Effect of Pentoxifylline, administered in Preterm Labour, on the Foetal–Placental Circulation and Neonatal Outcome: A Randomized, Prospective Pilot Study

Abstract

The aim of the study was to evaluate the pentoxifylline administration on the foetal-placental circulation and neonatal outcome in women with threatened preterm labour. Pentoxifylline was given as a supplement to standard tocolytic therapy in a group of 43 patients (pentoxifylline group) as an intravenous infusion and oral supplementation in a total dosage of 800 mg ⁄ day. The drug was administered within 3 weeks after admission. No pentoxifylline was given in the control group (53 patients). Doppler velocimetry of pulsatility indices (PI) of the umbilical (UA) and middle cerebral (MCA) arteries as well as cerebro-placental ratio (CPR) were calculated. Also, the neonatal outcome was estimated in both groups. From the second week of therapy with pentoxifylline, the PI decreased in umbilical artery and increased in the MCA, whereas in the control group, there were no changes. The value of PIUA, evaluated after the third week of pentoxifylline administration, was statistically significantly lower when compared to data obtained on admission (mean: 0.99 € 0.22 versus 0.82 € 0.12; p = 0.016). Pentoxifylline significantly increased CPR values calculated after third week of drug administration, which were statistically significantly higher in the pentoxifylline group when compared with respective data in the control group (mean: 2.30 versus 1.61; p = 0.001). The risk of severe neonatal complications was significantly lower in the pentoxifylline group (p = 0.026). Pentoxifylline changed foetal-placental blood circulation in patients with threatened preterm labour and improved neonatal outcome.Preterm labour is the most common obstetrical complication and occurs in about 20% of pregnant women [1]. Because no method has lead to an effective treatment for preterm labour, approximately 5-10% of deliveries occur at <37 weeks gestational age and cause 75-80% of the neonatal mortality and as much as 50% of the long-term neurological handicap [2]. There is epidemiological, microbiological and clinical evidence of an association between infection and preterm birth [3]. Bacterial colonization of the choriodecidual interface induces production of cytokines, including TNF-a, IL-6 and IL-8, leading to prostaglandin synthesis, which stimulate uterine contractions. Infants born to mothers with clinical chorioamnionitis are more likely to die, or they have increased risk of developing necrotizing enterocolitis, intraventricular haemorrhage, periventricular leukomalacia and bronchopulmonary dysplasia (BPD) [4]. These adverse outcomes are due not only to the infection itself, but mainly to foetal exposure to inflammatory products [5].Pentoxifylline, a synthetic theobromine derivative, is a non-selective inhibitor of phosphodiesterase and causes an increase in intracellular concentration of c-AMP. Inhibitors of phosphodiesterase can decrease uterine activity by increasing the intracellular concentration of c-AMP and thereby lowering the Ca ++ concentration [6]. Pentoxifylline also inhibits formation of phosphatidic acid, an impor...

Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia

“…Pentoxifylline not only improves placentation [89] but it may also alleviate maternal factors as well, which are the leading causes of maternal preeclampsia. Thereby, Pentoxifylline could hypothetically prevent both maternal and placental preeclampsia.…”

“…As mentioned earlier, increased generation of superoxide anions along with generation of lipid peroxides from placenta, inactivation of EDRF and impairment of ROS/RNS balance are of major causes of the disease [54,55]. Pentoxifylline enhances EDRF production, equilibrates ROS/RNS balance, increases endothelial NO synthesis in placenta and improves placental perfusion [89,[93][94][95], which are all disturbed in preeclampsia [34,52,54,60].…”

“…By suppressing TNF-a, IL-6 and IL-8, Pentoxifylline decreases prostaglandin synthesis [88] and it is shown that Pentoxifylline could postpone preterm labor and improve neonatal outcomes in pregnancies threatened with preterm labor [89]. Thereby it is hypothesized that Pentoxifylline decreases the risk of preterm labor in preeclamptic patients.…”

“…Pentoxifylline improves placental circulation and perfusion and since impairment of that process is the leading cause of preeclampsia, this intervention could significantly interfere with the disease process [30,[42][43][44][45][46]89]. In addition, 8-oxopentoxifylline is a metabolite of Pentoxifylline and it is a potent antioxidant and free radical scavenger which inhibits lipid-peroxidation and reduces ischemia-reperfusion injury [70].…”

“…As Pentoxifylline is metabolized to a potent antioxidant it ameliorates oxidative stress and improves endothelial function and placental circulation [89] and it is hypothesized that Pentoxifylline unsettles the vicious cycle of ''impaired placental perfusion/oxidative stress'' and countervail the pathogenesis of the disease.…”