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Hana Polachek,1,* Nir Debotton,2,* Valeria Feinshtein,1 Mazal Rubin,1 Zvi Ben-Zvi,1,‡ Gershon Holcberg,3 Riad Agbaria,1 Arik Dahan1 1Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2Department of Chemical Engineering, Shenkar College of Engineering and Design, Ramat-Gan, Israel; 3Division of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel *These authors contributed equally to this work ‡Professor Zvi Ben-Zvi passed away on August 4, 2017 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. Keywords: drug transport, fluoroquinolones, levofloxacin, ofloxacin, placenta, 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. [ABSTRACT FROM AUTHOR]

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.

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.

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.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (© 2013 John Wiley & Sons, Ltd.)

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.

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., (Copyright © 2013 Mosby, Inc. All rights reserved.)