Publications by authors named "Ronit Machtinger"

68 Publications

Pregnancy and neonatal outcomes of twin pregnancies - the role of maternal age.

J Perinat Med 2021 Feb 17. Epub 2021 Feb 17.

The Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan, Israel.

Objectives: We aim to study the association of maternal age with maternal and neonatal complications in twin pregnancies.

Methods: A retrospective cohort study of dichorionic-diamniotic twin pregnancies stratified into three groups according to maternal age ("A" <25, "B" 25-34 and "C" 35-44 years old). Outcome measures included pregnancy, delivery and neonatal complications. A sub-analysis of fertilization pregnancies only was conducted.

Results: Compared with younger women (groups A [n=65] and B [n=783]), older women [group C (n=392)] demonstrated significantly higher rates of gestational diabetes mellitus (B 6.6% vs. A 0%, p =0.027, C 10.2% vs. B 6.6%, p =0.032), were more likely to undergo cesarean deliveries (C 66.6%, B 57.6%, A 52.3%, p =0.007), and were at increased risk of having more than 20% difference in weight between the twins (C 24.5%, B 17.4%, A 16.9%, p =0.013). Other outcomes, including preeclampsia, did not differ between the groups. A sub-analysis of the fertilization only pregnancies was performed. Compared with younger women (groups A [n=18] and B [n=388]), older women (group C [n=230]) underwent more cesarean deliveries (p=0.004), and had more than 20% difference in weight between the twins (p<0.004). Other outcomes, including gestational diabetes mellitus rates and preeclampsia, did not differ between the groups.

Conclusions: Women at advanced maternal age with dichorionic twin pregnancies had significantly higher rates of gestational diabetes mellitus, cesarean deliveries and fetal weight discordancy as compared with younger women. In contrast, the incidence of preeclampsia was not affected by maternal age.
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http://dx.doi.org/10.1515/jpm-2020-0386DOI Listing
February 2021

Extracellular vesicles and female reproduction.

J Assist Reprod Genet 2021 Mar 20;38(3):549-557. Epub 2021 Jan 20.

Environmental Precision Biosciences Laboratory, Columbia University, Mailman School of Public Health, New York, NY, USA.

Extracellular vesicles (EVs) are nano-sized membrane bound complexes that have been identified as a mean for intercellular communication between cells and tissues both in physiological and pathological conditions. These vesicles contain numerous molecules involved in signal transduction including microRNAs, mRNAs, DNA, proteins, lipids, and cytokines and can affect the behavior of recipient cells. Female reproduction is dependent on extremely fine-tuned endocrine regulation, and EVs may represent an added layer that contributes to this regulation. This narrative review article provides an update on the research of the role of EVs in female reproduction including folliculogenesis, fertilization, embryo quality, and implantation. We also highlight potential pitfalls in typical EV studies and discuss gaps in the current literature.
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http://dx.doi.org/10.1007/s10815-020-02048-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910356PMC
March 2021

Cord blood androgen levels of females from same sex and opposite sex twins - A pilot study.

Clin Endocrinol (Oxf) 2021 Jan 30;94(1):85-89. Epub 2020 Nov 30.

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Israel.

Objective: Opposite-sex twins have shown behavioural and reproductive differences between females and males. These differences may be determined by higher intrauterine levels of androgens among females that were exposed to a male co-twin. The aim of this study was to compare cord blood androgen levels in females from same-sex and opposite-sex twins.

Design: A prospective study. In this pilot study, we compared cord blood androgens (DHEA-S, Δ-4 androstenedione, total testosterone-TT) and sex hormone-binding globulin (SHBG) levels in 20 females from same sex and 20 females from opposite-sex dichorionic diamniotic twins. We used generalized estimating equation (GEE) modelling to assess differences in cord blood androgens between females from same-sex twin pregnancies and females from opposite-sex twin pregnancies.

Patients: Twenty opposite-sex twin pairs (female-male twins) and 20 same-sex twin pairs (female-female).

Measurements: Cord blood total testosterone, Δ-4 androstenedione, DHEA-S and sex hormone-binding globulin (SHBG) levels.

Results: No difference in the levels of androgens as Δ-4 androstenedione, total testosterone and SHBG was identified between females that were exposed to a female co-twin compared with females that were exposed to a male co-twin. DHEA-S levels were significantly lower among females from opposite-sex twins compared with females from same-sex twins.

Conclusions: Our preliminary data do not support the hypothesis that females exposed to male co-twins are exposed to higher levels of androgens in utero compared with females exposed to female co-twins. Further studies are needed to explain the reported behavioural and reproductive differences among opposite-sex twins.
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http://dx.doi.org/10.1111/cen.14317DOI Listing
January 2021

Machine learning vs. classic statistics for the prediction of IVF outcomes.

J Assist Reprod Genet 2020 Oct 11;37(10):2405-2412. Epub 2020 Aug 11.

Department of Obstetrics and Gynecology, Sheba Medical Center, 52561, Ramat Gan, Israel.

Purpose: To assess whether machine learning methods provide advantage over classic statistical modeling for the prediction of IVF outcomes.

Methods: The study population consisted of 136 women undergoing a fresh IVF cycle from January 2014 to August 2016 at a tertiary, university-affiliated medical center. We tested the ability of two machine learning algorithms, support vector machine (SVM) and artificial neural network (NN), vs. classic statistics (logistic regression) to predict IVF outcomes (number of oocytes retrieved, mature oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births) based on age and BMI, with or without clinical data.

Results: Machine learning algorithms (SVM and NN) based on age, BMI, and clinical features yielded better performances in predicting number of oocytes retrieved, mature oocytes, fertilized oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births, compared with logistic regression models. While accuracies were 0.69 to 0.9 and 0.45 to 0.77 for NN and SVM, respectively, they were 0.34 to 0.74 using logistic regression models.

Conclusions: Our findings suggest that machine learning algorithms based on age, BMI, and clinical data have an advantage over logistic regression for the prediction of IVF outcomes and therefore can assist fertility specialists' counselling and their patients in adjusting the appropriate treatment strategy.
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http://dx.doi.org/10.1007/s10815-020-01908-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550518PMC
October 2020

Outcome of two sequential singleton pregnancies and twin pregnancies among primiparous women at advanced age undergoing IVF.

Arch Gynecol Obstet 2020 11 18;302(5):1113-1119. Epub 2020 Jul 18.

The Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan, Israel.

Purpose: To compare the obstetrical and detailed neonatal outcomes of primipara of advanced maternal age conceiving two sequential singleton pregnancies by IVF with those of primipara conceiving twins by IVF.

Methods: A retrospective study of all primiparous women aged ≤ 38 years and conceived by IVF who delivered sequential singletons or delivered twins at a single tertiary university affiliated medical center between 2011 and 2019. We performed two main comparisons: 1. First vs. second singleton pregnancies. 2. Two singleton pregnancies vs. twin pregnancies.

Results: Overall, there were 63 women with consecutive singleton IVF pregnancies. The median age was 40.0 at first pregnancy and 42.0 in the second pregnancy. Pregnancy and delivery complications rates did not differ significantly between the first and the second singleton pregnancies, including gestational hypertensive disorders (7 (11.1%) vs. 4 (6.3%), p = 0.530), gestational diabetes mellitus (13 (20.6%) vs 18 (28.5%), p = 0.410), intrauterine growth restriction (6 (9.5%) vs. 4 (6.3%), p = 0.744), or cesarean delivery (25 (39.7%) vs. 29 (46%), p = 0.589). Rates of delivery before 32 weeks gestation were similar for both first and second singleton pregnancies (1.6%, p > 0.999). The proportion of neonatal adverse outcome in both first and second singleton pregnancies groups was low and did not differ between the groups. Compared with women who delivered sequential singletons, women with twin pregnancies had significantly higher cesarean delivery rates (113 (83.7%) vs. 29 (46%), p < 0.001) and lower gestational ages at delivery (36.2 vs. 38.4, p < 0.001) than women with two singleton deliveries. Adverse neonatal outcomes were significantly higher for twin pregnancies, including birthweight < 1500 g (17 (12.6%) vs. 2 (3.2%), p = 0.036), neonatal intensive care unit admission (57 (42.2%) vs. 4 (6.3%), p < 0.001), neonatal hypoglycemia (23 (17%) vs. 3 (4.8%), p = 0.017), and respiratory distress syndrome (14 (10.4%) vs. 1 (1.6%), p = 0.040). Length of neonatal hospitalization was significantly longer for twins (9 vs. 5 days, p < 0.001). The rate of gestational hypertensive disorders (preeclampsia and gestational hypertension) was similar between the groups, but the rates of severe preeclampsia trended higher among women who carried twins (8 (5.9%) vs. 0, p = 0.057).

Conclusions: Sequential singleton pregnancies at primipara women of advanced maternal age have an overall very good outcome, with no clinically significant difference between the pregnancies. In addition, their outcome is much better compared with twins.
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http://dx.doi.org/10.1007/s00404-020-05700-5DOI Listing
November 2020

Obstetric, neonatal and child development outcomes following assisted hatching treatment: a retrospective cohort study.

Gynecol Endocrinol 2021 Jan 27;37(1):41-45. Epub 2020 Apr 27.

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Ramat-Gan, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Assisted hatching (AH) involves artificial disruption of the zona pellucida prior to embryo transfer. The purpose of this study is to examine the safety of AH technique and its effect on obstetrical, perinatal and neonatal outcomes and risk of developmental delay. This is a retrospective cohort of ART cycles using laser AH technique. The study group consisted of 120 cases of AH cycles resulting in singleton pregnancies and live births compared with 113 control cases. A current phone questionnaire was conducted to assess child development in the first year of life. AH was not associated with increased risk for all obstetrical and perinatal outcomes examined including PPROM, gestational diabetes, hypertensive diseases of pregnancy, delivery by cesarean section, gestational age at delivery, low birth weight (LBW), preterm birth and neonatal Apgar score (>.05). No significant differences were observed between AH and control group in rates and risk of congenital malformations (5.8 vs. 4.4%, respectively, OR 1.33, 95% CI 0.41-4.34) and developmental delay (19.2 vs. 12.8%, respectively, OR 1.62, 95% CI 0.74-3.52). AH did not increase the risk of obstetrical and neonatal complications in singleton pregnancies, including congenital malformations and child developmental delay. AH may therefore be considered a safe method of ART.
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http://dx.doi.org/10.1080/09513590.2020.1756248DOI Listing
January 2021

Impact of the mode of conception on gestational hypertensive disorders at very advanced maternal age.

Reprod Biomed Online 2020 Feb 7;40(2):281-286. Epub 2019 Nov 7.

Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Research Question: To study gestational hypertensive disorders in oocyte donation pregnancies compared with other modes of conception at very advanced maternal age.

Design: A historical cohort study of all women aged 45-47 years who gave birth to singletons at a tertiary medical centre between March 2011 and May 2018, at 24 weeks' gestation or later. Pregnancy outcomes were compared between donor oocyte (IVF-OD), IVF using autologous oocytes (IVF-A) and naturally conceived pregnancies. A multivariate logistic regression was used to evaluate the association between the mode of conception and gestational hypertensive disorders.

Results: The final analysis included 159, 68 and 73 patients in the IVF-OD, IVF-A and natural conception groups, respectively. The rate of gestational hypertensive disorders was significantly higher among those who conceived by IVF compared with those who conceived naturally but did not differ between the two IVF groups (27.0% for IVF-OD, 19.1% for IVF-A, P = 0.204; 5.5% for natural conception, P < 0.001 and P = 0.013 compared with IVF-OD and IVF-A, respectively). The results remained similar in a multivariate logistic regression analysis. The rate of Caesarean deliveries was significantly higher in the IVF-OD and IVF-A groups compared with the natural conception group (83.6%, 70.6% and 37.0%, respectively, P < 0.001), but other pregnancy outcomes did not differ between the groups.

Conclusions: IVF pregnancies in the late fifth decade of life were associated with significantly higher rates of gestational hypertensive disorders compared with naturally conceived pregnancies. No difference existed between the two IVF groups. These results may highlight the impact of IVF itself on gestational hypertensive disorders at very advanced maternal age.
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http://dx.doi.org/10.1016/j.rbmo.2019.10.017DOI Listing
February 2020

Body mass index in relation to extracellular vesicle-linked microRNAs in human follicular fluid.

Fertil Steril 2019 08 27;112(2):387-396.e3. Epub 2019 May 27.

Department of Obstetrics and Gynecology, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel. Electronic address:

Objective: To study whether increased body mass index is associated with altered expression of extracellular vesicle microRNAs (EV-linked miRNAs) in human follicular fluid.

Design: Cross-sectional study.

Setting: Tertiary-care university-affiliated center.

Patient(s): One hundred thirty-three women undergoing in vitro fertilization (IVF) were recruited from January 2014 to August 2016.

Interventions(s): None.

Main Outcome Measure(s): EV-linked miRNAs were isolated from follicular fluid and their expression profiles were measured with the use of the Taqman Open Array Human miRNA panel. EV-linked miRNAs were globally normalized and inverse-normal transformed. Associations between body mass index (BMI) and EV-linked miRNA outcomes were analyzed by means of multivariate linear regression and principal component analysis.

Result(s): Eighteen EV-linked miRNAs were associated with an increase in BMI after adjusting for age, ethnicity, smoking status, and batch effects. Hsa-miR-328 remained significant after false discovery rate adjustments. Principal component analyses identified the first principal component to account for 40% of the variation in our EV-linked miRNA dataset, and adjusted linear regression found that the first principal component was significantly associated with BMI after multiple testing adjustments. Using Kyoto Encyclopedia of Genes and Genomes enrichment analyses, we predicted gene targets of EV-linked miRNA in silico and identified PI3K-Akt signaling, ECM-receptor interaction, focal adhesion, FoxO signaling, and oocyte meiosis pathways.

Conclusion(s): These results show that a 1-unit increase in BMI is associated with altered follicular fluid expression of EV-linked miRNAs that may influence follicular and oocyte developmental pathways. Our findings provide potential insight into a mechanistic explanation for the reduced fertility rates associated with increased BMI.
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http://dx.doi.org/10.1016/j.fertnstert.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663626PMC
August 2019

Supraphysiological Concentrations of Bisphenol A Alter the Expression of Extracellular Vesicle-Enriched miRNAs From Human Primary Granulosa Cells.

Toxicol Sci 2019 05;169(1):5-13

Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Bisphenol A (BPA) is a widely used chemical that has been detected in follicular fluid and associated with adverse reproductive effects. Granulosa cells have an important role in follicular growth and oocyte maturation, however, little is known about the biological mechanisms of BPA toxicity on human granulosa cells. In this study, we exposed primary granulosa cells to different concentrations of BPA (0, 20, 200, 2000, and 20 000 ng/ml) and used quantitative polymerase chain reaction to measure the expression levels of miRNAs enriched in extracellular vesicles (EV-enriched miRNAs), and cellular levels of selected target genes of differentially expressed EV-enriched miRNAs. We found that exposure to 20 000 ng/ml BPA was associated with decreased levels of EV-miR-27b-3p (FC = 0.58, p = .04) and increased levels of its biologically relevant target genes FADD (FC = 1.22, p = .01), IGF1 (FC = 1.59, p = .06), and PPARG (FC = 1.73, p = .001) as compared with the control. In addition, we observed that under the same exposure conditions, the expression levels of miR-27b-3p in granulosa cells were also downregulated (FC = 0.65, p = .03) as compared with the control. Our findings suggest that both cellular and extracellular changes in gene expression may mediate BPA toxicity in granulosa cells.
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http://dx.doi.org/10.1093/toxsci/kfz020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804414PMC
May 2019

An optimized model for hCG stimulation of human mural granulosa cell culture.

Reprod Biol 2019 Mar 17;19(1):67-74. Epub 2019 Jan 17.

IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Ovarian follicular development and ovulation in mammals is a highly-regulated process. Most of the current knowledge of ovarian processes was obtained from the studies of non-human models. Molecular studies on human ovarian processes suffer from lack of material and appropriate research tools. Mural granulosa cells (MGCs) culture is a major tool for studying the effect of different substances but a major problem for using these primary MGCs is their unresponsiveness to hCG stimulation at the time of oocyte retrieval. It is acceptable that MGCs regain responsiveness during days in culture but when the best time is and how to accelerate the regenerative process are unknown. The aim of the current study was to establish an optimized protocol which will provide a practical and efficient tool to examine the effect of LH/hCG on different downstream targets in luteinized MGCs. hCG effects were examined according to days in culture and hCG stimulation time. As read-out, we analyzed the gene expression of known hCG targets, protein production, and progesterone secretion. Our results show that with a daily medium exchange, the strongest effect was achieved already 4 days after seeding. On day 4, hCG stimulation triggers two major patterns of gene expression. Early induced genes were highly expressed 6-8 h after hCG, while 24 h of hCG stimulation was needed for late induced genes. Based on our results, we suggest daily medium exchange for 4 days before adding hCG and examine its effect 6 and 24 h later.
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http://dx.doi.org/10.1016/j.repbio.2019.01.002DOI Listing
March 2019

Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid.

Environ Int 2019 02 24;123:20-28. Epub 2018 Nov 24.

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan 52561 and, Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address:

Background: Phenols and phthalates are potential endocrine disrupting chemicals (EDCs) that are associated with adverse health outcomes. These EDCs dysregulate a number of biomolecules and pathways, including microRNAs. MicroRNAs can be carried in transport systems called extracellular vesicles (EVs) that are present in most biofluids. EVs in the follicular fluid, which fills the ovarian follicle and influences oocyte developmental competency, carry microRNAs (EV-miRNAs) that have been associated with In Vitro Fertilization (IVF) outcomes. However, it remains unclear whether EDCs affect EV-miRNAs in follicular fluid.

Objectives: This study sought to determine whether urinary concentrations of phenols and phthalates biomarkers are associated with EV-miRNAs expression in follicular fluid collected from women undergoing IVF treatment.

Methods: This cross-sectional study included 130 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. Participants provided urine samples during ovarian stimulation and on the day of oocyte retrieval. We assessed urinary concentrations of five phenols, eight phthalate metabolites, and one phthalate alternative metabolite. EV-miRNAs were isolated from follicular fluid and their expression profiles were measured using the TaqMan Open Array® Human microRNA panel. We fitted multivariable linear regression models and principal component analysis to examine associations between individual and molar sums of exposure biomarkers and EV-miRNAs.

Results: Of 754 miRNAs tested, we detected 133 EV-miRNAs in the microRNA array which expressed in at least 50% of the follicular fluid samples. After adjusting for multiple testing, we identified eight EV-miRNAs associated with individual phenols and phthalate metabolites, as well as molar ΣDEHP that met a q < 0.10 false-discovery rate (FDR) threshold. Hsa-miR-125b, hsa-miR-106b, hsa-miR-374a, and hsa-miR15b was associated with mono(2-ethylhexyl) phthalate concentrations, hsa-let-7c with concentrations mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of metabolites of di(2-ethylhexyl) phthalate, hsa-miR-24 with mono-n-butyl phthalate concentrations, hsa-miR-19a with cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH), and hsa-miR-375 with ethyl paraben concentrations. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, gene targets and pathways of these EV-miRNAs were predicted in silico and 17 KEGG FDR-significant pathways related to follicular development and oocyte competence were identified.

Conclusions: Our results show that urinary concentrations of select phenol and phthalate metabolites are correlated with altered EV-miRNAs expression in follicular fluid. These findings may provide insight regarding the molecular mechanisms underlying adverse effects of phenol and phthalate exposure on female fertility.
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http://dx.doi.org/10.1016/j.envint.2018.11.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343661PMC
February 2019

Extracellular microRNAs profile in human follicular fluid and IVF outcomes.

Sci Rep 2018 11 19;8(1):17036. Epub 2018 Nov 19.

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan, 52561, Israel.

Encapsulated microRNAs (i.e., miRNAs within the extracellular vesicles, i.e., EV-miRNAs) have been detected in follicular fluid in both animal and human studies and different profiles have been associated with IVF cycle characteristics. However, limited studies to date have investigated other IVF outcomes, including fertilization status and embryo quality on day three". In this cohort, we performed a cross-sectional analysis on 126 women who contributed follicular fluid from a single follicle during a single IVF cycle. One hundred and ninety-two EV-miRNAs were assessed by univariable fold-change and multivariable logistic regression analyses. Hsa-miR-92a and hsa-miR-130b, were over-expressed in follicular fluid samples from oocytes that failed to fertilize compared to those that were normally fertilized. Additionally, hsa-miR-888 was over-expressed and hsa-miR-214 and hsa-miR-454 were under-expressed in samples that resulted in impaired day-3 embryo quality compared to top-quality day-3 embryos. After adjusting for confounders as BMI, smoking and total motile sperm, associations of these EV-miRNAs remained significant. In-silico KEGG pathway analyses assigned the identified EV-miRNAs to pathways of follicular growth and development, cellular signaling, oocyte meiosis, and ovarian function. Our findings suggest that EV-miRNAs may play a role in pathways of ovarian function and follicle development, which could be essential for understanding the molecular mechanisms that could lead to a successful pregnancy and birth.
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http://dx.doi.org/10.1038/s41598-018-35379-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242846PMC
November 2018

Outcomes of singleton versus twin pregnancies in the fifth and sixth decades.

Eur J Obstet Gynecol Reprod Biol 2018 Dec 6;231:255-261. Epub 2018 Nov 6.

The Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Background: Pregnancies in the fifth and sixth decades of life have been increasing, but current data are limited regarding the outcomes of twin compared with singleton pregnancies in this age group and to twin pregnancies at younger age.

Objective: To compare obstetrical and neonatal outcomes of IVF conceived pregnancies, in twin gestations of women who were ≥45 years old at delivery to singletons at similar age and twin gestations at the age of <35 years, and to assess if the complications are mainly influenced by the very advanced maternal age or by the multifetal pregnancy.

Study Design: A retrospective cohort study from a single tertiary medical center of women aged ≥45 at delivery between March 2011 and January 2018 and women aged <35 at delivery with twin pregnancies that conceived by IVF. Exclusion criteria were spontaneous pregnancies or pregnancies after ovulation induction, monochorionic twin pregnancies, higher order multiple gestations, or women that underwent fetal reduction. Pregnancy, delivery, postpartum and neonatal outcomes were compared between singleton and twin pregnancies. Multivariate logistic regression was used to evaluate the association between twin pregnancies and adverse outcomes.

Results: Out of 67,355 deliveries, 612 were of women ≥45 years old, of whom 492 women conceived via IVF (395 singleton and 97 twin pregnancies). Of those, 60 women were ≥50 years old, 49 of them carried singleton and 11 carried twin pregnancies. Baseline characteristics were similar between groups. Women at the fifth and sixth decades with twins had significantly higher rates of preeclampsia (32.0% vs. 10.9%, p < 0.001), gestational diabetes mellitus (35.4% vs. 23.8%, p = 0.020), preterm deliveries <32 weeks of gestation (8.2% vs. 1.3%, p = 0.001), and fetal growth restriction (18.6% vs. 7.6%, p = 0.001) compared with singleton pregnancies at similar maternal age. After multivariate analysis adjusting for confounders, the odds ratio for the composite of preeclampsia, gestational hypertension, intrauterine fetal growth restriction, and placental abruption was 3.19 for twin compared with singleton pregnancies and 1.73 for gestational diabetes mellitus. Pregnancy complications among older women with twins were also significantly higher when compared with younger women with twins (<35 years old). Women in the fifth and sixth decades with twins had higher rates of cesarean deliveries (91.8% vs. 56.4%, p<0.001), gestational hypertension, preeclampsia, and gestational diabetes mellitus (10.3% vs. 4.2%., p=0.016; 32.0% vs. 6.2%, p<0.001; 35.1% vs. 8.1%, p<0.001, respectively) than the younger group carrying twins.

Conclusions: Twin pregnancies in the fifth and sixth decades carry significantly higher complications rate compared with singleton pregnancies at the same age and twin pregnancies at younger age.
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http://dx.doi.org/10.1016/j.ejogrb.2018.11.007DOI Listing
December 2018

Long-term outcome of MR-guided focused ultrasound treatment and laparoscopic myomectomy for symptomatic uterine fibroid tumors.

Am J Obstet Gynecol 2018 10 11;219(4):375.e1-375.e7. Epub 2018 Sep 11.

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Fibroid tumors are the most common benign tumors in women of reproductive age. Treatment is usually indicated for those who are symptomatic, with different techniques being used.

Objective: The purpose of this study was to compare the long-term outcome of laparoscopic myomectomy with magnetic resonance-guided focused ultrasound for symptomatic uterine fibroid tumors.

Study Design: A cohort study was conducted on all patients with symptomatic uterine fibroid tumors who were admitted to a single tertiary care center and treated operatively with laparoscopic myomectomy or treated conservatively with magnetic resonance-guided focused ultrasound from January 2012 until January 2017. Assessment for further interventions and sustained fibroid-associated symptoms was performed, with the use of the Uterine Fibroid Symptom and Quality of Life symptom severity score.

Results: One hundred fifty-four women met the inclusion criteria. Complete follow-up evaluation was achieved for 64 women who underwent laparoscopic myomectomy and for 68 women who were treated by magnetic resonance-guided focused ultrasound. Follow-up time was similar for the 2 groups (median, 31 months [interquartile range, 17-51 months] vs 36 months [interquartile range, 24-41]; P=.95). The rate of additional interventions was 5 (7.8%) and 9 (13.2%), respectively (P=0.312). Similarly, the Uterine Fibroid Symptom and Quality of Life symptom severity score questionnaire score at follow-up interviews revealed comparable median scores of 17 (interquartile range, 12-21) vs 17 (interquartile range, 13-22) for laparoscopic myomectomy and magnetic resonance-guided focused ultrasound, respectively (P=.439). Analysis of each of the symptoms separately (bleeding, changes in menstruation, abdominal pain, bladder activity, nocturia, fatigue) did not change these findings, nor did a multivariate analysis.

Conclusion: Satisfaction with long-term outcome and rate of reinterventions after magnetic resonance-guided focused ultrasound treatment or laparoscopic myomectomy for uterine fibroid tumors was comparable. Further larger randomized trials are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.ajog.2018.09.002DOI Listing
October 2018

Urinary concentrations of phthalate metabolites, bisphenols and personal care product chemical biomarkers in pregnant women in Israel.

Environ Int 2018 07 11;116:319-325. Epub 2018 May 11.

Department of Obstetrics and Gynecology, Sheba Medical Center, Derech Sheba Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Mounting evidence suggests possible adverse effects of intrauterine exposure to certain phenols and phthalates, two classes of endocrine disruptor chemicals, on the developing fetus, with consequences into later life. These findings have contributed to the replacement of some chemicals, such as di‑2‑ethylhexyl phthalate (DEHP) and bisphenol A (BPA), in consumer products. For the current study we quantified urinary concentrations of biomarkers of exposure among 50 pregnant women in Israel to several phthalates, bisphenols and personal care product chemicals, as well as DEHP and BPA alternatives. We detected 14 of the 31 biomarkers in more than 90% of the women. We detected biomarkers of 1,2‑cyclohexane dicarboxylic acid, diisononyl ester (DINCH), bisphenol S, and bisphenol F not as frequently (27-56%). This study is the first to evaluate exposure to triclosan, bisphenols, parabens, and phthalates and BPA alternatives among Israeli pregnant women.
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http://dx.doi.org/10.1016/j.envint.2018.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983044PMC
July 2018

Maternal Phthalate and Personal Care Products Exposure Alters Extracellular Placental miRNA Profile in Twin Pregnancies.

Reprod Sci 2019 02 24;26(2):289-294. Epub 2018 Apr 24.

2 Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Prenatal exposure to endocrine-disrupting chemicals (EDCs) exerts both short- and long-term adverse effects on the developing fetus. However, the mechanisms underlying these effects have yet to be uncovered. Maternal-fetal signaling is mediated in part by signaling molecules (eg, microRNAs [miRNAs]) contained in extracellular vesicles (EVs) that are released by the placenta into the maternal circulation. We investigated whether maternal exposure to the EDCs phthalates and personal care products alters the miRNA profile of placental-derived EVs circulating in maternal blood. Blood and urine samples from pregnant women with uncomplicated term dichorionic, diamniotic twin pregnancies were analyzed as part of a larger study investigating correlations between exposure of phthalate and personal care products and epigenetic alterations in twin pregnancies. We explored correlations between maternal urinary levels of 13 phthalate and 12 personal care products metabolites and the miRNA profile of placental EVs (EV-miRNAs) circulating in maternal blood. The expression of miR-518e was highest among women with high urinary levels of monobenzyl phthalate and methyl paraben. miR-373-3p was the least expressed in women exposed to high levels of methyl paraben, and miR-543 was significantly downregulated in women exposed to high levels of paraben metabolites, dichlorophenol metabolites, and triclosan. In conclusion, this pilot study reveals that prenatal exposure to EDCs is associated with altered profile of circulating placenta-derived EV-miRNAs. Further studies are needed to generalize these results to singleton pregnancies and to assess whether these alterations are associated with pregnancy complications.
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http://dx.doi.org/10.1177/1933719118770550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728564PMC
February 2019

Corrigendum: Bisphenol-A exposure and gene expression in human luteinized membrana granulosa cells in vitro.

Hum Reprod 2018 05;33(5):989

Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Hashomer 52561, Israel.

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http://dx.doi.org/10.1093/humrep/dey068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527049PMC
May 2018

Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure.

Toxicol Sci 2018 05;163(1):116-122

Department of Environmental Health Sciences, Columbia University, Mailman School of Public Health, New York City, New York, USA.

Phthalates are endocrine-disrupting chemicals that can cross the placenta and affect the fetal epigenome. Among various epigenetic regulators of gene expression, long noncoding RNAs (lncRNAs) are important players that may also be involved in the manifestation of endocrine-disrupting chemical toxicity. We sought to explore the association between maternal urinary phthalate metabolite concentrations and lncRNA expression in human placenta to better understand potential mechanisms through which lncRNAs participate in mediating phthalate toxicity. Ten patients with uncomplicated dichorionic diamniotic twin pregnancies at term were included in this study. Urinary (n = 10) and placenta samples (n = 20) were collected for all participants. Urinary samples were analyzed for 15 phthalate metabolites and 2 phthalate alternative metabolites. Real-time PCR arrays were used to identify and quantify 87 lncRNAs from the placental samples. We tested the Spearman correlation matrix to compare prenatal phthalate measures against placental lncRNA levels. lncRNA levels showed large variations across samples, with no significant differences in lncRNA expression within twin pairs. Mono-(carboxynonyl) phthalate demonstrated consistently strong correlations with most lncRNAs. The strongest correlation was observed between mono-hydroxyisobutyl phthalate and LOC91450 (Rspearman = 0.88, p < .001). This correlation remained significant after Bonferroni adjustment. Other strong correlations were observed between mono-isobutyl phthalate, DPP10 and HOTTIP (Rspearman = -0.91, p < .001). AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 were strongly correlated with the greatest number of phthalate metabolites. Further studies are needed to validate these results and understand if the altered expression of lncRNAs in human placenta has clinical significance.
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http://dx.doi.org/10.1093/toxsci/kfy013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917778PMC
May 2018

Comparison of effects of thawing entire donor sperm vial vs. partial thawing (shaving) on sperm quality.

J Assist Reprod Genet 2018 Apr 15;35(4):645-648. Epub 2018 Jan 15.

Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Ramat Gan, Israel.

Purpose: Partial thawing of a vial of cryopreserved sperm (shaving) is sometimes applied as a measure to preserve sperm for further use, particularly in cases of very restricted sperm quantity. However, mechanical violence may disrupt the sperm-wall and lead to impaired in-vitro fertilization (IVF) outcomes.

Material And Methods: In a retrospective case-control study at a tertiary, university-affiliated medical center, we compared the IVF/intracytoplasmic sperm injection (ICSI) outcomes of patients who used donor sperm following partial thawing (shaving) of the vial of cryopreserved sperm (n = 99) to a control group consisting of patients for whom the vial of sperm was completely thawed before use (n = 99).

Results: While no differences were observed in the rates of oocyte fertilization, the mean number of top-quality embryos (TQE) was significantly lower in the shaving group than in the complete thawing group (1.33 ± 0.17 vs. 1.87 ± 0.17, p < 0.02). Experimental analysis of aliquots from the same donors revealed significantly reduced motility in sperm samples that were shaved vs. fully thawed (6.5 vs. 37.1%, p < 0.001).

Conclusions: In cases in which available cryopreserved sperm samples are limited, shaving of the vial without thawing can be used but with caution and only when absolutely necessary. Further, large prospective studies are needed to better clarify whether there is post-thawing sperm damage and to compare IVF outcomes after these two thawing methods.
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http://dx.doi.org/10.1007/s10815-018-1115-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949108PMC
April 2018

Outcome of magnetic resonance-Guided focused ultrasound surgery (MRgFUS) for FIGO class 1 fibroids.

Eur J Obstet Gynecol Reprod Biol 2018 Feb 14;221:119-122. Epub 2017 Dec 14.

Department of Gynecology, Sheba Medical Center, Tel Hashomer, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: Intracavitary uterine fibroids and fibroids that distort the uterine cavity are associated with excessive vaginal bleeding and infertility. While intracavitary fibroids smaller than 4 cm are usually treated safely by operative hysteroscopy, larger fibroids may require multiple surgeries or more extensive surgery with possible damage to the integrity of the uterine wall. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive approach for treating uterine fibroids, mainly the intramural type. We present the outcome of MRgFUS treatment for intracavitary fibroids (FIGO class 1) in cases that could not be treated by hysteroscopy due to either fibroid size or patient refusal. (Canadian Task Force II-1).

Study Design: A retrospective cohort study from a single tertiary referral center. A total of 68 patients were treated by MRgFUS for symptomatic uterine fibroids from January 2013 to December 2016. Six of them had FIGO class 1 fibroids. Adverse effects and short- and long-term outcomes (quality of life issues and need for additional surgical intervention) were assessed during ambulatory clinic visits and by phone interviews.

Results: The mean ± SD fibroid volume on MRI screening was 86.3 ± 60.9 cm. Six of those patients underwent the procedure (mean age 40.5 ± 5.6 years, range 33-48). The follow-up duration was 24.1 ± 12.0 months. Four patients were not interested in future fertility and did not undergo additional treatment, while the two who planned to conceive underwent another surgical intervention (one underwent operative hysteroscopy after reduction of fibroid size and the other underwent laparoscopic myomectomy).

Conclusion: This preliminary study shows that MRgFUS can be a feasible treatment option for FIGO class 1 uterine fibroids. Shrinkage of fibroids by MRgFUS can obviate or facilitate subsequent surgical intervention in selected cases.
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http://dx.doi.org/10.1016/j.ejogrb.2017.12.025DOI Listing
February 2018

Correction to: Parma consensus statement on metabolic disruptors.

Environ Health 2017 12 6;16(1):130. Epub 2017 Dec 6.

Department of Neuroscience, University of Parma, Parma, Italy.

Correction: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".
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http://dx.doi.org/10.1186/s12940-017-0343-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719727PMC
December 2017

Urinary concentrations of biomarkers of phthalates and phthalate alternatives and IVF outcomes.

Environ Int 2018 02 20;111:23-31. Epub 2017 Nov 20.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Phthalates are a class of chemicals found in a large variety of consumer products. Available experimental and limited human data show adverse effects of some phthalates on ovarian function, which has raised concerns regarding potential effects on fertility. The aim of the current study was to determine whether urinary concentrations of metabolites of phthalates and phthalate alternatives are associated with intermediate and clinical in vitro fertilization (IVF) outcomes. We enrolled 136 women undergoing IVF in a Tertiary University Affiliated Hospital. Participants provided one to two urine samples per cycle during ovarian stimulation and before oocyte retrieval. IVF outcomes were abstracted from medical records. Concentrations of 17 phthalate metabolites and two metabolites of the phthalate alternative di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) were measured. Multivariable Poisson regression models with log link were used to analyze associations between tertiles of specific gravity adjusted phthalate or DINCH metabolites and number of total oocytes, mature oocytes, fertilized oocytes, and top quality embryos. Multivariable logistic regression models were applied to evaluate the association between tertiles of specific gravity adjusted phthalate or DINCH metabolites and probability of live birth. Urinary concentrations of the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) and the individual metabolites mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, and mono-2-ethyl-5-carboxypentyl phthalate were negatively associated with the number of total oocytes, mature oocytes, fertilized oocytes, and top quality embryos. Of the low molecular weight phthalates, higher monoethyl phthalate and mono-n-butyl phthalate concentrations were associated with significantly fewer total, mature, and fertilized oocytes. None of the urinary phthalate metabolite concentrations were associated with a reduced probability implantation, clinical pregnancy or live birth. Metabolites of DINCH were not associated with intermediate or clinical IVF outcomes. Our results suggest that DEHP may impair early IVF outcomes, specifically oocyte parameters. Additional research is needed to elucidate the potential effect of DEHP on female fertility in the general population.
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http://dx.doi.org/10.1016/j.envint.2017.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800972PMC
February 2018

Association between preconception maternal beverage intake and in vitro fertilization outcomes.

Fertil Steril 2017 12 3;108(6):1026-1033. Epub 2017 Oct 3.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Objective: To study whether maternal intake of beverage type affects IVF outcomes.

Design: A prospective study.

Setting: Tertiary, university-affiliated center.

Patient(s): Three hundred forty women undergoing IVF from 2014 through 2016 for infertility as well as for pregenetic diagnosis for autosomal recessive diseases were enrolled during ovarian stimulation and completed a questionnaire describing their usual beverage consumption.

Intervention(s): None.

Main Outcome Measure(s): IVF outcomes were abstracted from medical records. Total caffeine intake was estimated by summing the caffeine content for specific beverages multiplied by frequency of intake. Associations between specific types of beverages and IVF outcomes were analyzed using Poisson and logistic regression models adjusting for possible confounders.

Result(s): Higher intake of sugared soda was associated with lower total, mature, and fertilized oocytes and top-quality embryos after ovarian stimulation. Women who consumed sugared soda had, on average, 1.1 fewer oocytes retrieved, 1.2 fewer mature oocytes retrieved, 0.6 fewer fertilized oocytes, and 0.6 fewer top-quality embryos compared with women who did not consume sugared soda. Furthermore, compared with women who did not drink sugared soda, the adjusted difference in percent of cycles resulting in live birth for women consuming 0.1-1 cups/day and >1 cup/day were -12% and -16%, respectively. No associations were found between consumption of coffee, caffeine, or diet sodas and IVF outcome.

Conclusion(s): Sugared beverages, independent of their caffeine content, may be a bigger threat to reproductive success than caffeine and caffeinated beverages without added sugar.
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http://dx.doi.org/10.1016/j.fertnstert.2017.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716855PMC
December 2017

In Vitro Exposure of Human Luteinized Mural Granulosa Cells to Dibutyl Phthalate Affects Global Gene Expression.

Toxicol Sci 2017 Nov;160(1):180-188

Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel-Aviv University, Israel.

Exposure to dibutyl phthalate (DBP) is ubiquitous among women of reproductive age. Previous studies in animal models and in human cells in vitro have shown that exposure to DBP disrupts ovarian function. Here, we examined the effect of DBP on global gene expression in mural granulosa cells (MGCs) in vitro. Primary cultures of MGC obtained from 48 patients undergoing IVF were treated with increasing concentrations of DBP (0, 0.01, 0.1, 1, 10, or 100 µg/ml) for 48 h. Microarray analysis was used to identify genes exhibiting expression changes following DBP exposure. When compared with untreated cells, exposure to 100 µg/ml DBP resulted in significant differences in expression of 346 annotated genes (> 2-fold; q value < .05). Of them, 151 were upregulated and 195 downregulated. The main functional annotations affected by DBP were associated with cell cycle, mitosis, Rho GTPases, PLK1, Aurora B signaling pathways, and E2F-mediated regulation of DNA replication. No significant differences in gene expression were observed for the lower concentrations of DBP (0.01, 0.1, 1, and 10 µg/ml) compared with controls for both the microarray analysis and genes validated by quantitative real-time (qRT)-PCR. This study provides important molecular inputs on the effect of short-term DBP exposure on human MGCs in vitro. Our results indicate that acute treatment with high concentrations of DBP alters gene expression pathways mainly associated with the cell cycle.
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http://dx.doi.org/10.1093/toxsci/kfx170DOI Listing
November 2017

Susceptibility of human cumulus cells to bisphenol a In vitro.

Reprod Toxicol 2017 12 22;74:189-194. Epub 2017 Sep 22.

Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address:

Bisphenol A (BPA) is detectable in follicular fluid. However, the effect of BPA exposure on human cumulus cells (CC) that surround the oocyte and are crucial for oocyte competence has been largely unexplored. We exposed primary cultures of CC to increasing concentrations of BPA [0,0.002, 0.02 and 20μg/mL] and tested the effects of BPA on the expression of genes associated with apoptosis using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR); we also assessed the effect of BPA on apoptosis by staining with anti-caspase 3. Exposure to 20μg/mL BPA led to significantly decreased expression of CDC20, BUB1B and HAS2 (p<0.03), increased expression of TRIB3 and LUM (p≤0.005), and increased frequency of cells positive for anti-CASP3 (p=0.03), compared to control. Our results imply that BPA may lead to ovarian toxicity by increasing CC apoptosis and provide an important molecular mechanism for the effect of BPA on human CC in vitro.
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http://dx.doi.org/10.1016/j.reprotox.2017.09.008DOI Listing
December 2017

Extracellular microRNAs in follicular fluid and their potential association with oocyte fertilization and embryo quality: an exploratory study.

J Assist Reprod Genet 2017 Apr 10;34(4):525-533. Epub 2017 Feb 10.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Purpose: The purpose of this study is to determine the profile of extracellular microRNAs (exmiRNAs) in follicular fluid (FF) and explore their association with fertilization potential and embryo quality.

Methods: We collected FF from single follicles containing mature oocytes from 40 women undergoing IVF and we screened for the expression of 754 exmiRNAs in FF using the TaqMan OpenArray® qPCR platform. To determine the association of exmiRNAs and IVF outcomes, we compared their expression levels in FF samples that differ by fertilization status (normally, abnormally, and failed to fertilize) and embryo quality (top vs. non-top).

Results: We detected 207 exmiRNAs, of which miR-30d-5p, miR-320b, miR-10b-3p, miR-1291, and miR-720 were most prevalent. We identified four exmiRNAs with significant fold change (FC) when FF that contained normally fertilized was compared to failed to fertilize oocytes [miR-202-5p (FC = 1.82, p = 0.01), miR-206 (FC = 2.09, p = 0.04), miR-16-1-3p (FC = 1.88, p = 0.05), and miR-1244 (FC = 2.72, p = 0.05)]. We also found four exmiRNAs to be significantly differentially expressed in FF that yielded top quality versus non-top quality embryos [(miR-766-3p (FC = 1.95, p = 0.01), miR-663b (FC = 0.18, p = 0.02), miR-132-3p (FC = 2.45, p = 0.05), and miR-16-5p (FC = 3.80, p = 0.05)]. In-silico analysis revealed that several of these exmiRNAs are involved in pathways implicated in reproductive system diseases, organismal abnormalities, and organ development.

Conclusions: Our findings suggest that exmiRNAs in the follicular fluid can lead to downstream events that will affect fertilization and day 3 embryo morphology. We encourage further observational and experimental studies to confirm our findings and to determine the role of exmiRNAs in human reproduction.
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http://dx.doi.org/10.1007/s10815-017-0876-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401697PMC
April 2017

Outcome of gestational surrogacy according to IVF protocol.

J Assist Reprod Genet 2017 Apr 8;34(4):445-449. Epub 2017 Feb 8.

In Vitro Fertilization Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Israel.

Purpose: Surrogacy remains the only option for having a biologic child for a unique population of women with severe medical conditions. However, no study has looked at surrogacy outcome as a result of the type of ovarian stimulation of the intended mother [controlled ovarian stimulation (COH), modified natural cycle (MNC), and in vitro maturation (IVM)] for oocyte retrieval.

Methods: This is a retrospective study, including all intended mothers and gestational carriers in a tertiary, university affiliated, medical center, from 1998 to 2016.

Results: Fifty-two women underwent 252 oocyte retrieval cycles. The pregnancy outcome of 212 embryo transfer cycles (64 gestational carriers) was reviewed according to the origin of the embryo. The number of retrieved oocytes was significantly higher following COH (n = 132) compared with IVM (n = 58) and MNC cycles (n = 62) (p = 0.013 and p < 0.0001, respectively). Pregnancy rates for embryos transferred according to each protocol were similar. All pregnancies that ended in live births when oocytes from IVM cycles were used derived from transfers of retrieved mature and mixed mature and immature oocytes. Pregnancies that involved embryos derived solely from immature oocytes that further matured in vitro and were transferred to gestational carriers were unsuccessful.

Conclusions: MNC protocol is a good option to achieve pregnancy for intended mothers using gestational surrogacy who have contraindications to COH. The yield of IVM cycles in which immature oocytes are retrieved is inconclusive.
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http://dx.doi.org/10.1007/s10815-017-0877-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401698PMC
April 2017

Dibutyl phthalate impairs steroidogenesis and a subset of LH-dependent genes in cultured human mural granulosa cell in vitro.

Reprod Toxicol 2017 04 16;69:13-18. Epub 2017 Jan 16.

Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address:

Exposure to di-butyl phthalate (DBP) exerts negative effects on female fertility in animal models, but human studies remain limited. Here, the effects of DBP exposure on mural granulosa cell function were investigated in primary cultures from women undergoing in vitro fertilization. Cultured cells treated with various doses of DBP (0, 0.01μg/mL, 0.1μg/mL, 1μg/mL, 10μg/mL, or 100μg/mL) for 48h were assessed using enzyme-linked immunosorbent assay and qRT-PCR. Treatment with 100μg/mL DBP resulted in significantly lower 17β-estradiol and progesterone production (p<0.01). It also resulted in altered mRNA expression of steroidogenic, angiogenic, and epidermal growth factor-like growth factor genes: CYP11A1 (p<0.001), CYP19A1 (aromatase) (p<0.001), VEGF-A (p<0.02), BTC (p=0.009), and EREG (p=0.04). StAR expression was impaired after exposure to both 10 and 100μg/mL (p<0.03 and p<0.001, respectively). Our results indicate that in vitro exposure of granulosa cells to high doses of DBP alters cell functions.
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http://dx.doi.org/10.1016/j.reprotox.2016.12.007DOI Listing
April 2017

Bisphenol-A exposure and gene expression in human luteinized membrana granulosa cells in vitro.

Hum Reprod 2017 02 15;32(2):409-417. Epub 2016 Dec 15.

Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Hashomer 52561, Israel

Study Question: Does bisphenol-A (BPA) affect gene expression in human membrana granulosa cells (MGC)?

Summary Answer: In vitro, short exposure to supra-physiological concentrations of BPA alters human MGC gene expression.

What Is Known Already: Exposure to BPA may interfere with reproductive endocrine signaling. In vitro studies, mostly in animal models, have shown an inverse correlation between exposure to BPA and follicular growth, meiosis, and steroid hormone production in granulosa cells.

Study Design, Size, Duration: Primary cultures of MGC obtained from 24 patients undergoing IVF (for PGD, male factor infertility or unexplained infertility) were exposed to various concentrations of BPA (0, 0.02, 0.2, 2 or 20 µg/ml) for 48 h.

Participants/materials, Setting, Methods: The study was conducted in a university-affiliated hospital. Microarray analysis was used to identify genes exhibiting expression changes following BPA exposure. Genes significantly altered were identified based on changes greater than 2-fold relative to the control group (not treated by BPA) and a Student's t-test P-value <0.05. Statistical significance was adjusted for multiple comparisons using the Benjamini-Hochberg method. Alterations in the expression of genes that are involved in the enriched functional annotations altered by BPA at the concentration of 20 µg/ml were confirmed by real-time PCR.

Main Results And The Role Of Chance: A distinct pattern of gene expression was observed in primary cultures of MGC exposed to the highest BPA concentration compared with untreated cells. We identified 652 genes that exhibited at least 2-fold differences in expression after BPA exposure (all P < 0.05 versus untreated). These genes were significantly enriched for annotations related to cell cycle progression, segregation of chromosomes, steroid metabolism, apoptosis, lipid synthesis, oocyte maturation and chromosomal alignment. No significant changes in gene expression were found at the lower doses of BPA most relevant to human exposure.

Large Scale Data: N/A.

Limitations, Reasons For Caution: Human exposure to BPA in vivo occurs over long periods of time. In this in vitro model, cells were exposed to the chemical for 48 h only. Thus, the effects of BPA on the human follicle might be underestimated.

Wider Implications Of The Findings: As BPA exposure is ubiquitous, understanding the effects of the chemical on the ovary, specifically in women of reproductive age, has public health significance. The clinical evidence to date points to an association between BPA exposure and impaired IVF outcome, although not all studies have shown negative effects. Our study adds valuable mechanistic information showing that exposure to BPA alters granulosa cell gene expression at high and supra-physiological doses.

Study Funding/competing Interests: This study was supported by grant number 1936/12 from the ISF. The authors have nothing to disclose.
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http://dx.doi.org/10.1093/humrep/dew316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260419PMC
February 2017

Metabolism disrupting chemicals and metabolic disorders.

Reprod Toxicol 2017 03 17;68:3-33. Epub 2016 Oct 17.

University of Missouri, Department of Biological Sciences, Columbia, MO, USA.

The recent epidemics of metabolic diseases, obesity, type 2 diabetes(T2D), liver lipid disorders and metabolic syndrome have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence that other environmental factors may contribute to the rapid increase in the incidence of these metabolic diseases. This review will examine changes to the incidence of obesity, T2D and non-alcoholic fatty liver disease (NAFLD), the contribution of genetics to these disorders and describe the role of the endocrine system in these metabolic disorders. It will then specifically focus on the role of endocrine disrupting chemicals (EDCs) in the etiology of obesity, T2D and NAFLD while finally integrating the information on EDCs on multiple metabolic disorders that could lead to metabolic syndrome. We will specifically examine evidence linking EDC exposures during critical periods of development with metabolic diseases that manifest later in life and across generations.
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http://dx.doi.org/10.1016/j.reprotox.2016.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365353PMC
March 2017