Publications by authors named "Mordechai Hallak"

84 Publications

The expression of heparanase in term and preterm human placentas.

J Matern Fetal Neonatal Med 2021 Mar 10:1-6. Epub 2021 Mar 10.

Laboratory for Reproductive Immunology, Department of Obstetrics and Gynecology, The Hillel Yaffe Medical Center, Hadera, Israel, The Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Purpose: Heparanase is an endo--glucuronidase that cleaves side chains of heparan-sulfate proteoglycans, an integral constituent of the extra cellular matrix. The abundance of heparanase in placental trophoblast cells implies its role in the processes of placentation and trophoblast invasion. This study aims to explore the involvement of heparanase in parturition and preterm deliveries (PTD).

Methods: Sixteen human placentas were collected following singleton spontaneous onset term vaginal deliveries ( = 6), spontaneous onset preterm vaginal deliveries ( = 7) and term elective cesarean sections ( = 3). Placentas were excluded in case of any maternal chronic illness, pregnancy or delivery complications apart from PTD. Placental tissue samples were dissected, homogenized and proteins were extracted. Additionally, cryosections were prepared from the placental tissues. Heparanase expression was evaluated utilizing western blot analysis and immunofluorescence staining using heparanase specific antibodies. Heparanase expression was compared between the study groups qualitatively and quantitatively.

Results: Western blot analysis results demonstrated higher expression of both pro-heparanase and heparanase in PTD placentas compared to term vaginal placentas. Accordingly, immunofluorescence staining shows elevated heparanase expression in PTD placentas compared to term vaginal placentas (5.1 ± 0.92 vs. 1.2 ± 0.18,  < .005). Expression level of heparanase was higher in term cesarean section placentas as compared to term vaginal deliveries placentas, but did not reach statistical significance (1.8 ± 0.39 vs. 1.2 ± 0.18,  = .06).

Conclusion: This study demonstrates for the first time that preterm vaginal deliveries are associated with higher expression of heparanase in placental tissue. This may imply a direct effect of heparanase on preterm labor. Further studies should evaluate the functional role by which heparanase influence preterm delivery.
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http://dx.doi.org/10.1080/14767058.2021.1895743DOI Listing
March 2021

The Accuracy of Sonographic Fetal Head Circumference in Twin Pregnancies.

J Obstet Gynaecol Can 2021 Feb 20. Epub 2021 Feb 20.

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel; The Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Objective: To assess the accuracy of sonographic estimation of fetal head circumference in twin gestations.

Methods: A retrospective analysis of sonographic evaluations of twin gestations >34 weeks, performed within 7 days of delivery, in a single university-affiliated medical centre. Sonographic head circumference was compared with neonatal head circumference. Measures of accuracy included systematic error, random error, proportion of estimates within 5% of neonatal head circumference, and reliability analysis. Accuracy of sonographic head circumference was compared between the first and second twin.

Results: Overall, 103 twin gestations were evaluated at a median of 4 days before delivery. The majority of twins were dichorionic-diamniotic (83%). Median gestational age at delivery was 37 weeks, with a median birthweight of 2645 grams for the first twin and 2625 grams for the second twin. For all fetuses, median sonographic head circumference was lower than the neonatal head circumference (first twin: 317.5 vs. 330 mm; second twin: 318.4 vs. 330 mm, P > 0.05 for both). Measures of accuracy showed no significant difference between first and second twin. There was no difference in the number of sonographic head circumference evaluations that were within 5% of the neonatal head circumference between fetuses (64% for both twins). Cronbach α value was higher for the second twin (0.746 vs. 0.613), suggesting higher accuracy for head circumference measurement for the second twin.

Conclusion: In our cohort, sonographic head circumference underestimated postnatal head circumference. Accuracy measurements were not significantly different between the first and second twin.
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http://dx.doi.org/10.1016/j.jogc.2021.02.114DOI Listing
February 2021

Parity and Interval from Previous Delivery-Influence on Perinatal Outcome in Advanced Maternal Age Parturients.

J Clin Med 2021 Jan 26;10(3). Epub 2021 Jan 26.

Obstetrics and Gynecology Department, Hillel Yaffe Medical Center, Hadera 38100, Israel.

Objective: To investigate the effect of parity and interpregnancy interval (IPI) on perinatal outcomes in advanced maternal age (AMA) parturients.

Methods: A population-based retrospective cohort study of all women older than 40 years, who had a singleton live birth after 24 weeks in the United States in 2017 Women were categorized to three groups by parity and interval from last delivery: primiparas, multiparas with IPI ≤ 5 years, and multiparas with IPI > 5 years. Primary outcome was composite adverse neonatal outcome (preterm delivery <34 weeks, birthweight <2000 g, neonatal seizure, neonatal intensive care unit admission, Apgar score <7 at 5 min, or assisted ventilation >6 h). Secondary outcome was composite adverse maternal outcome and other adverse perinatal outcomes. Univariate and multivariate analysis were used to compare between groups.

Results: During 2017, 3,864,754 deliveries were recorded into the database. Following exclusion, 109,564 AMA gravidas entered analysis. Of them, 24,769 (22.6%) were nulliparas, 39,933 (36.4%) were multiparas with IPI ≤ 5 years, and 44,862 (40.9%) were multiparas with IPI > 5 years. Composite neonatal outcome was higher in nulliparas and in multiparas with IPI > 5 years, in comparison to multiparas with IPI ≤ 5 years (16% vs. 13% vs. 10%, respectively, < 0.05). Maternal composite outcome was similar between groups. In the multivariable analysis, relative to nulliparas, only multiparity with IPI ≤ 5 years had a protective effect against the composite neonatal outcome (aOR 0.97, 95% CI 0.95-0.99, < 0.001).

Conclusion: Among AMA gravidas, multiparity with IPI ≤ 5 years has a significant protective effect against adverse neonatal outcomes when compared to nulliparas. Multiparity with IPI > 5 years is no longer protective.
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http://dx.doi.org/10.3390/jcm10030460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865726PMC
January 2021

Continuous Maternal Hemodynamics Monitoring at Delivery Using a Novel, Noninvasive, Wireless,PPG-Based Sensor.

J Clin Med 2020 Dec 22;10(1). Epub 2020 Dec 22.

Obstetrics and Gynecology department, Hillel Yaffe Medical Center, Hadera 38100, Israel.

Objective: To evaluate continuous monitoring of maternal hemodynamics during labor and delivery utilizing an innovative, noninvasive, reflective photoplethysmography-based device.

Study Design: The Biobeat Monitoring Platform includes a wearable wristwatch monitor that automatically samples cardiac output (CO), blood pressure (BP), stroke volume (SV), systemic vascular resistance (SVR), heart rate (HR) every 5 s and uploads all data to a smartphone-based app and to a data cloud, enabling remote patient monitoring and analysis of data. Low-risk parturients at term, carrying singletons pregnancies, were recruited at early delivery prior to the active phase. Big data analysis of the collected data was performed using the Power BI analysis tool (Microsoft). Next, data were normalized to visual presentation using Excel Data Analysis and the regression tool. Average measurements were compared before and after rupture of membranes, epidural anesthesia, fetal delivery, and placental expulsion.

Results: Eighty-one parturients entered analysis. Epidural anesthesia was associated with a slight elevation in CO (5.5 vs. 5.6, L/min, 10 min before and after EA, 0.05) attributed to a non-significant increase in both HR and SV. BP remained stable as of counter decrease in SVR (1361 vs. 1319 mmHg⋅min⋅mL, 10 min before and after EA, 0.05). Fetal delivery was associated with a peak in CO after which it rapidly declined (6.0 vs. 7.2 vs. 6.1 L/min, 30 min before vs. point of delivery vs. after delivery, 0.05). The mean BP remained stable throughout delivery with a slight increase at fetal delivery (92 vs. 95 vs. 92.1 mmHg, 0.05), reflecting the increase in CO and decrease in SVR (1284 vs. 1112 vs. 1280 mmHg⋅min⋅mL,0.05)with delivery. Placental expulsion was associated with a second peak in CO and decrease in SVR.

Conclusions: We presented a novel application of noninvasive hemodynamic maternal monitoring throughout labor and delivery for both research and clinical use.
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http://dx.doi.org/10.3390/jcm10010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793094PMC
December 2020

Abdominal circumference discordance for prediction of small for gestational age at birth in twin pregnancies.

J Matern Fetal Neonatal Med 2020 Oct 12:1-6. Epub 2020 Oct 12.

Department of Obstetrics and Gynecology, The Rappaport Faculty of Medicine, Hillel Yaffe Medical Center, Hadera, Israel.

Objective: To evaluate whether single sonographic abdominal circumference (AC) discordancy estimation can predict small for gestational age (SGA) at birth in twin gestations.

Methods: A retrospective analysis of prospectively collected data. Cohort included all twin gestations delivered at one university-affiliated medical center between 2010 and 2018, with available sonographic evaluation from 22 gestational weeks to term. Pregnancies complicated by fetal chromosomal abnormalities, major anomalies or twin to twin transfusion syndrome were excluded. One sonographic evaluation per pregnancy was selected randomly. AC discordance was calculated as (large twin AC - small twin AC)/large twin AC*100. Prediction of SGA at birth for at least one newborn (<10% percentile for gestational age by gender-specific local curves for multiples) was evaluated using ROC statistics with calculation of Youden index to establish best AC discordance cutoff. AC discordance prediction performance was compared to estimated fetal weight discordance performance. Results were adjusted for confounders using logistic regression analysis.

Results: After exclusion, 236 twin gestations entered analysis. Of them, 200/236 (84.7%) were dichorionic-diamniotic twins. Mean gestational age at ultrasound evaluation and at delivery were 30.9 ± 4.4 and 35.9 ± 2.4 weeks, respectively. In 28/236 (11.8%) pregnancies, at least one neonate was born SGA. AC discordance predicted SGA at birth as good as sonographic estimated fetal weight (sEFW) discordance: ROC-AUC 0.76, 95% CI 0.67-0.85 vs. 0.77 95% CI 0.66-0.87,  < .001 for all. Best AC discordance cutoff for prediction of SGA at birth was 7.1% (57% sensitivity, 87% specificity), ROC-AUC 0.72 (95% CI 0.61-0.84,  < .001). Results remained significant after adjustment for maternal age, nulliparity, chorionicity and ultrasound to delivery interval (aOR 1.21 95% CI 1.1-1.32,  < .001).

Conclusion: According to our results, AC discordance at single sonographic evaluation can predict SGA at birth in twin gestations as good as sEFW discordance. Best cutoff for SGA prediction was 7.1%.
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http://dx.doi.org/10.1080/14767058.2020.1832071DOI Listing
October 2020

The effect of endometrial thickness and pattern on the success of frozen embryo transfer cycles and gestational age accuracy.

Gynecol Endocrinol 2020 Sep 18:1-5. Epub 2020 Sep 18.

IVF Unit and Ultrasound Unit, Obstetric Gynecology Department, Hillel Yaffe Medical Center, Hadera, Israel.

Objective: To evaluate the relationship between endometrial thickness measured before embryo transfer, and pregnancy outcomes in frozen-thawed embryo transfer (FET).

Methods: We retrospectively analyzed outcomes of all consecutive FET cycles, from January 2012 to August 2018. Based on ROC analysis for endometrial thickness, we found 8 mm was a reliable cutoff point to predict pregnancy prior to embryo transfer. Accordingly, the cycles were divided into Group A: cycles with endometrial thickness ≤ 8 mm and Group B: > 8 mm.

Results: Group A included 485 FET cycles and group B included 626 cycles. Compared with group A, Group B had significantly higher chemical and clinical pregnancy rates (30.3 vs. 24.6%;  = .046, and 24.0 vs. 18.6%;  = .036), respectively. In multivariate analysis, endometrial thickness and the protocols used were the only parameters influencing the chance to achieve pregnancy, with odds ratio 1.54 (95%CI 1.07-2.22,  = .019) for the endometrium and odds ratio 1.95 (95%CI 1.31-2.9; = .001) to the protocol used. Endometrial thickness might predict crown-rump length (CRL) discordancy with odds ratio 4.61 ( = .001; 95% CI 1.42-14.92). Compared with group B, Group A had more cases of overt discordancy (13.3 vs. 4%;  = .016).

Conclusions: For patients undergoing FET cycles, endometrial thickness and treatment protocol may predict the chemical and clinical pregnancy rates, as well as CRL discordancy.

Summary: Endometrial thickness and preparation improved pregnancy rate in FET cycles and significantly greater crown-rump length discordancy was observed with thinner endometria.
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http://dx.doi.org/10.1080/09513590.2020.1821359DOI Listing
September 2020

Extremely high levels of alkaline phosphatase and pregnancy outcome: case series and review of the literature.

J Perinat Med 2021 Feb 14;49(2):191-194. Epub 2020 Sep 14.

The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.

Objectives: To evaluate the association between extremely elevated alkaline phosphatase (ALKP) levels (above 1000 U/L) and adverse perinatal outcome.

Methods: A retrospective case series of all parturients with extremely elevated ALKP levels taken throughout pregnancy at a single university-affiliated medical center (2010-2018). Demographics and medical data were retrieved. Following literature review, previously reported similar cases were added to the cohort. We report perinatal outcome of our cohort as well as literature review.

Results: During study period 11 parturients with high ALKP were identified. Ten more cases were retrieved from PubMed search. Overall, median ALKP levels were 1880 (range 1052-4488 U/L). Reasons for evaluation were mostly nonspecific symptoms (pruritus, headache, abdominal pain) or routine obstetrical evaluation. In 10/12 (83%) cases, elevated ALKP levels were of placental origin; the rest had osteal origin. Median gestational age at delivery was 38 (range 35-41); four (19%) women had preterm delivery. Six patients (29%) had gestational diabetes mellitus and six (29%) had hypertensive disorders. Histopathology of the placenta was available in eight cases: three normal histology (38%) and five with different non-specific pathologies.

Conclusions: We report the largest case series of extremely elevated levels of ALKP in pregnancy thus far. Our data suggest association with adverse perinatal outcome.
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http://dx.doi.org/10.1515/jpm-2020-0205DOI Listing
February 2021

Rapid intraoperative diagnosis of gynecological cancer by ATR-FTIR spectroscopy of fresh tissue biopsy.

J Biophotonics 2020 09 23;13(9):e202000114. Epub 2020 Jun 23.

Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

A rapid and reliable intraoperative diagnostic technique to support clinical decisions was developed using Fourier-transform infrared (FTIR) spectroscopy. Twenty-six fresh tissue samples were collected intraoperatively from patients undergoing gynecological surgeries. Frozen section (FS) histopathology aimed to discriminate between malignant and benign tumors was performed, and attenuated total reflection (ATR) FTIR spectra were collected from these samples. Digital dehydration and principal component analysis and linear discriminant analysis (PCA-LDA) models were developed to classify samples into malignant and benign groups. Two validation schemes were employed: k-fold and "leave one out." FTIR absorption spectrum of a fresh tissue sample was obtained in less than 5 minutes. The fingerprint spectral region of malignant tumors was consistently different from that of benign tumors. The PCA-LDA discrimination model correctly classified the samples into malignant and benign groups with accuracies of 96% and 93% for the k-fold and "leave one out" validation schemes, respectively. We showed that a simple tissue preparation followed by ATR-FTIR spectroscopy provides accurate means for very rapid tumor classification into malignant and benign gynecological tumors. With further development, the proposed method has high potential to be used as an adjunct to the intraoperative FS histopathology technique.
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http://dx.doi.org/10.1002/jbio.202000114DOI Listing
September 2020

IGF1R Axis Inhibition Restores Dendritic Cell Antitumor Response in Ovarian Cancer.

Transl Oncol 2020 Aug 16;13(8):100790. Epub 2020 May 16.

Gynecology Laboratory, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel; Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in several malignancies, including ovarian cancer. IGF1R targeting showed antiproliferative activity of EOC cells. However, clinical studies failed to show significant benefit. EOC cells suppress antitumor immune responses by inducing dendritic cell (DC) dysfunction. The IGF1 axis can regulate DC maturation. The current study evaluated involvement of the IGF1 axis in DC differentiation in EOC. Studies were conducted on EOC and on a human monocyte cell line. Tissue microarray analysis (TMA) was performed on 36 paraffin blocks from EOC patients. Expression of IGF1R, p53, Ki67, BRCA1, and DC markers was evaluated using immunohistochemistry. Co-culture of EOC cells with DC pretreated with IGF1R inhibitor blocked cancer cell migration. TMA demonstrated higher rate of IGF1R protein expression in patients with advanced (76.9%) as compared to early (40%) EOC. A negative correlation between IGF1R protein expression and the CD1c marker was found. These findings provide evidence that IGF1R axis inhibition could be a therapeutic strategy for ovarian cancer by restoring DC-mediated antitumor immunity.
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http://dx.doi.org/10.1016/j.tranon.2020.100790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232112PMC
August 2020

Determination of reference values for third trimester amniotic fluid index: a retrospective analysis of a large cohort of pregnancies with comparison to previous nomograms.

J Matern Fetal Neonatal Med 2020 Jan 12:1-7. Epub 2020 Jan 12.

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

To establish a new set of reference values for third-trimester amniotic fluid index (AFI) and compare them to other previously published normograms. A retrospective cross-sectional cohort analysis of all singleton sonographic evaluations >22 gestational weeks in one university affiliated medical center between 2013 and 2017. Pregnancies complicated by rupture of membranes, major anomalies/chromosomal abnormalities were excluded. One evaluation per patient per pregnancy was randomly selected. Reference values were constructed using a best-fit regression model for estimation of mean and standard deviation at each gestational age after normalization of variables and compared with previously published norms. A total of 7037 ultrasound evaluations entered the analysis. Correlation between AFI and gestational age was best represented by a first-degree polynomial equation. AFI decreased gradually from 16.4 at 22 weeks to 13.3 at 40 weeks (cm, median). The standard deviation increased with gestational age with AFI ranging from 12.9-20.2 at 22 weeks and 4.7-26.2 at 40 weeks (cm, 2.5-97.5 percentile). Compared to other curves, our reference values demonstrated a higher median AFI throughout all gestation. Reference values for the third trimester AFI were established. Curves should be correlated with perinatal outcome prior to wide clinical implementation.
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http://dx.doi.org/10.1080/14767058.2020.1712711DOI Listing
January 2020

Endometriosis-related Hemoperitoneum in Late Pregnancy.

Isr Med Assoc J 2019 Aug;21(8):557-559

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

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August 2019

New reference values for biometrical measurements and sonographic estimated fetal weight in twin gestations and comparison to previous normograms.

J Perinat Med 2019 Sep;47(7):757-764

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera 38100, Israel.

Objective To construct new reference values for biometrical measurements and sonographic estimated fetal weight (sEFW) in twin gestations and compare them to previously published normograms. Methods A retrospective analysis of sEFW evaluations of twin gestations was performed between 2011 and 2016 in a single university-affiliated medical center. sEFW was calculated using the Hadlock 1985 formula. To avoid selection bias, one evaluation per pregnancy was randomly selected. Following mathematical transformation to obtain normality of values, normograms were constructed using a best-fit regression model for estimation of mean and standard deviation at each gestational age (GA). Normograms were validated by applying all observations to ensure equal distribution at parallel percentiles. Our normograms were then compared to previously published sEFW normograms for twin gestations. Results A total of 864 sEFW evaluations were performed on 195 twin pregnancies at 22-39 gestational weeks. Of them, 390 entered the primary analysis. The rest were left for validation. Seventy percent of the cohort were dichorionic-diamniotic twins (136/195), 16% (32/195) were monochorionic-diamniotic twins and three (1.5%) were monochorionic-monoamniotic twins. Twenty-four fetuses lacked data on chorionicity. The rest were monochorionic twins or were of unknown chorionicity. Values corresponding to the 2.5th, 10th, 50th, 90th and 97.5th percentiles for sEFW are presented for every GA. Validation by applying all 864 evaluations on constructed normograms was achieved. Comparison to previously published twins' sEFW normograms demonstrated wide variation between curves. Conclusion New reference values for biometrical measurements and sEFW in twin gestations are presented for clinical and research use. Comparison to other curves demonstrates the wide variability and need for further investigation on twin's normal growth.
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http://dx.doi.org/10.1515/jpm-2019-0207DOI Listing
September 2019

Cesarean scar pregnancy managed with local and systemic methotrexate: A single center case series.

Eur J Obstet Gynecol Reprod Biol 2019 Jul 20;238:138-142. Epub 2019 May 20.

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel; The Rappaport Faculty of Medicine, The Technion Institute of Technology, Haifa, Israel.

Objective: To report the efficacy of combined systemic and local methotrexate treatment for cesarean scar pregnancy and review data from selected, similar case series.

Study Design: A retrospective case series of 12 patients with cesarean scar pregnancy treated in a university hospital between 2014 and 2018. The intervention was combined treatment of systemic and local methotrexate.

Results: Twelve patients were treated with combined systemic and local methotrexate. Clinical characteristics, clinical course and treatment efficacy were evaluated. Mean gestational age at diagnosis was 7.5 weeks (range 5.9-9.1). βhCG levels at diagnosis ranged from 1581 to 345,427 U/L with a mean of 77,795 U/L. All 12 patients were successfully treated without surgical intervention and with no significant side-effects. Mean hospitalization duration was 9 days (5.8-12.6) and mean time to normalization of βhCG levels was 98 days (63-132).

Conclusions: Treatment of cesarean scar pregnancy with a combination of systemic and local methotrexate was effective and safe. Although the treatment course tends to be longer than with other modalities, this protocol offers excellent success rates, with fertility preservation and few complications.
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http://dx.doi.org/10.1016/j.ejogrb.2019.05.014DOI Listing
July 2019

[THE PROLIFERATIVE EFFECT OF DENDRITIC CELLS IN OVARIAN CANCER AND THE RELATIONSHIP WITH THE IGF SIGNALING PATHWAY].

Harefuah 2019 Jan;158(1):30-34

Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

Introduction: Epithelial ovarian cancer (EOC) is the principal cause of death from gynecologic cancer in developed countries. While surgery and chemotherapy can improve survival, the mortality and morbidity rates remain significantly high. The insulin-like growth factor (IGF) axis has been shown to play an important part in carcinogenesis of several human malignancies. Preclinical studies reported a significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in ovarian malignancies, however, clinical studies have shown variable response rates. Recent data indicate that immunotherapy could hold promise in improving EOC treatment. Dendritic cells (DCs) which are antigen presenting cells evoke a positive immune response. Moreover, a recent study shows that IGF treatment can inhibit DC maturation.

Aims: To investigate the involvement of IGF1R signaling in DCs and the effect of combined DCs and IGF1R inhibitor treatment on EOC cells growth.

Methods: HL-60 leukemic cells were differentiated to DCs and ligand induced phosphorylated IGF1R levels were measured by Western blotting. Next, inhibition of IGF1R in DCs was applied and the effect of this inhibition on EOC cell lines ES2 and SKOV3 was examined using the migration assay method.

Results: The differentiation of HL-60 into DCs was associated with decreased levels of both IGF1R phosphorylation and total IGF1R protein. In addition, in-vitro growth assays (scratch assay) demonstrated an increased growth of both ES2 and SKOV3 cells into the scratch zone when co-cultured with DCs which were not pre-treated with IGF1R inhibitor as compared to treated DCs.

Conclusions: Preliminary data suggest that DC differentiation is associated with IGF1R signaling downregulation. Moreover, inhibition of IGF1R signaling in DCs might decrease EOC growth.
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January 2019

Progesterone treatment enhances the expansion of placental immature myeloid cells in a mouse model of premature labor.

J Reprod Immunol 2019 02 26;131:7-12. Epub 2018 Oct 26.

Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel; Rappaport faculty of Medicine, Techinon-Isarel Institute of Technology, Israel. Electronic address:

Introduction: immature-myeloid cells (IMCs) are proangiogenic bone marrow (BM)-derived cells that normally differentiate into inflammatory cells such as neutrophils, monocytes and dendritic cells (DCs). We characterized placental IMCs comparing their gene expression and subpopulations to tumor IMCs, and tested our hypothesis that progesterone that inhibits preterm labor, may affect their abundance and differentiation.

Methods: differences between IMC-subpopulations in subcutaneous tumors versus placentas in C57BL/6 or ICR (CD-1) mice were analyzed by flow cytometry and gene expression was detected by microarrays. BM- and placental cells were incubated with or without progesterone and IMC subpopulations were analyzed. For preterm labor induction pregnant mice pretreated or not with progesterone were or were not treated with Lipopolysaccharide (LPS).

Results: we detected enrichment of granulocytic-IMCs in placentas compared to tumors, paralleled by a decrease in monocytic-IMCs. mRNA expression of placenta- versus tumor IMCs revealed profound transcriptional alterations. Progesterone treated BM-CD11b cells ex-vivo induced enrichment of granulocytic-IMCs and a decrease in monocytic-IMCs and DCs. LPS treatment in-vivo led to an increase in BM-IMCs in both progesterone pretreated or non-pretreated mice. In the placenta LPS decreased the IMC population while progesterone led to complete abrogation of this effect.

Discussion: placental IMCs differ from tumor-IMCs in both subpopulations and gene expression. Progesterone enhances the proliferation of placenta-specific granulocytic IMCs ex-vivo and LPS induced labor is accompanied by a decrease in placental IMCs only in progesterone non-pretreated mice. We thus speculate that the protective effect of progesterone in preventing preterm labor may be explained at least in part by this specific anti-inflammatory effect.
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http://dx.doi.org/10.1016/j.jri.2018.10.003DOI Listing
February 2019

The Role of the Insulin-Like Growth Factor 1 Pathway in Immune Tumor Microenvironment and Its Clinical Ramifications in Gynecologic Malignancies.

Front Endocrinol (Lausanne) 2018 5;9:297. Epub 2018 Jun 5.

Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

Treatment of patients with gynecologic malignancies diagnosed at advanced stages remains a therapeutic challenge. Survival rates of these patients remain significantly low, despite surgery and chemotherapy. Advances in understanding the role of the immune system in the pathogenesis of cancer have led to the rapid evolution of immunotherapeutic approaches. Immunotherapeutic strategies, including targeting specific immune checkpoints, as well as dendritic cell (DC) immunotherapy are being investigated in several malignancies, including gynecological cancers. Another important approach in cancer therapy is to inhibit molecular pathways that are crucial for tumor growth and maintenance, such as the insulin-like growth factor-1 (IGF1) pathway. The IGF axis has been shown to play a significant role in carcinogenesis of several types of tissue, including ovarian cancer. Preclinical studies reported significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in gynecologic malignancies. However, recent clinical studies have shown variable response rates with advanced solid tumors. This study provides an overview on current immunotherapy strategies and on IGF-targeted therapy for gynecologic malignancies. We focus on the involvement of IGF1R signaling in DCs and present our preliminary results which imply that the IGF axis contributes to an immunosuppressive tumor microenvironment (TME). For the long term, we believe that restoring the TME function by IGF1R targeting in combination with immunotherapy can serve as a new clinical approach for gynecological cancers.
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http://dx.doi.org/10.3389/fendo.2018.00297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996273PMC
June 2018

Therapeutic N-Acetyl-Cysteine (Nac) Following Initiation of Maternal Inflammation Attenuates Long-Term Offspring Cerebral Injury, as Evident in Magnetic Resonance Imaging (MRI).

Neuroscience 2019 04 9;403:118-124. Epub 2018 Feb 9.

Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel.

Maternal infection/inflammation may induce fetal inflammatory responses, which have been associated with long-term offspring cerebral injury. We previously demonstrated that prophylactic N-Acetyl-Cysteine (NAC), administered prior to and following maternal lipopolysaccharide (LPS), reduced offspring cerebral injury as evident on MRI. In the present study, we used MRI to examine the effect of therapeutic NAC following maternal LPS-induced inflammation on neonatal brain injury. Pregnant Sprague-Dawley dams (n = 6) at day 18 of gestation received either intraperitoneal injection of LPS or saline (Control) at time 0. Animals were randomized to receive intravenous injection (tail vein) of NAC or saline at time +30 min. Pups were delivered spontaneously and allowed to mature until postnatal day 25. Male offspring (6-8 per group) were examined by MRI and analyzed using voxel-based analysis. Diffusion Tensor Imaging (DTI), an advanced MRI technique, was performed and quantitative parameters extracted (mean and radial diffusivity) and used to assess white and gray matter brain injury. Offspring of LPS-treated dams exhibited significantly increased mean, axial and radial diffusivity (RD) levels in white and gray matter consistent with cerebral injury. In contrast, offspring of NAC-treated LPS PS dams demonstrated reduced mean, axial and RD levels in most regions; similar to the saline group. Maternal NAC treatment following maternal inflammation significantly influenced brain micro-structure integrity as demonstrated by MRI-DTI scans. These findings suggest that maternal NAC therapy may be effective in human pregnancies associated with maternal/fetal inflammation, such as preterm rupture of membranes and chorioamnionitis.
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http://dx.doi.org/10.1016/j.neuroscience.2018.01.013DOI Listing
April 2019

Factors Associated with Compliance of Folic Acid Consumption among Pregnant Women.

Isr Med Assoc J 2017 Aug;19(8):494-498

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Background: The prevalence of major malformations in the general population is estimated at 5% of all live births. Prenatal diagnosis is an important scientific tool that allows reliable consultation and improves pregnancy outcome. In 2008, congenital malformations were the leading cause of death in Muslim infants and the second cause of death in Jewish infants in Israel. It is known that folic acid consumption prior to pregnancy decreases the rate of several fetal malformations.

Objectives: To assess the folic acid consumption rate and to characterize variables associated with its use among pregnant women attending a rural medical center.

Methods: A cross-sectional observational study was conducted at our institution. Pregnant women in the second or third trimester of pregnancy or within 3 days postpartum were interviewed. The main variable measured was the use of folic acid. Demographic variables and the rate of prenatal testing were assessed. A secondary analysis of the population that reported no consumption of folic acid was carried out.

Results: Out of 382 women who participated in the study, 270 (71%) reported consumption of folic acid. Using a multivariate analysis model, we found that maternal education, planning of pregnancy, and low parity were independent predictors of folic acid consumption. Women who were not consuming folic acid tended to perform fewer prenatal tests during pregnancy.

Conclusions: High maternal educational level, planning of pregnancy, and low parity are related to high consumption rates of folic acid. Women who were not taking folic acid performed fewer prenatal tests during pregnancy.
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August 2017

Amplified CPEs enhancement of chorioamnion membrane mass transport by encapsulation in nano-sized PLGA particles.

Eur J Pharm Biopharm 2017 Aug 30;117:292-299. Epub 2017 Apr 30.

Department of Chemical Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address:

Chemical penetration enhancers (CPEs) have long been used for mass transport enhancement across membranes. Many CPEs are used in a solution or gel and could be a solvent. The use of CPEs is mainly limited due to their toxicity/irritation levels. This study presents the evaluation of encapsulated CPEs in nano-sized polymeric particles on the chorioamnion (CA) membrane mass transport. CPEs' mass encapsulated in nanoparticles was decreased by 10,000-fold. Interestingly, this approach resulted in a 6-fold increase in mass transport across the CA. This approach may also be used with other CPEs' base applications necessitating lower CPE concentration. Applying Ultrasound (US) has shown to increase the release rate of and also the mass transport across the CA membrane. It is proposed that encapsulated CPEs penetrate into the CA membrane thus prolonging their exposure, possibly extending their penetration into the CA membrane, while insonation also deepens their penetration into the CA membrane.
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http://dx.doi.org/10.1016/j.ejpb.2017.04.031DOI Listing
August 2017

Magnesium and fetal brain.

Authors:
Mordechai Hallak

Magnes Res 2016 Apr;29(4):141-145

Department of Obstetrics and Gynecology, The Hillel Yaffe Medical Center, Hadera, Israel, The Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

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http://dx.doi.org/10.1684/mrh.2016.0415DOI Listing
April 2016

Isolated Oligohydramnios at Term as an Indication for Labor Induction: A Systematic Review and Meta-Analysis.

Fetal Diagn Ther 2016 4;40(3):161-173. Epub 2016 May 4.

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.

Objective: To investigate whether isolated oligohydramnios at term is associated with increased rates of perinatal morbidity and mortality and whether induction of labor in term pregnancies with isolated oligohydramnios is superior to conservative management in reducing perinatal morbidity and mortality.

Study Design: We searched databases from inception to May 2015. We included studies that evaluated isolated oligohydramnios at term and perinatal outcome. Each outcome was analyzed separately, performing a comparative analysis between the study and control groups.

Results: Twelve studies were included with 35,999 women: 2,414 (6.7%) with isolated oligohydramnios and 33,585 (93.29%) with normal amniotic fluid index. Patients with isolated oligohydramnios had significantly higher rates of labor induction [odds ratio (OR) 7.56, confidence interval (CI) 4.58-12.48] and Cesarean sections (OR 2.07, CI 1.77-2.41). There were higher rates of an Apgar score <7 at 1 and 5 min (OR 1.53, CI 1.03-2.26, and OR 2.01, CI 1.3-3.09, respectively) and admission to the neonatal intensive care unit (OR 1.47, CI 1.17-1.84). There were no significant differences in cord pH <7.1 and meconium-stained amniotic fluid. In the single randomized trial comparing induction of labor with expectant management, no differences were found in any significant maternal or neonatal outcomes.

Conclusion: Isolated oligohydramnios at term is associated with significantly higher rates of labor induction, Cesarean sections, and short-term neonatal morbidity.
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http://dx.doi.org/10.1159/000445948DOI Listing
February 2017

Pre-cesarean Staphylococcus aureus nasal screening and decolonization: a prospective randomized controlled trial.

J Matern Fetal Neonatal Med 2016 Dec 3;29(23):3906-11. Epub 2016 Mar 3.

a Department of Obstetrics & Gynecology , Hillel Yaffe Medical Center , Hadera , Israel and.

Objective: Staphylococcus aureus (S. aureus) is a common pathogen in surgical site infections (SSIs). Mupirocin ointment is an effective treatment for nasal carriers. We aimed to investigate whether screening for nasal colonization of S. aureus and treating carriers prior to a cesarean section (CS) decreases the likelihood of SSI.

Methods: This is a randomized controlled trial. All participants underwent nasal culture prior to the CS. Nasal carriers of S. aureus were treated with Mupirocin ointment according to a standardized protocol. In the control group, nasal cultures were obtained immediately prior to surgery and carriers were not treated.

Results: We recruited 568 patients. Demographic characteristics were comparable between the groups. S. aureus nasal colonization rates were 20.1% and 14.9% in the intervention and control groups, respectively (p = 0.12). S. aureus eradication rate with Mupirocin treatment was 88%. SSI rates were similar in the intervention and control groups (13.1% versus 12.1%, respectively, p = 0.78) and in treated carriers, untreated carriers, and non-carriers (7.4% versus 13.0% versus 13.1%, respectively, p = 0.69). Previous CS was the only factor found to independently predict SSI (OR 2.5, CI 1.09-5.65 p = 0.029).

Conclusion: Pre-cesarean screening for nasal S. aureus carriage and decolonization does not appear to be an effective intervention in reducing SSI rates.
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http://dx.doi.org/10.3109/14767058.2016.1152243DOI Listing
December 2016

Shortness of Breath During Pregnancy: Could a Cardiac Factor Be Involved?

Clin Cardiol 2015 Oct 28;38(10):598-603. Epub 2015 Sep 28.

Department of Cardiology, Hillel Yaffe Medical Center, Hadera, Israel, Affiliated With the Technion School of Medicine, Haifa, Israel.

Background: Shortness of breath (SOB) is common among healthy women with normal pregnancies. However, when no overt cardiac or extra cardiac etiology is found, a subtle cardiac source must be excluded.

Hypothesis: Pregnancy may induce or unmask myocardial dysfunction that may cause SOB.

Methods: Healthy pregnant women with significant SOB were recruited for this study. We performed a comprehensive echocardiographic assessment including tissue Doppler imaging (TDI) and 2- dimensional strain imaging (2DS). The echocardiographic data obtained were compared with that of a control group of pregnant women without SOB.

Results: Thirty pregnant women with SOB were enrolled in the study (age, 31.8 ± 4.9 years, and gestation, 38.2 ± 2.8 weeks) for whom no overt etiology for SOB was detected. Patients with SOB compared with controls had thicker hearts (septum: 10.1 ± 1.1 vs 8.9 ± 0.9 mm; P < 0.001; posterior wall: 9.4 ± 1.1 vs 8.9 ± 0.9 mm; P < 0.01), shorter E-wave deceleration time (158.0 ± 50.1 vs 187.1 ± 37.6 msec; P = 0.01), and higher pulmonary artery pressure (26.8 ± 6.2 vs 19.0 ± 6.5 mm Hg, P < 0.01). Women with SOB tended to have a lower S' velocity TDI (P = 0.05) and a trend toward increased torsion on 2DS (P = 0.09).

Conclusions: Significant SOB during otherwise normal pregnancy is associated with significant echocardiographic findings that may suggest a subtle cardiac involvement. Further investigation is necessary to verify such an association, which may have therapeutic implications for treating SOB of pregnancy.
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http://dx.doi.org/10.1002/clc.22452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490843PMC
October 2015

Inter-relationships between sexual abuse, female sexual function and childbirth.

Midwifery 2015 Nov 29;31(11):1087-95. Epub 2015 Jul 29.

Emili Sagol Creative Arts Therapies Research Center, University of Haifa, 3478601 Haifa, Israel; 'Tene' Center for the Treatment of the Sexually Abused, Obstetrics and Gynecology Department, the Baruch Padeh-Poriya Medical Center, 15208 Tiberias, Israel; Faculty of Medicine in the Galilee, Bar-Ilan University, 1311502 Safed, Israel.

Background: the present quantitative longitudinal study focuses on the inter-relationships between sexual abuse, distressed female sexual function and childbirth. Additional variables studied include depression, mode of delivery, subjective birth experience and traumatic life events other than sexual abuse.

Methods: data collection for the study was extended across three time periods: during the third trimester of pregnancy and approximately one and six months postpartum. Self-reported questionnaire responses of 300 women from two medical centres in Israel, as well as hospital records regarding their mode of childbirth, were included in the data analysis. Measures incorporated in the study included the Female Sexual Distress Scale-Revised, the Beck Depression Inventory and modified versions of the Traumatic Events Questionnaire, the Sexual Experiences Survey, and the Subjective Birth Experience Questionnaire.

Results: findings demonstrated that women with a lifetime history of sexual abuse compared to women without such history, are at an increased risk for distressed antenatal and postpartum female sexual function (Odds Ratio OR=2.66 and OR=2.26, respectively); and postpartum depression (OR=2.36). Antenatal depression was likewise shown to be significantly associated with antenatal and postpartum distressed female sexual function (OR=4.32 and OR=10.4, respectively), as well as with a more negatively experienced childbirth (T-Ratio, T=1.98, p<0.05). Moreover, distressed antenatal female sexual function was found to increase the risk for a more negatively experienced childbirth (T=2.04, p<0.05), and caesarean childbirth (OR=3.34).

Conclusions: the current study enriches the understanding of the inter-relationships between the antenatal, childbirth and postpartum variables studied herein; and has implications for evidence based practice in both preventative and intervention efforts. Recommendations for future research are presented and discussed.
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http://dx.doi.org/10.1016/j.midw.2015.07.011DOI Listing
November 2015

Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring.

Am J Obstet Gynecol 2015 Dec 30;213(6):851.e1-8. Epub 2015 Jul 30.

Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel. Electronic address:

Objective: Maternal chorioamnionitis is associated with newborn neurologic injury. Recent evidence suggests that maternal administration of magnesium sulphate (MG) may protect fetuses from white matter injury. Previously we demonstrated evidence by magnetic resonance imaging that MG may prevent maternal inflammation-induced gray matter injury of offspring. Thus, we sought to determine the potential of maternal inflammation to induce fetal neurological/behavioral deficits and assess whether maternal MG attenuates these effects.

Study Design: Pregnant rats at day 18 received injections of intraperitoneal lipopolysaccharide (LPS) or saline. Dams were treated with subcutaneous saline/MG (270 mg/kg followed by 27 mg/kg every 20 minutes) for 2 hours before and following LPS/saline injections. Pups were delivered spontaneously. At 1 and 3 months of age, 11-12 offspring of each group (saline, LPS, MG, LPS-MG) underwent a 2-way shuttle box avoidance testing. The shuttle box is divided in half and the animal moves between compartments to avoid an electric shock in response to an auditory stimulus.

Results: Control offspring demonstrated significantly improved learning and memory abilities from age 1 to 3 months. At 1 month, LPS-treated dams' offspring were similar to controls with no improvement in learning abilities at 3 months. MG treatment of LPS dams significantly improved offspring learning at 3 months, to equal or better than that of controls.

Conclusion: LPS-stimulated inflammation during pregnancy impairs offspring learning ability and memory, which is ameliorated by maternal MG treatment. These results suggest that maternal MG therapy may prevent white and gray matter injuries associated with maternal infection/inflammation.
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http://dx.doi.org/10.1016/j.ajog.2015.07.042DOI Listing
December 2015

Maternal characteristics of pregnancies with intrauterine fetal demise.

J Perinat Med 2016 Oct;44(7):779-784

Objective: To identify maternal characteristics independently associated with pregnancies resulting in intrauterine fetal demise (IUFD).

Study Design: This was a population-based cohort study of all births taking place at the McGill University Health Centre in Montreal, Canada, between 2001 and 2007, using the McGill University Obstetrics and Neonatal Database. Maternal characteristics were compared between pregnancies that resulted in IUFD and control pregnancies resulting in live newborns. A logistic regression analysis was constructed to identify parameters independently associated with IUFD.

Results: We identified 20,744 births during the study period, 87 of which were complicated by IUFD. Mothers with IUFD were more likely to be younger, with less formal education, higher rates of smoking during pregnancy, and more fetal anomalies (42.5% vs. 7.5%, P<0.001). After exclusion of pregnancies with congenital and/or chromosomal abnormalities, less formal education (7 vs. 13.6 school years, P<0.001) and smoking during pregnancy (24% vs. 7.7%, P<0.001) remained significantly more common in pregnancies resulting in IUFD. In the multivariable regression analysis both smoking and number of maternal school years were independently associated with IUFD pregnancies (OR 2.22 for smoking, P=0.007 and OR 0.865 for number of school years, P<0.001).

Conclusion: Lower levels of education and smoking during pregnancy are independent predictors of IUFD.
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http://dx.doi.org/10.1515/jpm-2015-0135DOI Listing
October 2016

Mechanical labor induction in the obese population: a secondary analysis of a prospective randomized trial.

Arch Gynecol Obstet 2016 Jan 9;293(1):75-80. Epub 2015 Jun 9.

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, affiliated with the Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, P.O.B. 169, 38100, Hadera, Israel.

Objective: The objective of this study was to estimate the influence of maternal body mass index (BMI) on progress and outcomes of labor induction using mechanical devices.

Methods: This study was a secondary analysis of data collected during the Cook Catheter vs. Foley Catheter study, a series of prospective randomized trials of women requiring cervical ripening for labor induction. The duration, characteristics, and outcomes of labor were analyzed after stratification by BMI categories. Outcomes assessed included time from device insertion to delivery, successful ripening, cesarean delivery rates, and any maternal and neonatal adverse events.

Results: One hundred and eighty-one patients were stratified according to BMI categories, with 102 study participants classified as normal weight (BMI ≤30) and 79 as obese (BMI >30). Maternal satisfaction from the induction process was significantly lower in the obese group compared to the normal weight group (5.95 ± 3.14 vs. 7.58 ± 2.7, respectively, in a 1-10 scale, p = 0.009). The cesarean delivery rate was similar in the normal weight and the obese groups (17.6 vs. 25.3 %, respectively, p = 0.27). No statistical differences were found in all other outcomes evaluated, including a sub-analysis of the different mechanical devices.

Conclusions: During the process of mechanical cervical ripening, maternal satisfaction, but not objective obstetrical parameters, was influenced by increased maternal BMI. The trial is registered at ClinicalTrials.gov, no: NCT00604487. Trial registry name is "Induction of Labor in Patients with Unfavorable Cervical Conditions."
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http://dx.doi.org/10.1007/s00404-015-3765-3DOI Listing
January 2016

The synergistic effect of ultrasound and chemical penetration enhancers on chorioamnion mass transport.

J Control Release 2015 Feb 22;200:35-41. Epub 2014 Dec 22.

Department of Chemical Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address:

In our previous study we proposed the use of chemical penetration enhancers for noninvasive detection of fetus abnormalities that can also be utilized for direct fetal drug delivery. In an attempt to further increase the mass transport rate across the amniotic membrane, thus shortening the procedure and improving the applicability of the proposed procedure, the effect and mechanism of combining ultrasound exposure with chemical penetration enhancers' application were assessed. The combined effect was evaluated in vitro on post-delivery human amniotic membrane and ex vivo on rat's whole amniotic sac. Ultrasound effect has been assessed by dye experiments using a customized image analysis program. Additional insights of ultrasound effect's mechanism on biological membranes are presented. Previously we have determined that chemical penetration enhancers affect the fetal membranes via two mechanisms termed as 'extractors' and 'fluidizers'. In this study, we found that combining ultrasound with a 'fluidizer' CPE (e.g. bupivacaine) results in a synergistic enhancement (90-fold) of fetal membrane's mass transport, while combining ultrasound with 'extractors' (e.g. ethanol and NMP) results in an antagonistic effect. The combined procedure is faster and gain greater accuracy than the applications of sole chemical penetration enhancers.
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http://dx.doi.org/10.1016/j.jconrel.2014.12.025DOI Listing
February 2015

Can the practice of nonclosure of visceral and parietal peritoneum during cesarean delivery be justified? Reply.

Am J Obstet Gynecol 2015 Apr 12;212(4):550-1. Epub 2014 Dec 12.

Department of Obstetrics & Gynecology, Hillel Yaffe Medical Center, Hadera, Israel; Bruce and Ruth Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

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http://dx.doi.org/10.1016/j.ajog.2014.12.009DOI Listing
April 2015

The unborn smoker: association between smoking during pregnancy and adverse perinatal outcomes.

J Perinat Med 2015 Sep;43(5):553-8

Objective: To evaluate a possible dose-response relationship between active maternal smoking during pregnancy and adverse perinatal outcome.

Design: Retrospective cohort study.

Setting: Population-based in Montreal, Quebec, Canada.

Population: Women who gave birth to a liveborn or stillborn infant during the period of January 2001 to December 2007.

Methods: Active smokers of different daily cigarette consumption (n=1646) were identified through maternal self-reporting. The reference group comprised 19,292 non-smoking women who delivered during the same period.

Main Outcome Measures: Birth weight, preterm delivery rate, fetal and neonatal mortality and morbidity, and congenital malformations.

Results: Preterm delivery rate was significantly higher in the smoking group compared with controls (22.2% vs. 12.4%, P<0.05), as was intrauterine fetal demise (1.4% vs. 0.3%, P<0.05). Newborns of active smokers were more likely to weigh less (3150±759 g vs. 3377±604 g, P<0.05), suffer from respiratory distress syndrome (2.5% vs. 1.3%, P<0.05), suffer from a cardiac malformation (1.5% vs. 0.8%, P<0.05), and die (neonatal death 1.2% vs. 0.6%, P<0.05). A dose-response relationship was demonstrated between levels of daily cigarette smoking and several adverse outcomes. Using multiple regression models, smoking was found to be an independent predictor of preterm delivery (odds ratios (OR) 1.9, 95% confidence intervals (95%CI) 1.6-2), and intrauterine fetal demise (OR 2.4, 95%CI 1.4-4.2).

Conclusion: Any amount of daily smoking appears to harm the fetus and newborn. As pregnancy may be a "window of opportunity" for behavioural changes, efforts to promote smoking cessation should be encouraged.
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http://dx.doi.org/10.1515/jpm-2014-0299DOI Listing
September 2015