Objective
Clinical observations suggest a role for the fetus in the maternal manifestations of preeclampsia, but the possible signaling mechanisms remain unclear. This study compares the fetal plasma concentrations of adenosine from normal pregnancies with those from preeclampsia.
Study Design
This secondary data analysis included normal pregnancies (n = 27) and patients with preeclampsia (n = 39). Patients with preeclampsia were subclassified into patients with (n = 25) and without (n = 14) abnormal uterine artery Doppler velocimetry (UADV).
Results
Fetal plasma concentrations of adenosine were significantly higher in patients with preeclampsia (1.35 ± 0.09 μmol/L) than in normal pregnancies (0.52 ± 0.06 μmol/L; P < .0001). Fetal plasma concentrations of adenosine in patients with preeclampsia with abnormal UADV (1.78 ± 0.15 μmol/L), but not with normal UADV (0.58 ± 0.14 μmol/L), were significantly higher than in normal pregnancies ( P < .0001).
Conclusion
Patients with preeclampsia with sonographic evidence of chronic uteroplacental ischemia have high fetal plasma concentrations of adenosine.
Several mechanisms of disease have been implicated in the pathophysiology of preeclampsia that include (1) chronic uteroplacental ischemia, (2) immune maladaptation, (3) very low-density lipoprotein toxicity, (4) genetic imprinting, (5) increased trophoblast apoptosis/necrosis, and (6) an exaggerated maternal inflammatory response to deported trophoblast. More recently, angiogenic imbalances have been implicated in the mechanisms of disease of preeclampsia. These imbalances are characterized by low maternal serum concentration of vascular endothelial growth factors (VEGF), placental growth factor, and high maternal serum concentration of antiangiogenic factors that include the soluble form of VEGF receptor 1 (sVEGFR-1 or sFlt-1) and soluble endoglin. However, the contribution of the fetus to the pathophysiology of preeclampsia has received less attention. Clinical and sonographic observations in patients with preeclampsia suggest that the fetus may play a role in the maternal manifestations of this pregnancy complication. A striking example of the role of the fetus is remission of preeclampsia after the death of the growth-restricted fetus in discordant twins or after correction of fetal hydrops in parvovirus infection. Moreover, increased impedance to blood flow in the umbilical artery (a surrogate marker of impaired fetal perfusion of the placenta) is associated with elevated maternal plasma concentration of antiangiogenic factors (sVEGFR-1) and reduced maternal plasma concentrations of angiogenic factors (placental growth factor).
The term feto-maternal antiangiogenic response syndrome has been coined to refer to a possible fetal signaling mechanism in preeclampsia. An important candidate as a mediator of fetal signaling is adenosine. The role of this nucleoside in fetal signaling is supported by the following observations: (1) In vitro studies that have used isolated dual-perfused human placental cotyledons demonstrated that that cessation of “maternal” perfusion is associated with a 2- to 6-fold increase in fetal venous perfusate concentrations of adenosine. (2) In normoxic conditions, exogenous adenosine administration to rat placental explants significantly increases the supernatant concentration of sFlt-1 (an antiangiogenic factor that is involved in the pathophysiology of preeclampsia). Moreover, the addition of dipyridamole (an adenosine transporter antagonist that increases extracellular adenosine) to cell cultures leads to a 1.6-fold increase in the concentrations of sFlt-1 in the supernatants. (3) All 4 known adenosine receptors are expressed in the human placenta. (4) Adenosine receptor protein and messenger RNA expression are significantly higher in placentas from preeclamptic pregnancies with or without small-for-gestational-age neonates but not in placentas from patients who deliver small-for-gestational-age neonates in the absence of preeclampsia. (5) In vitro exposure of placental villous explants to hypoxia increased the expression of the A(2A) adenosine receptor.
The objective of this study was to compare the fetal plasma concentration of adenosine from normal pregnancies and that from patients with preeclampsia according to the impedance to blood flow in the uterine arteries.
Materials and Methods
This is a secondary data analysis of previously published data that aimed to compare the fetal plasma concentration of adenosine from normal singleton pregnancies (n = 27) and that from patients with preeclampsia (n = 39). Preeclampsia was defined in the presence of gestational hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on 2 determinations at least 6 hours apart) and proteinuria (≥300 mg in a 24-hour urine collection). Patients with multiple gestations, chronic hypertension, diabetes mellitus, and renal disease were excluded from the study. Patients with preeclampsia were subclassified according to the impedance to blood flow in both uterine arteries (as determined by Doppler ultrasound scan) into groups of patients with (n = 25) and without (n = 14) abnormal uterine artery Doppler velocimetry (UADV). UADV was measured before cord blood sampling, as previously described. Abnormal UADV was defined as a mean pulsatility index 2 SDs below the mean for gestational age. Cord blood samples were taken at the time of UADV, as previously described, and a stop solution was used to prevent adenosine degradation. Fetal plasma adenosine concentration was determined with the use of high-performance liquid chromatography. The detection limit was at least 10 μmol/L, and the intra- and interassay coefficients of variation were 4.8% and 6.7%, respectively. All patients signed consent forms that had been approved by the local Human Investigation Committee, as previously described.
Data are presented as mean ± SEM. Comparisons were performed with the unpaired t test. The statistical packages that were used were SPSS (version 12.0; SPSS Inc, Chicago, IL) and MedCalc (version 7.4.4.1; MedCalc Software, Mariakerke, Belgium). A probability value of < .05 was considered significant.
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