Olga Sapir

Increased production of tumor necrosis factor-α TNF-α by IUGR human placentae

Objective: To evaluate the effect of pathological placental conditions such as intrauterine growth restriction (IUGR) or exposure to angiotensin II (AII) on TNF-a secretion in the vasculature of isolated human placental cotyledons. Study design: Isolated placental cotyledons from 10 normal and four intrauterine growth restricted fetuses were dually perfused. Perfusate samples from the fetal circulation were collected every 30 min during 120 min. TNF-a levels in the fetal–placental perfusate were evaluated using specific 29 24 commercial ELISA kits. In three additional normal placentae, bolus injections of angiotensin II (10 –10 mol / l) were given into the fetal–placental circulation and perfusate samples were collected. Statistical significance of difference TNF-a levels between different conditions was determined by analysis of variance (ANOVA) and paired t-test. Results: TNF-a levels were significantly higher in the perfusate of IUGR placentae as compared with normal placentae after 120 min of perfusion (mean 4106121 vs. 39614 pg/ml, P 5 0.005). There was a significant dose-dependent increase in TNF-a levels in the placental perfusate after a bolus injection of AII 66 29 25 pg /ml with AII 10 mol / l vs. 97 pg/ml with AII 10 mol / l (P 5 0.004), respectively. Conclusions: Placental pathology related to condition IUGR might induce the secretion of proinflammatory cytokines such as TNF-a, which may enhance the vasoconstriction of the fetal placental vascular bed.  2001 Elsevier Science Ireland Ltd. All rights reserved.

Placental Secretion of Interleukin-1 and Interleukin-1 Receptor Antagonist in Preeclampsia: Effect of Magnesium Sulfate

Preeclampsia is a pregnancy-specific disorder characterized by hypertension and systemic endothelial dysfunction. Interleukin (IL)-1β is a possible mediator of maternal endothelial dysfunction in preeclampsia. Serum IL-1β as well as its natural inhibitor IL-1 receptor antagonist (IL-1Ra) were reported to be increased in women with preeclampsia. In the current study, we addressed the role of the placenta in controlling the circulatory levels of IL-1β and its natural inhibitor IL-1Ra in preeclampsia, and the possible effect of magnesium sulfate (MgSO(4)) on these levels. Using an ex vivo placental perfusion system, placentas from preeclamptic (n = 9) and normotensive (n = 6) pregnancies were perfused in presence or absence of MgSO(4). Perfusate samples were collected from the maternal and the fetal circulations of the perfusion system, and IL-1β and IL-1Ra were examined by enzyme-linked immunoassay (ELISA). Preeclamptic placentas secreted higher levels of IL-1β (P < 0.001), and a tendentious higher levels of IL-1Ra, mainly into the maternal circulation, as compared with normotensive placentas, although no differences in IL-1β:IL-1Ra ratio were detected. However, there was only tendentious increase in the secretion levels of IL-1β or IL-1Ra into the fetal circulation of preeclamptic placentas, when compared with normotensive placentas. Administration of MgSO(4) to preeclamptic placentas resulted in an attenuation of the increased secretion of IL-1β into the maternal circulation (P < 0.001), and in a tendentious reduction in IL-1Ra. However, IL-1β:IL-1Ra ratio in preeclamptic placentas was not affected by MgSO(4). Interestingly, exposure of normotensive placenta to MgSO(4) resulted only in increased levels of IL-1Ra in the maternal circulation, without affecting IL-1β levels or IL-1β:IL-1Ra ratio. These findings suggest that the placenta may contribute to the elevation in serum IL-1β and IL-1Ra in preeclampsia by increased secretion of these cytokines into the maternal circulation, and that MgSO(4) is able to attenuate this increased secretion of IL-1β, and possibly IL-1Ra, in preeclampsia.

Lack of interaction of digoxin and P-glycoprotein inhibitors, quinidine and verapamil in human placenta in vitro

OBJECTIVE To determine the effect of quinidine and verapamil, known antiarrhythmic agents and P-glycoprotein (Pgp) inhibitors, on digoxin transport from the maternal to the fetal compartment in the isolated perfused human placenta. STUDY DESIGN Isolated placental cotyledons from normal human placentae (n=20) were dually perfused with M199 medium enriched with albumin (0.3%) and glucose (0.1%). The maternal and the fetal circulation flow rates were 12 and 6 ml/min, respectively. Closed circulations were used to evaluate steady state transplacental gradient formation. In six placentae quinindine was added to the maternal circuit; after 45 min of perfusion, digoxin was added to the maternal circulation. The effect of verapamil on digoxin transfer from the maternal to the fetal compartments was explored in five placentae. In six additional placentae the transfer of digoxin was studied in the absence of quinidine. Transplacental passage of digoxin was calculated from repeated fetal and maternal perfusate samples. Digoxin levels were determined in perfusate samples by fluorescence polarization immunoassay. Antipyrine was added to the maternal reservoir of all placentae as reference substance. RESULTS The transfer of digoxin (alone) and in the presence of quinidine or verapamil was 10.93+/-3.71, 9.00+/-5.2 and 12.94+/-4.86%, respectively. The levels of digoxin in the fetal compartment, 0.62+/-0.20, 0.48+/-0.29 and 0.60+/-0.26 ng/ml, respectively, were not significantly affected by quinidine and verapamil. These Pgp modulators, also did not influence significantly the steady state levels of digoxin in the maternal compartment. CONCLUSION Neither quinidine nor verapamil affected the transplacental transfer of digoxin in vitro in normal human placentae. In contrast to the other tissues, they do not inhibit Pgp activity in term human placentae.

Vasoconstrictive activity of meconium stained amniotic fluid in the human placental vasculature

OBJECTIVE The purpose of this study was to study was to determine the effect of meconium stained amniotic fluid on the vasculature of isolated perfused human placental cotyledon. STUDY DESIGN Isolated placental cotyledons were dually perfused. Fetal perfusion pressure was used as an index of vascular resistance. Meconium stained amniotic fluid (MSAF) was collected from patients after artificial rupture of membranes in term gestation. A dilution of meconium (1:2; 1:4; 1:8; 1:16) was performed. Optical density (OD) of MSAF varied between 0 and 35.0 units/g as determined by spectrophotometry. Bolus injections of 1.0 ml of MSAF at different concentrations were injected into the fetal circulation. Heated and dialyzed MSAF after adequate dilution and evaluation of optical density were injected into fetal circulation in separate experiments. RESULTS Analysis of variance (ANOVA) and paired t-test were used for statistical analysis. Bolus injections of MSAF into the fetal circulation resulted in a concentration-dependent increase in perfusion pressure. MSAF with the highest OD resulted in a greater change in perfusion pressure as compared to more dilute MSAF (P=0.0001). After high OD amniotic fluid injections the provoked contractions lasted longer compared to dilute MSAF (P=0.006). MSAF after dialyzation did not exhibit any vasoconstrictive effect. CONCLUSION Meconium is a vasoconstrictive agent in the fetal-placental vasculature and has a concentration dependent effect.

Neurofibromatosis in pregnancy: Maternal and perinatal outcome

OBJECTIVE The aim of this study was to assess the maternal and perinatal outcome in pregnant patients with neurofibromatosis (NF). STUDY DESIGN During the period between January 1994 and December 1996 eight women with NF were delivered at the Soroka University Medical Center. Maternal age, parity, gravidy and ethnic origin were matched with a control group that included 65 healthy parturients out of a total of 31,642 deliveries that occurred in our institution during this period. Maternal outcome and perinatal complications were compared between the two groups. RESULTS The prevalence of NF during the study period was 1:2434 deliveries. The mean gestational age at delivery was significantly lower in the study group as compared to the control group, 36.8+/-3.3 vs. 39.2+/-1.5 weeks, respectively (P=0.029). The rate of intrauterine growth restriction was significantly higher in the study group, (46.2% vs. 8.95%, respectively, P=0.0005), as well as stillbirth rate (23% vs. 1.5%, respectively, P=0.011) and cesarean section rate (38.5% vs. 7.7%, respectively, P=0.01). CONCLUSION Patients with NF have an increased risk of perinatal complications. Thus, close antenatal observation at high risk tertiary centers is required.

Selective Vasodilator Effect of Magnesium Sulfate in Human Placenta

Problems:  To determine if magnesium sulfate (MgSO4) attenuates the vasoconstrictor effect of angiotensin II (Ag II), endothelin‐1 (ET‐1) and thromboxane mimetic (TX) in the human fetal–placental vasculature and if interleukin‐1 beta (IL‐1β) is involved in this process.

Indomethacin activity in the fetal vasculature of normal and meconium exposed human placentae

OBJECTIVE To study the effect of indomethacin on the vasculature of isolated perfused human placental cotyledon in normal and meconium pretreated placentae. STUDY DESIGN Isolated placental cotyledons were dually perfused and fetal perfusion pressure was used as an index of vascular resistance. Meconium-stained amniotic fluid (MSAF) was collected from patients after artificial rupture of membranes, diluted 1:2, 1:4, 1:16 and 1:32 and a spectrophotometric determination of meconium concentration in amniotic fluid was performed. Only MSAF with an optical density of 20.0 units per gram was used in this study. In five placentae, the effect of indomethacin (100 microg/ml continuous perfusion from the fetal site) on basal pressure of the fetal-placental vasculature was established. In five more placentae, the effect of indomethacin on MSAF-induced vasoconstriction was established when a bolus injections of 1 ml MSAF was made into the fetal circulation. The statistical significance of response to MSAF injection was determined by paired t-test and ANOVA repeated measurements. RESULTS A significant vasoconstrictor response to MSAF was achieved in normal placentae. Bolus injections of MSAF into the fetal circulation resulted in a significant increase in perfusion pressure (P=0.0026). Indomethacin was capable of significantly reducing the basal perfusion pressure (P=0.03). Significant attenuation of vasoconstrictor response to MSAF occurred in the presence of indomethacin (P=0.0016). CONCLUSION Indomethacin causes a significant reduction in basal pressure of fetal placental vasculature in the human placental circulation in vitro and is capable of attenuating the vasoconstrictory activity of MSAF. The mechanism of such activity may be explained partially by the inhibitory effect of indomethacin on the PG-mediated pathways.

Thalassemia intermedia and cavernous transformation of portal vein thrombosis in pregnancy

We report a rare case of a cavernous transformation of portal vein (CTPV) thrombosis accompanied by Thalassemia and thrombophilia during pregnancy that was successfully treated by low molecular weight heparin. The clinical presentation, diagnosis and the treatment are discussed.

Vasoconstrictive activity of oxytocin in meconium impregnated human placentas.

OBJECTIVE The aim of our study is to determine whether oxytocin acts differently on the fetal-placental vascular bed of normal and meconium impregnated placentas. STUDY DESIGN Isolated placental cotyledons (n=10) were dually perfused with fetal perfusion pressure used as an index of vascular resistance. As perfusion medium we used lactated Ringer salt solution, containing polyvinylpyrolidone (25 g/l), bovine serum albumin (0.1 mg/ml), glucose (1.0 g/l), heparin (20 IU/ml) and gentamycin (48 microg/ml). The pH of the medium was adjusted to 7.4 with bicarbonate. The maternal site was gassed with 95% O(2):5% CO(2) and in the fetal site with 95% N(2):5% CO(2) at 37 degree C. Perfusion rates were 4-6 and 10-12 ml/min in the fetal and maternal circulation, respectively. TNF-alpha and IL-beta1 levels in the fetal-placental perfusate were evaluated using specific commercial ELISA kits. RESULTS No significant changes in the amount of TNF-alpha release were observed after injection of oxytocin into the fetal circulation (31+3pg/ml; P=0.5). No IL-beta1 activity was observed in the fetal perfusate of normal and meconium impregnated placentas during the experiments. No significant difference was seen in basal perfusion pressure in normal and meconium impregnated placentas, however, a bolus injection of oxytocin (10U/ml) resulted in a significant increase in perfusion pressure in meconium impregnated placentas from basal pressure of s45+5 to 88+4 mm Hg after injection of oxytocin, (P=0.004, ANOVA). CONCLUSION Vasoconstrictive effect of oxytocin was observed only in meconium impregnated placentas and no vascular effect of oxytocin was documented in normal placentas. The clinical implication of our findings is that one should use oxytocin for stimulation of labor with caution in the presence of meconium stained amniotic fluid.

Maternal serum concentrations of CA-125 in second trimester pregnancy complicated by congenital fetal anomalies

OBJECTIVE The purpose of the study was to determine the value of maternal serum CA-125 concentrations in pregnancies complicated by fetal anomalies with or without hydramnios. STUDY DESIGN The study population (n=40) consisted of the following four groups of patients: (1) 10 women with abnormal maternal serum alpha fetal protein (MSAFP) in whom no fetal anomalies were observed; (2) 10 women in whom fetal anomalies were diagnosed in addition to abnormal MSAFP; (3) 10 women with fetal anomalies accompanied by hydramnios and abnormal MSAF, and (4) 10 women had normal MSAFP and were diagnosed with hydramnios without fetal anomaly. The control group consisted of 10 patients who were matched for gestational age with normal MSAFP and normal ultrasonographic examination. In all 50 cases MSAFP and maternal serum CA-125 levels were assessed. CA-125 was measured using OC 125 monoclonal antibody (IMX CA-125, Abott Lab. IL) and a value of >20 U/ml was defined as abnormal. RESULTS Maternal serum CA-125 levels were significantly higher in the study group than in the control group, 19.8+/-15.9 U/ml and 9.9+/-4.0 U/ml (P=0.015). The difference was even greater when patients with malformed fetuses and hydramnios were compared to those with fetal anomalies and normal amount of amniotic fluid, 32.4+/-12.7 U/ml and 7.2+/-2.1 U/ml, respectively (P=0.0005). The maternal serum CA-125 levels in patients with hydramnios but without fetal anomalies were significantly lower when compared with those of the malformed fetuses and hydramnios, 9.8+/-2.3 U/ml and 32.4+/-12.7 U/ml, respectively (P=0.002). CONCLUSION Maternal serum CA-125 is lacking in value for screening fetal structural anomalies as a significant increase in maternal serum CA-125 levels was found only in patients with fetal anomalies accompanied by hydramnios.