Gershon Holcberg

Risk factors associated with true knots of the umbilical cord

OBJECTIVE To determine obstetrical risk factors and pregnancy outcome of fetuses with true knot of the umbilical cord. METHODS Study population included 69,139 singleton deliveries occurring between the years 1990-1997. Data were retrieved from the database of the Soroka University Medical Center. Fetuses with malformations were excluded. RESULTS The incidence of true knots was 1.2% (841/69,139). In a multivariate analysis the following factors were found to be significantly associated with true knot of cord: grandmultiparity, chronic hypertension, hydramnios, patients who undergone genetic amniocentesis, male gender and cord problems (prolapse of cord and cord around the neck). The incidence of fetal distress and meconium stained amniotic fluid was significantly higher among patients with true knots of cord (7% versus 3.6%, P<0.001 and 22% versus 16%, respectively, P<0.0001). Moreover, there was a four-fold higher rate of antepartum fetal death among those fetuses (1.9% versus 0.5%, P<0.0001). In addition, fetuses with true knots of the umbilical cord were more often delivered by a cesarean section (130/841 versus 711/68,298, P<0.0001). The following obstetrical factors were found to be significantly correlated to true knots of the umbilical cord in a multiple logistic regression model: gestational diabetes, hydramnios, patients undergoing genetic amniocentesis, male fetuses. CONCLUSIONS Patients with hydramnios, who underwent genetic amniocentesis and those carrying male fetuses are at an increased risk for having true knots of the umbilical cord. Thus, careful sonographic and Doppler examinations should be seriously performed in these patients for detection of the complication of the umbilical cord.

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.

Inflammatory bowel disease and preterm delivery

Objective: The present study investigates pregnancy outcome in women with IBD and examines the effect of pregnancy on the severity of IBD. Method: A case‐control study comparing deliveries by mothers with IBD between January 1988 and January 2005 was performed. For every birth by a mother with IBD, four births by non‐IBD mothers were randomly selected and adjusted for ethnicity and year of delivery. Result: During the study period there were 48 deliveries to patients with Crohns disease and 79 deliveries to patients with ulcerative colitis. Higher rates of preterm delivery (< 37 weeks) were found among patients with IBD as compared to the controls (odds ratios (OR) = 2.2; 95% confidence interval (CI) = 1.3–3.8). This association remained significant after adjustment for labor induction and multiple gestations, using the Mantel–Haenszel technique (weighted OR = 2.1; 95% CI 1.3–3.5 and weighted OR = 2.0; 95% CI 1.2–3.5; P = 0.012; respectively). In addition, these patients had higher rates of fertility treatments (OR = 2.2; 95% CI = 1.1–4.4). Using a multivariate analysis, controlling for maternal age and fertility treatments, preterm delivery was seen to be significantly associated with IBD (adjusted OR = 2.0; 95% CI = 1.2–3.5). Perinatal outcomes, such as perinatal mortality, low Apgar scores, and congenital malformations, were comparable to the outcomes in the control group. Conclusion: Maternal IBD is an independent risk factor for preterm delivery. IBD is not associated with adverse perinatal outcome.

Placental abruption: critical analysis of risk factors and perinatal outcomes

Objective. To investigate risk factors and pregnancy outcome of patients with placental abruption. Methods. A population-based study comparing all pregnancies of women with and without placental abruption was conducted. Stratified analysis using multiple logistic regression models was performed to control for confounders. Results. During the study period there were 185,476 deliveries, of which 0.7% (1365) occurred in patients with placental abruption. The incidence of placental abruption increased between the years 1998 to 2006 from 0.6 to 0.8%. Placental abruption was more common at earlier gestational age. The following conditions were significantly associated with placental abruption, using a multivariable analysis with backward elimination: hypertensive disorders, prior cesarean section, maternal age, and gestational age. Placental abruption was significantly associated with adverse perinatal outcomes such as Apgar scores <7 at 1 and 5 min and perinatal mortality. Patients with placental abruption were more likely to have cesarean deliveries, as well as cesarean hysterectomy.Using another multivariate analysis, with perinatal mortality as the outcome variable, controlling for gestational age, hypertensive disorders, etc., placental abruption was noted as an independent risk factor for perinatal mortality. Conclusions. Placental abruption is an independent risk factor for perinatal mortality. Since the incidence of placental abruption has increased during the last decade, risk factors should be carefully evaluated in an attempt to improve surveillance and outcome.

Risk factors for intrauterine fetal death (1988–2009)

Objective. To determine risk factors for intrauterine fetal death (IUFD). Study design. A retrospective population-based study, of all singleton deliveries between the years 1988–2009 was conducted. Intrapartum deaths, postpartum death, and multiple gestations were excluded. A multiple logistic regression model was used to determine independent risk factors. Results. During the study period, out of 228,239 singleton births, 1694 IUFD cases were recorded (7.4 per 1000 births). The following independent risk factors were identified in the logistic regression executed: Oligohydramnios (OR 2.6, 95% CI 2.1–3.2, p-value < 0.001), polyhydramnios (OR 1.8, 95% CI 1.4–2.2, p-value < 0.001), previous adverse perinatal outcome (OR 1.7, 95% CI 1.5–2.1, p-value < 0.001), congenital malformations (OR 2.0, 95% CI 1.8–2.3, p-value < 0.001), true knot of cord (OR 3.7, 95% CI 2.8–4.9, p-value < 0.001), meconium stained amniotic fluid (OR 2.7, 95% CI 2.3–3.0, p-value<0.001), placental abruption (OR 2.9, 95% CI 2.4–3.5, p-value < 0.001), advanced maternal age (OR 1.03, 95% CI 1.02–1.04, p-value < 0.001), and hypertensive disorders (OR 1.24, 95% CI 1.0–1.4, p-value = 0.026). Jewish ethnicity (versus Bedouin – OR 0.64, 95% CI 0.57–0.72, p-value < 0.001), gestational diabetes (OR 0.7, 95% CI 0.5–0.8, p-value = 0.001), previous cesarean section (OR 0.8, 95% CI 0.7–0.97, p-value = 0.019), and recurrent abortions (OR 0.8, 95% CI 0.6–0.9, p-value = 0.011) were negatively associated with IUFD. Conclusion. Several independent risk factors were identified, suggesting a possible cause of death. Other pathologic conditions that facilitate tighter pregnancy surveillance and active management were found protective, pointing the benefit of such management approaches in high-risk pregnancies.

Peripartum cesarean hysterectomy: critical analysis of risk factors and trends over the years

Objective. To investigate time trends and risk factors for peripartum cesarean hysterectomy. Methods. A population-based study comparing all deliveries that were complicated with peripartum hysterectomy to deliveries without this complication was conducted. Deliveries occurred during the years 1988–2007 at a tertiary medical center. A multiple logistic regression model was constructed to find independent risk factors associated with peripartum hysterectomy. Results. Emergency peripartum cesarean hysterectomy complicated 0.06% (n = 125) of all deliveries in the study period (n = 211,815). The incidence of peripartum hysterectomy increased over time (1988–1994, 0.04%; 1995–2000, 0.05%; 2001–2007, 0.095%). Independent risk factors for emergency peripratum hysterectomy from a backward, stepwise, multivariable logistic regression model were: uterine rupture (OR = 487; 95% CI 257.8–919.8, p < 0.001), placenta previa (OR = 66.4; 95% CI 39.8–111, p < 0.001), postpartum hemorrhage (PPH) (OR = 40.8; 95% CI 22.4–74.6, p < 0.001), cervical tears (OR = 22.3; 95% CI 10.4–48.1, p < 0.001), second trimester bleeding (OR = 6; 95% CI 1.8–20, p = 0.003), previous cesarean delivery (OR = 5.4; 95% CI 3.5–8.4, p < 0.001), placenta accreta (OR = 4.7; 95% CI 1.9–11.7, p = 0.001), and grand multiparity (above five deliveries, OR = 4.1; 95% CI 2.5–6.6, p < 0.001). Newborns of these women had lower Apgar scores (<7) at 1 and 5 min (32.7% vs.4.4%; p < 0.001, and 10.5% vs. 0.6%; p < 0.001, respectively), and higher rates of perinatal mortality (18.4% vs. 1.4%; p < 0.001) as compared to the comparison group. Conclusion. Significant risk factors for peripartum hysterectomy are uterine rupture, placenta previa, PPH, cervical tears, previous cesarean delivery, placenta accreta, and grand multiparity. Since the incidence rates are increasing over time, careful surveillance is warranted. Cesarean deliveries in patients with placenta previa-accreta, specifically those performed in women with a previous cesarean delivery, should involve specially trained obstetricians, following informed consent regarding the possibility of peripartum hysterectomy.

Drug transport across the placenta.

It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. In recent years, research on human placental transporters has been developing due to the increase of knowledge technology in pharmacology. In this review we will focus on the main placental transporters which are known today. The P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP/ABCG2) and Multidrug resistance associated protein 2 (MDR2) transporters are expressed at the apical surface of the syncytiotrophoblast, and have a protective effect. Transporters for 5-HT (SERT) and NE (NET) are also expressed at the apical surface and regulate extracellular concentrations of monoamines. The physiologic function of Multidrug resistance associated protein (MRP) transporters (which is expressed at the basal surface of the syncytiotrophoblast) may be the removal of metabolic end products from the fetus. Some of the members of the organic anion transporters are also expressed at the basolateral surface of the syncytiotrophoblast.

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.

Decreased perinatal mortality among women with diet-controlled gestational diabetes mellitus.

To examine pregnancy outcomes associated with diet‐controlled gestational diabetes mellitus (GDM A1).

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.