Riccardo Pfister

Incidence of Early Neonatal Mortality and Morbidity After Late-Preterm and Term Cesarean Delivery

OBJECTIVE. To determine the age-stratified risk of intrapartum and neonatal mortality as well as morbidities of clinical relevance after elective cesarean delivery (ECD). METHODS. This work was a cohort study including 56 549 prospectively recorded late-preterm and term deliveries. We analyzed the effect of cesarean delivery (CD) before the onset of labor on the following multiple neonatal outcomes before hospital discharge, compared with planned vaginal delivery (PVD) and emergency CD: mortality, birth depression, special care admission, and respiratory morbidity. We adjusted for confounders by multivariate analysis and stratified the risk according to gestational age (GA). RESULTS. Mortality and morbidities had a strong GA-related trend with the lowest incidences consistently found between 38 and 40 weeks of gestation independent of delivery mode. Compared with infants delivered via PVD, infants delivered via ECD had significantly higher rates of mortality (adjusted risk ratio [aRR]: 2.1), risk of special care admission (aRR: 1.4), and respiratory morbidity (aRR: 1.8) but not of depression at birth (aRR: 1.1). Compared with emergency CD, newborns delivered via ECD had less depression at birth (aRR: 0.6) and admission to special care (aRR: 0.8), but mortality (aRR: 0.8) and respiratory morbidity (aRR: 1.0) rates were similar. CONCLUSIONS. Gestational age–specific risk estimates are lowest between 38 and 40 weeks and should be included in the informed-consent process. The information should also be used to allow for appropriate preparation with respect to adequate staff and equipment. ECD is consistently associated with increased intrapartum and neonatal mortality, risk of admission, and respiratory morbidity compared with PVD and has no advantage over emergency CD in terms of mortality. Neonatal morbidities are lower after ECD than emergency CD only with term births. Our data provide evidence that ECD should not be performed before term.

Use of a systematic risk analysis method to improve safety in the production of paediatric parenteral nutrition solutions

Background: Until recently, the preparation of paediatric parenteral nutrition formulations in our institution included re-transcription and manual compounding of the mixture. Although no significant clinical problems have occurred, re-engineering of this high risk activity was undertaken to improve its safety. Several changes have been implemented including new prescription software, direct recording on a server, automatic printing of the labels, and creation of a file used to pilot a BAXA MM 12 automatic compounder. The objectives of this study were to compare the risks associated with the old and new processes, to quantify the improved safety with the new process, and to identify the major residual risks. Methods: A failure modes, effects, and criticality analysis (FMECA) was performed by a multidisciplinary team. A cause-effect diagram was built, the failure modes were defined, and the criticality index (CI) was determined for each of them on the basis of the likelihood of occurrence, the severity of the potential effect, and the detection probability. The CIs for each failure mode were compared for the old and new processes and the risk reduction was quantified. Results: The sum of the CIs of all 18 identified failure modes was 3415 for the old process and 1397 for the new (reduction of 59%). The new process reduced the CIs of the different failure modes by a mean factor of 7. The CI was smaller with the new process for 15 failure modes, unchanged for two, and slightly increased for one. The greatest reduction (by a factor of 36) concerned re-transcription errors, followed by readability problems (by a factor of 30) and chemical cross contamination (by a factor of 10). The most critical steps in the new process were labelling mistakes (CI 315, maximum 810), failure to detect a dosage or product mistake (CI 288), failure to detect a typing error during the prescription (CI 175), and microbial contamination (CI 126). Conclusions: Modification of the process resulted in a significant risk reduction as shown by risk analysis. Residual failure opportunities were also quantified, allowing additional actions to be taken to reduce the risk of labelling mistakes. This study illustrates the usefulness of prospective risk analysis methods in healthcare processes. More systematic use of risk analysis is needed to guide continuous safety improvement of high risk activities.

Use of Diagnostic Microarrays for Determination of Virulence Gene Patterns of Escherichia coli K1, a Major Cause of Neonatal Meningitis

ABSTRACT Forty Escherichia coli strains isolated primarily from neonatal meningitis, urinary tract infections and feces were screened for the presence of virulence genes with a newly developed microarray on the array tube format. A total of 32 gene probes specific for extraintestinal as well as intestinal E. coli pathotypes were included. Eighty-eight percent of the analyzed strains were positive for the K1-specific probe on the microarray and could be confirmed with a specific antiserum against the K1 capsular polysaccharide. The gene for the hemin receptor ChuA was predominantly found in 95% of strains. Other virulence genes associated with K1 and related strains were P, S, and F1C fimbriae specific for extraintestinal E. coli, the genes for aerobactin, the α-hemolysin and the cytotoxic necrotizing factor. In two strains, the O157-specific catalase gene and the gene for the low-molecular-weight heat-stable toxin AstA were detected, respectively. A total of 19 different virulence gene patterns were observed. No correlation was observed between specific virulence gene patterns and a clinical outcome. The data indicate that virulence genes typical of extraintestinal E. coli are predominantly present in K1 strains. Nevertheless, some of them can carry virulence genes known to be characteristic of intestinal E. coli. The distribution and combination of virulence genes show that K1 isolates constitute a heterogeneous group of E. coli.

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland 2011 Revision of the Swiss recommendations

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infants and pregnant womans best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infants clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infants burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ.

Background Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. Methodology/Principal Findings We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. Conclusion/Significance Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.

Safety of Early High-Dose Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants.

OBJECTIVE To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. STUDY DESIGN Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. RESULTS There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. CONCLUSIONS Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. TRIAL REGISTRATION ClinicalTrials.gov: NCT00413946.

Intrapartum Group B streptococcus detection by rapid polymerase chain reaction assay for the prevention of neonatal sepsis.

Group B streptococcus (GBS) is a leading cause of infectious neonatal morbidity and mortality. Timely and accurate identification of colonized mothers is imperative so that antibioprophylaxis can be implemented during labour to reduce the risk of neonatal sepsis. We planned our study to analyse the diagnostic accuracy of an intrapartum PCR assay to identify GBS-colonized women and to allow the implementation of correct (i.e. at least 4 h) intrapartum antibiotic prophylaxis based on the PCR results. We included 695 women in labour who were tested for rectovaginal GBS carriage by culture and PCR. Women were also screened at 35-37 weeks of gestation. Intrapartum GBS colonization was 19.3%. Assay sensitivity was 81.0% for antenatal culture and 85.0% for intrapartum PCR; p 0.72. GBS colonization (n = 107) was known at least 4 h before delivery in 68 (64%) and 73 (68%) women based on antenatal culture and intrapartum PCR, respectively. Among 43 women delivering preterm, correct status was known at least 4 h before delivery in 10 (23%) and 32 (74%) women according to antenatal culture and intrapartum PCR, respectively. These results support the concept that GBS screening can be performed routinely during labour in a clinical setting. The intrapartum approach is at least as accurate as the antenatal screening, with the additional advantage of identifying women delivering preterm or not followed during pregnancy.

Secular trends in antibiotic use among neonates: 2001-2008

Background: Few data exist on time trends of antibiotic consumption among neonates. Objectives: To assess secular trends in antibiotic consumption in the context of an antibiotic policy and the effect of antibiotic use on the development of antimicrobial resistance and outcome among neonates in a single center. Methods: We performed a prospective cohort study between 2001 and 2008 to monitor antibiotic consumption among neonates. In parallel, we initiated a policy to shorten antibiotic therapy for clinical sepsis and for infections caused by coagulase-negative staphylococci and to discontinue preemptive treatment when blood cultures were negative. Time trend analyses for antibiotic use and mortality were performed. Results: In total, 1096 of 4075 neonates (26.7%) received 1281 courses of antibiotic treatment. Overall, days of therapy were 360 per 1000 patient-days. Days of therapy per 1000 patient-days decreased yearly by 2.8% (P < 0.001). Antibiotic-days to treat infections decreased yearly by 6.5% (P = 0.01) while antibiotic-days for preemptive treatment increased by 3.4% per year (P = 0.03). Mean treatment duration for confirmed infections decreased by 2.9% per year (P < 0.001). No significant upward trend was observed for infection-associated mortality. Of 271 detected healthcare-associated infections, 156 (57.6%) were microbiologically documented. The most frequent pathogens were coagulase-negative staphylococci (48.5%) followed by Escherichia coli (13.5%) and enterococci (9.4%). Rates for extended-spectrum beta-lactamase-producing microorganisms and methicillin-resistant Staphylococcus aureus remained low. Conclusions: Shortening antibiotic therapy and reducing preemptive treatment resulted in a moderate reduction of antibiotic use in the neonatal intensive care unit and did not increase mortality.

Risk and pharmacoeconomic analyses of the injectable medication process in the paediatric and neonatal intensive care units

OBJECTIVE To analyse safety risks in injectable medications. To assess the potential impact and pharmacoeconomic aspects of safety tools. DESIGN The injectable drug process was prospectively assessed using a failure modes, effects and criticality analysis. Criticality indexes were estimated based on their likelihood of occurrence, detection probability and potential severity. The impact of 10 safety tools on the criticality index was calculated and extrapolated to all drugs injected daily. Yearly costs for a reduction in criticality by 1 point (=1 quali) per day were estimated. SETTING Paediatric and neonatal intensive care units in a University Hospital. PARTICIPANTS Two paediatric nurses, a neonatologist, three hospital pharmacists. INTERVENTIONS Qualitative and quantitative risk assessment. MAIN OUTCOME MEASURES Failure modes, criticality indexes, cost-efficacy ratios. RESULTS Thirty-one failure modes identified, with the mean of their entire criticality indexes totalling 4540. The most critical failure mode was microbial contamination. The following gains were predicted: 1292 quali (46 500 per day by extrapolation) from ready-to-use syringes, 1201 (72 060) by employing a clinical pharmacist, 996 (59 780) from double check by nurses and 984 (59 040) with computerized physician order entry. The best cost-efficacy ratios were obtained for a clinical pharmacist (1 quali = 0.54 euros), double check (1 quali = 0.71 euros) and ready-to-use syringes (1 quali = 0.72 euros). Computerized physician order entry showed the worst cost-efficacy ratio due to a very high investment costs (1 quali = 22.47 euros). CONCLUSION Based on our risk and pharmacoeconomic analyses, clinical pharmacy and ready-to-use syringes appear as the most promising safety tools.

Recurrence of Cardiorespiratory Events following Repeat DTaP-Based Combined Immunization in Very Low Birth Weight Premature Infants

We evaluated the tolerance to immunization of 64 very low birth weight preterm infants. Thirty-three of the infants experienced a cardiorespiratory event after the first vaccination, and 6 of these 33 (18%) had a recurrence after the second vaccination, including 2 infants previously discharged to home. A cardiorespiratory event associated with the first vaccination was the sole risk factor for recurrence identified.