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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology and Department of Internal Medicine, University of Messina, Messina Italy; and the Department of Obstetrics and Gynecology, University of Modena, Modena, Italy.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: A nested case-control study was carried out on a cohort of 1,842 pregnant women who participated in the first-trimester Down syndrome screening program; 34 developed preeclampsia and 48 gestational hypertension. A control group of 82 nonhypertensive uneventful pregnancies was selected. Plasma adiponectin was determined using an enzyme-linked immunosorbent assay (ELISA).
Results: Adiponectin median concentrations in the group which subsequently became hypertensive were significantly lower than those in the control group (7.6 versus 13.0 µg/mL) (P < .001). When the 2 hypertensive subgroups were considered, the plasma adiponectin median value in the preeclampsia group was significantly lower than that in the gestational hypertension group (6.6 versus 9.3 µg/mL) (P = .01). Regression analysis showed an inverse correlation between plasma adiponectin concentrations and maternal age, gestational age, body mass index, systolic blood pressure, and proteinuria. Approximately 34% of hypertensive pregnancies, compared with 7% of controls (P < .001), had plasma adiponectin concentrations less than 6.4 µg/mL (mean value of lower quartile of distribution among control patients). After adjusting for maternal age, all these women experienced a 6.6-fold (95% confidence interval 2.5–17.8) increased risk of pregnancy hypertension, compared with those women who had higher concentrations
Conclusion: Our findings suggest a strong association between hypoadiponectinemia and the risk of hypertensive disorders in pregnancy, especially with preeclampsia.
Level of Evidence: II-2
Adiponectin is an exclusively adipose tissue–derived protein with important metabolic effects. In particular, adiponectin has been found to be reduced in patients with obesity2 and type 2 diabetes,3 whereas it is inversely correlated with insulin resistance,4 and it is well known that insulin resistance is highly correlated with hypertension.5 In a recent review, several mechanisms through which insulin resistance could increase blood pressure in pregnancy have been summarized. They included sympathetic nervous system activation, renal sodium retention, and endothelial dysfunction.6
Experimental data has demonstrated that adiponectin acts as an endogenous modulator, attenuating the excessive inflammatory response in the vascular wall.7 Therefore, plasma adiponectin may be considered a useful marker of endothelial function, particularly in hypertensive patients. In fact, the adiponectin concentration was significantly lower in hypertensive than in normotensive men regardless of insulin resistance.8
In the literature, there is only one study on adiponectin and hypertension in late pregnancy, which reports a paradoxical elevation of plasma adiponectin concentrations in women affected by preeclampsia when compared with control subjects.9 In our study we evaluated first-trimester plasma adiponectin levels in pregnant women who subsequently developed hypertensive disorders.
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MATERIALS AND METHODS |
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The control group of 82 nonhypertensive pregnant women who participated during the same period in the Down syndrome screening were selected among those who delivered an adequate gestational age fetus in our hospital after an uncomplicated pregnancy. The random assignment of the patients was done by utilizing as controls each first normotensive patient with an uneventful pregnancy, which was just after the hypertensive patient in the list of that day in which venous blood sampling of the Down syndrome screening was performed. So these patients were well-matched with the hypertensive groups for the length of storage of frozen samples, prepregnancy body mass index (BMI), and BMI and gestational age at blood collection. All the patients were nonsmokers. The study was approved by the Institutional Review Board, and all the patients gave their informed consent.
Samples were taken after an overnight fast. Time of sampling was standardized: 8–9 am. The samples were venous blood, and the anticoagulant used was tripotassium ethylenediamine tetraacetic acid (K3EDTA). The average time between the centrifugation and freezing of samples was approximately 5 minutes, after which samples were stored at –80°C. Plasma adiponectin was evaluated in the blood samples of the hypertensive and the control groups after the Down syndrome screening (9th to 13th weeks of gestation) and was measured by Sandwich ELISA with a commercially available adiponectin ELISA kit (Linco Research Inc, St. Charles, MO).
Determinations were performed only in one batch. The lower limit of the sensitivity of the assay was 0.8 ng/mL. In our laboratory, at a 30 ng/mL level, the intra-assay and inter-assay coefficients of variation were 1.9% and 7.5%, respectively.
The Mann-Whitney U test or t test was used to compare continuous variables between the 2 groups, whereas for noncontinuous variables, 
2 test was used. Furthermore, when more than 2 groups were considered, comparison across the groups was performed by the Kruskal-Wallis test. An analysis of covariance (ANCOVA) was performed to adjust for differences in adiponectin concentrations for covariates, such as maternal age and gestational age at blood collection.
Associations of maternal adiponectin concentrations with covariates were estimated with Spearman correlation coefficients. Multiple linear regression analysis was used to determine which factors were significantly and independently correlated with plasma adiponectin variations, in a model consisting of maternal age, parity, prepregnancy BMI, BMI and gestational age at blood collection, birth weight, proteinuria, and systolic and diastolic blood pressures.
We considered each subject according to the quartiles determined by the distribution of adiponectin among the control patients. We used a multiple logistic regression to derive relative risk estimates: odds ratio (OR) and 95% confidence interval (CI).
The statistical analysis was performed with SPSS 11.5 (SPSS Inc, Chicago, IL). Continuous variables are presented as mean ± standard deviation and as median and interquartile range. All reported CI values were calculated at the 95% level. P < .05 was considered statistically significant.
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RESULTS |
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With univariate correlation analysis, plasma adiponectin concentrations in the preeclampsia group inversely correlated with prepregnancy BMI (r = –0.45, P = .008), BMI at the blood collection (r = –0.42, P = .01), fetal birth weight (r = –0.36, P = .03), proteinuria (r = –0.44, P = .01), and systolic blood pressure (r = –0.42, P = .01); there was no correlation with diastolic blood pressure (r = –0.14, P = .40) or maternal age (r = –0.08, P = .63). In the gestational hypertension group, adiponectin values directly correlated with maternal age (r = 0.89, P < .001) and inversely correlated with fetal birth weight (r = –0.40, P = .004), prepregnancy BMI (r = –0.34, P = .02), and systolic blood pressure (r = –0.71, P < .001); there was no correlation with BMI at blood collection (r = –0.19, P = .19) or diastolic blood pressure (r = –0.06, P = .67).
When all of those in the hypertensive group were considered, adiponectin concentration was inversely associated with maternal age (r = –0.47, P < .001), gestational age (r = –0.43, P = .001) and BMI at blood collection (r = –0.27, P = .001), prepregnancy BMI (r = –0.35, P = .001), systolic blood pressure (r = –0.6, P < .001), and proteinuria (r = 0.46, P < .001). There was no correlation with fetal birth weight (r = –0.13, P = .2) or diastolic blood pressure (r = –0.18, P = .9).
When multiple linear regression analysis was performed in the hypertensive group, again maternal age (ß = 0.49; 0.45 to 0.79), parity (ß = –0.25; –2.5 to –0.89), BMI at blood collection (ß = 4.4; 2.0 to 5.5), prepregnancy BMI (ß = –4.6; –5.8 to –2.2), systolic blood pressure (ß = –0.19; –0.09 to –0.02), and proteinuria (ß = –0.31; –0.02 to –0.009) were independently related to adiponectin plasma levels.
Approximately 34% of hypertensive pregnancies, compared with 7% of controls (P < .001), had plasma adiponectin concentrations less than 6.4 µg/mL, which was the mean value in the lower quartile of distribution among the control patients. All these women experienced a 6.5-fold increased risk of pregnancy hypertension, compared with those women who had higher concentrations (unadjusted OR 6.5; 95% CI 2.5–16.9). This association also did not change after adjustment for maternal age (OR 6.6; 95% CI 2.5–17.8) (Table 2).
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When we considered the plasma adiponectin values distribution of the 2 hypertensive subgroups in the lowest quartile, we found that 25% of gestational hypertension patients and 47% of patients with preeclampsia had plasma adiponectin concentration less than 6.4 µg/mL (P < .01). This means that the OR was increased in the preeclampsia group (11.2, 95% CI 3.8–32.8) and in the gestational hypertension group (4.2, 95% CI 1.4–12.1). After adjustment for maternal age, the OR was 9.4 (95% CI 3.2–27.9) and 4.6 (95% CI 1.5–14.1) in the preeclampsia group and gestational hypertension group, respectively (Table 2).
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DISCUSSION |
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It is not known what the relationship between adiponectin and blood pressure is, but adiponectin's effects on the endothelium probably play an important role. Experimental data has demonstrated that adiponectin is a strong anti-inflammatory agent that acts through the nuclear factor kappa B (NF-
B) pathway,11 and furthermore, it may inhibit the production of C-reactive protein,12 a marker of inflammation.
On the other hand, adiponectin has been shown to increase nitric oxide production, activating the endothelial nitric oxide synthase (eNOS) enzyme and increasing its expression.13 Moreover, it directly correlates with vasodilator response to reactive hyperemia.14 Then, it seems that adiponectin may protect the endothelium, attenuating the excessive inflammatory response in the vascular wall and increasing the vasodilatory condition. All these effects might positively influence the preservation of a normal blood pressure.
We have also studied plasma adiponectin concentrations in the 2 subgroups of hypertensive patients, and the relative risk is somewhat increased in the preeclampsia subgroup, where almost 50% of the patients had adiponectin plasma levels below the lowest quartile mean value, compared with only one fourth of the gestational hypertension subgroup. This strong association between hypoadiponectinemia and preeclampsia (in which subgroup, the adjusted OR in the lower quartile reached a 9.4-fold increased risk of hypertensive disease compared with those patients with higher adiponectin concentrations) could not be influenced only by insulin resistance, because the first trimester of pregnancy is characterized by a modest increase in insulin resistance.15 In this way, our results might be considered contradictory: low adiponectin levels in a period of not particularly high insulin resistance. Also in Ramsay et al's experience,9 and very recently in the Naruse et al study,16 there were contradictory results that the authors considered paradoxical: high adiponectin levels when insulin resistance is highest. In pregnant women who suffer preeclampsia, it seems that adiponectin plasma level behavior is completely different from that in normal pregnancies and might probably explain conflicting results about insulin resistance and preeclampsia, the relationship of which is far from being elucidated.
In conclusion, this is the first study examining plasma adiponectin behavior before the clinical manifestations of gestational hypertension or preeclampsia. We suggest that hypoadiponectinemia might be considered predictive of pregnancy-induced hypertension syndromes and that it might be involved in the pathogenesis of hypertensive disorders in pregnancy, especially preeclampsia.
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Footnotes |
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doi:10.1097/01.AOG.0000168441.79050.03
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REFERENCES |
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