbilical venous leptin levels were significantly higher than arterial leptin levels, vaginal delivery and cesarean cases were not separated.

Why does placental leptin release increase during advanced labor? Reasons may include the following. First, placental leptin synthesis is augumented in preeclampsia, probably because of placental hypoxia.12,13 Leptin synthesis in the placenta may be one of the generalized hypoxic responses of trophoblast cells in preeclampsia.12 Unfortunately, we did not measure umbilical arterial or venous blood gas. However, even in normal pregnancy without preeclampsia or placental dysfunction, the fetus is exposed to hypoxia during advanced labor as a result of intermittent uterine contraction. Thus, it is plausible that hypoxia due to uterine contraction may contribute in part to higher umbilical venous and arterial leptin levels in vaginal compared with cesarean deliveries. Second, the major difference between vaginal and cesarean delivery is the degree of fetal exposure to stress. Several studies indicate that the stress of labor increases fetal serum cortisol levels.14–18 Serum cortisol levels are reported to be associated with serum leptin levels in adults,19,20 and cortisol-induced increases in plasma leptin levels are dose-dependent.19 Thus, augumented placental leptin release is attributable in part to increased stress and/or fetal cortisol levels during advanced labor. Third, augumented placental leptin synthesis may be associated with the activation of the sympathetic nervous system and/or increased plasma cytokin levels, because placental leptin synthesis is reported to be stimulated by activations of the protein kinase A and C pathways during advanced labor.21 Thus, the mechanism of increased placental leptin release during advanced labor could be multifactorial.

It remains unclear whether increased placental leptin release during advanced labor is of physiologic significance. It has been suggested that placenta-derived leptin in the umbilical vein regulates fetal development and metabolism.11 Postnatal decrease in plasma leptin levels may be a physiologically feasible adaptation to profound alterations in fuel homeostasis during the first days of extrauterine life.22 Fetuses delivered vaginally are prone to undergo more stress during labor than those delivered by cesarean.6 Thus, leptin may play an important role in fetal adaptation to stress and energy expenditure not only during early neonatal life but also during advanced labor.


   Footnotes
 
PII S0029-7844(00)00927-3

Received November 23, 1999. Received in revised form March 7, 2000. Accepted March 16, 2000.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Rechberger KB, Kaminski K, Rechberger T. Serum leptin concentration in fetal and maternal compartments. Ginekol Pol 1998;69: 725–7.[Medline]

2. 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: Relation to neonatal and placental weight. J Clin Endocrinol Metab 1997;82:1480–3.[Abstract/Free Full Text]

3. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, et al. Non-adipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans. Nat Med 1997;3:1029–33.[Medline]

4. Senaris R, Garcia-Caballero T, Casabielle X, Gallego R, Castro R, Considine RV, et al. Synthesis of leptin in human placenta. Endocrinology 1997;138:4501–4.[Abstract/Free Full Text]

5. Haning RV Jr, Barrett DA, Alberino SP, Lynski MT, Donabedian R, Speroff L. Interrelationships between maternal and cord prolactin, progesterone, estradiol, 13, 14-dihydro- 15-keto-prostaglandin F2alpha, and cord cortisol at delivery with respect to initiation of parturition. Am J Obstet Gynecol 1978;130:204–10.[Medline]

6. Yoshimitsu N, Douchi T, Yamasaki H, Nagata Y, Andoh T, Hatano H. Differences in umbilical serum lipid levels with mode of delivery. Br J Obstet Gynaecol 1999;106:144–7.[Medline]

7. Ose L, Iden A, Bakke T, Aarskog D. Neonatal screening for hyperlipidaemia. Postgrad Med 1975;51(Suppl 8):88–92.

8. Tome MA, Lage M, Camina JP, Garcia-Mayor RV, Dieguez C, Casanueva FF. Sex-based differences in serum leptin concentrations from umbilical cord blood at delivery. Eur J Endocrinol 1997;137:655–8.[Abstract]

9. 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.[Abstract/Free Full Text]

10. Yura S, Sagawa N, Mise H, Mori T, Masuzaki H, Ogawa Y, et al. A positive umbilical venous-arterial difference of leptin level and its rapid decline after birth. Am J Obstet Gynecol 1998;178:926–30.[Medline]

11. Sivan E, Lin WM, Homko CJ, Reece EA, Boden G. Leptin is present in human cord blood. Diabetes 1997;46:917–9.[Abstract]

12. Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, et al. Augumented placental production of leptin in preeclampsia: Possible involvement of placental hypoxia. J Clin Endocrinol Metab 1998;83:3225–9.[Abstract/Free Full Text]

13. Kokot F, Wiecek A, Adamczak M, Ulman I, Spiechowicz U, Cieplok J, et al. Pathophysiological role of leptin in patients with chronic renal failure, in kidney transplant patients, in patients with essential hypertension, and in pregnant women with preeclampsia. Artif Organs 1999;23:70–4.[Medline]

14. Haukkamaa M, Lähteenmäk P. Steroids in human myometrium and maternal and umbilical cord plasma before and during labor. Obstet Gynecol 1979;53:617–22.[Abstract/Free Full Text]

15. Jolivet A, Blanchier H, Gautray JP, Dhem N. Blood cortisol variation during late pregnancy and labor. Am J Obstet Gynecol 1974;119:775–83.[Medline]

16. Cawson MJ, Anderson ABM, Turnbull AC, Lampe L. Cortisol, cortisone, and 11-deoxycortisol levels in human umbilical and maternal plasma in relation to the onset of labour. J Obstet Gynaecol Br Commonw 1974;81:737–45.[Medline]

17. Ohrlander S, Gennser G, Eneroth P. Plasma cortisol levels in human fetus during parturition. Obstet Gynecol 1976;48:381–7.[Abstract/Free Full Text]

18. Sybulski S, Maughan GB. Cortisol levels in umbilical cord plasma in relation to labor and delivery. Am J Obstet Gynecol 1976;125: 236–8.[Medline]

19. Newcomer JW, Selke G, Melson AK, Gross J, Vogler GP, Dagogo-Jack S. Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans. Arch Gen Psychiatry 1998;55: 995–1000.[Abstract/Free Full Text]

20. Elimam A, Knutsson U, Bronnegard M, Stierna P, Albertsson-Wikland K, Marcus C. Variations in glucocorticoid levels within the physiological range affect plasma leptin levels. Eur J Endocrinol 1998;139:615–20.[Abstract]

21. Yura S, Sagawa N, Ogawa Y, Masuzaki H, Mise H, Matsumoto T, et al. Augumentation of leptin synthesis and secretion through activation of protein kinase A and C in cultured human trophoblastic cells. J Clin Endocrinol Metab 1998;83:3609–14.[Abstract/Free Full Text]

22. Hytinantti T, Koistinen HA, Koivisto VA, Karonen SL, Andersson S. Changes in leptin concentration during the early postnatal period: Adjustment to extrauterine life? Pediatr Res 1999;45:197–201.[Medline]




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