Hematotoxicity of magnetite nanoparticles coated with polyethylene glycol: in vitro and in vivo studies

Accepted Manuscript.-- et al.Hematotoxicity of magnetite nanoparticles coated with dimercaptosuccinic acid (DMSA) and polyethylene glycol (PEG) has been evaluated by determining their safety in vitro and in vivo in a rat model up to 30 days after administration of a single dose. The in vitro analysis consists of global plasma coagulation (PT, aPTT, and fibrinogen) and platelet aggregation tests while the hematotoxicity studies in vivo include a complete blood count and the possible genotoxic effect analysis in the bone marrow hematopoietic function. Prolonged aPTT values indicate a higher anticoagulant effect for NP-DMSA compared with PEG-coated nanoparticles as a consequence of the higher surface charge of the former. The in vivo tests showed that these bioferrofluids do not cause genotoxic effects, affect erythropoiesis or increase the number of immature erythrocytes in the bone marrow at the analyzed dose. However, nanoparticle administration showed a significant effect on the leukocyte counts in animals treated with DMSA coated nanoparticles 24 h after injection. This response is not observed in animals treated with PEG modified nanoparticles which justifies the use of this polymer in biomasking strategies.L.M.A.A. acknowledges financial support from the Spanish Ministry of Science and Innovation FPI research grants. Technical support from the University Hospital Lozano Blesa, Zaragoza, Spain and from María Angeles Gracia, Ana Isabel Martínez de Ternero, Maria Rosa Borrell Sanz. AR holds a predoctoral fellowship from a CSIC-CITMA collaborative project (B01CU2009; ICMM, 2011–2014) and a short-term fellowship from CNPq (DTI-2; 383934/2013-3). This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (MAT2011-23641 and MAT2011-25991).Peer Reviewe

Circulating kisspeptin and anti-müllerian hormone levels, and insulin resistance in women with polycystic ovary syndrome: a systematic review, meta-analysis, and meta-regression

Objective: This systematic review and meta-analysis aimed to summarize the available evidence regarding circulating kisspeptin and anti-müllerian hormone (AMH) and the homeostasis model assessment of insulin resistance (HOMA-IR) index in adolescents and women with and without polycystic ovary syndrome (PCOS). Method: We performed a comprehensive literature search in Medline, Embase, Cochrane, Scopus, and Web of Science for studies evaluating circulating kisspeptin levels in women with and without PCOS published until September 24th, 2020. Co-primary outcomes were the HOMA-IR index and AMH. The quality of included studies was assessed using the Newcastle-Ottawa Scale. Random-effects models were used to estimate outcomes, and effects reported as mean difference (MD) or standardized MD (SMD) and their 95 % confidence interval (CI). The systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42020205030. Results: We evaluated 18 studies including, 1282 PCOS cases and 977 controls. Participants with PCOS were younger (MD = −2.38 years, 95 %CI -4.32 to -0.44), with higher BMI (MD = 1.16, 95 % CI 0.54–1.78), waist-to-hip ratio (MD = 0.04, 95 %CI 0.02 to 0.05), circulating kisspeptin (SMD = 1.15, 95 %CI 0.68–1.62), luteinizing hormone (SMD = 1.29, 95 %CI 0.76–1.83), AMH (SMD = 0.97, 95 %CI 0.60–1,34), total testosterone (SMD = 2.48, 95 %CI 1.73–3.23), free testosterone (SMD = 1.37, 95 %CI 0.56–2.17), and dehydroepiandrosterone sulphate (SMD = 0.72, 95 %CI 0.32–1.13) levels, and Ferriman-Gallwey score (SMD = 5.08, 95 %CI 2.76–7.39), and lower sex hormone-binding globulin level (SMD = −1.34, 95 %CI −2.15 to −0.52). Besides, participants with PCOS had higher HOMA-IR index (SMD = 0.76, 95 %CI 0.35–1.17), and circulating insulin (SMD = 0.75, 95 %CI 0.30–1.19), leptin (SMD = 2.82, 95 %CI 1.35–4.29), and triglycerides (SMD = 2.15, 95 %CI 1.08–3.23) levels than participants without the syndrome. The meta-regression did not identify significant factors influencing circulating kisspeptin. Conclusion: Patients with PCOS showed higher kisspeptin, LH, insulin, AMH, and androgen levels and HOMA-IR index, and lower sex hormone-binding globulin levels than those without the syndrome

Coronavirus disease 2019 (COVID-19) and human pregnancy: a scoping review

The coronavirus disease 2019 (COVID-19) is caused by the infection with a coronavirus (SARS-CoV-2). Pregnants present mild or moderate symptoms, with 5% presenting as a severe pneumonia. Prevalence and evolution of COVID-19 in pregnancy is similar to that of the general population, including the risk of maternal death. Radiography, computed tomography or ultrasound imaging are pivotal for the diagnosis and given the clinical suspicion of COVID-19 pneumonia. Lab findings include lymphocytopenia, thrombocytopenia, leukopenia, and the elevation of D-dimer and ferritin. To date, there is no specific treatment or vaccination for COVID-19; yet clinical management in pregnants is also similar to that of the general population, with prophylactic antibiotic treatment for bacterial pneumonia and oxygen support. Thromboprophylaxis should be indicated in severe cases, given that pregnancy is a hypercoagulable state that may be exacerbated by COVID-19. Hospital management should focus on treating the mother and protecting the newborn and the health personnel. Regarding COVID-19 and perinatal outcomes, premature deliveries are mainly associated to iatrogenic pregnancy termination through cesarean section aimed conserving maternal well-being. To date, vertical transmission to the fetus has not been demonstrated, neither intrauterine, nor through the birth canal. The virus has not been detected in vaginal fluids, or in breast milk. Breastfeeding may be allowed depending on maternal and neonatal health status. There are still many unknown issues, although there is a continuous update of scientific information related to pregnancy and COVID-19

Prediction of large for gestational age by ultrasound at 35 weeks and impact of ultrasound-delivery interval: Comparison of 6 standards

Objective: The aim of the study was to assess the predictive ability of the ultrasound estimated percentile weight (EPW) at 35 weeks to predict large for gestational age (LGA) at term delivery according to 6 growth standards, including population, population-customized, and international references. The secondary objectives were to determine its predictive ability to detect adverse perinatal outcomes (APOs) and whether the ultrasound-delivery interval influences the detection rate of LGA newborns. Methods: This was a retrospective cohort study of 9, 585 singleton pregnancies. Maternal clinical characteristics, fetal ultrasound data obtained at 35 weeks, and pregnancy and perinatal outcomes were used to calculate EPWs to predict LGAs at delivery according to the customized and the non-customized (NC) Miguel Servet University Hospital (MSUH), the customized Figueras, the NC Fetal Medicine Foundation (FMF), the NC INTERGROWTH-21st, and the NC World Health Organization (WHO) standards. Results: For a 10% false-positive rate, detection rates for total LGAs at delivery ranged from 31.2% with the WHO (area under the curve [AUC] 0.77; 95% confidence interval [CI], 0.76-0.79) to 56.5% with the FMF standard (AUC 0.85; 95% CI, 0.84-0.86). Detection rates and values of AUCs to predict LGAs by ultrasound-delivery interval (range 1-6 weeks) show higher detection rates as the interval decreases. APO detection rates ranged from 2.5% with the WHO to 12.6% with the Figueras standard. Conclusion: The predictive ability of ultrasound estimated fetal weight at 35 weeks to detect LGA infants is significantly greater for FMF and MSUH NC standards. In contrast, the APO detection rate is significantly greater for customized standards. The shorter ultrasound-delivery interval relates to better prediction rates

Personalized Model to Predict Small for Gestational Age at Delivery Using Fetal Biometrics, Maternal Characteristics, and Pregnancy Biomarkers: A Retrospective Cohort Study of Births Assisted at a Spanish Hospital

Small for gestational age (SGA) is defined as a newborn with a birth weight for gestational age < 10th percentile. Routine third-trimester ultrasound screening for fetal growth assessment has detection rates (DR) from 50 to 80%. For this reason, the addition of other markers is being studied, such as maternal characteristics, biochemical values, and biophysical models, in order to create personalized combinations that can increase the predictive capacity of the ultrasound. With this purpose, this retrospective cohort study of 12,912 cases aims to compare the potential value of third-trimester screening, based on estimated weight percentile (EPW), by universal ultrasound at 35–37 weeks of gestation, with a combined model integrating maternal characteristics and biochemical markers (PAPP-A and β-HCG) for the prediction of SGA newborns. We observed that DR improved from 58.9% with the EW alone to 63.5% with the predictive model. Moreover, the AUC for the multivariate model was 0.882 (0.873–0.891 95% C.I.), showing a statistically significant difference with EPW alone (AUC 0.864 (95% C.I.: 0.854–0.873)). Although the improvements were modest, contingent detection models appear to be more sensitive than third-trimester ultrasound alone at predicting SGA at delivery

Integrated study of factors affecting fetal weight in singleton pregnancies. Nomogram and development of basic and advanced fetal growth customized models

We have performed a multivariate analysis to explore the influence on birth and ultrasound fetal weight estimation of traditional factors as biochemical data and maternal characteristics in combination with non- traditionally explored predictors as paternal height, Pregnancy-associated plasma protein A (PAPP-A), single umbilical artery or Free-beta Human Chorionic Gonadotropin (fß- HCG). The study was performed for a Spanish population (region of Aragon) in singleton pregnancies at term (37-42 weeks). Also, we have created a nomogram and in order to predict the occurrence of SGA (small for gestational age) and LGA (large for gestational age) cases we provide a multivariate predictive model of fetal weight that have been compared with other models in the prediction of ultrasound and birth weights. After study we have created a software application for automated calculation of percentile fetal weight, adjusting the variables when they were significant

Risk factors for premature aging of placenta: comparative study of perinatal outcomes between grannum grade III placentas and grannum grade I-II placentas

Introduction: The placenta aging has been related with intrauterine fetal growth, low maternal age, Caucasian, multiparity, hypertensive states and smoking habit. Grannum P. classification is the most used for its assessment. The association between grade III placenta (G3P) and ex-smoking or smokeexposed pregnants has not been studied Main outcome: To asses if smoking, being an ex-smoker or a passive-smoker is a risk factor for developing grade III placenta, as well as if there is a smoking-free period of time to avoid the effect of smoking over placenta Material and methods: A retrospective case-control study of single pregnancies followed-up at the Obstetric Ultrasound Unit between January 2013 and January 2014. Placental grading according to Grannum classification was stablished through abdominal approach between 34-36 weeks of gestation and two groups were established: grade III placenta and grade I-II placenta (G1-2P) Maternal and paternal characteristics, type of delivery and perinatal outcomes were collected Results: Baseline characteristics were similar between the two groups. In G3P the incidence of hypertensive disease of pregnancy was higher(p=0,0107). The percentage was similar for premature birth, 1st and 5th minute Apgar, type of delivery and cesarean due to risk of loss of fetal wellbeing. A lower neonatal weight was found in G3P, at the same median days at delivery, with a mean difference of 148,156(p=0,008313. Regarding weight percentile, it was found a p35 in G3P and a p47,5 in G1- 2P(p=0,08235) 15% of the total pregnant were smokers. In G3P group it was found a higher frequency of smokers and ex-smokers since 1st trimester of pregnancy (p=0.0001), as well as pregnant non-smokers with an smoking partner(p=0,0001). There was an strong evidence for association between pregnant smokers and smoking partners(p=0,0001). No difference was found regarding to neonatal weight comparing smokers, ex-smokers and ex-smokers since 1st trimester of pregnancy. The length of pregnancy was lower between G3P pregnant smokers compared to G1-2P pregnant smokers, with a mean difference of 8 days (p=0,00091) Conclusions: There is a strong evidence for association between smoking during pregnancy, quitting smoking at the beginning of the pregnancy or being a passive smoker with development of G3P Some pregnant smokers don`t develop premature aging of placenta, it could be due to either other parameters or a later aging (data were collected between 34-36 weeks). The association between quitting smoking at the beginning of the pregnancy and not having a smoking partner reduces the risk of developing G3

Machine learning algorithms combining slope deceleration and fetal heart rate features to predict acidemia

Electronic fetal monitoring (EFM) is widely used in intrapartum care as the standard method for monitoring fetal well-being. Our objective was to employ machine learning algorithms to predict acidemia by analyzing specific features extracted from the fetal heart signal within a 30 min window, with a focus on the last deceleration occurring closest to delivery. To achieve this, we conducted a case–control study involving 502 infants born at Miguel Servet University Hospital in Spain, maintaining a 1:1 ratio between cases and controls. Neonatal acidemia was defined as a pH level below 7.10 in the umbilical arterial blood. We constructed logistic regression, classification trees, random forest, and neural network models by combining EFM features to predict acidemia. Model validation included assessments of discrimination, calibration, and clinical utility. Our findings revealed that the random forest model achieved the highest area under the receiver characteristic curve (AUC) of 0.971, but logistic regression had the best specificity, 0.879, for a sensitivity of 0.95. In terms of clinical utility, implementing a cutoff point of 31% in the logistic regression model would prevent unnecessary cesarean sections in 51% of cases while missing only 5% of acidotic cases. By combining the extracted variables from EFM recordings, we provide a practical tool to assist in avoiding unnecessary cesarean sections

Obstetric and perinatal outcomes of pregnancies with COVID 19: a systematic review and meta-analysis

Objective. This meta-analysis aimed at comparing obstetric and perinatal outcomes in laboratory-tested pregnant women for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection before delivering. Method. We performed a comprehensive systematic review of electronic databases for studies reporting pregnant women with and without SARS-CoV-2 infection, as determined by polymerase chain reaction (PCR) before delivery, during the pandemic period published up to June 25, 2021. Results are reported as mean difference (MD) or odds ratio (OR) and their 95% confidence interval (CI). Results. Seventeen observational studies with low to moderate risk of bias, reported on 2,769 pregnant women with a positive SARS-CoV-2 PCR test and 13,807 with a negative test. Pregnant women with a positive PCR test delivered at an earlier gestational age (MD −0.19; 95% CI −0.36 to −0.02 weeks), smoked less (OR 0.75; 95% CI 0.61–0.94) and were associated with higher odds for preeclampsia (OR 1.30; 95% CI 1.09–1.54), NICU admissions (OR 2.37; 95% CI 1.18–4.76), stillbirths (OR 2.70; 95% CI, 1.38–5.29), and perinatal mortality (OR 3.23; 95% CI 1.23–8.52). There were no significant differences between positive and negative tested women in terms of nulliparity, multiple pregnancies, gestational diabetes, route of delivery, labor induction, preterm birth, infant birth weight, 5 min Apgar scores < 7, small-for-gestational-age infants and fetal malformations. Eleven studies included neonatal PCR SARS-CoV-2 testing which was performed on 129 infants, of which 20 were positive. Conclusion. Positive SARS-CoV-2 tested pregnant women had higher odds for preeclampsia/hypertensive disorders of pregnancy, NICU admissions, stillbirths and perinatal mortality

Are congenital malformations more frequent in fetuses with intrahepatic persistent right umbilical vein? A comparative study

Objective Persistent right umbilical vein (PRUV) is a vascular anomaly where the right umbilical vein remains as the only conduit that returns oxygenated blood to the fetus. It has classically been described as associated with numerous defects. We distinguish the intrahepatic variant (better prognosis) and the extrahepatic variant (associated with worse prognosis). The objective of this study was to compare rates of congenital malformations in fetuses with intrahepatic PRUV (I-PRUV) versus singleton pregnancies without risk factors. Materials and Methods A multicenter, crossover design, comparative study was performed between 2003 and 2013 on fetuses diagnosed with I-PRUV (n = 56), and singleton pregnancies without congenital malformation risk factors (n = 4050). Results Fifty-six cases of I-PRUV were diagnosed (incidence 1:770). A statistically significant association between I-PRUV and the presence of congenital malformations (odds ratio 4.321; 95% confidence interval 2.15–8.69) was found. This positive association was only observed with genitourinary malformations (odds ratio 3.038; 95% confidence interval 1.08–8.56). Conclusion Our rate of malformations associated with I-PRUV (17.9%) is similar to previously published rates. I-PRUV has shown a significant increase in the rate of associated malformations, although this association has only been found to be statistically significant in the genitourinary system. Noteworthy is the fact that this comparative study has not pointed to a significant increase in the congenital heart malformation rate. Diagnosis of isolated I-PRUV does not carry a worse prognosis