This study reports for the first time profiles of plasma GPBB concentration in normal pregnancy and in pregnancy complicated with preeclampsia. The primary novel findings of this study are: (1) there is a physiologic increase in plasma GPBB concentration during pregnancy; (2) preterm but not term preeclampsia is characterized by a further increase in plasma GPBB concentration; (3) GPBB is readily detected in the placenta and its abundance is decreased in preterm preeclampsia cases; (4) SGA gestation does not affect plasma GPBB concentration; and (5) there was no difference in maternal plasma GPBB concentration between women with and without labor at term.
Normal tissues abundant in GPBB are the brain and the myocardium,1
and the placenta turned out to be an additional source of the enzyme. While pregnancy is clearly a physiological state, the median plasma GPBB concentration in normal pregnant women is almost three times higher than the cut-off value (10 ng/ml) used for the diagnosis of acute coronary syndromes in non-pregnant patients.5,6
Pregnancy remarkably alters cardiovascular functions with increased cardiac output, but electrocardiographic changes are restricted to only left-axis deviation, and there is no evidence that pregnancy increases the risk of ischemic myocardial damage.7
Pregnancy can also change cerebrovascular blood flow, such as the decrease in the mean blood flow of the middle and the posterior cerebral arteries, but does not affect cerebrovascular autoregulation;20
and the blood-brain-barrier (BBB) remains intact in healthy pregnant women.21
Therefore, it is less likely that the increase in the plasma GPBB concentration during normal pregnancy is solely attributed to the GPBB release from the heart or the brain. Instead, additional GPBB release from the placenta would be a reasonable expectation.
Preeclampsia is a pregnancy-specific syndrome characterized by hypertension and proteinuria, and it occurs in 5–8% of all pregnancies worldwide.22,23
and anti-angiogenic conditions in maternal and fetal compartments24–27
are reported as key steps for the occurrence of preeclampsia. It has been proposed that preeclampsia is a two-stage disorder: stage 1 (placental preeclampsia): abnormal placentation leading to placental hypoxia, and stage 2 (maternal preeclampsia): maternal symptoms of preeclampsia originating from placenta-derived circulating factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng).28,29
Higher maternal plasma GPBB concentration and lower placental GPBB expression in preterm preeclampsia patients in the current study are very likely to be associated with uteroplacental hypoxia leading to the conversion of GPBB into soluble form and to the release of placental GPBB into the bloodstream. However, in contrast to normal pregnancy, increased GPBB released from the heart and the brain would also be possible in patients with preeclampsia. Hypertensive disorders in pregnancy are associated with the aberrations of cardiovascular functions such as hyperdynamic ventricular function and low intravascular blood volume.30,31
Moreover, Ladner et al have reported that essential hypertension and preeclampsia are associated with the development of acute myocardial infarction during pregnancy.32
Melchiorre et al also have reported that about 20% of patients with preeclampsia at term show evident myocardial damage.33
In addition, increased BBB permeability and brain edema are found in both preeclampsia and eclampsia patients.21,34
However, no patient of the current study was diagnosed with acute myocardial infarction or brain damage during the index pregnancy.
Studies about preeclampsia have shown that there are significant differences in the pathogenesis, blood biomarker profiles, and clinical presentations according to the gestational age at disease onset.26,35–39
Preeclampsia developing before 37 weeks of gestation (preterm preeclampsia) is a more severe and complicated maternal phenotype of preeclampsia than that developing at term (term preeclampsia) in general.39
The risk of the recurrence in later pregnancies,35
the long-term risk of mortality from the following cardiovascular causes,36
the proportion of SGA neonates,37,38
and the concentrations of maternal serum liver enzymes39
are higher in preterm preeclampsia patients than in term preeclampsia patients. Huppertz recently proposed that these features largely comprise the phenotype of early-onset but not late-onset preeclampsia.40
Our observation of a significant increase in maternal plasma GPBB concentration in preterm preeclampsia, but not in term preeclampsia, further supports the opinion that preeclampsia can be subclassified according to the gestational age at disease onset.41
Pregnancies presenting SGA neonates and preeclampsia have been reported to share common features of shallow placentation and uteroplacental insufficiency.42
However, maternal manifestation of these conditions differs from each other, and some investigators have proposed that they are biologically different disease entities.43
In the present study, an additional effect of SGA birth on maternal GPBB concentration in preeclampsia cases was not found, which suggests that the increased maternal GPBB concentration is mainly related to preeclampsia. This finding was consistent with that from the analysis of GPBB concentration according to SGA births among normotensive pregnant women. Although an SGA gestation is one of the indicators for severity of preeclampsia,16
and commonly associated with preeclampsia,38,44
an SGA gestation alone was less likely to affect maternal GPBB concentration.
Previous studies of placental metabolism in preeclampsia have shown abnormalities in glycogen metabolism.45–49
Bloxam et al demonstrated impaired glycolysis in the placentas of women with preeclampsia by showing decreased concentrations of pyruvate and lactate but not glycogen and glucose.46
Arkwright et al also have shown that glycogen content is increased in the syncytiotrophoblast of preeclampsia cases, which was accompanied by 16-fold and 3-fold increases of glycogen synthase content and glycogen phosphorylase activity.47
Increased placental glycogen phosphorylase activity in preeclampsia cases is quite consistent with our observation that release of GPBB is increased in pregnant women with preeclampsia, which would lead to a higher plasma concentration of GPBB and less abundance in placental GPBB.
There are limitations in our study. As postpartum blood samples were unavailable, maternal GPBB concentration during the postpartum period could not be examined. The change in GPBB concentration after delivery would be a key piece of data in support of our hypothesis that increased GPBB concentration during pregnancy originates from placental tissue. Another limitation is that the blood samples and placental samples were not obtained from the same pregnant women and the analysis using the blood and placental samples from the same pregnant women would have been more relevant for the determination of placental origin of peripheral blood GPBB, although it was not feasible for us. In this study, there were differences of racial distribution and parity for each of the analyses such as (1) non-pregnant women vs. pregnant women with a normal pregnancy, (2) preeclampsia vs. SGA gestation vs. controls in preterm gestation, and (3) preeclampsia vs. SGA gestation vs. controls in term gestation. Although the differences in plasma GPBB concentration remained significant after adjusting for these confounding factors, future studies designed on a large scale are needed to address this issue.