Dear Editor
We read with interest the case report of Jank et al. (Citation1). The authors described the kinetics of sFlt-1 and PlGF and their ratio following feticide and induction of labor in a patient with severe early-onset preeclampsia. There is limited literature in this regard and the case report provides important insight into the changes of angiogenic-related factors following termination of pregnancy. However, we believe that the author’s statement that “an intact fetoplacental component is not needed for an angiogenic imbalance” is not supported by the data presented. This requires a different study design comparing feticide alone or induction of labor and subsequent changes in the circulating concentrations of angiogenic-related factors. As the authors pointed out in references 9–12, remission of preeclampsia or mirror syndrome can follow the death of the growth-restricted fetus in discordant twins or following feticide of the hydropic fetus in multiple pregnancies; by definition, these cases did not require placental delivery.
There is no doubt that the excess of antiangiogenic factors in preeclampsia and other pregnancy complications have a placental origin. However, experimental and clinical observations suggest that the fetus plays a central role in the clinical manifestations of preeclampsia. These observations include (Citationi) remission of preeclampsia after resolution of mirror syndrome in parvovirus infection (Citation2). In this case, improvement in the fetal status and presumably subsequent improvement in fetal perfusion of the placenta lead to the resolution of mirror syndrome and preeclampsia, without placental delivery. (Citationii) In molar pregnancies, the prevalence of preeclampsia is much higher when a fetus is present. Indeed, preeclampsia is present in 41.9% of pregnancies with partial mole (Citation3). In contrast, the prevalence of preeclampsia in complete mole significantly decreased from 12% (41/347) in the period of 1966–1972 to 1.3% (1/74) in the period of 1988–1993 (Citation4), presumably due to earlier diagnosis and uterine evacuation, which may have prevented the subsequent development of preeclampsia. (Citationiii) The conventional view is that placental villi in partial and complete mole are “avascular” or limited to villous capillary remnants (Citation5). However, this notion was recently challenged by the observation that vascular endothelial cells are present in the villous stroma of complete moles (Citation6). It is possible that the lack of fetoplacental circulation in complete moles may lead to ischemia of these endothelial and trophoblast cells leading into an excessive placental secretion of antiangiogenic factors. Thus, the absence of a fetus in complete mole does not disprove the fetal role in preeclampsia. On the contrary, the lack of fetal perfusion of the placenta in complete moles may represent an extreme in the spectrum of ischemic disease of the trophoblast, leading to angiogenic imbalances and early-onset preeclampsia before 20 weeks.
The fetal endothelium is continuous with that of the villus capillaries, and it is possible that in response to ischemia, endothelial signaling in villus capillaries may lead to placental overexpression and secretion of an excess of antiangiogenic factors. This is supported by studies using placental explants where the fetal compartment and the intervillous space are perfused under controlled conditions. In one study, the authors determined the adenosine concentrations in fetal venous perfusates using isolated dual-perfused human placental cotyledons. The authors reported that cessation of “maternal” perfusion was associated with a two- to sixfold increase in fetal venous perfusate concentrations of adenosine and a concomitant increase in fetoplacental perfusion pressure. Furthermore, perfusate pressure and the concentration of adenosine in the fetal compartment returned to baseline levels on reperfusion of the “maternal” circuit (Citation7). Thus, in the absence of fetus, the fetal endothelium in the placental villi is capable of increasing the concentrations of adenosine in response to reduced perfusion. Adenosine is a nucleoside that has been implicated in the placental expression of sFlt-1 under both normoxic and hypoxic conditions (Citation8).
In summary, the case report of Jank et al. provides additional information of the kinetics of sFlt-1 and PlGF following feticide and induction of labor. However, we believe that the data presented in the case report do not disprove an important fetal role in preeclampsia.
Declaration of Interest
The author does not have a conflict of interest.
REFERENCES
- Jank A, Kratzsch J, Stepan H. Effect of terminated fetal circulation on maternal angiogenic factors in severe early preeclampsia. Hypertens Pregnancy 2012; 31:201–206.
- Duthie SJ, Walkinshaw SA. Parvovirus associated fetal hydrops: Reversal of pregnancy induced proteinuric hypertension by in utero fetal transfusion. Br J Obstet Gynaecol 1995; 102:1011–1013.
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- Soto-Wright V, Bernstein M, Goldstein DP, Berkowitz RS. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol. 1995; 86:775–779.
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- Qiao S, Nagasaka T, Nakashima N. Numerous vessels detected by CD34 in the villous stroma of complete hydatidiform moles. Int J Gynecol Pathol 1997; 16:233–238.
- Slegel P, Kitagawa H, Maguire MH. Determination of adenosine in fetal perfusates of human placental cotyledons using fluorescence derivatization and reversed-phase high-performance liquid chromatography. Anal. Biochem. 1988; 171:124–134.
- George EM, Cockrell K, Adair TH, Granger JP. Regulation of sFlt-1 and VEGF secretion by adenosine under hypoxic conditions in rat placental villous explants. Am J Physiol Regul Integr Comp Physiol 2010; 299:R1629–R1633.