Department of MaternalFetal Medicine, Division of Paediatrics, Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea & Westminster Hospital, London, UK
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Abstract |
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Key words: leptin/pre-eclampsia/pregnancy
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Introduction |
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Materials and methods |
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In the longitudinal study, samples were obtained from seven nulliparous women with normal uncomplicated pregnancies and eight women who subsequently developed pre-eclampsia. The aim of the longitudinal study was to establish the timing of the increase in circulating leptin concentrations in pregnancies destined to be complicated by pre-eclampsia. In order to recruit the appropriate number of subjects for the study, a power calculation was performed using the cross-sectional data. The mean SD of the data was 4.9 and the difference between the groups 11.6. In order to be able to show a significant difference in leptin concentrations with established pre-eclampsia at P = 0.05 and with a power of 95%, it was calculated that a sample size of seven in each arm would be needed. pre-eclampsia was defined according to the criteria of hypertension, proteinuria, hyperuricaemia and reversal of hypertension and proteinuria after the pregnancy. Hypertension was defined as an increase of 30 mmHg systolic or diastolic blood pressure increase of 15 mmHg compared to values before 20 weeks of pregnancy or an absolute blood pressure >140/90 mmHg after 20 weeks gestation if the earlier values were unknown. Proteinuria was defined as >0.5 g urinary protein excretion in 24 h (Davey and MacGillivray, 1988). Exclusion criteria were diabetes, chronic hypertension, known history of peripheral vascular disease and booking BMI <19 or >30 kg/m2. The samples were taken at 16, 20, 24, 28, 32, 36, and 38 weeks gestation. Blood pressure was taken at each sampling visit and the urine tested. If proteinuria of
1 was present on reagent strip, analysis a 24 h urine collection for protein excretion was carried out. Blood samples for leptin concentrations were collected into lithium heparin tubes, centrifuged immediately at 6420 g (4°C) and stored at 70°C until assayed. Samples were also taken for full blood count, creatinine and uric acid concentrations.
Total circulating leptin concentrations (ng/ml) were measured in duplicate by radioimmunoassay as described previously (Ma et al., 1996). The assay employed a polyclonal (rabbit) antibody raised against recombinant human leptin. Standards and I125-tracer were also made from recombinant human leptin (Ma et al., 1996
). The average intra- and inter-assay coefficients of variation were 3% and 8% respectively. The local Ethics Committee approved the study, and informed consent was obtained from all the recruits.
Statistical analysis
The cross-sectional plasma leptin values were not normally distributed and the data are presented as median (range). The data were normalized by log-transformation and comparisons made using an unpaired t-test. The rest of the cross-sectional and all of the longitudinal data were normally distributed and are presented as mean ± SD. The longitudinal data were compared using analysis of variance (ANOVA) for repeated measures. Pearson's correlation coefficients were calculated and a multiple regression analysis performed to determine which of the variables were independently related to plasma leptin concentrations. For all comparisons, statistical significance was defined as P < 0.05. The Statistical Package for Social Sciences (SPSS), version 8, was used for statistical analysis.
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Results |
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Discussion |
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Animal studies have shown that leptin may influence autonomic and cardiovascular function (Haynes et al., 1997; Shek et al., 1998
), and its receptors are present in central neural structures that regulate circulatory control (Tartaglia et al., 1995
). Chronic infusion of leptin in animal models causes an increase in heart rate and the development of hypertension, and similar findings have been observed in essential hypertension (Narkiewicz et al., 1999
). The data in this study show strong associations between the pattern of change of plasma leptin concentrations and blood pressure. It is possible that leptin released from placenta stimulates central receptors that regulate blood pressure and/or heart rate (Tartaglia et al., 1995
). Furthermore, a strong association was found between plasma leptin and uric acid concentrations in the pre-eclampsia group. This relationship may have several explanations. Both leptin and urate may be markers of pre-eclampsia and their strong relationship may simply be a reflection of this. In non-pregnant diabetics, leptin is closely related to urate concentrations, independent of BMI and blood pressure (Fruehwald-Schultes et al., 1999
), which suggests that one may affect the circulating concentrations of the other. Leptin may contribute to the increased uric acid concentrations as plasma uric acid concentrations are increased by oxidative stress (Davidge, 1998
) and leptin has been reported to induce oxidative stress in cultured human endothelial cells (Bouloumie et al., 1999
). Thus, there are several possible explanations for the higher leptin concentrations in pregnancies destined to develop pre-eclampsia. Moreover, they may play a role in the development of pre-eclampsia. This possibility requires further evaluation.
Although in this study it was observed that leptin concentrations in pre-eclampsia were independently related to maternal pre-pregnancy BMI in the pre-eclampsia group, other studies have failed to observe such a relationship during normal pregnancy (Highman et al., 1998) and pre-eclampsia (Williams et al., 1999
). This may be because weight gain during pregnancy is not solely due to fat deposition (the most important factor for regulating plasma leptin in non-pregnant women). There was no significant difference in haematocrit values and plasma creatinine concentrations between the two groups. Thus, it seems unlikely that haemoconcentration or impaired renal function, which are recognized pathophysiological components of pre-eclampsia, contributed to the high leptin observed in the disease. Although the number of patients in this study is limited, the highly significant statistical difference between the groups favours a true biological finding.
In summary, the data confirm that plasma leptin concentrations are higher in established pre-eclampsia. This study has shown for the first time that this increase pre-dates the development of pre-eclampsia, the occurrence of which is associated with a further marked increase in plasma leptin concentrations. The mechanisms responsible for this increase and the role played by leptin in the development of pre-eclampsia require further study.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 4, 2000; accepted on June 6, 2000.