Papers by Irit Szaingurten-Solodkin
American Journal of Perinatology, Dec 13, 2019
Objective Animal studies indicate a possible intrauterine immunological imprinting in pregnancies... more Objective Animal studies indicate a possible intrauterine immunological imprinting in pregnancies complicated by hypothyroidism. We aimed to evaluate whether exposure to maternal hypothyroidism during pregnancy increases the risk of long-term infectious morbidity of the offspring. Study Design A retrospective cohort study compared the long-term risk of hospitalization associated with infectious morbidity in children exposed and unexposed in utero to maternal hypothyroidism. Outcome measures included infectious diagnoses obtained during any hospitalization of the offspring (up to the age of 18 years). Results The study included 224,950 deliveries. Of them, 1.1% (n = 2,481) were diagnosed with maternal hypothyroidism. Children exposed to maternal hypothyroidism had a significantly higher rate of hospitalizations related to infectious morbidity (13.2 vs. 11.2% for control; odds ratio: 1.2; 95% confidence interval: 1.08–1.36; p = 0.002). Specifically, incidences of ear, nose, and throat; respiratory; and ophthalmic infections were significantly higher among the exposed group. The Kaplan–Meier curve indicated that children exposed to maternal hypothyroidism had higher cumulative rates of long-term infectious morbidity. In the Cox proportional hazards model, maternal hypothyroidism remained independently associated with an increased risk of infectious morbidity in the offspring while adjusting for confounders. Conclusion Maternal hypothyroidism during pregnancy is associated with significant pediatric infectious morbidity of the offspring.
Zygote, Feb 18, 2022
SummaryA time-lapse monitoring system provides a complete picture of the dynamic embryonic develo... more SummaryA time-lapse monitoring system provides a complete picture of the dynamic embryonic development process and simultaneously supplies extensive morphokinetic data. The objective of this study was to investigate whether the use of the morphokinetic parameter of time of starting blastulation (tSB) can improve the implantation rate of day-5 transferred blastocyst selected based on morphological parameters. In this retrospective study we analyzed the morphokinetics of 196 day-5 transferred blastocysts, selected solely based on morphological parameters. The interval time from intracytoplasmic sperm injection (ICSI) to time of starting blastocyst formation (tSB) was calculated for each embryo. The overall implantation rate of transferred blastocyst, selected based only on morphological parameters, was 49.2%. Implantation rate, determined retrospectively, was significantly higher (58.8% versus 42.6%, P = 0.02) for embryos with a short interval time to tSB (78–95.9 h) compared with embryos with a longer timeframe (96–114 h). Time of expanded blastocyst (tEB) post-ICSI was also significantly associated with implantation; however, this parameter was not available for all the embryos at time of transfer. When we tested only high ranked KIDScore day-3 sub-group embryos, the implantation rate was significantly higher in short interval time embryos compared with longer interval time embryos (62.2% vs. 45.5%, respectively, P = 0.02).These observations emphasize the importance of the timing of starting blastulation over blastocyst morphological parameters and may provide a preferable criterion for good morphology day-5 blastocyst selection.
American Journal of Perinatology, Feb 12, 2016
Objective To investigate whether patients with a history of preeclampsia have an increased risk o... more Objective To investigate whether patients with a history of preeclampsia have an increased risk of long-term ophthalmic complications. Study Design A population-based study comparing the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of preeclampsia. Results During the study period, a total of 103,183 deliveries met the inclusion criteria; 8.1% (n = 8,324) occurred in patients with a diagnosis of preeclampsia during at least one of their pregnancies. Patients with preeclampsia had a significantly higher incidence of long-term ophthalmic morbidity such as diabetic retinopathy and retinal detachment. In addition, a positive linear correlation was found between the severity of preeclampsia and the prevalence of future ophthalmic morbidities (0.3 vs. 0.5 vs. 2.2%, respectively). Kaplan-Meier survival curve indicated that women with preeclampsia had higher rates of total ophthalmic morbidity (0.2 vs. 0.4%, for no preeclampsia and with preeclampsia, respectively; odds ratio = 2.06, 95% confidence interval: 1.42-2.99; p < 0.001). In a Cox proportional hazards model, adjusted for confounders, a history of preeclampsia remained independently associated with ophthalmic complications. Conclusion Preeclampsia is an independent risk factor for long-term maternal ophthalmic morbidity, specifically diabetic retinopathy and retinal detachment. This risk is more substantial depending on the severity of the disease.
Glia, Apr 17, 2012
Microglia are myeloid-derived cells that colonize the central nervous system (CNS) at early stage... more Microglia are myeloid-derived cells that colonize the central nervous system (CNS) at early stages of development and constitute up to 20% of the glial populations throughout life. While extensive progress has been recently made in identifying the cellular origin of microglia, the mechanism whereby the cells acquire the unique ramified and quiescent phenotype within the CNS milieu remains unknown. Here, we show that upon co-culturing of either CD117 1 /Lin 2 hematopoietic progenitors or CD11c 1 bone marrow derived cells with organotypic hippocampal slices or primary glia, the cells acquire a ramified morphology concomitant with reduced levels of CD86, MHCII, and CD11c and up-regulation of the microglial cell-surface proteins CX 3 CR1 and Iba-1. We further demonstrate that the transforming growth factor beta (TGF-b) signaling pathway via SMAD2/3 phosphorylation is essential for both primary microglia and myeloid-derived cells in order to acquire their quiescent phenotype. Our study suggests that the abundant expression of TGF-b within the CNS during development and various inflammatory processes plays a key role in promoting the quiescent phenotype of microglia and may thus serve as a target for therapeutic strategies aimed at modulating the function of microglia in neurodegenerative diseases such as Alzheimer's and prion. V
Glia, Dec 1, 2009
In Alzheimer's disease, extracellular deposits of amyloid beta(1-42) (Abeta(1-42)) may in... more In Alzheimer's disease, extracellular deposits of amyloid beta(1-42) (Abeta(1-42)) may induce activation of microglial cells by releasing proinflammatory factors that contribute to the neurodegeneration process. Since the activation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) has been reported in inflammatory conditions, its role in primary rat microglial cell activated by aggregated Abeta(1-42) was elucidated. The results of the present study show that activation of microglia by 5 microM aggregated Abeta(1-42) (as evident by the amoeboid morphology and increased CD68 immunofluorescence reactivity) caused an immediate activation of cPLA(2)alpha, measured by its phosphorylated form and its specific activity, followed by a gradual elevation of its expression and activity during 24 h. Inhibition of cPLA(2)alpha expression and activity by the presence of 1 microM specific antisense resulted in a significant decrease in NADPH oxidase activity that releases superoxides, PGE(2) formation, iNOS expression, and NO production, indicating a major role for cPLA(2)alpha in the regulation of these inflammatory processes. NADPH oxidase activity, which is under cPLA(2)alpha regulation, was found to upregulate cPLA(2)alpha and COX-2 protein expression through the redox-sensitive NFkappaB activation as evident by its phosphorylation on Ser-536, resulting in increased PGE(2) formation. The secreted PGE(2) induced the synthesis of iNOS and the production of NO through the PKA-CREB pathway. Taken together, our results suggest that the response of cPLA(2)alpha to aggregated Abeta(1-42) is probably a key player in the oxidative stress present in AD, regulating potent oxidative agents: the production of superoxides by NADPH oxidase and NO formation by iNOS.
Prenatal Diagnosis, 2014
Background S100B is a brain damage biomarker. When measured immediately after birth, it reflects ... more Background S100B is a brain damage biomarker. When measured immediately after birth, it reflects neonatal brain damage following asphyxia. In this study, we used feticide as a novel model of fetal brain damage. We examined whether such damage is reflected by a rise in S100B in maternal blood before delivery. Methods Eight pregnant women were recruited between January and July 2012. Maternal blood samples were drawn before and after feticide at predetermined time points (0, 15, 30, 60, 120, and 240 min). S100B, lactate dehydrogenase, creatine kinase, and creatinine concentrations were measured by standard human ELISA and chemical analyzer. Results No significant difference was noted between S100B levels before and after feticide, neither in non-specific cell death markers (lactate dehydrogenase and creatine kinase), which remained within normal range. S100B ranged between 0.015-0.04 μg/L through all the predetermined time points. Conclusion No statistically significant differences were demonstrated in S100B levels before and after feticide.
Scientific Reports, Aug 21, 2020
eliahu Levitas 3 & iris Har-Vardi 3* the present study investigated the association between oocyt... more eliahu Levitas 3 & iris Har-Vardi 3* the present study investigated the association between oocyte zona pellucida shear modulus (ZpSM) and implantation rate (IR). Ninety-three oocytes collected from 38 in-vitro fertilization patients who underwent intracytoplasmic sperm injection were included in this case-control study. the Zp was modeled as an isotropic compressible hyperelastic material with parameter C 10 , which represents the ZpSM. computational methodology was used to calculate the mechanical parameters that govern Zp deformation. fifty-one developed embryos were transferred and divided into two groups-implanted and not implanted. Multivariate logistic regression analysis was performed to identify the association between ZpSM and iR while controlling for confounders. Maternal age and number of embryos per transfer were significantly associated with implantation. The IR of embryos characterized by C 10 values in the range of 0.20-0.40 kPa was 66.75%, while outside this range it was 6.70%. This range was significantly associated with implantation (p < 0.001). Geometric properties were not associated with implantation. Multivariate logistic regression analysis that controlled for relevant confounders indicated that this range was independently associated with implantation (adjusted OR 38.03, 95% confidence interval 4.67-309.36, p = 0.001). The present study suggests that ZPSM may improve the classic embryo selection process with the aim of increasing iR. The zona pellucida (ZP) is a non-cellular layer of glycoproteins surrounding the oocyte 1. Over the years, numerous studies have described an association between the physical state of a cell and its function or fate 2-5. One of the most studied physical properties of oocytes is zona hardening, resulting from cortical granule release during fertilization 6. This physical property, aimed to prevent polyspermy 6,7 , also occurs spontaneously in response to post-ovulatory aging, and results in poor fertilization rates 8-10. Furthermore, spontaneous zona hardening is associated with exposure to in-vitro culture conditions 11,12 that may consequently hinder the blastocyst's potential to hatch the ZP. Although many studies have investigated animal oocytes or embryos, their observations link physical parameters to fertilization and developmental potential and not to implantation potential. Several approaches have been described in the literature to measure the mechanic properties of the ZP 13 by oocyte indentation 14,15 , compression 16 , or aspiration 17,18. Based on these capabilities, two studies have used the physical inputs as selection criteria for embryos. Murayama et al. measured mouse ZP elasticity using a micro tactile sensor (MTS) system. They demonstrated specific changes in this elasticity during oocyte maturation, fertilization, and embryo development, and concluded that the MTS system can be applied to assisted reproductive technology (ART) to evaluate embryo quality 19. Yanez et al. studied the mechanistic properties of human and
American Journal of Obstetrics and Gynecology, 2018
characteristic (ROC) curves were constructed for biochemical markers and clinical prediction. Dis... more characteristic (ROC) curves were constructed for biochemical markers and clinical prediction. Disagreement between specialists was defined as a difference of 2 points or more in a given score. RESULTS: Of the 58 FGR cases included, 30 were complicated by adverse neonatal outcome (52%). The predictive values of the clinical assessments and of the bio-marker ratios are presented in the Table. Areas under the curve (AUCs)are presented in the Figure. Disagreement between specialists was identified in 19 cases-32%. In 18 (95%) of these cases the marker predicted outcome accurately. CONCLUSION: Maternal serum sFlt-1/PlGF ratio can substantially improve clinical prediction of adverse neonatal outcome in FGR management. Furthermore, these biochemical tools appear to have a unique role in cases of disagreement between MFM specialists managing these cases.
PLOS ONE, Feb 15, 2017
Introduction Research in animal models and preliminary clinical studies in humans support the use... more Introduction Research in animal models and preliminary clinical studies in humans support the use of pravastatin for the prevention of preeclampsia. However, its use during pregnancy is still controversial due to limited data about its effect on the human placenta and fetus. Methods In the present study, human placental cotyledons were perfused in the absence or presence of pravastatin in the maternal reservoir (PraM). In addition, placental explants were treated with pravastatin for 5, 24 and 72 h under normoxia and hypoxia. We monitored the secretion of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS) expression and activation and the fetal vasoconstriction response to angiotensin-II. Results The concentrations of PlGF, sFlt-1 and sEng were not significantly altered by pravastatin in PraM cotyledons and in placental explants compared to control. Under hypoxic conditions, pravastatin decreased sFlt-1 concentrations. eNOS expression was significantly increased in PraM cotyledons but not in pravastatin-treated placental explants cultured under normoxia or hypoxia. eNOS phosphorylation was not significantly affected by pravastatin. The feto-placental vascular tone and the fetal vasoconstriction response to angiotensin-II, did not change following exposure of the maternal circulation to pravastatin. Conclusion We found that pravastatin does not alter the essential physiological functions of the placenta investigated in the study. The relevance of the study lays in the fact that it expands the PLOS ONE |
American Journal of Obstetrics and Gynecology, 2016
OBJECTIVE: Leptin while known to regulate energy and glucose metabolism, has also been shown to i... more OBJECTIVE: Leptin while known to regulate energy and glucose metabolism, has also been shown to increase blood pressure (BP) through receptors in the hypothalamus. Pregnancy is a state of hyperleptinemia and of leptin resistance through decreased expression of receptors in the hypothalamus and decreased transport to the brain. Abnormally increased circulating leptin levels have been observed during pre-eclampsia. Given these associations, we hypothesize that leptin may have a role in the pathogenesis of preeclampsia. STUDY DESIGN: Wild-type mice were separated into non-pregnant (NP, n¼4), pregnant with saline pumps (P+S, n¼4), and pregnant with leptin pumps (P+L, n¼6) infusing 2.4 mcg/g/d with all mice being assessed for BP, body weight (BW), serum leptin, and urine protein. After delivery, each placenta was weighed and the pups measured for BW and length. A separate group of wild-type mice had intracerebroventricular (ICV) cannulation, and then were separated into ICV with saline (ICV P+S) versus ICV with leptin (ICV P+L) of 2mcg/day and were assessed for BP and BW. RESULTS: P+L had elevated leptin levels in the blood compared to NP (p < 0.001) and P+S (p < 0.001). P+S had elevated leptin levels compared to NP (p < 0.05). When compared to P+S, P+L had smaller placentas (p < 0.01), pups with lower BW (p < 0.05), and shorter length (p < 0.05). Urine protein levels were not statistically different between P+S and P+L. BP was not statistically different between the 3 experimental groups. However, when ICV leptin was given (ICV P+L), a significant increase in BP was observed compared to ICV P+S (p < 0.01). ICV leptin administration did not affect body weight gain compared to saline ICV administration (ICV P+S). CONCLUSION: Peripheral administration of leptin had a significant effect on placental weight and pup growth. However, only centrally administered leptin altered BP. Given known changes in leptin receptors and transport into the brain during pregnancy, our results suggest that the abnormal increase in leptin levels during preeclampsia may be involved in the pathogenesis of the disorder. While peripheral leptin may interfere with the placental and embryo growth, derangements in leptin transport into the brain in preeclamptic patients may affect blood pressure.
Reproductive Biomedicine Online, 2021
RESEARCH QUESTION Are obstetric and perinatal complications associated with morphokinetic paramet... more RESEARCH QUESTION Are obstetric and perinatal complications associated with morphokinetic parameters of embryo development? DESIGN This proof-of-concept pilot study included a retrospective analysis of embryo morphokinetic parameters of 85 live births following day 5 single blastocyst transfer. Kinetic variables included time interval (hours) from time of pronuclei fading (tPNf) to: time of 2 cells (tPNf-t2), 9 cells (tPNf-t9), morula (tPNf-tM), start of blastulation (tPNf-tSB), full blastocyst (tPNf-tB) and expanded blastocyst (tPNf-tEB). Multivariable logistic models were used to calculate the risk of perinatal complications after adjustment for confounders. RESULTS The mean interval of tPNf-tSB was significantly longer for newborns with congenital anomalies compared with healthy newborns (79.49 ± 5.78 versus 71.7 ± 6.3, respectively, P = 0.01) and for embryos of women who had gestational diabetes mellitus compared with normoglycemic women (76.56 ± 7.55 versus 71.5 ± 6.13, respectively, P = 0.015). The mean interval of tPNf-t9 was significantly longer for low-birthweight newborns compared with normal weight (49.25 ± 5.54 versus 45.47 ± 4.77, respectively, P = 0.01). Preterm delivery was associated with several longer intervals of cell divisions compared with delivery at term (tPNf-t5: 28.76 ± 3.13 versus 26.64 ± 2.40, respectively, P = 0.01; tPNf-t6: 30.10 ± 3.05 versus 27.68 ± 2.30, respectively, P < 0.001; tPNf-t7: 32.08 ± 4.11 versus 28.70 ± 2.67, respectively, P < 0.001; tPNf-t8: 34.75 ± 4.95 versus 30.70 ± 4.10, respectively, P < 0.001; tPNf-t9: 50.23 ± 5.87 versus 45.44 ± 4.67, respectively, P < 0.001). For each of the outcomes, the association remained significant after adjusting for confounders. CONCLUSION This study indicates that there may be a possible association between adverse perinatal outcomes and morphokinetic parameters. Larger studies are needed to establish this association.
Journal of Maternal-fetal & Neonatal Medicine, Nov 30, 2015
To investigate whether patients with a history of obesity during pregnancy have an increased risk... more To investigate whether patients with a history of obesity during pregnancy have an increased risk for subsequent long-term ophthalmic complications, after controlling for diabetes and preeclampsia. A population-based study compared the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of obesity during pregnancy. Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years. During the study period 106 220 deliveries met the inclusion criteria; 2.2% (n = 2353) occurred in patients with a diagnosis of obesity during at least one of their pregnancies. These patients had a significantly higher incidence of ophthalmic complications in total and specifically of diabetic retinopathy. Using a Kaplan-Meier survival curve, we found that patients with a history of obesity during pregnancy had a significantly higher cumulative incidence of ophthalmic complications. Using a Cox proportional hazards model, adjusted for confounders such as maternal age, preeclampsia and diabetes mellitus, we found obesity during pregnancy remained independently associated with ophthalmic complications (adjusted HR, 2.4; 95% CI, 1.4-4.2; p = 0.003). Obesity during pregnancy is an independent risk factor for long-term ophthalmic complications, and specifically diabetic retinopathy.
The Journal of Clinical Endocrinology and Metabolism, Apr 1, 2015
Context: Gestational diabetes mellitus (GDM) was found to be an independent risk factor for recur... more Context: Gestational diabetes mellitus (GDM) was found to be an independent risk factor for recurrent long-term type 2 diabetes mellitus, cardiovascular morbidity, and vascular endothelial dysfunction. However, data on the link between GDM and future risk for long-term maternal renal disease are limited. Objective: The purpose of this study was to investigate whether GDM poses a risk for subsequent long-term maternal renal morbidity. Design: A population-based noninterventional study compared the incidence of future renal morbidity in a cohort of women with and without previous GDM. Deliveries occurred during a 25-year period, with a mean follow-up duration of 11.2 years.
Archives of Gynecology and Obstetrics, Oct 3, 2017
morbidity compared to newborns without iSUA (7.6 vs 5.5%, p = 0.01). Using a Kaplan-Meier surviva... more morbidity compared to newborns without iSUA (7.6 vs 5.5%, p = 0.01). Using a Kaplan-Meier survival curve, newborns with iSUA had a significantly higher cumulative incidence of respiratory hospitalizations (log rank = 0.006). In the Cox model, while controlling for the maternal age, gestational age, and birthweight, iSUA at term was found to be an independent risk factor for long-term respiratory morbidity (adjusted HR = 1.39, 95% CI 1.08-1.81; p = 0.012). Conclusion Newborns with iSUA are at an increased risk for long-term respiratory morbidity.
American Journal of Perinatology, 2022
Objective: To determine whether maternal blood angiogenic factors in suspected-small-for-gestatio... more Objective: To determine whether maternal blood angiogenic factors in suspected-small-for-gestational-age-fetuses (sSGA) can predict critical adverse perinatal outcome (CAPO) and improve risk assessment. Methods: Women with singleton pregnancies diagnosed with sSGA, between 24 and 35 6/7 weeks’ gestation, were included. Clinical and sonographic comprehensive evaluations were performed at enrolment. Plasma angiogenic factors: soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), were obtained at diagnosis. In parallel, three attending maternal-fetal-medicine specialists predicted the risk (1-5 scale) of these pregnancies to develop CAPO, based on the clinical presentation. CAPOs were defined as: prolonged neonatal intensive care unit hospitalization, fetal or neonatal death, and major neonatal morbidity. Statistical analysis included sensitivity, specificity, positive and negative predictive values and receiver–operating characteristics (ROC) curves analyses....
American Journal of Perinatology, 2018
Objective Previous studies suggested maternal hypothyroidism during pregnancy to be associated wi... more Objective Previous studies suggested maternal hypothyroidism during pregnancy to be associated with cognitive impairment of the offspring. Scarce data exist regarding long-term endocrine health of the offspring. This study was aimed to assess whether children born to mothers with hypothyroidism during pregnancy are at an increased risk for long-term endocrine morbidity. Study Design A retrospective population-based cohort study compared long-term endocrine morbidity of children born between the years 1991 and 2014 to mothers with and without hypothyroidism. Multiple gestations, fetuses with congenital malformations, and women lacking prenatal care were excluded. Hospitalizations of the offspring up to the age of 18 years involving endocrine morbidity were evaluated according to a predefined set of ICD-9 codes. Kaplan–Meier's survival curves were used to compare the cumulative risk and a Cox multivariable model was used to adjust for confounders. Results During the study period, ...
American Journal of Obstetrics and Gynecology, 2018
PloS one, 2017
Research in animal models and preliminary clinical studies in humans support the use of pravastat... more Research in animal models and preliminary clinical studies in humans support the use of pravastatin for the prevention of preeclampsia. However, its use during pregnancy is still controversial due to limited data about its effect on the human placenta and fetus. In the present study, human placental cotyledons were perfused in the absence or presence of pravastatin in the maternal reservoir (PraM). In addition, placental explants were treated with pravastatin for 5, 24 and 72 h under normoxia and hypoxia. We monitored the secretion of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS) expression and activation and the fetal vasoconstriction response to angiotensin-II. The concentrations of PlGF, sFlt-1 and sEng were not significantly altered by pravastatin in PraM cotyledons and in placental explants compared to control. Under hypoxic conditions, pravastatin decreased sFlt-1 concentrations. e...
American Journal of Obstetrics and Gynecology, 2017
OBJECTIVE: Relaxin is a peptide hormone that allows vasodilation and plays an important role in t... more OBJECTIVE: Relaxin is a peptide hormone that allows vasodilation and plays an important role in the process of parturition. The
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Papers by Irit Szaingurten-Solodkin