Rinat Gabbay-Benziv

Birth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis.

Currently, 60 million women of reproductive age (18-44 years old) worldwide, and approximately 3 million American women have diabetes mellitus, and it has been estimated that this number will double by 2030. Pregestational diabetes mellitus (PGD) is a significant public health problem that increases the risk for structural birth defects affecting both maternal and neonatal pregnancy outcome. The most common types of human structural birth defects associated with PGD are congenital heart defects and central nervous system defects. However, diabetes can induce birth defects in any other fetal organ. In general, the rate of birth defects increases linearly with the degree of maternal hyperglycemia, which is the major factor that mediates teratogenicity of PGD. Stringent prenatal care and glycemic control are effective means to reduce birth defects in PGD pregnancies, but cannot reduce the incidence of birth defects to the rate of that is seen in the nondiabetic population. Studies in animal models have revealed that PGD induces oxidative stress, which activates cellular stress signalling leading to dysregulation of gene expression and excess apoptosis in the target organs, including the neural tube and embryonic heart. Activation of the apoptosis signal-regulating kinase 1 (ASK1)-forkhead transcription factor 3a (FoxO3a)-caspase 8 pathway causes apoptosis in the developing neural tube leading to neural tube defects (NTDs). ASK1 activates the c-Jun-N-Terminal kinase 1/2 (JNK1/2), which leads to activation of the unfolded protein response and endoplasmic reticulum (ER) stress. Deletion of the ASK1 gene, the JNK1 gene, or the JNK2 gene, or inhibition of ER stress by 4-Phenylbutyric acid abrogates diabetes-induced apoptosis and reduces the formation of NTDs. Antioxidants, such as thioredoxin, which inhibits the ASK1-FoxO3a-caspase 8 pathway or ER stress inhibitors, may prevent PGD-induced birth defects.

Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome

Apoptosis signal–regulating kinase 1 (ASK1) is activated by various stresses. The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response (UPR) that leads to ER stress. Deleting Ask1 abrogated diabetes-induced UPR by suppressing phosphorylation of inositol-requiring enzyme 1α (IRE1α), and double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) blocked the mitochondrial translocation of proapoptotic Bcl-2 members and ER stress. ASK1 participated in the IRE1α signalosome, and removing ASK1 abrogated the proapoptotic kinase activity of IRE1α. Ask1 deletion suppressed diabetes-induced IRE1α endoriboneclease activities, which led to X-box binding protein 1 mRNA cleavage, an ER stress marker, decreased expression of microRNAs, and increased expression of a miR-17 target, thioredoxin-interacting protein (Txnip), a thioredoxin binding protein, which enhanced ASK1 activation by disrupting the thioredoxin-ASK1 complexes. ASK1 is essential for the assembly and function of the IRE1α signalosome, which forms a positive feedback loop with ASK1 through Txnip. ASK1 knockdown in C17.2 neural stem cells diminished high glucose– or tunicamycin-induced IRE1α activation, which further supports our hypothesis that ASK1 plays a causal role in diabetes-induced ER stress and apoptosis.

Superoxide dismutase 2 overexpression alleviates maternal diabetes-induced neural tube defects, restores mitochondrial function and suppresses cellular stress in diabetic embryopathy

Pregestational diabetes disrupts neurulation leading to neural tube defects (NTDs). Oxidative stress resulting from reactive oxygen species (ROS) plays a central role in the induction of NTD formation in diabetic pregnancies. We aimed to determine whether mitochondrial dysfunction increases ROS production leading to oxidative stress and diabetic embryopathy. Overexpression of the mitochondrion-specific antioxidant enzyme superoxide dismutase 2 (SOD2) in a transgenic (Tg) mouse model significantly reduced maternal diabetes-induced NTDs. SOD2 overexpression abrogated maternal diabetes-induced mitochondrial dysfunction by inhibiting mitochondrial translocation of the pro-apoptotic Bcl-2 family members, reducing the number of defective mitochondria in neuroepithelial cells, and decreasing mitochondrial membrane potential. Furthermore, SOD2 overexpression blocked maternal diabetes-increased ROS production by diminishing dihydroethidium staining signals in the developing neuroepithelium, and reducing the levels of nitrotyrosine-modified proteins and lipid hydroperoxide level in neurulation stage embryos. SOD2 overexpression also abolished maternal diabetes-induced endoplasmic reticulum stress. Finally, caspase-dependent neuroepithelial cell apoptosis enhanced by oxidative stress was significantly reduced by SOD2 overexpression. Thus, our findings support the hypothesis that mitochondrial dysfunction in the developing neuroepithelium enhances ROS production, which leads to oxidative stress and endoplasmic reticulum (ER) stress. SOD2 overexpression blocks maternal diabetes-induced oxidative stress and ER stress, and reduces the incidence of NTDs in embryos exposed to maternal diabetes.

First trimester thyroid stimulating hormone as an independent risk factor for adverse pregnancy outcome

Abstract Purpose: Maternal thyroid gland dysfunction may adversely affect pregnancy outcome. We aimed to examine the association between subclinical thyroid dysfunction, both hypothyroidism and hyperthyroidism, to adverse pregnancy outcome. Materials and methods: Retrospective cohort study of all women with an available first trimester thyroid function testing and known pregnancy outcome, categorized to subclinical hypothyroidism, or hyperthyroidism and evaluated for complication during gestation and delivery. Results: Four thousand five hundred and four women were included in the final analysis – 3231 were euthyroid, 73 (1.6%) were categorized as subclinical hyperthyroidism and 1200 (26.6%) had subclinical hypothyroidism. Low thyroid-stimulating hormone (TSH) levels, i.e. subclinical hyperthyroidism, correlates with higher rates of placental abruption and extremely low birth weight, below 1500 g. Also, the risk for preterm delivery prior to 34 gestational weeks is higher among women with subclinical hypothyroidism, with greater risk among those with a higher TSH level. (OR 1.81, 95% CI 1.0–3.28 for TSH 2.5–4.0 mIU/L and OR 2.33, 95% CI 1.11–4.42 for those with TSH > 4 4.0 mIU/L). Conclusions: Subclinical hypothyroidism is associated with an increased risk for preterm delivery prior to 34 gestational weeks. Additionally, subclinical hyperthyroidism may also have a role in adverse pregnancy outcome – low birth weight and placental abruption – although this needs to be further explored.

Prediction of Small for Gestational Age: Accuracy of Different Sonographic Fetal Weight Estimation Formulas.

Objective: To compare the accuracy of various sonographic estimated fetal weight (sEFW) formulas for the prediction of small for gestational age (SGA) neonates. Methods: A retrospective analysis of 6,126 fetal biometrical measurements performed within 3 days of delivery. SGA prediction was evaluated for various sEFW formulas by calculating the sensitivity, specificity, positive/negative predictive value (PPV/NPV), likelihood ratio (+LR/-LR), overall accuracy and area under the receiver operating characteristic curve (AUC). Systematic error, random error, proportion of estimates >10% of birth weights, actual and absolute weight differences were compared between SGA and non-SGA neonates. Results: Overall, 638 (10.4%) neonates were SGA. There was considerable variation among formulas in sensitivity (mean ± SD, 62 ± 14.4%; range, 32.4-91.2), PPV (72.5 ± 10.7%; 45.8-95.6) and +LR (24.2 ± 10.9; 7.2-57.3), mild variation in specificity (96.6 ± 2.7%; 87.4-99.4), NPV (94.6 ± 5.3%; 72.2-98.9) and -LR (0.4 ± 0.1; 0.1-0.7) and minimal variation in AUC (mean, 0.93; range, 0.91-0.93). The majority of formulas had a lower accuracy for the SGA neonates, with systematic error and random error ranging from -4.2 to 14.3% and from 8.4 to 12.9% for SGA, and from -8.7 to 16.1% and from 7.2 to 10.5% for non-SGA, respectively. Conclusion: sEFW formulas differ in their accuracy for SGA prediction. In our population, the most accurate formula for SGA prediction was Hadlocks formula utilizing femur length, abdominal and head circumference.

Nomograms for Fetal Cardiac Ventricular Width and Right-to-Left Ventricular Ratio.

To establish nomograms for right ventricular (RV) and left ventricular (LV) widths and their ratio from 16 to 38 gestational weeks.

First trimester prediction of maternal glycemic status

Abstract Objective: To predict gestational diabetes mellitus (GDM) or normoglycemic status using first trimester maternal characteristics. Methods: We used data from a prospective cohort study. First trimester maternal characteristics were compared between women with and without GDM. Association of these variables with sugar values at glucose challenge test (GCT) and subsequent GDM was tested to identify key parameters. A predictive algorithm for GDM was developed and receiver operating characteristics (ROC) statistics was used to derive the optimal risk score. We defined normoglycemic state, when GCT and all four sugar values at oral glucose tolerance test, whenever obtained, were normal. Using same statistical approach, we developed an algorithm to predict the normoglycemic state. Results: Maternal age, race, prior GDM, first trimester BMI, and systolic blood pressure (SBP) were all significantly associated with GDM. Age, BMI, and SBP were also associated with GCT values. The logistic regression analysis constructed equation and the calculated risk score yielded sensitivity, specificity, positive predictive value, and negative predictive value of 85%, 62%, 13.8%, and 98.3% for a cut-off value of 0.042, respectively (ROC-AUC – area under the curve 0.819, CI – confidence interval 0.769–0.868). The model constructed for normoglycemia prediction demonstrated lower performance (ROC-AUC 0.707, CI 0.668–0.746). Conclusions: GDM prediction can be achieved during the first trimester encounter by integration of maternal characteristics and basic measurements while normoglycemic status prediction is less effective.

Retrospective case series examining the clinical significance of subjective fetal cardiac ventricular disproportion.

To evaluate fetal cardiac ventricular disproportion as a marker of cardiac anomalies.

Incorporating first trimester analytes to predict delivery of a large for gestational infant in women with impaired glucose tolerance.

Abstract Aim: To investigate first trimester maternal characteristics of women with impaired glucose tolerance that deliver large for gestational age (LGA) infants. Methods: Nested analysis from a prospective study of singleton pregnancies enrolled at first trimester. We studied women with an abnormal 1 h glucose challenge test that had normal follow-up oral glucose tolerance testing. Maternal characteristics, ultrasound parameters and serum analytes were stratified by subsequent delivery of an LGA infant. Parameters identified as significant on univariate analysis were used for a derivation of prediction by logistic regression. Odds ratio and prediction performance was determined using receiver operator curve (ROC) statistics. Results: A total of 33/114 (28.9%) women meeting the criteria delivered LGA infants. Maternal height (cm), and first trimester pregnancy-associated protein-A and free β-hCG (MoM) predicted delivery of an LGA infant (ROC area under curve 0.73; 95% CI 0.63–0.83). At a cutoff value of 0.172 the prediction rule achieved 91% sensitivity, 44% specificity, 41% positive predictive and 92% negative predictive value. Conclusion: Maternal height and first trimester high free β-hCG and PAPP-A levels may be used as predictors for delivery of LGA infants in women with impaired glucose tolerance.

Sonographic prediction of small and large for gestational age in breech-presenting fetuses

Abstract Introduction: To evaluate various sonographic estimated fetal weight (sEFW) formulas’ accuracy for small- and large-for-gestational age (SGA/LGA) prediction in breech-presenting fetuses. Materials and methods: A retrospective analysis of all ultrasound-based fetal biometrical measurements performed within 3 days of delivery in term pregnancies, in one medical center (2007–2014). Overall, 274 breech-presenting fetuses (study group) were compared to 274 vertex-presenting fetuses (control group) matched by gender, gestational age and birth weight. sEFW was calculated by six previously published formulas. Accuracy was compared utilizing systematic error and random error for every formula. Prediction precision of SGA and LGA was evaluated by calculating each formula’s sensitivity, specificity, +/− predictive value, and the area under the receiver-operating characteristic (ROC) curve (AUC). Results: Systematic error and random error varied greatly between formulas, ranging from −7.4% to 3.1%, 7.3% to 8.3% for the vertex-presenting fetuses and −8.9% to 1.9%, 7.9% to 8.6% for the breech-presenting fetuses, respectively. There was no statistical difference in small- or large-for-gestational age prediction parameters between the groups. The highest sensitivity and specificity for prediction was achieved by same formula regardless of presentation. Conclusion: In our cohort, overall accuracy was slightly superior among vertex-presenting fetuses without difference in prediction accuracy for small- and large-for-gestational age neonates.