Emmanuel Lopez

Delivery for women with a previous cesarean: guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF).

The primary cause of uterine scars is a previous cesarean. In women with a previous cesarean, the risks of maternal complications are rare and similar after a trial of labor after cesarean (TOLAC) and after an elective repeat cesarean delivery (ERCD), but the risk of uterine rupture is higher with TOLAC (level of evidence [LE]2). Maternal morbidity in women with previous cesareans is higher when TOLAC fails than when it leads to successful vaginal delivery (LE2). Although maternal morbidity increases progressively with the number of ERCD, maternal morbidity of TOLAC decreases with the number of successful previous TOLAC (LE2). The risk-benefit ratio considering the risks of short- and long-term maternal complications is favorable to TOLAC in most cases (LE3). Globally, neonatal complications are rare regardless of the mode of delivery for women with previous cesareans. The risks of fetal, perinatal, and neonatal mortality during TOLAC are low. Nonetheless, these risks are significantly higher than those associated with ERCD (LE2). The risks of mask ventilation, intubation for meconium-stained amniotic fluid, and neonatal sepsis all increase in TOLAC (LE2). The risk of transient respiratory distress increases in ERCD (LE2). To reduce this risk, and except in particular situations, ERCD must not be performed before 39 weeks (grade B). TOLAC is possible for women with a previous cesarean before 37 weeks, with 2 previous cesareans, with a uterine malformation, a low vertical incision or an unknown incision, with a myomectomy, postpartum fever, an interval of less than 6 months between the last cesarean delivery and the conception of the following pregnancy, if the obstetric conditions are favorable (professional consensus). ERCD is recommended in women with a scar in the uterine body (grade B) and a history of 3 or more cesareans (professional consensus). Ultrasound assessment of the risk of uterine rupture in women with uterine scars has not been shown to have any clinical utility and is therefore not recommended during pregnancy to help decide the mode of delivery (professional consensus). Use of X-ray pelvimetry to decide about TOLAC is associated with an increase in the repeat cesarean rate without any reduction in the rate of uterine rupture (LE2). It is unnecessary for deciding mode of delivery and for managing labor during TOLAC (grade C). TOLAC should be encouraged for women with a previous vaginal delivery either before or after the cesarean, a favorable Bishop score or spontaneous labor, and for preterm births (grade C). For women with a fetus with an estimated weight of more than 4500 g, especially in the absence of a previous vaginal delivery and those with supermorbid obesity (BMI>50), ERCD must be planned from the outset (grade C). For all of the other clinical situations envisioned (maternal age>35 years, diabetes, morbid obesity, prolonged pregnancy, breech presentation and twin pregnancy), TOLAC is possible but the available data do not allow specific guidelines about the choice of mode of delivery, in view of the low levels of proof (grade C). The decision about planned mode of delivery must be shared by the patient and her physician and made by the 8th month, taking into account the individual risk factors for TOLAC failure and uterine rupture (professional consensus). TOLAC is the preferred choice for women who do not have several risk factors (professional consensus). The availability onsite of an obstetrician and anesthetist must be pointed out to the patient. If the woman continues to prefer a repeat cesarean after adequate information and time to think about it, her preference should be honored (professional consensus). Labor should be induced in woman with a previous cesarean only for medical indications (professional consensus). Induction of labor increases the risk of uterine rupture, which can be estimated at 1% if oxytocin is used and 2% with vaginal prostaglandins (LE2). Mechanical methods of induction have not been studied sufficiently. Misoprostol appears to increase the risk of uterine rupture strongly (LE4). Based on the information now available, its use is not recommended (professional consensus). Routine use of internal tocodynamometry does not prevent uterine rupture (professional consensus). The increased risk of uterine rupture associated with oxytocin use is dose-dependent (LE3). In the active phase, it is recommended that the total duration of failure to progress should not exceed 3h; at that point, a cesarean should be performed (professional consensus). Epidural analgesia must be encouraged. The simple existence of a uterine scar is not an indication for a routine manual uterine examination after VBAC (grade C).

Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring

Objective Because pharmacokinetic data are limited, continuous infusions of vancomycin in neonates are administered using different dosing regimens. The aim of this work was to evaluate the results of vancomycin therapeutic drug monitoring (TDM) under three different dosing regimens and to optimise vancomycin therapy. Methods Vancomycin TDM concentrations were noted and compared prospectively in three hospitals. Population pharmacokinetic analysis was performed to optimise dosing using NONMEM software. Patient-tailored optimised dosing regimens were evaluated in a prospective study. Results Two hundred and seven serum vancomycin concentrations from 116 neonates were analysed. Only 48 neonates (41%) had serum vancomycin concentrations within the therapeutic range of 15–25 mg/l using a current dosing regimen. Concentrations ranged from 5.1 to 61.5 mg/l. Loading doses were required to decrease the risk of sub-therapeutic levels during early treatment. An optimised dosing regimen, taking into account birth weight, current weight, postnatal age and serum creatinine, was developed based on a one-compartment pharmacokinetic model. A prospective validation study in 58 neonates demonstrated a higher percentage of neonates (70.7%, n=41) reaching the therapeutic range and early dosage adaptation (6–12 h post-dose) using an optimised dosing regimen. Conclusions A patient-tailored optimised dosing regimen should be used routinely to individualise vancomycin continuous infusion therapy in neonates.

Capnography in spontaneously breathing preterm infants with bronchopulmonary dysplasia.

In adult patients with chronic obstructive pulmonary disease, there is a gradient between end‐tidal carbon dioxide (EtCO2) and arterial carbon dioxide pressure (PaCO2), and the slope of the ascending phase of the capnogram is decreased due to obstruction. Corresponding data are lacking in infants with bronchopulmonary dysplasia (BPD).

Evidence for transmission of Escherichia coli from mother to child in late-onset neonatal infection.

Genetic characterization of non-K1 Escherichia coli strains isolated from a mother and her neonate allowed us to provide evidence of the maternal origin of a late-onset neonatal infection. The use of ante- and peripartum antimicrobial prophylaxis with amoxicillin may have promoted the vertical transmission of this amoxicillin-resistant E. coli from mother to newborn. It allowed us to clarify the natural history of the disease.

Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

During the perinatal period, lungs undergo changes to adapt to air breathing. The genes involved in these changes are developmentally regulated by various signaling pathways, including the cyclic nucleotide cAMP. As PDE4s are critical enzymes for regulation of cAMP levels, the objective of this study was to investigate PDE4s ontogeny in developing rat lung during the perinatal period. Pulmonary PDE4 activity, PDE4A‐D, PDE4B, and PDE4D variant expression levels, PDE4B and PDE4D protein levels, and PDE4D localization in distal lung were determined. PDE4 activity increased towards term, dropped at birth, and increased thereafter to reach a plateau at the end of the second week of life. PDE4B2 and PDE4D long forms demonstrated a pattern of expression that increased markedly at birth. After birth, PDE4D was expressed in alveolar epithelial and mesenchymal cells. The study, therefore, evidenced striking variations in expression patterns among the PDE4 family that differed from changes in global PDE4 activity. Developmental Dynamics 239:2470–2478, 2010.

Shoulder dystocia: guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)

Shoulder dystocia (SD) is defined as a vaginal delivery in cephalic presentation that requires additional obstetric maneuvers to deliver the fetus after the head has delivered and gentle traction has failed. It complicates 0.5-1% of vaginal deliveries. Risks of brachial plexus birth injury (level of evidence [LE]3), clavicle and humeral fracture (LE3), perinatal asphyxia (LE2), hypoxic-ischemic encephalopathy (LE3) and perinatal mortality (LE2) increase with SD. Its main risk factors are previous SD and macrosomia, but both are poorly predictive; 50-70% of SD cases occur in their absence, and most deliveries when they are present do not result in SD. No study has proven that the correction of these risk factors (except gestational diabetes) would reduce the risk of SD. Physical activity is recommended before and during pregnancy to reduce the occurrence of some risk factors for SD (Grade C). In obese women, physical activity should be coupled with dietary measures to reduce fetal macrosomia and weight gain during pregnancy (Grade A). Women with gestational diabetes require diabetes care (diabetic diet, glucose monitoring, insulin if needed) (Grade A) because it reduces the risk of macrosomia and SD (LE1). Only two measures are proposed for avoiding SD and its complications. First, induction of labor is recommended in cases of impending macrosomia if the cervix is favorable at a gestational age of 39 weeks or more (professional consensus). Second, cesarean delivery is recommended before labor in three situations and during labor in one: (i) estimated fetal weight (EFW) >4500g if associated with maternal diabetes (Grade C), (ii) EFW >5000g in women without diabetes (Grade C), (iii) history of SD associated with severe neonatal or maternal complications (professional consensus), and finally during labor, (iv) in case of fetal macrosomia and failure to progress in the second stage, when the fetal head station is above +2 (Grade C). In cases of SD, it is recommended to avoid the following actions: excessive traction on the fetal head (Grade C), fundal pressure (Grade C), and inverse rotation of the fetal head (professional consensus). The McRoberts maneuver, with or without suprapubic pressure, is recommended first (Grade C). If it fails and the posterior shoulder is engaged, Woods maneuver should be performed preferentially; if the posterior shoulder is not engaged, it is preferable to attempt to deliver the posterior arm next (professional consensus). It appears necessary to know at least two maneuvers to perform should the McRoberts maneuver fail (professional consensus). A pediatrician should be immediately informed of SD. The initial clinical examination should check for complications, such as brachial plexus injury or clavicle fracture (professional consensus). If no complications are observed, neonatal monitoring need not be modified (professional consensus). The implementation of practical training with simulation for all care providers in the delivery room is associated with a significant reduction in neonatal (LE3) but not maternal (LE3) injury. SD remains an unpredictable obstetric emergency. All physicians and midwives should know and perform obstetric maneuvers if needed, quickly but calmly.

Efficacy of a First Course of Ibuprofen for Patent Ductus Arteriosus Closure in Extremely Preterm Newborns According to Their Gestational Age-Specific Z-Score for Birth Weight

Objective Therapeutic strategies for patent ductus arteriosus (PDA) in very preterm infants remain controversial. To identify infants likely to benefit from treatment, we analysed the efficacy of a first course of ibuprofen in small-for-gestational age (SGA) newborns. Study design This single-centre retrospective study included 185 infants born at 24+0–27+6 weeks of gestation with haemodynamically significant PDA, who were treated by intravenous ibuprofen (Pedea): 10 mg/kg on day one and 5 mg/kg on days two and three. Birth weight and gestational age (GA) were analysed with reference to the standard deviations from the Olsen growth curve to define GA-specific Z-scores for birth weights. The efficacy of treatment was evaluated by echocardiography 48 hours after the last dose of ibuprofen. The primary outcome was failure of the first course of ibuprofen associated in a composite criterion with the most severe outcomes. Results The risk of treatment failure increased according to a continuous gradient in SGA neonates. A higher risk was observed on multiple regression analysis (crude OR: 3.8; 95% CI [1.2–12.3] p = 0.02; adjusted OR: 12.8; 95% CI [2.3–70.5] p=0.003). Conclusion There is a linear relationship between infant birth weight and PDA treatment: the failure rate of a first course of ibuprofen increases with increasing degree of growth restriction.

THE CLINICAL UTILITY AND SAFETY OF A MODEL-BASED PATIENT-TAILORED DOSE REGIMEN OF VANCOMYCIN IN NEONATES

Background and objective Pharmacokinetic modeling approach is often applied to evaluate antimicrobials in neonates. However, the clinical application of the model-based personalized antimicrobial therapy is still limited. Our objective is to evaluate the clinical utility and safety of the model-based patient-tailored dosing of vancomycin in neonates. Methods A model-based vancomycin dosing calculator, which was developed using the pharmacokinetic information from our previously published population pharmacokinetic model, has been integrated into the routine clinical care in 3 NICUs (Cochin, Robert Debré and Clocheville Hospitals) between June 2012 and November 2014. The target attainment rate was selected as the endpoint for evaluating the clinical utility. The percentage of patients achieving the target concentration of vancomycin was calculated using the first TDM samples taken 6–24 hours after starting vancomycin treatment. The safety evaluation was focused on nephrotoxicity, which was evaluated based on changes in serum creatinine concentration from a baseline value obtained within the 48 hours of starting vancomycin treatment. Results A total of 190 neonates were included. The mean of the 190 first TDM vancomycin concentrations was 20.0 mg/L (10th-90th percentiles: 13.1–27.6). After receiving patient-tailored doses, the target attainment rate was 71.6% (n=136) within the range of 15–25 mg/L (90.5%, n=172, within the range of 10–30 mg/L). None of the included patients has developed vancomycin-related nephrotoxicity. Conclusion The present work provides an evidence-based study to demonstrate the clinical utility and safety of a model-based patient-tailored dose regimen of vancomycin in neonates. The results from population pharmacokinetic study were successfully integrated in neonatal clinical practice to individualise vancomycin therapy.

Aspects fondamentaux de la toxicite éventuelle des drogues anesthésiques

Brain development is a complex phenomenon in which several stages of production, maturation, and organization of neural cells in a network succeed each other. Various environmental factors can disrupt these stages. During the last decade, numerous in vitro and in vivo experimental studies in newborn animal models have established the neurotoxic effects of most anesthetic and sedative drugs used in pediatrics. These effects are essentially responsible for neuronal apoptosis and have been associated with learning disorders in adulthood. This neurotoxicity is time-varying: there is a vulnerability period during synaptogenesis. These toxic effects were attributed to agonist properties on GABA receptors or antagonist properties on NMDA receptors, which are characteristics of all implicated anesthetics. Excessive activation of the GABA pathway and/or excessive inhibition of the NMDA pathway activate cellular mechanisms leading to apoptosis. The intensity of neurotoxic effects is dose- and time-exposure-dependent. These numerous experimental data must be interpreted with caution with regard to their validity in humans, mainly because of interspecies differences as well as differences between experimental conditions and clinical practice. Today, these data are insufficient to change our practices, taking into account the indisputable benefits of the use of anesthetics and sedative drugs. However, progress in experimental research will help us identify the safest therapeutic strategies and neuroprotective treatments.