The Prenatal Hypoxic Pathology Associated with Maternal Stress Predisposes to Dysregulated Expression of the chrna7 Gene and the Subsequent Development of Nicotine Addiction in Adult Offspring.

INTRODUCTION: Previous studies have shown that fetal hypoxia predisposes individuals to develop addictive disorders in adulthood. However, the specific impact of maternal stress, mediated through glucocorticoids and often coexisting with fetal hypoxia, is not yet fully comprehended. METHODS: To delineate the potential effects of these pathological factors, we designed models of prenatal severe hypoxia (PSH) in conjunction with maternal stress and prenatal intrauterine ischemia (PII). We assessed the suitability of these models for our research objectives by measuring HIF1α levels and evaluating the glucocorticoid neuroendocrine system. To ascertain nicotine dependence, we employed the conditioned place aversion test and the startle response test. To identify the key factor implicated in nicotine addiction associated with PSH, we employed techniques such as Western blot, immunohistochemistry, and correlational analysis between chrna7 and nr3c1 genes across different brain structures. RESULTS: In adult rats exposed to PSH and PII, we observed increased levels of HIF1α in the hippocampus (HPC). However, the PSH group alone exhibited reduced glucocorticoid receptor levels and disturbed circadian glucocorticoid rhythms. Additionally, they displayed signs of nicotine addiction in the conditioned place aversion and startle response tests. We also observed elevated levels of phosphorylated DARPP-32 protein in the nucleus accumbens (NAc) indicated compromised glutamatergic efferent signaling. Furthermore, there was reduced expression of α7 nAChR, which modulates glutamate release, in the medial prefrontal cortex (PFC) and HPC. Correlation analysis revealed strong associations between chrna7 and nr3c1 expression in both brain structures. CONCLUSION: Perturbations in the glucocorticoid neuroendocrine system and glucocorticoid-dependent gene expression of chrna7 associated with maternal stress response to hypoxia in prenatal period favor the development of nicotine addiction in adulthood.

Fetal chronic hypoxia does not affect urinary presepsin levels in newborns at birth.

OBJECTIVES: Early sepsis detection and diagnosis still constitutes an open issue since the accuracy of standard-of care parameters is biased by a series of perinatal factors including hypoxia. Therefore, we aimed at investigating the effect of fetal chronic hypoxia insult on urine levels of a promising new marker of sepsis, namely presepsin (P-SEP). METHODS: We conducted a prospective case-control study in 22 cases of early-intrauterine growth restriction (E-IUGR) compared with 22 small-for-gestational-age (SGA) newborns and 66 healthy controls. P-SEP urine samples were collected over the first 72 h from birth. Blood culture and C-reactive protein (CRP) blood levels were measured in E-IUGR and SGA infants. Perinatal standard monitoring parameters and main outcomes were also recorded. RESULTS: No significant urinary P-SEP differences (p>0.05, for all) were observed among studied groups. Moreover, no significant correlations (p>0.05, for both) between urinary P-SEP and blood CRP levels in both E-IUGR and SGA groups (R=0.08; R=0.07, respectively) were observed. CONCLUSIONS: The present results showing the lack of influence of fetal chronic hypoxia on urinary P-SEP levels offer additional data to hypothesize the possible use of urinary P-SEP measurement in neonates in daily clinical practice. Further multicenter prospective data are needed, including infants with early-onset sepsis.

Large-scale analysis of interobserver agreement and reliability in cardiotocography interpretation during labor using an online tool.

BACKGROUND: While the effectiveness of cardiotocography in reducing neonatal morbidity is still debated, it remains the primary method for assessing fetal well-being during labor. Evaluating how accurately professionals interpret cardiotocography signals is essential for its effective use. The objective was to evaluate the accuracy of fetal hypoxia prediction by practitioners through the interpretation of cardiotocography signals and clinical variables during labor. MATERIAL AND METHODS: We conducted a cross-sectional online survey, involving 120 obstetric healthcare providers from several countries. One hundred cases, including fifty cases of fetal hypoxia, were randomly assigned to participants who were invited to predict the fetal outcome (binary criterion of pH with a threshold of 7.15) based on the cardiotocography signals and clinical variables. After describing the participants, we calculated (with a 95% confidence interval) the success rate, sensitivity and specificity to predict the fetal outcome for the whole population and according to pH ranges, professional groups and number of years of experience. Interobserver agreement and reliability were evaluated using the proportion of agreement and Cohen's kappa respectively. RESULTS: The overall ability to predict a pH level below 7.15 yielded a success rate of 0.58 (95% CI 0.56-0.60), a sensitivity of 0.58 (95% CI 0.56-0.60) and a specificity of 0.63 (95% CI 0.61-0.65). No significant difference in the success rates was observed with respect to profession and number of years of experience. The success rate was higher for the cases with a pH level below 7.05 (0.69) and above 7.20 (0.66) compared to those falling between 7.05 and 7.20 (0.48). The proportion of agreement between participants was good (0.82), with an overall kappa coefficient indicating substantial reliability (0.63). CONCLUSIONS: The use of an online tool enabled us to collect a large amount of data to analyze how practitioners interpret cardiotocography data during labor. Despite a good level of agreement and reliability among practitioners, the overall accuracy is poor, particularly for cases with a neonatal pH between 7.05 and 7.20. Factors such as profession and experience level do not present notable impact on the accuracy of the annotations. The implementation and use of a computerized cardiotocography analysis software has the potential to enhance the accuracy to detect fetal hypoxia, especially for ambiguous cardiotocography tracings.

Prenatal Hypoxia Triggers a Glucocorticoid-Associated Depressive-like Phenotype in Adult Rats, Accompanied by Reduced Anxiety in Response to Stress.

Fetal hypoxia and maternal stress frequently culminate in neuropsychiatric afflictions in life. To replicate this condition, we employed a model of prenatal severe hypoxia (PSH) during days 14-16 of rat gestation. Subsequently, both control and PSH rats at 3 months old were subjected to episodes of inescapable stress to induce learned helplessness (LH). The results of the open field test revealed an inclination towards depressive-like behavior in PSH rats. Following LH episodes, control (but not PSH) rats displayed significant anxiety. LH induced an increase in glucocorticoid receptor (GR) levels in extrahypothalamic brain structures, with enhanced nuclear translocation in the hippocampus (HPC) observed both in control and PSH rats. However, only control rats showed an increase in GR nuclear translocation in the amygdala (AMG). The decreased GR levels in the HPC of PSH rats correlated with elevated levels of hypothalamic corticotropin-releasing hormone (CRH) compared with the controls. However, LH resulted in a reduction of the CRH levels in PSH rats, aligning them with those of control rats, without affecting the latter. This study presents evidence that PSH leads to depressive-like behavior in rats, associated with alterations in the glucocorticoid system. Notably, these impairments also contribute to increased resistance to severe stressors.

Construction of a ferroptosis and hypoxia-related gene signature in cervical cancer to assess tumour immune microenvironment and predict prognosis.

BACKGROUND: This study aimed to investigate the potential role of ferroptosis/hypoxia-related genes in cervical cancer to improve early management and treatment of cervical cancer. METHODS: All data were downloaded from public databases. Ferroptosis/hypoxia-related genes associated with cervical cancer prognosis were selected to construct a risk score model. The relationship between risk score and clinical features, immune microenvironment and prognosis were analysed. RESULTS: Risk score model was constructed based on eight signature genes. Drug prediction analysis showed that bevacizumab and cisplatin were related to vascular endothelial growth factor A. Risk score, as an independent prognostic factor of cervical cancer, had a good survival prediction effect. The two groups differed significantly in degree of immune cell infiltration, gene expression, tumour mutation burden and somatic variation. CONCLUSIONS: We developed a novel prognostic gene signature combining ferroptosis/hypoxia-related genes, which provides new ideas for individual treatment of cervical cancer.

Ferroptosis, hypoxia and immune regulation play important roles in cervical cancer progression. In this study, we developed a novel prognostic signature combining ferroptosis and hypoxia-related genes, which provides new ideas for individual treatment of cervical cancer patients. The risk score established by ferroptosis and hypoxia-related gene as an independent prognostic factor of cervical cancer has a good survival prediction effect. High and low risk groups showed significant differences in TIME, prognosis, biological metabolic pathway and tumour mutation burden. In addition, we found drugs associated with signature genes. In short, this study has laid a theoretical foundation for exploring the related molecular mechanisms and prognosis of cervical cancer. It also contributes to the exploration of clinical management and treatment.

Fetal monitoring technologies for the detection of intrapartum hypoxia - challenges and opportunities.

Intrapartum fetal hypoxia is related to long-term morbidity and mortality of the fetus and the mother. Fetal surveillance is extremely important to minimize the adverse outcomes arising from fetal hypoxia during labour. Several methods have been used in current clinical practice to monitor fetal well-being. For instance, biophysical technologies including cardiotocography, ST-analysis adjunct to cardiotocography, and Doppler ultrasound are used for intrapartum fetal monitoring. However, these technologies result in a high false-positive rate and increased obstetric interventions during labour. Alternatively, biochemical-based technologies including fetal scalp blood sampling and fetal pulse oximetry are used to identify metabolic acidosis and oxygen deprivation resulting from fetal hypoxia. These technologies neither improve clinical outcomes nor reduce unnecessary interventions during labour. Also, there is a need to link the physiological changes during fetal hypoxia to fetal monitoring technologies. The objective of this article is to assess the clinical background of fetal hypoxia and to review existing monitoring technologies for the detection and monitoring of fetal hypoxia. A comprehensive review has been made to predict fetal hypoxia using computational and machine-learning algorithms. The detection of more specific biomarkers or new sensing technologies is also reviewed which may help in the enhancement of the reliability of continuous fetal monitoring and may result in the accurate detection of intrapartum fetal hypoxia.

A sustained decrease in the systolic/diastolic ratio may be a sign of severe adverse events in the umbilical cord: a report of eight cases.

A high systolic/diastolic (S/D) ratio of umbilical cord blood is a manifestation of intrauterine hypoxia. However, the clinical significance of a persistently decreased S/D ratio of umbilical cord blood has not been reported. We report eight cases of a persistently decreased S/D ratio of umbilical cord blood, with two cases of umbilical thrombus, five cases of excessive torsion, and one case of a true cord knot. Fetuses with a persistently decreased S/D ratio of umbilical cord blood may be at risk, and it may be an important indication of umbilical cord lesions.

Successful management of fetal hypoxia due to amniotic banding at 26 weeks of pregnancy: A case report of a rare survival.

BACKGROUND: Amniotic banding is a rare condition that can lead to structural limb anomalies, fetal distress and adverse obstetric outcomes. The main hypothesis for its etiology is a rupture of the amniotic membrane in early pregnancy, with the formation of tightly entangling strands around the fetus. These strands can constrict, incise, and subsequently amputate limb parts, the neck or head. More rarely, the amniotic banding can affect the umbilical cord, leading to fetal distress or potential intra-uterine fetal demise. OBJECTIVE: We present a unique case of a 26-week pregnant woman who attended a polyclinical consultation due to reduced fetal movements with concerning cardiotocography (CTG) findings. A review of the literature about amniotic banding of the umbilical cord was conducted as well, identifying diagnostic and interventional options for the obstetrician's practice. STUDY DESIGN: This is a case report, alongside a review of the literature. RESULTS: The CTG indicated fetal distress, prompting an emergency caesarean section (C-section). Upon delivery, the neonate exhibited signs of amniotic band sequence, with distal phalangeal defects on the right hand and severe constriction of the umbilical cord caused by amniotic strands, the latter precipitating fetal hypoxia. Direct ultrasound diagnosis remains a challenge in the absence of limb amputation, yet indirect signs such as distal limb or umbilical doppler flow abnormalities and distal limb edema may be suggestive of amniotic banding. MRI is proposed as an adjuvant diagnostic tool yet does not present a higher detection rate compared to ultrasound. Fetoscopic surgery to perform lysis of the amniotic strands with favorable outcome has been described in literature. CONCLUSION: This case presents the first reported survival of an extremely preterm fetus in hypoxic distress as a cause of amniotic banding of the umbilical cord, with a rare degree of incidental timing. Ultrasound diagnosis remains the gold standard. Obstetrical vigilance is warranted, with fetal rescue proven to be feasible.

Machine learning on cardiotocography data to classify fetal outcomes: A scoping review.

INTRODUCTION: Uterine contractions during labour constrict maternal blood flow and oxygen delivery to the developing baby, causing transient hypoxia. While most babies are physiologically adapted to withstand such intrapartum hypoxia, those exposed to severe hypoxia or with poor physiological reserves may experience neurological injury or death during labour. Cardiotocography (CTG) monitoring was developed to identify babies at risk of hypoxia by detecting changes in fetal heart rate (FHR) patterns. CTG monitoring is in widespread use in intrapartum care for the detection of fetal hypoxia, but the clinical utility is limited by a relatively poor positive predictive value (PPV) of an abnormal CTG and significant inter and intra observer variability in CTG interpretation. Clinical risk and human factors may impact the quality of CTG interpretation. Misclassification of CTG traces may lead to both under-treatment (with the risk of fetal injury or death) or over-treatment (which may include unnecessary operative interventions that put both mother and baby at risk of complications). Machine learning (ML) has been applied to this problem since early 2000 and has shown potential to predict fetal hypoxia more accurately than visual interpretation of CTG alone. To consider how these tools might be translated for clinical practice, we conducted a review of ML techniques already applied to CTG classification and identified research gaps requiring investigation in order to progress towards clinical implementation. MATERIALS AND METHOD: We used identified keywords to search databases for relevant publications on PubMed, EMBASE and IEEE Xplore. We used Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Reviews (PRISMA-ScR). Title, abstract and full text were screened according to the inclusion criteria. RESULTS: We included 36 studies that used signal processing and ML techniques to classify CTG. Most studies used an open-access CTG database and predominantly used fetal metabolic acidosis as the benchmark for hypoxia with varying pH levels. Various methods were used to process and extract CTG signals and several ML algorithms were used to classify CTG. We identified significant concerns over the practicality of using varying pH levels as the CTG classification benchmark. Furthermore, studies needed to be more generalised as most used the same database with a low number of subjects for an ML study. CONCLUSION: ML studies demonstrate potential in predicting fetal hypoxia from CTG. However, more diverse datasets, standardisation of hypoxia benchmarks and enhancement of algorithms and features are needed for future clinical implementation.

Computer Vision for Identification of Increased Fetal Heart Variability in Cardiotocogram.

INTRODUCTION: Increased fetal heart rate variability (IFHRV), defined as fetal heart rate (FHR) baseline amplitude changes of >25 beats per minute with a duration of ≥1 min, is an early sign of intrapartum fetal hypoxia. This study evaluated the level of agreement of machine learning (ML) algorithms-based recognition of IFHRV patterns with expert analysis. METHODS: Cardiotocographic recordings and cardiotocograms from 4,988 singleton term childbirths were evaluated independently by two expert obstetricians blinded to the outcomes. Continuous FHR monitoring with computer vision analysis was compared with visual analysis by the expert obstetricians. FHR signals were graphically processed and measured by the computer vision model labeled SALKA. RESULTS: In visual analysis, IFHRV pattern occurred in 582 cardiotocograms (11.7%). Compared with visual analysis, SALKA recognized IFHRV patterns with an average Cohen's kappa coefficient of 0.981 (95% CI: 0.972-0.993). The sensitivity of SALKA was 0.981, the positive predictive rate was 0.822 (95% CI: 0.774-0.903), and the false-negative rate was 0.01 (95% CI: 0.00-0.02). The agreement between visual analysis and SALKA in identification of IFHRV was almost perfect (0.993) in cases (N = 146) with neonatal acidemia (i.e., umbilical artery pH <7.10). CONCLUSIONS: Computer vision analysis by SALKA is a novel ML technique that, with high sensitivity and specificity, identifies IFHRV features in intrapartum cardiotocograms. SALKA recognizes potential early signs of fetal distress close to those of expert obstetricians, particularly in cases of neonatal acidemia.

EUROPEAN ASSOCIATION OF PERINATAL MEDICINE (EAPM) Position statement: Use of appropriate terminology for situations related to inadequate fetal oxygenation in labor.

In high-resource countries, adverse perinatal outcomes are currently rare in term, non-malformed fetuses, undergoing labor, but they remain a leading cause of medico-legal dispute. Precise terminology is important to describe situations related to inadequate fetal oxygenation in labor, to ensure appropriate communication between healthcare professionals and adequate transmission of information to parents. This position statement provides consensus definitions from European perinatologists and midwives regarding the most appropriate terminology to describe situations related to inadequate fetal oxygenation in labor: suspected fetal hypoxia, severe newborn acidemia, newborn metabolic acidosis, and hypoxic-ischemic encephalopathy. It also identifies terms that are imprecise or nonspecific to this situation, and should therefore be avoided by healthcare professionals: fetal well-being, fetal stress, fetal distress, non-reassuring fetal state, and birth asphyxia.

Umbilical Cord pH Levels and Neonatal Morbidity and Mortality.

Importance: Umbilical cord pH (UC-pH) level is an important objective indicator of intrapartum fetal hypoxia and is used to predict neonatal morbidity and mortality. A UC-pH value of less than 7.00 is often defined as a threshold for severe acidosis, but existing evidence is divergent and largely based on UC-pH measurements from selected populations; consequently, the results are challenging to interpret. Objective: To investigate the association between UC-pH levels and the risk of adverse neonatal outcomes in a national setting with universal UC-pH measurement. Design, Setting, and Participants: This national, population-based cohort study included all liveborn, singleton, full-term infants without malformations born in Denmark from January 1, 2012, to December 31, 2018. Data were analyzed from January 1, 2023, to March 1, 2024. Exposure: Umbilical cord pH level categorized as less than 7.00, 7.00 to 7.09, 7.10 to 7.19 and 7.20 to 7.50 (reference group). Main Outcomes and Measures: The primary outcome was a composite of severe adverse neonatal outcomes: neonatal death, therapeutic hypothermia, mechanical ventilation, treatment with inhaled nitric oxide, or seizures. Secondary outcomes were individual components of the primary outcome, Apgar score, respiratory outcomes, and hypoglycemia. Data are presented as adjusted risk ratios (ARRs) with 95% CIs. Results: Among the 340 431 infants included, mean (SD) gestational age was 39.9 (1.6) weeks; mean (SD) birth weight was 3561 (480) g; and 51.3% were male. Umbilical cord pH of less than 7.20 was observed more often among infants with a gestational age of 40 or 41 weeks (31.6%-33.6% compared with 18.2%-20.2% at a gestational age of 39 weeks) and among male infants (53.9%-55.4% vs 44.6%-46.1% among female infants). Compared with the pH reference group (576 of 253 540 [0.2%]), the risk for the primary outcome was increased for the groups with UC-pH levels of less than 7.00 (171 of 1743 [9.8%]), 7.00 to 7.09 (101 of 11 904 [0.8%]), and 7.10 to 7.19 (259 of 73 244 [0.4%]). Comparable patterns were observed for the individual outcomes, except for neonatal death, which was only increased in the group with UC-pH levels of less than 7.10. The risk of treatment with continuous positive airway pressure was increased when UC-pH levels were less than 7.20, and the risk of hypoglycemia was 21.5% if UC-pH levels were less than 7.10. Conclusions and Relevance: In this cohort study of 340 431 newborn infants, results support and extend previous studies indicating a higher risk of adverse outcomes even at UC-pH levels above 7.00. The threshold for more intensive observation and treatment may be reconsidered.

Sex-specific differences in the mechanisms for enhanced thromboxane A2-mediated vasoconstriction in adult offspring exposed to prenatal hypoxia.

BACKGROUND: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. METHODS: Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. RESULTS: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. CONCLUSIONS: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.

Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease.

Indicadores de calidad de la atención a neonatos con patologías seleccionadas: estudio piloto / Quality care indicators for neonates with selected pathologies: pilot study

Resumen: Objetivo: Desarrollar y pilotar indicadores de calidad de la atención a neonatos con padecimientos relevantes en México (prematuridad, sepsis neonatal, asfixia perinatal e hipoxia intrauterina). Material y métodos: Se construyeron indicadores propios a partir de recomendaciones clave de las guías de práctica clínica nacionales e indicadores encontrados en repositorios internacionales. Previa búsqueda, selección y priorización, los indicadores fueron pilotados en dos hospitales. Se analizó la factibilidad de medición, fiabilidad (índice kappa) y utilidad para detectar problemas de calidad. Resultados: Se seleccionaron y pilotaron 23 indicadores; 12 eran compuestos. Del total, nueve fueron factibles y fiables. La calidad de la información en los hospitales fue diversa y frecuentemente deficiente, limitando tanto la factibilidad como la fiabilidad de los indicadores. Los niveles de cumplimiento identificaron oportunidades de mejora. Conclusiones: Se propone un set de nueve indicadores válidos, factibles, fiables y útiles para la monitorización de la calidad en la atención a neonatos patológicos.

Abstract Objective: Develop and pilot indicators of quality of care to neonates with relevant conditions in Mexico (prematurity, neonatal sepsis, perinatal asphyxia, and intrauterine hypoxia). Materials and methods: Own indicators were built based on key recommendations of national clinical practice guidelines and indicators found in international repositories. With previous search, selection and prioritization, the indicators were piloted within two hospitals. The feasibility of measuring, (kappa index) reliability and usefulness was analyzed to detect quality problems. Results: 23 indicators were selected and piloted, 12 are compounds, of the total, nine were feasible and reliable. The quality of the hospital's information was diverse and often poor, limiting both the feasibility and the reliability of the indicators. Improvement opportunities were identified thorough the compliance levels. Conclusions: A set of nine indicators valid, reliable, feasible and useful indicators is proposed in order to monitor the quality of care of pathological neonates.

Assessing the association between hypoxia during craniofacial development and oral clefts

Abstract Objectives To evaluate the association between hypoxia during embryo development and oral clefts in an animal model, and to evaluate the association between polymorphisms in the HIF-1A gene with oral clefts in human families. Material and Methods The study with the animal model used zebrafish embryos at 8 hours post-fertilization submitted to 30% and 50% hypoxia for 24 hours. At 5 days post-fertilization, the larvae were fixed. The cartilage structures were stained to evaluate craniofacial phenotypes. The family-based association study included 148 Brazilian nuclear families with oral clefts. The association between the genetic polymorphisms rs2301113 and rs2057482 in HIF-1A with oral clefts was tested. We used real time PCR genotyping approach. ANOVA with Tukey's post-test was used to compare means. The transmission/disequilibrium test was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring. Results For the hypoxic animal model, the anterior portion of the ethmoid plate presented a gap in the anterior edge, forming a cleft. The hypoxia level was associated with the severity of the phenotype (p<0.0001). For the families, there was no under-transmitted allele among the affected progeny (p>0.05). Conclusion Hypoxia is involved in the oral cleft etiology, however, polymorphisms in HIF-1A are not associated with oral clefts in humans.

Papel do Doppler do ducto venoso na restrição de crescimento intrauterino / Ductus venosus Doppler assessment in intrauterine growth restriction

Objetivo: O crescimento intrauterino restrito (CIUR) por insuficiência placentária persiste como grande desafio obstétrico. A interrupção da gestação representa a única estratégia de condução e baseia-se na predição de desfechos adversos. O Doppler tem valor reconhecido na avaliação seriada das alterações circulatórias nesses fetos, em geral sequenciais e proporcionais à gravidade do insulto hipóxico. Este estudo objetiva revisar as evidências do papel do Doppler de ducto venoso (DV) na predição de morbimortalidade perinatal em gestações complicadas por CIUR placentário grave e precoce. Métodos: Realizou-se revisão narrativa, com busca de artigos publicados nos últimos 10 anos nas bases Medline/PubMed, Lilacs e Scielo, sendo encontradas 132 referências. Pesquisas com animais e gestações múltiplas foram excluídas. Dos 115 artigos selecionados, 34 foram excluídos por inadequação ao tema. A revisão baseou-se nas demais 81 referências, além de trabalhos de reconhecida relevância no tema. Resultados: Estudos demonstram evidência consistente do papel do Doppler de DV na avaliação de fetos com CIUR, com bom valor preditivo para acidemia fetal e desfecho perinatal adverso. As principais estratégias de monitorização se baseiam na combinação do Doppler de vasos arteriais/venosos e parâmetros biofísicos, mas o Doppler de DV seria o melhor parâmetro isolado para predição de comprometimento fetal grave. Conclusão: A incorporação do Doppler de DV na monitorização de fetos com CIUR grave e precoce é capaz de predizer desfechos perinatais críticos. A avaliação de múltiplos vasos fetais parece aumentar a acurácia, porém não há evidência para embasar a definição de protocolos para o manejo clínico.(AU)

Objective: Intrauterine growth restriction (IUGR) due to early onset placental insufficiency remains to be a great challenge in obstetrical practice. Delivery is still the only available strategy of management, and timing such intervention depends on prediction of adverse outcomes. Dopplervelocimetry studies have recognized value in the evaluation of the sequential hemodynamic changes that are stablished in the arterial and venous circulation of these fetuses, which correlate with the severity of hypoxemic insult. This study aims to review evidence on ductus venosus (DV) Doppler`s role as a predictor of perinatal outcome in pregnancies complicated by severe early onset IUGR. Methods: A Medline/PubMed, Lilacs and Scielo search was performed to identify original articles and systematic reviews published in the last 10 years. Eighty-one references were included in this review, in addition to other papers of recognized relevance in the subject. Results: Studies demonstrate consistent evidence on DV Doppler`s role in the longitudinal evaluation of IUGR fetuses, with adequate predictive value for fetal acidemia and adverse outcome. Monitoring strategies are usually based on a combination of arterial and venous Doppler assessment, in addition to biophysical parameters, but DV Doppler seems to be the best single parameter for prediction of severe fetal compromise. Conclusion: Monitoring of fetuses with severe early-onset IUGR through DV Doppler is able to predict critical perinatal outcomes. Evaluation of multiple fetal vessels seems to increase accuracy of prediction, but to this moment there is not enough evidence to recommend protocols of management.(AU)

Antropometría neonatal a término en una población rural y urbana a 3 400 metros de altura / Anthropometry in at-term neonates in a rural and an urban population at 3 400 meters altitude / Antropometria de recém-nascidos a termo em uma população da zona rural e da zona urbana a uma altitude de 3 400 metros

RESUMEN Objetivo Averiguar si hay diferencias en las medidas antropométricas de neonatos a término en una población rural y urbana a 3 400 m de altura. Material y métodos Estudio descriptivo poblacional de neonatos a término sin enfermedades en el Hospital Nacional Adolfo Guevara Velasco del Cusco (HNAGV) y el Centro de Salud de Huanoquite (CSH), entre 2005 y 2010. Se calcularon medidas de tendencia central, las medias se compararon con la prueba t de Student, el modelo final se ajustó por sexo neonatal y se calcularon las odds ratios (OR) y sus IC95% para estimar la fuerza de la asociación entre tener un neonato pequeño para la edad gestacional (PEG) según el P10 del peso y del índice ponderal (IP) en los recién nacidos de madres que viven en el distrito de Huanoquite y cuyo parto fue atendido en el CSH. Resultados En el HNAGV y el CSH se estudiaron 372 y 368 los neonatos, respectivamente. Las medias de la edad materna fueron 31,7 y 27,0 años, las gestaciones previas, 2,4 y 3,4, los abortos, 0,4 y 0,0, los hijos nacidos vivos, 1,0 y 2,3 (p < 0,001), y el peso, la talla y el IP, 3 311,8 g, 49,5 cm, 2,73 y 3 008,9 g, 48,4 cm, 2,66, respectivamente (p < 0,001). Tras ajustar por sexo, el peso, la talla y el IP por categoría edad gestacional para los dos centros fueron: (37-38 semanas) 3 185,1 g, 49,18 cm, 2,67, y 3 009,8 g, 48,5 cm, 2,64; (39-40 semanas) 3 385,9 g, 49,9, 2,73, y 3 051,8 g, 48,6 cm, 2,66; (41-42 semanas) 3 461, 6 g, 50,2 cm, 2,73, y 3 072,2 g, 49,1 cm, y 2,6, respectivamente (p < 0,001). La OR de nacer PEG en el CSH fue 3,52 (2,4-5,1) según el peso y 2,05 (1,3-3,1) según el IP respecto a nacer en el HNAGV. Conclusión El peso, la talla y el IP de los neonatos del CSH fueron menores que los del HNAGV y las OR de tener un neonato PEG fueron 3,52 según el peso y 2,05 según el IP, respectivamente.

Objective Ascertain whether there are differences in the anthropometric measurements of at-term neonates in a rural population and an urban population at 3 400 m altitude. Material and methods Descriptive population study of healthy at-term neonates in the Adolfo Guevara Velasco National Hospital (HNAGV) in Cusco and in the Huanoquite Health Center (CSH), [both at 3 400 m altitude in Peru], between 2005 and 2010. Measures of central tendency were calculated, the averages were compared with a Student's t-test, the final model was adjusted by neonatal sex, and the odds ratios (OR) and corresponding confidence intervals (CI95%) were calculated to estimate the strength of association between small for gestational age (SGA) infants (according to weight under P10 and ponderal index [PI]) in mothers who live in the Huanoquite district and those who gave birth in the CSH. Results In the HNAGV and the CSH, 372 and 368 neonates were studied, respectively. The average maternal age was 31.7 and 27.0 years; previous pregnancies, 2.4 and 3.4; miscarriages, 0.4 and 0.0; live births, 1.0 and 2.3 (p<0.001); and weight, height and PI, 3 311.8 g, 49.5 cm, 2.73, and 3,008.9 g, 48.4 cm, 2.66, respectively (p<0.001). The weight, height, and PI for the two centers were, after adjusting for sex and by gestational age bracket: (37-38 weeks) 3,185.1 g, 49.18 cm, 2.67, and 3,009.8 g, 48.5 cm, 2.64; (39-40 weeks) 3 385.9 g, 49.9, 2.73, and 3 051.8 g, 48.6 cm, 2.66; (41-42 weeks) 3 461, 6 g, 50.2 cm, 2.73, and 3,072.2 g, 49.1 cm, and 2.6, respectively (p<0.001). The OR of SGA births in the CSH was 3.52 (2.4-5.1) according to weight and 2.05 (1.3-3.1) according to PI, compared to birth in the HNAGV. Conclusion The weight, height, and PI of infants born in the CSH were lower than those born in the HNAGV, and the OR of SGA births was 3,52 according to weight and 2,05 according to PI, respectively.

Resumo Objetivo Examinar se existem diferenças antropométricas em recém-nascidos a termo em uma população da zona rural e da zona urbana vivendo a uma altitude de 3.400 m. Materiais e métodos Estudo descritivo populacional de recém-nascidos a termo sem doenças associadas realizado no Hospital Nacional Adolfo Guevara Velasco, em Cusco (HNAGV), e no Centro de Saúde, em Huanoquite (CSH), entre 2005 e 2010. Foram calculadas as medidas de tendência central e as médias comparadas com o teste t de Student. O modelo final foi ajustado por sexo do recém-nascido e calculados os odds ratios (OR) e seus respectivos intervalos de confiança de 95% (IC95%) para estimar a força da associação entre ser pequeno para idade gestacional (PIG) segundo o percentil 10 (P10) do peso e o índice ponderal (IP) nos recém-nascidos de mães que vivem no distrito de Huanoquite cujo parto foi assistido no CSH. Resultados Foram estudados 372 e 368 recém-nascidos no HNAGV e no CSH, respectivamente. A idade média materna foi de 31,7 e 27,0 anos, as mães tiveram em média 2,4 e 3,4 gestações anteriores, 0,4 e 0,0 abortos, 1,0 e 2,3 nascidos vivos (p < 0,001) com peso, comprimento e IP foi de 3 311,8 g, 49,5 cm e 2,73 e 3 008,9 g, 48,4 cm e 2,66, respectivamente (p < 0,001). Após ajuste para o sexo, o peso, o comprimento e o IP por categoria de idade gestacional nos dois centros estudados foram: (37-38 semanas) 3 185,1 g, 49,18 cm e 2,67 e 3 009,8 g, 48,5 cm e 2,64; (39-40 semanas) 3 385,9 g, 49,9 e 2,73 e 3 051,8 g, 48,6 cm e 2,66; (41-42 semanas) 3 461,6 g, 50,2 cm e 2,73 e 3 072,2 g, 49,1 cm e 2,6, respectivamente (p < 0,001). Os OR dos recém-nascidos PIG no CSH foram de 3,52 (2,4-5,1) segundo o peso e 2,04 (1,3-3,1) segundo o IP ao nascimento no HNAGV. Conclusão O peso, o comprimento e o IP dos recém-nascidos no CSH foram menores que os dos recém-nascidos no HNAGV e o OR de ser PIG foi de 3,52 segundo o peso e 2,05 segundo o IP, respectivamente.

Óbito polimalformado ocasionado por padre portador de aberración cromosómica equilibrada / Death caused by a balanced-chromosomic-aberration-carrier parent

Introducción: Se define como óbito fetal a la pérdida fetal en el embarazo luego de las 20 semanas de gestación o con un peso al nacimiento mayor de 500 g. Las anomalías congénitas constituyen el 16,5% de los casos, de estas: 9,8% por múltiples malformaciones y el 6,7% por malformaciones de un órgano o sistema. Caso: Óbito fetal polimalformado de 26 semanas. Pareja de padres no consanguíneos sin antecedentes de importancia, producto del primer embarazo. Se encuentran alteraciones: Pie bott bilateral y disrupción facial parcial, hipertelorismo ocular, micrognatia ligera, orejas de implantación baja, escoliosis. El estudio citogenético reveló cariotipo femenino numéricamente normal pero con una aberración cromosómica estructural desequilibrada consistente en la deleción de un fragmento del brazo corto del cromosoma 5 (46, XX del 5pter→p15). Una vez detectada esta anormalidad, se realizó análisis citogenético a ambos padres. El padre era portador de una aberración cromosómica estructural equilibrada: [46, XY, ins (5; 12) (p15.1; pter]. Discusión: Los resultados concuerdan que el cromosoma 5p- es de herencia paterna en el 80% de los casos. Se recalca la importancia de realizar un estudio citogenético en óbitos malformados. En caso de anomalías cromosómicas se vuelve imperativo el estudio citogenético de los padres. En el presente caso, el riesgo de recurrencia es aproximadamente del 5 %.

Introduction: Stillbirth is either a fetus loss after 20 weeks of gestation or with a birth weight greater than 500 g. Congenital malformations accounts for 16.5% of all cases, of which 9.8% have multiple malformations and 6.7% have only a single organ or system affected. Case report: A 26 weeks-old stillbirth affected by multiple malformations. Parents were young, without consanguinity between them. Nothing was remarkable in their past history. Malformations found were: rocker-bottom feet; facial dysruption; hypertelorism; micrognathia; scoliosis; down slanting ears. Femenin karyotype showing a structural chromosomal imbalance: a deletion on the short arm of chromosome 5 (46, XX del 5pter→p15). Since this chromosomal abnormality was found, both parents underwent cytogenetic analysis. The father was found to have an insertion: 46, XY, ins (5; 12) (p15.1 →pter). Discussion: The results agreed that chromosome 5pis of paternal inheritance in 80% of cases. This report highlights the importance of the cytogenetic analysis in fetal dymorphic deaths. It also showed the value of the parental chromosomic studies when a structural aberration is found. In this case, according to the reported chromosomal findings, the risk of recurrence might be 5%.

Tyrosine phosphorylation of Kv1. 5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension

Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.