Maternal serum and umbilical cord blood leptin concentrations with fetal growth restriction

OBJECTIVE: To ascertain whether fetal growth restriction is associated with alterations of leptin concentrations in umbilical cord blood and maternal serum. METHODS: Maternal serum and umbilical cord blood leptin concentrations were determined by immunoradiometric assay at term in 43 women with uncomplicated singleton pregnancies (group A) and in 27 women with singleton pregnancies complicated by fetal growth restriction (group B), all with normal pregravid body mass index (BMI). RESULTS: Maternal serum leptin concentrations were significantly higher in group B compared with group A (45.0 ng/mL [range 34.2-54.9] versus 29.0 ng/mL [range 24.7-33.3]; P<.01). Umbilical cord blood leptin levels were significantly lower in group B compared with group A (8.4 ng/mL [range 3.6-13.2] versus 13.1 ng/mL [9.7-16.5]; P<.01). Maternal serum leptin levels were not significantly correlated with maternal BMI or with neonatal birth weight in either group. Umbilical cord blood leptin concentrations were significantly correlated with neonatal birth weight in both groups. CONCLUSION: Growth restricted fetuses at term show umbilical cord blood leptin concentrations significantly lower than those in normal fetuses, suggesting that fetal adipose tissue is a major source of leptin. Maternal serum leptin concentrations are higher in the presence of a growth restricted fetus. This increase might be due to an intrinsic placental mechanism, by which small placentas produce more leptin as a compensatory mechanism, or to early hypoxia.     

Maternal serum leptin concentrations do not correlate with cord blood leptin concentrations in normal pregnancy

OBJECTIVE: To determine whether there is a difference in maternal leptin concentration and cord blood concentration, consistent with the hypothesis of a noncommunicating, two-compartement model of fetoplacental leptin regulation. METHODS: Blood samples were collected from 139 women, identified as having an uncomplicated pregnancy, from an antecubital vein at delivery. Cord blood samples were taken from the umbilical vein. Leptin was measured by radioimmunoassay, and its relationship to fetal and maternal anthropometrics was assessed by Spearman correlation. Differences in maternal and cord blood leptin levels between male and female infants were tested with the Mann-Whitney Utest. Maternal and cord blood leptin were compared by the Wilcoxon signed rank test. The outcome measures were maternal and cord blood leptin at delivery, fetal birth weight, length, weight/length ratio, and ponderal index, maternal prepregnancy body mass index, pregnancy weight gain, relative weight gain, and body mass index at delivery. RESULTS: No correlations were found between maternal and cord blood leptin concentrations. Fetal leptin level correlated with birth weight (rho = 0.665; P <.0001), length (rho = 0.490; P <.0001), ponderal index (rho = 0.260; P =.002), and weight/length ratio (rho = 0.625; P <.0001). Median leptin concentrations were higher in female (9.3 ng/mL, range 1.5-34.4 ng/mL) than in male (8.2 ng/mL, range 1.6-38.3 ng/mL) neonates, but this difference was statistically not significant. Logistic regression analysis showed a significant influence on umbilical venous leptin concentration for birth weight (P <.0001) but not for gender. Maternal leptin concentrations were significantly higher than cord leptin concentrations (P <.0005 for the male and female neonates and the entire group). CONCLUSION: There was no correlation between maternal and cord leptin, which supports the hypothesis of a noncommunicating, two-compartment model of fetoplacental leptin regulation.     

Leptin secretion to both the maternal and fetal circulation in the ex vivo perfused human term placenta

The contribution of placental leptin, if any, to both the fetal and maternal circulation and its role in pregnancy remains to be determined. In an experiment to investigate this, 27 placentae from term pregnancies were perfused ex vivo (gestational age=39.5 s.d. 1.2; range=38-42 weeks: fetal weight=3285 s.d. 482; range=2480-4420; birthweight centile range=4th to the 98th) at both the maternal and fetal interface. Placental leptin was exported into both the maternal and fetal circulations. The log leptin production by the maternal side of the placenta was significantly greater (P=0.001) than that for the fetal side (5.193 s.d.1.049 versus 4.387 s.d. 0.768 ng/placenta/min). There was no significant relationship between maternal and fetal log leptin production and maternal body mass index, birthweight, birthweight centile, ponderal index or gestational age or with cord blood pO(2), pCO(2) and pH. There was however, a significant increase in the maternal log leptin production with increasing fetal to placental weight ratio (P=0.017; r(2)=20.7 per cent) but no corresponding relationship for fetal leptin production. It is proposed that such a mechanism would allow the placenta to modulate fat supply to the fetus in response to the fetal demand relative to placental supply.     

Characterization of changes in leptin and leptin receptors in a rat model of preeclampsia

OBJECTIVE: The purpose of this study was to determine the influence of reduced uteroplacental perfusion pressure on plasma leptin and placental leptin receptor expression in rats that develop hypertension in the third trimester of pregnancy. STUDY DESIGN: The ovarian arteries and abdominal aortae of pregnant Sprague-Dawley rats (n=9) were constricted surgically on day 14 of gestation and were matched with sham controls. Systolic blood pressure and weight were measured biweekly. Maternal plasma leptin levels, placental leptin receptor abundance, fetal number, fetal weight, and placental weight were determined. RESULTS: Reductions in perfusion pressure induced a significant decrease in maternal plasma leptin. Maternal systolic blood pressure and leptin receptor protein abundance was increased in the experimental group. Litter size and fetal and placental weight were significantly decreased in response to reduced perfusion pressure. CONCLUSION: Reduced uteroplacental perfusion pressure reduces litter size, fetal and placental weights, and maternal plasma leptin levels and increases placental expression of leptin receptors.     

Leptin concentrations in maternal serum and cord blood: relationship to maternal anthropometry and fetal growth.

OBJECTIVE: To determine 1. the relationship between maternal serum leptin concentrations and maternal anthropometry and 2. the relationship between cord serum leptin concentrations at birth and neonatal anthropometry. DESIGN: Prospective cohort study of fetal growth in low-risk pregnancies. SETTING: University teaching hospital. SAMPLE: Thirty-nine women and their babies taking part in a fetal growth study. METHODS: Blood was taken from the women between 10-20 weeks of gestation and from the umbilical cord of their babies at delivery. Serum leptin was measured by radio-immunoassay. Maternal anthropometric measurements were recorded at booking. Neonatal anthropometric measurements were recorded within 48 hours after delivery. Linear regression analysis was used to explore the relationship between serum leptin concentrations and anthropometric measures and multiple regression analysis then applied to determine which variables remained independently associated with leptin. RESULTS: The median (range) leptin concentration in maternal serum was 11.8 ng/mL (1.7-39.7) and in cord blood was 4.2 ng/mL (0.6-21.4). Maternal leptin levels correlated with maternal weight, body mass index, midarm circumference and skinfold thickness, but not with birthweight, placental weight or maternal height. Body mass index and midarm circumference remained significant after multiple regression analysis. Cord leptin levels correlated with birthweight, birthlength, placental weight and skinfold thickness but not with ponderal index. Birthweight and subscapular skinfold thickness remained significant after multiple regression analysis. Cord leptin concentrations did not correlate with maternal leptin concentrations. CONCLUSIONS: We suggest that there are very strong associations between maternal leptin and maternal adiposity in pregnancy, and between cord leptin at delivery and birthweight, as well as other anthropometric markers of fetal growth.     

Leptin as an acute stress-related hormone in the fetoplacental circulation

OBJECTIVE: To investigate the relationship between fetoplacental leptin secretion and blood gases. METHODS: We measured the levels of umbilical arterial and venous leptin, umbilical cord gas, umbilical venous blood glucose, and estradiol-17beta (E2) in 89 pregnant women. Correlation between the leptin levels and other variables (gestational age, birth weight, maternal body weight, height, body mass index, maternal body weight gain, placental weight, umbilical cord gas data, and levels of umbilical venous blood glucose and E2) were examined statistically. RESULTS: Umbilical arterial and venous leptin levels were 7.64 +/- 12.76 and 7.76 +/- 13.17 (ng/mL), respectively, correlating positively with carbon dioxide pressure levels (r = 0.446, P <.001; r = 0.406, P <.001, respectively) and correlating inversely with pH (r = -0.337, P =.001; r = -0.247, P =.019, respectively). Umbilical venous glucose, E2, and other factors did not correlate with leptin levels. CONCLUSION: Leptin secretion into the fetoplacental circulation may be associated with fetal hypercapnia, suggesting two important roles for leptin: one for basal control of fetal fat tissue and one as an acute stress-related hormone.     

Serum leptin concentrations during the perinatal period

We aimed to study maternal and infant serum leptin concentrations during the perinatal period and their relationship to the body weight of mothers and newborns. Serum leptin values were measured by enzyme-linked immunoadsorbent assay (ELISA) (R&D systems) in 26 healthy, term neonates during the first (N1) and fifth (N5) day after birth and were compared with serum leptin values in maternal blood (MS), amniotic fluid (AF), and umbilical cord (UC) at delivery. Twenty-five healthy, nonpregnant women, age and body weight-matched to the mothers, were used as controls (C). Infant serum leptin concentrations declined significantly after birth from UC to the N5 samples (p<0.003). MS leptin values were significantly higher than UC, N1, N5, and C values (p<0.001), while AF values were significantly lower than in controls (p<0.001). UC, but not MS leptin values correlated significantly with the birth weight of infants (r = 0.6; p<0.03). The elevated values of leptin in maternal serum and the regressing pattern of infant leptin values after birth suggest an additional, probably placental source of this protein during pregnancy, possibly contributing to the regulation of fetal body weight.     

Differences in umbilical cord serum lipid levels with mode of delivery

Objective To investigate whether umbilical cord serum lipid levels differ with mode of delivery.
Design Retrospective observation study.
Population Two hundred and ninety mothers aged 29.1 years (SD 4.7) who had vaginal delivery, and 44 mothers aged 30.4 years (SD 4.7) who had elective caesarean section were enrolled.
Main outcome measures Maternal and umbilical cord blood were obtained immediately after delivery. Serum lipid levels including total cholesterol, high density lipoprotein cholesterol, saturated fatty acid, mono-unsaturated fatty acid and polyunsaturated fatty acid were measured. Obstetric variables and serum lipid levels were compared between the two groups. In each group the correlations of fetal serum lipid levels with maternal serum lipid levels were investigated.
Results There were no significant differences in maternal age, neonatal weight, gestational duration, placental weight and neonatal gender distribution between the two groups. Only the two fetal serum lipid levels (including total cholesterol and non-high density lipoprotein cholesterol) showed a correlation with maternal fetal lipid levels with correlation coefficients > 0.3 in the caesarean section group. However, saturated fatty acid, mono-unsaturated fatty acid and total fatty acid levels in the non-high density lipoprotein low density lipoprotein, very low density lipoprotein, intermediate density lipoprotein and free fatty acid fraction in the umbilical cord serum were significantly higher in the vaginal delivery cases (   P < 0.01  ).
Conclusions Umbilical cord serum levels of saturated and mono-unsaturated fatty acids increase during vaginal delivery.     

Relation between leptin and cortisol values in umbilical vessels at normal vaginal delivery.

To study the role of various hormones in the control of fetal leptin secretion during labour, 33 pregnant women with normal singleton term pregnancy were recruited. At the time of spontaneous vaginal delivery, a venous blood sample was taken from the women together with a venous and an arterial cord blood sample. In all blood samples, leptin, cortisol, prolactin and progesterone were measured. Serum leptin and cortisol values were significantly higher, while those of prolactin and progesterone were significantly lower in the mother than in the two umbilical vessels (p < 0.01). Cortisol levels were significantly higher in the umbilical artery than in the umbilical vein (p < 0.01). Serum leptin values in the umbilical artery and vein correlated significantly with the corresponding values of cortisol (r = 0.523 and r = 0.580 respectively, p < 0.01), but not with those of prolactin and progesterone. A weak but significant correlation was found between leptin values in the two umbilical vessels and birth weight (r = 0.385 and r = 0.401 respectively, p < 0.05). In multiple regression analysis, cortisol values but not birth weight was the most important determinant of leptin values. Birth weight, however, correlated significantly with placental weight (r = 0.776, p < 0.001). These results demonstrate for the first time that leptin concentrations in the umbilical vessels at normal vaginal delivery correlate significantly with cortisol values, thus providing evidence that cortisol mediates a labour stimulating effect on fetal leptin secretion. It is suggested that cord blood leptin values at delivery are not a good predictor of neonatal weight.     

瘦素在胎盘组织中的表达及其与新生儿体重的关系

目的探讨瘦素在胎盘组织中的表达及其与新生儿体重的关系.方法采用放射免疫法(RIA)检测100例足月孕妇静脉血及其新生儿脐血瘦素水平,根据新生儿出生体重分为大于胎龄儿(LGA)组19例,适于胎龄儿(AGA)组65例,小于胎龄儿(SGA)组16例,同时采用逆转录-聚合酶链反应(RT-PCR)技术,检测41例胎盘组织中瘦素mRNA表达水平.结果(1)胎盘组织中瘦素mRNA表达水平为0.97±0.04,与新生儿体重呈显著正相关关系(r=0.43,P＜0.01).其中LGA组(1.01±0.03)显著高于AGA组(0.97±0.02),SGA组(0.93±0.03)显著低于AGA组,差异均有极显著性(P＜0.01).(2)母血瘦素水平为(14.22±7.66)μg/L,与新生儿体重无相关关系(r=0.11,P＞0.05).(3)新生儿脐血瘦素水平为(7.58±5.15)μg/L,与新生儿体重呈显著正相关关系(r=0.57,P＜0.01),其中LGA组脐血瘦素水平为(13.38±6.75)μg/L,显著高于AGA组的(7.40±4.45)μg/L,SGA组为(2.79±1.54)μg/L,显著低于AGA组,差异有极显著性(P＜0.01).结论脐血及胎盘组织中瘦素水平与胎儿生长发育状态密切相关;母血瘦素水平与新生儿体重无关;孕期胎儿瘦素的重要来源是胎盘组织.     

Is an atherogenic lipoprotein profile in the fetus a prerequisite for placental vascular disease?

Objective To measure the blood apolipoprotein A-1 and apolipoprotein B in the fetal circulation in normal pregnancy and in pregnancy with evidence of vascular disease in the fetal umbilical placental circulation defined in the antenatal period by Doppler ultrasound study.
Design An observational study to compare fetal plasma apolipoprotein levels in normal and complicated pregnancy.
Setting A university hospital tertiary referral obstetric unit.
Samples Umbilical vein blood was collected at delivery from 22 normal fetuses delivered by elective caesarean section for non fetal reasons and 30 fetuses with evidence of umbilical placental vascular disease identified antenatally by Doppler ultrasound study.
Methods Plasma apolipoprotein A-1 and B were determined using an enzyme-linked immunosorbent assay (ELISA) methods.
Main outcome measures Fetal plasma levels of apolipoprotein A-1 and B were measured.
Results There was a significantly lower level of fetal plasma apolipoprotein A-1 in placental insufficiency [placental insufficiency vs normal pregnancy, median 0.30 g/L (interquartile range 0.24, 0.39 g/L) vs 0.35 g/L (0.31, 0.42 g/L),   P = 0.045  ]. In contrast, the levels of fetal plasma apolipoprotein B in placental insufficiency [0.20 g/L (0.17, 0.26 g/L)] were significantly increased compared with normal pregnancy [0.16 g/L (0.14, 0.20 g/L),   P = 0.03  ]. The ratio of fetal plasma apolipoprotein B to A-1 was also substantially higher in placental insufficiency [0.68 (0.55, 0.83)] than in normal pregnancy [0.45 (0.36, 0.60),   P = 0.0003  ].
Conclusions Our study has demonstrated that levels of fetal plasma apolipoprotein A-1, apolipoprotein B and the ratio of apolipoprotein B to A-1 were altered in the fetuses who are victims of umbilical placental insufficiency in the same direction as in adults associated with a high risk of atherogenesis.     

Discordant fetal leptin levels in monochorionic twins with chronic midtrimester twin-twin transfusion syndrome

The objective of this study was to determine the plasma leptin concentrations in monochorionic twin fetuses with and without twin-twin transfusion syndrome (TTTS). Paired maternal and fetal blood samples were obtained at birth from monochorionic twin pregnancies complicated with (n=12) or without TTTS (n=12). Amniotic fluid samples were also collected from twin pairs at amnioreduction and/or fetal blood sampling in utero. Plasma and amniotic fluid leptin concentrations were measured by radio-immunoassay. Fetal leptin levels in the growth-restricted donor were lower than the recipient twin of the TTTS group (Delta mean 3.7; CI 2.6 to 4.7 ng/ml; P< 0.001). Fetal leptin levels were comparable between non-TTTS twin pairs (Delta mean 0.9; CI 0.1 to 1.4 ng/ml; P=0.10) and recipient twins of TTTS (P=NS). Maternal plasma concentrations of leptin were comparable between the two groups and were higher than the fetal levels. There was a positive association between cord leptin levels and birthweight of twin pairs (y=0.002x-0.37; r=0.58; P< 0.01; n=48). A significant positive relation was also found between delta leptin levels and percentage discordance in birthweight in the TTTS group (y=0.25x-2.21; r=0.82; P< 0.001, n=12). In conclusion, leptin levels in the recipient twins were three times higher than their growth restricted donor twins. However further studies are warranted to elucidate the underlying mechanism.     

Placental leptin

Placental tissues from humans, rodents and farm animals contain leptin and its receptor. Leptin produced by the human placenta has the same size, charge and immunoreactivity as leptin produced by adipose tissue. However, the expression of human placental leptin appears to be regulated by a placenta-specific upstream enhancer. In this review the occurrence of leptin and its receptor in a range of species and placental types is described, and its significance during pregnancy discussed. Placental leptin contributes to the increase in maternal circulating concentrations of leptin during late pregnancy when it is likely to have an endocrine role in regulating maternal energy balance. Placental leptin may have angiogenic and immunomodulatory activities, which affect the placenta in an autocrine or paracrine manner. It also appears to affect fetal growth and development by binding to leptin receptors present in fetal organs.     

Placental leptin and pregnancy pathologies

Leptin, the protein encoded by the Ob gene, is produced by the white adipose tissue and by the placenta during pregnancy. Placental leptin production makes a substantial contribution to maternal circulating levels during pregnancy which rapidly decrease and return to normal after delivery. Leptin has been detected in fetal plasma as early as week 18 of gestation, and umbilical leptin concentrations are closely related to birth weight. This has led to the hypothesis that fetal fat mass mainly determines fetal circulating leptin. Placental leptin production is increased in choriocarcinoma, preeclampsia and type 1 diabetes. Estrogens, hypoxia and insulin have been suggested as positive regulators of placental leptin production. Maternal leptinemia might act as a sensor of energy balance during pregnancy. The presence of both leptin and leptin receptors in the placenta suggests that leptin can act by autocrine or endocrine pathways in the human placenta. The roles of fetal leptin and consequences of increased placental leptin production in pathological pregnancies have yet to be elucidated.     

Umbilical venous leptin concentration and gender in newborns

OBJECTIVE: To investigate the relationship between umbilical venous leptin concentration and gender in 20 pairs of newborns matched 1:1 for birth weight and gestational age at sampling. MATERIALS: Blood samples were obtained from 40 women at delivery, identified as having an uncomplicated pregnancy. Umbilical venous blood samples were obtained from their newborns (20 males and 20 females) at birth. Specimens were analyzed using a human leptin 125-I radioimmunoassay. RESULTS: Fetal leptin correlated positively with birth weight (rs = 0.541; P < .001). Umbilical venous leptin concentrations in female newborns (median: 10.7 ng/mL, range: 3.5-34.4 ng/mL) were significantly higher (P = .028) than in male newborns (median: 7.7 ng/mL, range: 2.0-19.3 ng/mL). There was no significant correlation between maternal and fetal leptin concentrations. Multiple logistic regression analysis revealed birth weight and gender to be independent factors influencing fetal cord leptin. CONCLUSION: Our results suggest that in the fetus, as in children and adults, gender and weight are the major determinants of circulating leptin levels.     

Serum ferritin and cobalamin in growth retarded fetuses

Objective To examine fetal and maternal serum cobalamin and ferritin concentrations in pregnancies complicated by fetal growth retardation.
Setting Harris Birthright Research Centre for Fetal Medicine, King's College Hospital Medical School, London.
Design Cross sectional study.
Subject Fetal blood samples obtained by cordocentesis from 20 growth retarded fetuses at 26 to 36 weeks of gestation. Maternal venous blood was also collected and serum ferritin and cobalamin concentrations were measured by radio-immunoassay in the fetal and maternal samples.
Results In the growth retarded group, the mean fetal serum concentration of cobalamin was higher than the normal mean for gestation (   t = 3.27  ,   P < 0.01  ), and this increase was significantly associated with fetal acidaemia (   r =−0.686  ,   P < 0.001  ) and erythroblastosis (   r = 0.731  ,   P < 0.001  ). In contrast, the fetal to maternal ferritin ratio was significantly reduced; there was a nonsignificant decrease in fetal serum and an increase in maternal serum ferritin concentration. There was an association between fetal serum ferritin concentration and erythrocyte count (   r =–0.612  ,   P < 0.01  ).
Conclusions In placental insufficiency, as in postnatal starvation and Kwashiorkor syndrome, uptake and storage of cobalamin by the fetal liver may be impaired. The decrease in fetal to maternal ratio of ferritin could be the consequence of impaired placental perfusion.     

Leptin levels in maternal and cord serum: relationship with fetal development and placental weight

OBJECTIVE: To test the hypothesis that the circulating levels of leptin in the maternal and cord serum correlate with the birthweight of the newborns and with the weight of the placenta. METHODS: In a population of 85 women from northern Greece who gave birth to an equal number of full-term infants, we calculated the concentration of leptin in the maternal serum as well as in the cord serum, right after delivery, by using an immunoradiometric assay. The correlation between these values, the maternal BMI before pregnancy and at the time of delivery, the neonatal BMI, Ponderal Index, and the placental weight was studied. RESULTS: Mean maternal leptin showed a statistically significant difference from mean cord serum leptin (14.7 and 7.07 ng/ml, respectively) and was positively correlated to the maternal BMI at the time of delivery (r = 0.3, P = 0.016), but not to neonatal BMI. A positive correlation between the mean cord serum leptin and the BMI of the neonates (r = 0.26, P = 0.031 ) was found. There was no correlation between the maternal BMI at the time of delivery and the neonatal BMI. Similarly, no correlation could be established between the placental weight and the levels of leptin in the maternal or in the cord serum but a positive correlation between placental weight, neonatal BMI and weight, and mothers' BMI was observed. Finally, although a noteworthy difference between the mean leptin levels of neonates of two different sexes was observed (male 5.9 ng/ml, female 7.8 ng/ml), that difference never reached a statistically significant level. CONCLUSIONS: The maternal leptin level could not be used as a reliable marker of fetal growth but a positive correlation between cord serum leptin and fetus growth is suggested.     

Associations between the levels of soluble (pro)renin receptor in maternal and umbilical cord blood and hypertensive disorder of pregnancy

IntroductionThe prorenin (PR) receptor [(P)RR] contributes to the regulation of the tissue renin-angiotensin system (RAS) and Wnt signaling, which is involved in embryogenesis and the pathological progression of malignant tumors and diabetes mellitus. Placental (P)RR is significantly upregulated in placental tissues from preeclamptic women. However, because it cannot be examined during pregnancy, the chronological relationship between the acceleration of tissue RAS and the disease state of hypertensive disorder of pregnancy (HDP) has not been reported. In this study, we examined whether chronological changes in placental tissue RAS can be assessed by measuring soluble (P)RR [s(P)RR].MethodsWe obtained maternal and umbilical cord blood samples from 517 pregnant women (441 singleton and 76 twin pregnancies). The concentrations of s(P)RR and prorenin (PR) were measured using enzyme-linked immunosorbent assays.ResultsMultivariate analysis showed that maternal serum s(P)RR levels were significantly higher in patients with HDP or fetal growth restriction (FGR) and were positively correlated with serum PR levels. Furthermore, the maternal s(P)RR level was significantly higher in HDP with severe hypertension and after the onset of HDP. However, maternal s(P)RR levels were not affected by the severity of proteinuria. Serum s(P)RR levels in umbilical cord blood of singleton pregnancies were significantly correlated with gestational week at delivery and PR level.DiscussionMaternal serum s(P)RR concentrations may reflect acceleration of tissue RAS in the placenta and blood pressure severity; however, the umbilical serum s(P)RR concentration was not affected by maternal HDP.