Fetal heart rate variability analysis for neonatal acidosis prediction.

Fetal well-being during labor is usually assessed by visual analysis of a fetal heart rate (FHR) tracing. Our primary objective was to evaluate the ability of automated heart rate variability (HRV) analysis methods, including our new fetal stress index (FSI), to predict neonatal acidosis. 552 intrapartum recordings were analyzed. The analysis occurred in the last 90 min before birth and was conducted during two 5-min intervals: (i) a stable period of FHR and (ii) the period corresponding to the maximum FSI value. For each period, we computed the mean FHR, FSI, short-term variability (STV), and long-term variability (LTV). Visual FHR interpretation was performed using the FIGO classification. The population was separated into two groups: (i) an acidotic group with an arterial pH at birth ≤ 7.10 and a control group. Prediction of a neonatal pH ≤ 7.10 was assessed by computing the receiver-operating characteristic area under the curve (AUC). FHR, FSI, STV, and LTV did not differ significantly between groups during the stable period. During the FSI max peak period, LTV and STV correlated significantly in the acidotic group (- 5.85 ± 2.19, p = 0.010 and - 0.62 ± 0.29, p = 0.037, respectively). The AUC values were 0.569 for FIGO classification, 0.595 for STV, and 0.622 for LTV. The multivariate model (FIGO, FSI, FC, STV, LTV) had the greatest accuracy for predicting acidosis (AUC = 0.719). FSI was not predictive of neonatal acidosis probably because of the low quality of the FHR signal in cardiotocography. When used separately, HRV indexes and visual FHR analysis were poor predictors of neonatal acidosis. Including all indexes in a multivariate model increased the predictive ability.

Review shows that implementing a nationwide protocol for congenital diaphragmatic hernia was a key factor in reducing mortality and morbidity.

The French Rare Disease Reference Center for congenital diaphragmatic hernia (CDH) was created in 2008, to implement a national protocol for foetuses and children with this serious condition. Neonatal mortality from CDH is 30-40%, mainly due to pulmonary hypoplasia and persistent pulmonary hypertension, and half of those who live have high respiratory, nutritional and digestive morbidity. CDH management requires long-term and specialised multidisciplinary care. It has been well established that a standardised management protocol improves the prognosis of children with CDH. CONCLUSION: Organising health care and implementing a nationwide French protocol were key factors for reducing mortality and morbidity from CDH.

Review shows that using surfactant a number of times or as a vehicle for budesonide may reduce the risk of bronchopulmonary dysplasia.

AIM: Bronchopulmonary dysplasia (BPD) remains the most common respiratory morbidity in immature infants. This review describes the diagnosis of BPD has evolved and summarises the therapeutic approaches that have made it possible to limit the incidence of BPD. METHOD: We reviewed the literature from the first definition of BPD by Northway in 1967 to the surfactant treatment policies that are currently in use, drawing on more than 50 papers up to 2017. RESULTS: Our review showed that improvements in neonatal survival have been associated with an increased risk of severe BPD, significant levels of long-term morbidity and the increased use of healthcare resources. These issues have encouraged researchers to explore potential new treatments that limit the incidence of BPD. Repeated surfactant instillation and the use of surfactant as a vehicle for budesonide are promising strategies for alleviating the burden of chronic lung disease. Ongoing research on surfactant or stem cell therapy may further improve the respiratory prognosis for prematurely born children. CONCLUSION: Considerable research has been carried out into the increase in BPD, which has resulted from improvements in neonatal survival. Key areas of research include repeated surfactant administration, using surfactant as a vehicle for budesonide and stem cell therapy.

Placental antiangiogenic prolactin fragments are increased in human and rat maternal diabetes.

INTRODUCTION/OBJECTIVES: The role of the placenta in diabetic mothers on fetal development and programming is unknown. Prolactin (PRL) produced by decidual endometrial cells may have an impact. Although full-length PRL is angiogenic, the processed form by bone morphogenetic protein-1 (BMP-1) and/or cathepsin D (CTSD) is antiangiogenic. The objectives were to investigate the involvement of decidual PRL and its antiangiogenic fragments in placentas from type-1 diabetic women (T1D) and from pregnant diabetic rats with lower offspring weights than controls. METHODS: PRL, BMP-1, and CTSD gene expressions and PRL protein level were assessed in T1D placentas (n=8) at delivery and compared to controls (n=5). Wistar rats received, at day 7 of pregnancy, streptozotocin (STZ) (n=5) or nicotinamide (NCT) plus STZ (n=9) or vehicle (n=9). Placental whole-genome gene expression and PRL western blots were performed at birth. RESULTS: In human placentas, PRL (p<0.05) and BMP-1 (p<0.01) gene expressions were increased with a higher amount of cleaved PRL (p<0.05) in T1D than controls. In rats, diabetes was more pronounced in STZ than in NCT-STZ group with intra-uterine growth restriction. Decidual prolactin-related protein (Dprp) (p<0.01) and Bmp-1 (p<0.001) genes were up-regulated in both diabetic groups, with an increased cleaved PRL amount in the STZ (p<0.05) and NCT-STZ (p<0.05) groups compared to controls. No difference in CTSD gene expression was observed in rats or women. CONCLUSIONS: Alterations in the levels of the PRL family are associated with maternal diabetes in both rats and T1D women suggesting that placental changes in these hormones impact on fetal development.

Assessment of anti-factor Xa activity of heparin in binary parenteral nutrition admixtures for premature neonates.

An in vitro study was carried out to determine the anti-Xa activity of heparin in binary parenteral nutrition (BPN) admixtures for premature neonates in our neonatal intensive care unit (NICU) after a 24-hour infusion, as well as to assess drug interaction with a 50% glucose solution. Two types of bags were prepared: (1) BPN admixtures (composition defined in the NICU) including sodium heparin at 77 UI/mL and (2) bags containing only G50% with sodium heparin at 193 UI/mL. The anti-Xa activity of heparin was measured in bags at T0, after the 24-hour infusion and in eluates at the outlet of the infusion line after 24hours, using a validated chromogenic anti-Xa method. Comparisons of the mean concentration observed with the theoretical value for anti-Xa activity were performed with the Student t-test. Mean values of anti-Xa activity do not differ significantly from the values expected for all conditions. We found a slight variation in anti-Xa activity when infused over 24hours for both types of bags, with and without in-line filtration, showing that heparin remains stable during this infusion period in both BPN admixtures and G50%.

Transposition of the great arteries: factors influencing prenatal diagnosis.

OBJECTIVE: The objective of this study is to highlight the factors that may affect prenatal diagnosis of transposition of the great arteries (TGA) in order to improve it. METHODS: This is a retrospective study performed between 2004 and 2009 in the maternity units from North of France. We identified a total of 68 cases of TGA (isolated or associated with only VSD or coarctation of aorta), of which 32 (47.1%) had prenatal diagnosis (PND+) and 36 did not (PND-). Maternal characteristics and ultrasound factors were studied in relation to PND. RESULTS: Maternal weight and body mass index were significantly higher in the PND- group (70.4 kg and 26.5 kg/m(2) vs 63.6 kg and 23.6 kg/m(2) , respectively). Maternal obesity (body mass index >30) was significantly more frequent in the PND- group (27.8% vs 12.5%). More than a quarter of TGA (28.1%) were diagnosed during the third trimester. CONCLUSION: Obesity is the main cause of missed PND of TGA. Obese patients with suboptimal prenatal scans may benefit from reassessment of fetal cardiac anatomy and/or from referral for fetal echocardiography.

Heart rate markers for prediction of fetal acidosis in an experimental study on fetal sheep.

To overcome the difficulties in interpreting fetal heart rate (FHR), several tools based on the autonomic nervous system and heart rate variability (HRV) have been developed. The objective of this study was to use FHR and HRV parameters for the prediction of fetal hypoxia. It was an experimental study in the instrumented fetal sheep. Repeated umbilical cord occlusions were performed to achieve severe acidosis. Hemodynamic parameters, ECG, and blood gases were analyzed. The variables used were heart rate baseline, HRV analysis (RMSSD, SDNN, LF, HF, HFnu, Fetal Stress Index (FSI), …), and morphological analysis of decelerations. The gold standard used to classify hypoxia was the fetal arterial pH (pH < 7.10). Different multivariable statistical methods (logistic regression and decision trees) were applied for the detection of acidosis. 21 lambs were instrumented. A total of 130 pairs of FHR/fetal pH analysis were obtained of which 29 in the acidosis group and 101 in the non-acidosis group. After logistic regression model with bootstrap resampling and stepwise backward selection, only one variable was selected, FSI. The AUC of FSI alone in this model was 0.81 with a sensitivity of 0.66, specificity of 0.88, PPV of 0.61, and NPV of 0.90 considering a threshold of 68. Decision trees with CHAID and CART algorithms showed a sensitivity of 0.48 and 0.59, respectively, and a specificity of 0.94 for both. All employed methods identified HRV variables as the most predictive of acidosis. The primary variables selected automatically were those from the HRV. Supporting the use of FHRV measures for the screening of fetal acidosis during labour is interesting.

Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants.

BACKGROUND: Inhaled nitric oxide (iNO), commonly used for hypoxic neonates, may react with haemoglobin to form methaemoglobin (MetHb). MetHb monitoring during iNO therapy has been questioned since low doses of iNO are used. AIM: To evaluate the incidence of and identify risk factors associated with elevated MetHb in neonates treated with iNO. METHODS: Neonates who were treated with iNO and had at least one MetHb measurement were included. Demographic characteristics and methods of iNO administration (dosage, duration) at the time of each MetHb measurement were analysed. RESULTS: Four hundred and fifty-two MetHb measurements from 81 premature and 82 term and near-term infants were analysed. MetHb was above 5% in one-term infant, and between 2.5-5% in 16 infants. A higher maximum dose of iNO (22.7 vs 17.7 p.p.m.), but not gestational age, was a significant risk factor for elevated MetHb. Significantly higher oxygen levels (75.5% vs 51.7%) were associated with higher MetHb in term infants. Preterm infants had no risk for high MetHb when iNO was kept below 8 p.p.m. These data suggest the possibility of limiting blood withdrawal when low doses iNO are used. CONCLUSION: High MetHb is exceptional in neonates treated with low dose iNO. Associated risk factors are related to high iNO dose and the simultaneous use of high concentrations of oxygen.

Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study.

OBJECTIVES: To investigate the value of the observed to expected fetal lung area to head circumference ratio (o/e LHR) and liver position in the prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia (CDH). METHODS: Neonatal morbidity was recorded in 100 consecutive cases with isolated CDH diagnosed in fetal medicine units, which were expectantly managed in the prenatal period, were delivered after 30 weeks and survived until discharge from hospital. Regression analysis was used to identify the significant predictors of morbidity, including prenatal and immediate neonatal findings. RESULTS: The o/e LHR provided significant prediction of the need for prosthetic patch repair, duration of assisted ventilation, need for supplemental oxygen at 28 days, and incidence of feeding problems. An additional independent prenatal predictor of the need for patch repair was the presence of fetal liver in the chest. CONCLUSIONS: In isolated CDH the prenatally assessed size of the contralateral lung is a significant predictor of the need for prosthetic patch repair, the functional consequences of impaired lung development and occurrence of feeding problems.

Influence of averaged fetal heart rate in heart rate variability analysis.

In high-income countries, fetal hypoxia affects 3 to 8 newborns per 1000 live births with subsequent moderate or severe Hypoxic-Ischemic Encephalopathy (HIE) in 0.5 to 1 per 1000 live births. Visual interpretation of FHR signal issued from a Doppler ultrasound cardiotocography is the gold standard to monitor fetal condition. Unfortunately, its analysis presents a high rate of inter-observer variability and a low specificity to predict poor neonatal outcomes. Under hypoxia, the fetus develops several adaptive mechanisms regulated by the autonomic nervous system inducing changes in the fetal heart rate variability. Though fetal heart rate variability methods demonstrated abilities to predict perinatal asphyxia, most of the Doppler ultrasound technologies used in clinical practice do not provide sufficiently accurate fetal heart rate signals for heart rate variability analysis. Indeed, Doppler ultrasound cardiotocography usually provides fetal heart rate values averaged over 2 or 3 beats which can constitute a limitation for spectral analysis. We developed a fetal heart rate variability analysis method: the Fetal Stress Index (FSI). The objective of this study was to investigate the influence of averaged fetal heart rate on this new index in order to check the feasibility of computing the FSI from the signal issued from Doppler ultrasound cardiotocography.

How Does a Delay Between Temperate Running Exercise and Hot-Water Immersion Alter the Acute Thermoregulatory Response and Heat-Load?

Hot-water immersion following exercise in a temperate environment can elicit heat acclimation in endurance-trained individuals. However, a delay between exercise cessation and immersion is likely a common occurrence in practice. Precisely how such a delay potentially alters hot-water immersion mediated acute physiological responses (e.g., total heat-load) remains unexplored. Such data would aid in optimizing prescription of post-exercise hot-water immersion in cool environments, relative to heat acclimation goals. Twelve male recreational runners (mean ± SD; age: 38 ± 13 years, height: 180 ± 7 cm, body mass: 81 ± 13.7 kg, body fat: 13.9 ± 3.5%) completed three separate 40-min treadmill runs (18°C), followed by either a 10 min (10M), 1 h (1H), or 8 h (8H) delay, prior to a 30-min hot-water immersion (39°C), with a randomized crossover design. Core and skin temperatures, heart rate, sweat, and perceptual responses were measured across the trials. Mean core temperature during immersion was significantly lower in 1H (37.39 ± 0.30°C) compared to 10M (37.83 ± 0.24°C; p = 0.0032) and 8H (37.74 ± 0.19°C; p = 0.0140). Mean skin temperature was significantly higher in 8H (32.70 ± 0.41°C) compared to 10M (31.93 ± 0.60°C; p = 0.0042) at the end of the hot-water immersion. Mean and maximal heart rates were also higher during immersion in 10M compared to 1H and 8H (p < 0.05), despite no significant differences in the sweat or perceptual responses. The shortest delay between exercise and immersion (10M) provoked the greatest heat-load during immersion. However, performing the hot-water immersion in the afternoon (8H), which coincided with peak circadian body temperature, provided a larger heat-load stimulus than the 1 h delay (1H).

[Umbilical and peripherally inserted venous central catheterization of the newborn]. / Le cathétérisme veineux ombilical et épicutanéocave chez le nouveau-né

Umbilical venous and peripherally inserted venous central catheters are widely used to perfuse low-weight preterm and term newborns in intensive care units. This catheter must be inserted carefully and monitored rigorously to prevent complications. This paper develops today's knowledge on the use and complications in the newborn population.

Passive Heating: Reviewing Practical Heat Acclimation Strategies for Endurance Athletes.

Heat acclimation protocols-both active and passive-have been employed by athletes in an effort to attenuate the detrimental effects of heat stress on physical capacities and sports performance. Active strategies have been extensively reviewed, but have various practical and economic limitations. The purpose of this review was therefore to provide an overview of the passive strategies that have received less attention, yet may be more practical or economically viable; recommendations for athletes are also provided. With a systematic search of the relevant databases ending in June 2018, 16 articles on passive heat acclimation that met the inclusion criteria were included in the review. The review highlighted that passive heat acclimation strategies can successfully induce heat adaptations, evident by reports of improved exercise performance, thermoregulatory, cardiovascular, and perceptual responses accompanying such interventions. Based on the review it is apparent that the use of sauna, hot-water immersion and environmental chambers may be used to provide heat stress under passive conditions, for the purpose of acclimation. To maximize the thermoregulatory-adaptive responses, exercise bouts should be employed prior to passive heat stress, rather than passive heating alone, with a minimal delay between exercise and the application of heat stress. Heating bouts should have a minimum duration of 30 min per session and be employed on consecutive days, when possible, with a minimum of 6-7 exposures to induce adaptation. This review identified that information regarding the magnitude of performance changes that can occur, as well as the perceptual responses to passive heating protocols is limited. Future research should investigate the use of passive heat exposures before and/or after repeated heat training sessions, to assess if a further boost to heat adaptation can be achieved with this strategy.

Correlation of a new index reflecting the fluctuation of parasympathetic tone and fetal acidosis in an experimental study in a sheep model.

The autonomic nervous system plays a leading role in the control of fetal homeostasis. Fetal heart rate variability (HRV) analysis is a reflection of its activity. We developed a new index (the Fetal Stress Index, FSI) reflecting parasympathetic tone. The objective of this study was to evaluate this index as a predictor of fetal acid-base status. This was an experimental study on chronically instrumented fetal lambs (n = 11, surgery at 128 +/- 2 days gestational age, term = 145 days). The model was based on 75% occlusion of the umbilical cord for a maximum of 120 minutes or until an arterial pH ≤ 7.20 was reached. Hemodynamic, gasometric and FSI parameters were recorded throughout the experimentation. We studied the FSI during the 10 minutes prior to pH samplings and compared values for pH>7.20 and pH≤ 7.20. In order to analyze the FSI evolution during the 10 minutes periods, we analyzed the minimum, maximum and mean values of the FSI (respectively FSImin, FSImax and FSImean) over the periods. 11 experimentations were performed. During occlusion, the heart rate dropped with an increase in blood pressure (respectively 160(155-182) vs 106(101-120) bpm and 42(41-45) vs 58(55-62) mmHg after occlusion). The FSImin was 38.6 (35.2-43.3) in the group pH>7.20 and was higher in the group pH less than 7.20 (46.5 (43.3-52.0), p = 0.012). The correlation of FSImin was significant for arterial pH (coefficient of -0.671; p = 0.004) and for base excess (coefficient of -0.632; p = 0.009). The correlations were not significant for the other parameters. In conclusion, our new index seems well correlated with the fetal acid-base status. Other studies must be carried out in a situation close to the physiology of labor by sequential occlusion of the cord.

When should foetal pH measurements be performed after a prolonged deceleration? An experimental study in a fetal sheep model.

OBJECTIVE: The aim of fetal heart rate monitoring during labour is to identify and prevent foetal distress, but its evaluation is not perfect. Fetal scalp blood sampling for pH measurement is one of the second-line methods of monitoring when fetal heart rate is classified as suspicious. This study aims to determine when pH testing should be performed after a prolonged deceleration. STUDY DESIGN: This was an experimental study in a fetal sheep model. A partial umbilical cord occlusion was performed for seven minutes followed by a recuperation period of 30 min. Hemodynamic parameters (heart rate, mean blood pressure and intra-amniotic pressure) and blood gases were recorded before occlusion (T0), during occlusion (T4), just after the end of occlusion (T7), and then 10, 20 and 30 min after occlusion (T17, T27 and T37 respectively). RESULTS: Ten experiments were carried out. During partial cord occlusion, the fetal pH decreased significantly to acidosis. After a prolonged deceleration with fetal acidosis, the pH recovered to a normal value, defined by a pH greater than or equal to 7.25, after 20 min of recuperation. CONCLUSION: After a prolonged deceleration, fetal pH normalizes between 20 and 30 min thereafter. Thus, if a foetal blood sample is indicated, this delay must be respected in order to avoid inducing an unnecessary intervention decision.

Exploring fetal response to acidosis in ewes: Choosing an adequate experimental model.

INTRODUCTION: Knowledge of fetal physiology during labor has been largely generated from animal models. Our team recently developed a new index to assess parasympathetic activity using different experimental protocols to obtain acidosis. The objective of the present study was to discuss the different protocols and to review other models proposed in the literature. MATERIAL AND METHODS: Pregnant ewes underwent a surgical procedure at the 123±2 days gestational age (term=145 days). Three experimental protocols were used: protocol A consisted of 25%, 50% and 75% umbilical cord occlusion (UCO) for 20min. Protocol B consisted of partial 75% UCO until reaching a pH<7.10. Protocol C consisted of brief, repetitive complete occlusion until severe acidosis occurred. Hemodynamic and blood gas parameters were compared to those of the stability period before UCO. RESULTS: Protocol A led to a progressive response depending on the degree of occlusion (decrease in fetal heart rate, arterial hypertension and pH). Protocol B led to severe acidosis, although the duration of UCO varied per animal. Protocol C also progressively led to acidosis. We observed high inter individual variability in the acidosis response. CONCLUSION: Pregnant ewes are a relevant model for exploring fetal response to acidosis. The frequency of UCO and partial or complete occlusion should be adapted to the expected effects. Knowledge of these protocols is important to respect ethical guidelines and to reduce the required number of animals. Moreover, it is important to consider the high individual variability of the acidosis response in the interpretation of the results.

Effect of two-weeks endurance training wearing additional clothing in a temperate outdoor environment on performance and physiology in the heat.

This investigation assessed performance, physiological and perceptual responses to wearing additional clothing during endurance training for two-weeks in temperate environments, to determine if this approach could be used as a practical, alternative, heat acclimation strategy for athletes. Fifteen trained male triathletes assigned to performance-matched groups completed a two-week unsupervised endurance cycling and running program in either (i) shorts and a short sleeve top (CON; n = 8) or (ii) additional clothing of full-length pants, a "winter" jacket and gloves made from nylon, polyurethane and polyester (AC; n = 7). Participants completed three separate (i.e. familiarisation, pre-program and post-program), identical, pre-loaded cycling time-trials (20 min at 180 W followed by a 40 min self-paced time trial) in 32.5 ± 0.1°C and 55 ± 6% RH. Core and skin temperatures, heart rate, sweat rate, perceived exertion, thermal sensation and thermal comfort were measured across the pre-loaded time trials, and heart rate and thermal sensation were measured across the training program. All of the participants recorded in their diaries that they completed all of the programmed training sessions in the required attire. Mean thermal sensation was most likely hotter in AC (5.5 ± 0.4 AU) compared to CON (4.4 ± 0.4 AU; ES = 1.61, ± 0.68) during the training sessions. However, follow up tests revealed no physiological or perceptual signs of heat acclimation, and the change in time-trial performance from pre-post between groups was trivial (CON: -3.5 ± 12.0 W, AC: -4.1 ± 9.6 W; difference = -0.7%, ± 5.4%). Training in additional clothing for two-weeks in a temperate environment was not an effective heat acclimation strategy for triathletes.

Early hemodynamic consequences of patent ductus arteriosus in preterm infants with intrauterine growth restriction.

OBJECTIVE: To test the hypothesis that significant patent ductus arteriosus (PDA) may occur very early after birth in preterm infants with intrauterine growth restriction (IUGR), we compared the longitudinal changes in left-to-right shunting through DA between eutrophic and preterm infants with IUGR. STUDY DESIGN: The preterm infants -26 to 32 weeks gestational age (GA), admitted in our neonatal intensive care unit from February to May 2004 were included. They were separated into an "IUGR of placental origin" group and an "eutrophic" group. Significant PDA was assessed by Doppler echocardiography at 6, 24, and 48 hours of age. RESULTS: Thirty-one eutrophic (GA = 29 +/- 1.4 weeks; birth weight [BW] = 1300 +/- 160 g) and 17 infants with IUGR (GA = 29.3 +/- 1.5 weeks; BW = 810 +/- 140 g) were studied. Six hours after birth, the rate of significant PDA was higher in the IUGR than in the eutrophic group (10/17 [60%] vs 5/31 [15%]; P < .05). More DA became significant in infants with IUGR (11/17 [65%]) than in eutrophic infants (12/31 [40%]) (P < .05) within the 48 hours after birth. CONCLUSION: Markers of high pulmonary blood flow and systemic vascular steal occur more frequently and earlier after birth in IUGR of placental origin than in eutrophic preterm infants. The management of preterm infants with severe IUGR of placenta origin should include early echocardiographic monitoring to assess for markers of significant PDA.

[Consequences of premature rupture of the membranes in the perinatal lung]. / Physiopathologie des conséquences respiratoires néonatales de la rupture prématurée des membranes: application à la prise en charge néonatale.

Early premature rapture of the membranes (PROM) during pregnancy is associated with a high risk of perinatal morbidity and mortality. Early PROM impairs lung structures and function through 3 mechanisms : 1) oligo-hydramnios ; 2) fetal inflammatory syndrome ; and 3) prematurity. Thus, the related causes of respiratory failure at birth after PROM are: hyaline membrane disease, persistent pulmonary hypertension induced by impaired endothelial function and/or lung hypoplasia, materno-fetal infection, and bronchopulmonary dysplasia resulting at least in part from the fetal inflammatory syndrome. Severity of the respiratory morbidity is largely unpredictable. Even if gestational age at PROM is considered as a prognostic factor, survival without morbidity exist after PROM as early as 18 weeks GA. Better knowledge of the pathophysiology improved the outcome of the preterm infants born after early PROM. Optimal management of the respiratory failure including minimizing barotrauma is required to prevent from bronchopulmonary dysplasia.