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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.)

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

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.

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).

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.

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.

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To investigate pregnancy outcome in patients with condyloma acuminata., Methods: A retrospective cohort study comparing pregnancy outcome of women with and without condyloma acuminata was performed. A sub-group analysis was performed between patients with localized disease (n = 40), extended disease (n = 25) and no condyloma acuminata (n = 227,202)., Results: Using a multivariate logistic regression model, condyloma acuminata was significantly associated with cesarean delivery (OR = 3.4; 95% CI 1.9-5.8; P < 0.001), nulliparity (OR = 4.8; 95% CI 2.6-9.0; P < 0.001), and Jewish ethnicity (vs. Bedouin Arabs; OR = 2.3; 95% CI 1.3-4.1; P < 0.001). A significant linear association was found between the three subgroup (extended condyloma, localized condyloma and no condyloma) and cesarean delivery (40.0% in the extended disease vs. 32.5% in the localized disease vs. 13.0% in the comparison group P < 0.001). No significant differences were noted between the groups in terms of perinatal outcomes, such as low Apgar score (<7) at 1 min (4.2 vs. 1.6%; P = 0.298) and 5 min (0.6 vs. 0.0% P = 0.534) and perinatal mortality (1.4 vs. 1.5% P = 0.912)., Conclusions: Women with condyloma acuminata are at an increased risk for cesarean delivery, while the risk for cesarean delivery is higher for pregnancies with extended when compared with localized disease. Nevertheless, condyloma acuminata is not associated with adverse perinatal outcome.

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.

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.

Objective: The objective of the study was to assess the factors affecting the latency period in woman with preterm premature rupture of membranes (PPROM) and evaluate morbidity associated with prolonged latency., Study Design: A population-based retrospective study including all women with PPROM (prior to 37 weeks' gestation) during the years 1998-2008 was conducted. Comparison of the latency period was conducted by the Mann-Whitney U test since the latency period was not normally distributed (most delivered in 24 h). Multivariable logistic regression model was constructed to find independent factors associated with prolonged latency period (>72 h)., Results: During the study period, there were 1,399 singleton deliveries of patients with PPROM; 24.6% (345) occurred prior to 34 weeks' gestation. The duration of the latency period was significantly longer among woman with PPROM before 34 weeks as compared to PPROM after 34 weeks' gestation (5.78 vs. 2.02 days; p < 0.001). Other factors associated with longer latency period were multiparity (more than one previous delivery) and maternal age >35. Using a multivariable analysis, the following factors were significantly associated with latency period >72 h: lower gestational age (weeks, OR = 0.8, 95% CI 0.77-0.84; p < 0.001) and multiparity (OR = 1.7, 95% CI 1.3-2.2; p < 0.001). Prolonged latency period (>72 h) was significantly associated with chorioamnionitis (OR = 2.095, 95% CI 1.44-3.04; p < 0.001) and oligohydramnios (OR = 3.041, 95% CI 1.43-6.45; p = 0.004) but not with placental abruption (OR = 0.854, 95% CI 0.41-1.78; p = 0.674) or perinatal mortality (OR = 1.2, 95% CI 0.6-2.2; p = 0.556)., Conclusion: The duration of the latency period is inversely associated with gestational age. Nulliparity is associated with lower latency period. Prolonged latency is a significant risk factor for chorioamnionitis.

Objective: The present study was aimed to investigate perinatal outcome of elderly nulliparous patients., Study Design: A retrospective study was performed comparing pregnancy outcomes of nulliparous patients at three age groups: less than 35 years (reference group), 35-40 years, and above 40 years. The linear-by-linear association test was used to examine linear association between advanced maternal age and adverse pregnancy outcomes. A multiple logistic regression model was used to control for confounders., Results: Out of 45,033 nulliparous women with singleton gestations, 1,036 were of women over the age of 35, and 188 over 40. A significant linear association was documented between advanced maternal age and adverse outcomes, such as intra uterine growth restriction, low birth weight, congenital malformations, and perinatal mortality. Using a multiple logistic regression model, controlling for gestational age, IUGR and malformations, advanced maternal age was not found to be an independent risk factor for perinatal mortality (adjusted odds ratio = 1.04, 95% confidence interval 0.7-1.4)., Conclusion: A significant linear association exists between advanced maternal age and adverse maternal and perinatal outcomes. Nevertheless, in our population, advanced maternal age is not an independent risk factor for perinatal mortality.

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 peripartum 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.

Objective: To evaluate perinatal outcome of fetuses with isolated single umbilical artery (SUA), and specifically to examine whether an isolated SUA is an independent risk factor for perinatal mortality., Methods: A population-based study was conducted, comparing pregnancies of women with and without SUA. Deliveries occurred between the years 1988-2006, in a tertiary medical center. Multiple gestations, chromosomal abnormalities and malformations were excluded from the analysis. Stratified analysis was performed using multiple logistic regression models to evaluate the association between SUA and perinatal mortality, while controlling for confounders., Results: Out of 194,809 deliveries, 243 (0.1%) were of fetuses with isolated SUA. Fetuses with SUA were smaller (2,844 ± 733 vs. 3,197 ± 530 g, P < 0.001), and were delivered at an earlier gestational age (38.3 ± 3.0 vs. 39.3 ± 2.1 weeks, P < 0.001), when compared with fetuses with normal umbilical vessels. Mothers to fetuses with isolated SUA tended to have a history of infertility treatments (4.5 vs. 1.7%; P = 0.001) when compared with the comparison group. Fetuses with SUA had more complications, including fetal growth restriction (FGR 9.5 vs. 1.9%, P < 0.001), polyhydramnios (11.5 vs. 3.7%; P < 0.001) and oligohydramnios (6.6 vs. 2.2%; P < 0.001). Deliveries of SUA fetuses had higher rates of placental abruption (3.3 vs. 0.7%; P < 0.001), placenta previa (1.2 vs. 0.4%; P = 0.03) and cord prolapse (2.9 vs. 0.4%; P < 0.001). Higher rates of cesarean deliveries were noted in this group (23.9 vs. 12.2%; P < 0.001). SUA newborns had higher rates of low Apgar scores (<7) in one (11.8 vs. 3.7%; P < 0.001) and 5 min (3.5 vs. 0.4%; P < 0.001). Higher rates of perinatal mortality were noted in the SUA group, as compared to fetuses with normal umbilical vessels (6.6 vs. 0.9%, OR 7.78; 95% CI 4.7-13.0; P < 0.001). Using a multiple logistic regression model, controlling for possible confounders, such as FGR, oligohydramnios, polyhydramnios, prolapse of cord, maternal hypertension and diabetes mellitus, isolated SUA remained an independent risk factor for perinatal mortality (adjusted OR = 3.91, 95% CI 2.06-7.43; P < 0.001)., Conclusion: Isolated SUA in our population was noted as an independent risk factor for perinatal mortality.

Timing of elective repeat caesarean section should take into account both fetal and maternal considerations. The percentage of caesarean deliveries has dramatically increased during the last decades. It undoubtedly leads to an increase in the number of women having multiple caesarean sections. While maternal morbidity increases with increased number of caesarean sections, when compared with their term counterparts, late pre-term infants face increased morbidity. Establishing the optimal time of delivery for both mother and child is a major challenge faced by clinicians. The aim of this review is to better understand neonatal and maternal morbidity and mortality that are associated with elective repeat caesarean section, and to provide an educated decision regarding the optimal timing for elective repeat caesarean section.

Objective: To identify the incidence, risk factors, and perinatal outcome of newborns with congenital finger or toe (digital) anomalies., Method: A retrospective study including all neonates born at a tertiary medical center during 2001-2006 with congenital digital anomalies was conducted. The comparison group consisted of newborns without such anomalies born during the same period., Results: Of 115,876 newborns delivered during the study period, 360 (31 per 10,000) were diagnosed with digital anomalies. Polydactyly was the most common diagnosis (n = 263; 73% of digital anomalies). Associated anomalies in these patients were congenital heart malformations (n = 93; 25.8% of the newborns with congenital digital anomalies), central nervous system anomalies (n = 17; 4.7%), and musculoskeletal anomalies (n = 13; 3.6%). Newborns with congenital digital anomalies were more likely to be males (62.2 vs. 37.8%; P < 0.001), and of a Bedouin Arab descent compared to Jewish ethnicity (61.4 vs. 38.6%; P = 0.004). Significantly higher rates of severe pre-eclampsia, recurrent abortions, transverse lie, and low birth-weight (<2,500 g) infants were found among newborns with digital anomalies., Conclusions: The incidence of digital anomalies can vary according to the population characteristics. It may be associated with other skeletal and non-skeletal malformations as well as with certain adverse obstetrical and perinatal outcomes. If a fetal digit anomaly is suspected, a detailed assessment of fetal anatomy is mandatory to exclude other malformations.