The role of various transporters in the placental uptake of ofloxacin in an in vitro model of human villous trophoblasts.

INTRODUCTION: Six years after the US Food and Drug Administration approval of the broad-spectrum antibiotic ofloxacin (OFLX), the chiral switching of this racemic mixture resulted in a drug composed of the L-optical isomer levofloxacin (LVFX). Since both fluoroquinolones (FQs) were introduced to the pharmaceutical market, they have been widely prescribed by physicians, with careful administration during pregnancy and breastfeeding. Therefore, the role of the influx and efflux placental transporters in the concentrations of these drugs that permeate through human placental barrier model was investigated in this study. METHODS: The contribution of major carriers on the transplacental flux of OFLX and LVFX uptake into choriocarcinoma BeWo cells was evaluated in the presence vs absence of well-known inhibitors. RESULTS: Our results reveal that neither the influx transporters such as organic cation transporters, organic anion transporters, and monocarboxylate transporters nor the efflux transporters such as P-glycoprotein or breast cancer resistance protein significantly affected the transport of OFLX. In contrast, multiple transporters revealed pronounced involvement in the transfer of the levorotatory enantiomer in and out of the in vitro placental barrier. These data suggest a non-carrier-mediated mechanism of transport of the racemic mixture, while LVFX is subjected to major influx and efflux passage through the placental brush border membranes. CONCLUSION: This study provides underlying insights to elucidate the governing factors that influence the flux of these FQs through organ barriers, in view of the controversial safety profile of these drugs in pregnant population.

The effects of pravastatin on the normal human placenta: Lessons from ex-vivo models.

INTRODUCTION: Research in animal models and preliminary clinical studies in humans support the use of pravastatin for the prevention of preeclampsia. However, its use during pregnancy is still controversial due to limited data about its effect on the human placenta and fetus. METHODS: In the present study, human placental cotyledons were perfused in the absence or presence of pravastatin in the maternal reservoir (PraM). In addition, placental explants were treated with pravastatin for 5, 24 and 72 h under normoxia and hypoxia. We monitored the secretion of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS) expression and activation and the fetal vasoconstriction response to angiotensin-II. RESULTS: The concentrations of PlGF, sFlt-1 and sEng were not significantly altered by pravastatin in PraM cotyledons and in placental explants compared to control. Under hypoxic conditions, pravastatin decreased sFlt-1 concentrations. eNOS expression was significantly increased in PraM cotyledons but not in pravastatin-treated placental explants cultured under normoxia or hypoxia. eNOS phosphorylation was not significantly affected by pravastatin. The feto-placental vascular tone and the fetal vasoconstriction response to angiotensin-II, did not change following exposure of the maternal circulation to pravastatin. CONCLUSION: We found that pravastatin does not alter the essential physiological functions of the placenta investigated in the study. The relevance of the study lays in the fact that it expands the current knowledge obtained thus far regarding the effect of the drug on the normal human placenta. This data is reassuring and important for clinicians that consider the treatment of high-risk patients with pravastatin, a treatment that exposes some normal pregnancies to the drug.

In first-time mothers, post-partum depressive symptom prospectively predict symptoms of post-traumatic stress.

BACKGROUND: Symptoms of both depression and Post-Traumatic Stress Disorder (PTSD) are prevalent among first-time mothers following birth. However, the direction of the association between the two types of symptoms is unclear. METHODS: Ninety six first-time mothers giving birth via vaginal delivery (N=38), emergency C-Section (N=27) and planned C-Section (N=21) were assessed for depression and PTSD twice: Six weeks post-partum and six-weeks later. RESULTS: Cross-lagged Structural Equation Modeling (SEM) analyses revealed a prospective effect of depressive symptoms on PTSD symptoms. No moderating factors were identified. LIMITATIONS: A relatively modest sample size and only two assessment waves. CONCLUSIONS: An early detection and intervention with symptoms of post-partum depression might also prevent the development of PTSD symptoms.

The physiologic anticoagulant and anti-inflammatory role of heparins and their utility in the prevention of pregnancy complications.

Accumulating evidence supports the concept of increased thrombin generation, placental vascular lesions, and inflammation as crucial points in the development of the great obstetrical syndromes [preeclampsia, intrauterine growth restriction (IUGR), preterm labor (PTL), preterm prelabor rupture of membranes (PROM), fetal demise and recurrent abortions]. In light of this, the role of heparins for primary or secondary prevention of these syndromes is becoming more and more apparent, mainly due to the antithrombotic and anti-inflammatory effects of heparins. There is agreement regarding the use of heparin in the prevention of gestational complications in patients with antiphospholipid syndrome, while its use for other obstetrical complications is under debate. In the present review we will describe the physiologic role of heparins on coagulation and inflammation and we will discuss current evidence regarding the use of heparins for the prevention/treatment of obstetrical syndromes.

The physiologic and therapeutic role of heparin in implantation and placentation.

Implantation, trophoblast development and placentation are crucial processes in the establishment and development of normal pregnancy. Abnormalities of these processes can lead to pregnancy complications known as the great obstetrical syndromes: preeclampsia, intrauterine growth restriction, fetal demise, premature prelabor rupture of membranes, preterm labor, and recurrent pregnancy loss. There is mounting evidence regarding the physiological and therapeutic role of heparins in the establishment of normal gestation and as a modality for treatment and prevention of pregnancy complications. In this review, we will summarize the properties and the physiological contributions of heparins to the success of implantation, placentation and normal pregnancy.

Recurrent pregnancy loss: a risk factor for long-term maternal atherosclerotic morbidity?

OBJECTIVE: We sought to investigate whether patients with a history of recurrent pregnancy loss (RPL) have an increased risk for future maternal atherosclerotic morbidity. STUDY DESIGN: A population-based study compared the incidence of long-term atherosclerotic morbidity (renal and cardiovascular) in a cohort of women with and without a diagnosis of RPL. Patients had a mean follow-up duration of more than a decade. Women with known atherosclerotic disease were excluded from the study. Cardiovascular morbidity was divided into 4 categories according to severity and type including simple and complex cardiovascular events and invasive and noninvasive cardiac procedures. Kaplan-Meier survival curves were used to estimate cumulative incidence of cardiovascular and renal hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios for cardiovascular and renal morbidity. RESULTS: During the study period 99,285 patients were included; of these 6.7% (n = 6690) had a history of RPL. Patients with RPL had higher rates of renal and cardiovascular morbidity including cardiac invasive and noninvasive diagnostic procedures, simple as well as complex cardiovascular events, and hospitalizations due to cardiovascular causes. Using Kaplan-Meier survival curves, patients with a previous diagnosis of RPL had a significantly higher cumulative incidence of cardiovascular but not renal hospitalizations. Using a Cox proportional hazards model, adjusted for confounders such as preeclampsia, diabetes mellitus, obesity, and smoking, a history of RPL remained independently associated with cardiovascular hospitalizations (adjusted hazard ratio, 1.6; 95% confidence interval, 1.4-1.8; P = .001). CONCLUSION: RPL is an independent risk factor for long-term maternal cardiovascular complications.

Detection of S100B in maternal blood before and after fetal death.

BACKGROUND: S100B is a brain damage biomarker. When measured immediately after birth, it reflects neonatal brain damage following asphyxia. In this study, we used feticide as a novel model of fetal brain damage. We examined whether such damage is reflected by a rise in S100B in maternal blood before delivery. METHODS: Eight pregnant women were recruited between January and July 2012. Maternal blood samples were drawn before and after feticide at predetermined time points (0, 15, 30, 60, 120, and 240 min). S100B, lactate dehydrogenase, creatine kinase, and creatinine concentrations were measured by standard human ELISA and chemical analyzer. RESULTS: No significant difference was noted between S100B levels before and after feticide, neither in non-specific cell death markers (lactate dehydrogenase and creatine kinase), which remained within normal range. S100B ranged between 0.015-0.04 µg/L through all the predetermined time points. CONCLUSION: No statistically significant differences were demonstrated in S100B levels before and after feticide.

Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines.

Objectives. Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus. We evaluated the impact of cannabidiol (CBD), a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp) for comparison). Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24-72 h) exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3) and rhodamine123(rh123)). Cyclosporine A (CsA) served as a positive control. Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3) and rh123) was inhibited upon short-term exposure to CBD. Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function. We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics.

Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study.

OBJECTIVE: Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exerts its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2 hours) exposure to cannabidiol, a major phytocannabinoid, on human placental breast cancer resistance protein function. STUDY DESIGN: The in vitro effect of short-term exposure to cannabidoil on breast cancer resistance protein in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with mitoxantrone uptake, and nicardipine was used as positive control. The ex vivo perfused cotyledon system was used for testing the effect of cannabidoil on glyburide transport across the placenta. Glyburide (200 ng/mL) was introduced to maternal and fetal compartments through a recirculating 2 hour perfusion, and its transplacental transport was tested with (n = 8) or without (n = 8) cannabidoil. RESULTS: (1) Cannabidoil inhibition of breast cancer resistance protein-dependent mitoxantrone efflux was concentration dependent and of a noncell type specific nature (P < .0001); (2) In the cotyledon perfusion assay, the administration of cannabidoil to the maternal perfusion media increased the female/male ratio of glyburide concentrations (1.3 ± 0.1 vs 0.8 ± 0.1 at 120 minutes of perfusion, P < .001). CONCLUSION: (1) Placental breast cancer resistance protein function is inhibited following even a short-term exposure to cannabidoil; (2) the ex vivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and (3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are breast cancer resistance protein substrates is questionable during cannabis consumption by pregnant women.

The effects of magnesium sulfate on placental vascular endothelial growth factor expression in preeclampsia.

OBJECTIVE: To evaluate the effect of magnesium sulfate (MgSO(4)) on placental expression levels of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Cotyledons of term normotensive and preeclamptic placentas were dually perfused for 6 h, with MgSO(4) (6-7 mg%) in the maternal reservoir [normotensive (n = 3); preeclamptic (n = 4)] and with the control medium (without MgSO(4)) [normotensive (n = 3); preeclamptic (n = 6)]. After perfusion, placental tissue samples were collected from four different placental compartments (amnion, chorion, placental villous and decidua). The collected placental tissues were homogenized and examined for VEGF by ELISA. Statistical significance was determined using a two-way analysis of variance. RESULTS: After perfusion with control medium, significantly lower levels of VEGF were detected in the chorion and placental villous compartments of preeclamptic placentas (70 ± 24 pg/g protein and 29 ± 11 pg/g protein; respectively), as compared with normotensive placentas (172 ± 80 pg/g protein and 51 ± 17 pg/g protein; respectively; p < 0.05). Exposure of preeclamptic placentas to MgSO(4) resulted in decreased VEGF levels by the amnion (57 ± 26 pg/g protein), as compared with the control group (153 ± 62 pg/g protein) (p < 0.05). On the other hand, MgSO(4) significantly increased VEGF levels by the placental villous and the decidua (58 ± 15 pg/g protein, 70 ± 29 pg/g protein; respectively), as compared with the control group (29 ± 11 pg/g protein, 33 ± 14 pg/g protein; respectively) (p < 0.01, p < 0.05; respectively). Exposure to MgSO(4) did not affect VEGF levels in normotensive placentas. CONCLUSION: Reduced levels of VEGF are expressed by some placental compartments in preeclampsia compared with normotensive pregnancy. Perfusion with MgSO(4) affects VEGF expression differently by preeclamptic and normotensive placentas. Increased production of placental VEGF in preeclampsia may play a role in the therapeutic action of MgSO(4).

An association between preterm delivery and long-term maternal cardiovascular morbidity.

OBJECTIVE: The purpose of this study was to investigate whether a history of preterm delivery (PTD) poses a risk for subsequent maternal long-term cardiovascular morbidity. STUDY DESIGN: A population-based study compared the incidence of cardiovascular morbidity in a cohort of women who delivered preterm (<37 weeks' gestation) and those who gave birth at term at the same period. Deliveries occurred during the years 1988-1999 with follow up until 2010. Kaplan-Meier survival curves were used to estimate cumulative incidence of cardiovascular hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios for cardiovascular hospitalizations. RESULTS: During the study period 47,908 women met the inclusion criteria; 12.5% of the patients (n = 5992) delivered preterm. During a follow-up period of >10 years, patients with PTD had higher rates of simple and complex cardiovascular events and higher rates of total cardiovascular-related hospitalizations. A linear association was found between the number of previous PTD and future risk for cardiovascular hospitalizations (5.5% for ≥2 PTDs; 5.0% for 1 PTD vs 3.5% in the comparison group; P < .001). The association remained significant for spontaneous vs induced PTD and for early (<34 weeks) and late (34 weeks to 36 weeks 6 days' gestation) PTD. In a Cox proportional hazards model that adjusted for pregnancy confounders such as labor induction, diabetes mellitus, preeclampsia, and obesity, PTD was associated independently with cardiovascular hospitalizations (adjusted hazard ratio, 1.4; 95% confidence interval, 1.2-1.6). CONCLUSION: PTD is an independent risk factor for long-term cardiovascular morbidity in a follow-up period of more than a decade.

Low levels of circulating alpha-1 antitrypsin are associated with spontaneous abortions.

OBJECTIVE: Alpha-1 antitrypsin (AAT), a circulating anti-inflammatory molecule, rises four- to sixfold during acute phase responses and during pregnancy. AAT deficiency is linked with various pregnancy complications. The aim of this study is to determine plasma concentrations and activity of AAT and serum cytokine levels in blood samples from women undergoing spontaneous abortions as compared with elective abortions. METHODS: A prospective case-control study consisted of patients with sporadic abortions (n = 15), recurrent spontaneous abortions (n = 14) and healthy pregnancies going through elective terminations (n = 11). Circulating AAT and cytokine levels were determined before dilatation and curettage. RESULTS: AAT levels were lower in both recurrent and sporadic spontaneous abortion groups compared with healthy pregnancies (1.421 ± 0.08, 1.569 ± 0.14 and 3.224 ± 0.45 mg/ml, respectively, p < 0.001). Reduced AAT levels correlated with elevated proinflammatory cytokines. CONCLUSIONS: AAT levels in patients with either sporadic or recurrent spontaneous abortions were lower than normal pregnancies, and were associated with an inflammatory profile. Future studies should examine larger cohort groups, effects of earlier time-points and the influence of antithrombotic therapy in such patients who are diagnosed with relatively low levels of circulating AAT, in an effort to improve pregnancy outcomes.

Perfusion with magnesium sulfate increases sFlt-1 secretion only in the fetal side of placenta of women with preeclampsia.

OBJECTIVE: To examine the effect of magnesium sulfate (MgSO(4)) on sFlt (soluble fms-like tyrosine kinase)-1 in the fetal and maternal compartments of normotensive and preeclamptic placentas. METHODS: Cotyledons of term normotensive and preeclamptic placentas were dually perfused for six hours, with control medium and MgSO(4) (6-7 mg %) in the maternal reservoir. Perfusate sFlt-1 concentrations were measured. RESULTS: Median sFlt-1 concentration was higher in the maternal than in the fetal side in both groups and perfusion media (p < 0.0001). When perfused with control medium, the maternal side median sFlt-1 concentration was higher in the preeclampsia than in the control group (p < 0.0001). After perfusion with MgSO(4), the median maternal and fetal sides perfusate sFlt-1 concentration were higher in the preeclampsia than in the control group (p < 0.0001). In comparison to perfusion with control medium, the median sFlt-1 concentration of normal pregnant women decreased in the fetal and increased in the maternal side. In the preeclampsia group, only median fetal side sFlt-1 concentration increased. CONCLUSION: In contrast to normal pregnant women, perfusion with MgSO(4) of preeclamptic placentas did not increase their sFlt-1 concentration. This may indicate that MgSO(4) role may be limited to its anti-eclamptic and does not affect the anti-angiogenic state associated with preeclampsia.

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)-1ß is a possible mediator of maternal endothelial dysfunction in preeclampsia. Serum IL-1ß 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-1ß 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-1ß and IL-1Ra were examined by enzyme-linked immunoassay (ELISA). Preeclamptic placentas secreted higher levels of IL-1ß (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-1ß:IL-1Ra ratio were detected. However, there was only tendentious increase in the secretion levels of IL-1ß 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-1ß into the maternal circulation (P < 0.001), and in a tendentious reduction in IL-1Ra. However, IL-1ß: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-1ß levels or IL-1ß:IL-1Ra ratio. These findings suggest that the placenta may contribute to the elevation in serum IL-1ß 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-1ß, and possibly IL-1Ra, in preeclampsia.

Lower circulation levels and activity of α-1 antitrypsin in pregnant women with severe preeclampsia.

OBJECTIVE: α-1 antitrypsin (AAT) is an anti-protease, anti-inflammatory and tissue-protective molecule. Normal circulating levels are <3.5 mg/dl and rise during pregnancy. Although AAT deficiency is associated with several pregnancy and placental disorders, little is known regarding AAT levels and preeclampsia. Since unopposed inflammation might contribute to preeclampsia, we studied whether preeclampsia is associated with lower than normal levels and activity of AAT. METHODS: In a prospective case-control study, we compared maternal serum AAT activity and levels between patients with severe preeclampsia (n = 23) and without preeclampsia (n = 18). RESULTS: AAT levels were 1.91 ± 0.08-fold lower in the preeclampsia group compared to healthy group (3.854 ± 0.26 vs. 7.397 ± 0.34 mg/ml; p < 0.001), and correlated with protease inhibitory capacity (46.56 ± 2.08% vs. 67.08 ± 1.74%; p < 0.001). CONCLUSIONS: Our findings show association between lower AAT levels and severe preeclampsia during pregnancy. Further studies are required to identify the mechanism behind the association, and the possibility of safe AAT augmentation for individuals with insufficient circulating AAT.

α1-antitrypsin insufficiency is a possible contributor to preterm premature rupture of membranes.

OBJECTIVE: α1-antitrypsin (AAT) is protective of tissue damage induced by enzymes of inflammatory cell source. Inflammatory cells are involved in preterm labor, preterm premature rupture of membrane (PPROM) and term premature rupture of membrane (PROM). The purpose of this research was to examine whether plasma concentration and activity of AAT differ between these manifestations. METHODS: In a prospective case control study, blood samples were assayed for AAT concentration and activity in 71 individuals. AAT concentration and activity were measured by standard methods. RESULTS: No significant differences were found between AAT levels (p = 0.497) and activity (p = 0.879) in preterm and term labor. AAT levels and activity in PPROM and PROM were not significantly different as well (p = 0.748 and p = 0.880, respectively). While 69 out of 71 patients displayed normal circulating levels of AAT, 2 PPROM patients out of 15 had abnormally low, previously undiagnosed,AAT concentrations, and had subsequently developed complications that were absent in the other groups. CONCLUSIONS: No statistically significant differences were demonstrated in the levels of AAT between patients with preterm and term labor, nor between preterm and term PROM. Yet, unexpectedly, patients that had marked AAT deficiency belonged exclusively to the PPROM group.

Passive fetal monitoring by adaptive wavelet denoising method.

Fetal Heart Rate (FHR) monitoring is one of the most important fetal well being tests. Existing FHR monitoring methods are based on Doppler ultrasound technique, which has several disadvantages. Passive fetal monitoring by phonocardiography is an appropriate alternative; however, its implementation is a challenging task due to low energy of fetal heart sounds and multiple interference signals presence. In this paper, an advanced signal processing method for passive fetal monitoring based on adaptive wavelet denoising is presented. The method's performance is compared with Doppler ultrasound monitor. The results show 94-97.5% accuracy, including highly disturbed cases.

An initial miscarriage is associated with adverse pregnancy outcomes in the following pregnancy.

OBJECTIVE: The objective of the study was to determine whether 1 previous miscarriage is associated with an increased rate of adverse pregnancy outcomes in the following pregnancy. STUDY DESIGN: Second pregnancies of women with and without a miscarriage in their initial pregnancy were compared. Multivariable logistic regression models were constructed to control for confounders. RESULTS: Of 35,125 singleton deliveries in the second pregnancy, 5777 (16.4%) were of patients with an initial miscarriage. Multivariable analysis showed a significant association between a previous miscarriage and the following adverse pregnancy outcomes including premature rupture of membranes (odds ratio [OR], 2.22; 95% confidence interval [CI], 2.01-2.44), preterm delivery (OR, 1.34; 95% CI, 1.21-1.48), intrauterine growth restriction (OR, 1.24; 95% CI, 1.04-1.47), hypertensive disorders (OR 1.41; 95% CI 1.07-1.85), preeclampsia (OR, 1.63; 95% CI, 1.22-2.18), and cesarean delivery (OR, 1.59; 95% CI, 1.46-1.73). Perinatal mortality was significantly higher among women with an initial miscarriage (1.6% vs 1.0%; P < .001). CONCLUSION: An initial miscarriage is independently associated with adverse pregnancy outcomes.

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.

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.