Effect of fluconazole prophylaxis on Candida fluconazole susceptibility in premature infants.

Objectives: Extremely premature infants are at high risk of developing invasive candidiasis; fluconazole prophylaxis is safe and effective for reducing invasive candidiasis in this population but further study is needed. We sought to better understand the effect of prophylactic fluconazole on a selection of fluconazole-resistant Candida species. Methods: We evaluated the susceptibility to fluconazole of Candida isolates from premature infants (<750 g birth weight) enrolled in a multicentre, randomized, placebo-controlled trial of fluconazole prophylaxis. Candida species were isolated through surveillance cultures at baseline (study day 0-7), period 1 (study day 8-28) and period 2 (study day 29-49). Fluconazole MICs were determined for all Candida isolates. Results: Three hundred and sixty-one infants received fluconazole (n = 188) or placebo (n = 173). After the baseline period, Candida colonization was significantly lower in the fluconazole group compared with placebo during periods 1 (5% versus 27%; P < 0.001) and 2 (3% versus 27%; P < 0.001). After the baseline period, two infants (1%) were colonized with at least one fluconazole-resistant Candida in each group. Median fluconazole MIC was similar in both treatment groups at baseline and period 1. However, in period 2, median MIC was higher in the fluconazole group compared with placebo (1.00 versus 0.50 mg/L, P = 0.01). There was no emergence of resistance observed and no patients developed invasive candidiasis with a resistant Candida isolate. Conclusions: Fluconazole prophylaxis decreased Candida albicans and 'non-albicans' Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates.

Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists.

This is an executive summary of a workshop on the management and counseling issues of women anticipated to deliver at a periviable gestation (broadly defined as 20 0/7 through 25 6/7 weeks of gestation) and the treatment options for the newborn infant. Upon review of the available literature, the workshop panel noted that the rates of neonatal survival and neurodevelopmental disabilities among the survivors vary greatly across the periviable gestations and are significantly influenced by the obstetric and neonatal management practices (eg, antenatal steroid, tocolytic agents, and antibiotic administration; cesarean birth; and local protocols for perinatal care, neonatal resuscitation, and intensive care support). These are, in turn, influenced by the variations in local and regional definitions of limits of viability. Because of the complexities in making difficult management decisions, obstetric and neonatal teams should confer prior to meeting with the family, when feasible. Family counseling should be coordinated with the goal of creating mutual trust, respect, and understanding and should incorporate evidence-based counseling methods. Since clinical circumstances can change rapidly with increasing gestational age, counseling should include discussion of the benefits and risks of various maternal and neonatal interventions at the time of counseling. There should be a plan for follow-up counseling as clinical circumstances evolve. The panel proposed a research agenda and recommended developing educational curricula on the care and counseling of families facing the birth of a periviable infant.

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

IMPORTANCE: Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539.

Fundamentals of designing high-quality surveys: revisiting neonatal perinatal medicine survey applications.

Surveys in neonatal perinatal medicine are practical instruments for gathering information about medical practices, and outcomes related to the care of newborns and infants. This includes research for identifying needs, assessing requirements, analyzing the effects of change, creating policies, and developing curriculum initiatives. Surveys also provide useful data for enhancing the provision of healthcare services, assessing medical specialties, and evaluating training programs. However, creating a high-quality survey can be difficult for many practitioners, particularly when deciding how to formulate the right questions, whether to utilize various types of questions and how best to arrange or format the survey tool for effective responses. Problems with design principles have been evident in many surveys submitted for dissemination to the members of the Section of Neonatal Perinatal Medicine (SoNPM). To prevent potential measurement errors and increase the quality of surveys, it is crucial to follow a systematic approach in developing surveys by adhering to the principles of effective survey design. This review article provides a brief summary of survey use within the SoNPM, and offers guidance for creating high-quality surveys, including identifying important factors to consider in survey development and characteristics of well-written and effective questions. We briefly note techniques that optimize survey design for distribution through digital media.

Ecological-niche modeling reveals current opportunities for Agave dryland farming in Sonora, Mexico and Arizona, USA.

For centuries, humans occupying arid regions of North America have maintained an intricate relationship with Agave (Agavoideae, Asparagaceae). Today Agave cultivation, primarily for beverage production, provides an economic engine for rural communities throughout Mexico. Among known dryland-farming methods, the use of rock piles and cattle-grazed areas stand out as promising approaches for Agave cultivation. Identifying new cultivation areas to apply these approaches in Arizona, USA and Sonora, Mexico warrants a geographic assessment of areas outside the known ranges of rock piles and grasslands. The objective of this study was to predict areas for dryland-farming of Agave and develop models to identify potential areas for Agave cultivation. We used maximum entropy (MaxEnt) ecological-niche-modeling algorithms to predict suitable areas for Agave dryland farming. The model was parameterized using occurrence records of Hohokam rock piles in Arizona and grassland fields cultivated with Agave in Sonora. Ten environmental-predictor variables were used in the model, downloaded from the WorldClim 2 climate database. The model identified potential locations for using rock piles as dryland-farming methods from south-central Arizona to northwestern Sonora. The Agave-grassland model indicated that regions from central to southern Sonora have the highest potential for cultivation of Agave, particularly for the species Agave angustifolia. Results suggest that there are many suitable areas where rock piles can be used to cultivate Agave in the Sonoran Desert, particularly in the border of southeastern Arizona and northwest Sonora. Likewise, cattle-grazing grasslands provide a viable environment for cultivating Agave in southern Sonora, where the expanding bacanora-beverage industry continues to grow and where different Agave products (e.g., syrups, fructans, saponins, and medicinal compounds) can potentially strengthen local economies.

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

BACKGROUND: Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. METHODS: Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score. RESULTS: Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%. CONCLUSIONS: Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success. CLINICAL TRIALS REGISTRATION: NCT00621192.

Absence of relationship between serum cortisol and critical illness in premature infants.

BACKGROUND: Inadequate cortisol production in response to critical illness in extremely preterm infants may exacerbate poor outcomes. Despite commonly measuring cortisol concentration and administering hydrocortisone for presumed adrenal insufficiency, the relationship between serum cortisol concentration and illness severity remains unclear in this unique population. OBJECTIVE: To determine the relationship between cortisol concentrations and illness severity as measured by the Score for Neonatal Acute Physiology II, neonatal Sequential Organ Failure Assessment and Vasoactive-Inotropic Score in premature infants. DESIGN/METHODS: This retrospective, single-center cohort study included preterm infants born <30 weeks gestational age admitted to a level IV neonatal intensive care unit (NICU) between June 2011 and July 2018, who had a serum cortisol obtained for clinical indications before 36 weeks PMA. Demographic data were collected on infants and mothers. Nine clinical variables were identified a priori that could potentially modify cortisol concentration including critical illness. Univariate and multivariable analyses determined the relationship between cortisol concentration and each of these variables. RESULTS: A total of 224 preterm infants with pretreatment serum cortisol concentration met criteria for inclusion. The median (IQR) gestational age at birth was 25 weeks (24, 26) and at cortisol measurement was 26 weeks (25, 28). The median cortisol was 13.3 ug/dL. Non-survivors had the highest values. Cortisol concentration did not correlate with any of the selected illness severity scores. CONCLUSIONS: Cortisol concentrations in extremely preterm infants did not correlate with illness severity regardless of gestational age. Further studies are needed to identify clinically useful mediators of adrenal dysfunction and to guide clinical management.

Detection of SARS-CoV-2-Specific IgA in the Human Milk of COVID-19 Vaccinated Lactating Health Care Workers.

Background: In 2019, a deadly virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), emerged. In December 2020, two mRNA-based COVID-19 vaccines were approved for use in the United States, which provide immunity to those receiving the vaccine. Maternally derived antibodies are a key element of infants' immunity. Certain vaccines given to pregnant and lactating mothers provide immunity to infants through transmission across the placenta, umbilical cord (IgG), and human milk (IgA). Human milk produced by mothers with a history of COVID-19 infection contains SARS-CoV-2 IgA and IgG. The purpose of this study is to determine whether SARS-CoV-2-specific immunoglobulins are found in human milk after the COVID-19 vaccination, and to characterize the types of immunoglobulins present. Methods: This is a prospective observational study conducted at Shands Hospital, University of Florida, from December 2020 to March 2021. Twenty-two lactating health care workers who received the SARS-CoV-2 mRNA vaccine (Pfizer/BioNTech or Moderna) made up the sample group. Plasma and human milk were collected at three time points (prevaccination, post-first vaccine dose, and post-second vaccine dose). SARS-CoV-2-specific IgA and IgG in human milk and in plasma were measured by enzyme-linked immunosorbent assay (ELISA). Maternal demographics were compiled. Results: We found significant secretion of SARS-CoV-2-specific IgA and IgG in human milk and plasma after SARS-CoV-2 vaccination. Conclusions: Our results show that the mRNA-based COVID-19 vaccines induce SARS-CoV-2-specific IgA and IgG secretion in human milk. Further studies are needed to determine the duration of this immune response, its capacity to neutralize the COVID-19 virus, the transfer of passive immunity to breastfeeding infants, and the potential therapeutic use of human milk IgA to combat SARS-CoV-2 infections and COVID-19.

Gastroschisis with jejunal and colonic atresia, and isolated colonic atresia in dichorionic, diamniotic twins.

Despite the increasing incidence of gastroschisis, the cause remains unknown. Genetic factors may contribute to bowel anomalies as demonstrated by cases of gastroschisis in twins and siblings, and other types of bowel anomalies in twins. Atresia of the colon represents one of the rarest causes of neonatal intestinal obstruction. We present the first case of dichorionic, diamniotic male twins in which there was gastroschisis with jejunal and colonic atresia in Twin A and isolated colonic atresia in Twin B.

Clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal bloodstream infection in premature infants.

OBJECTIVE: To determine if INH-A21, an intravenous immune globulin (IGIV) derived from donors with high titers of antibody to surface adhesins of Staphylococcus epidermidis and S. aureus prevents late-onset sepsis (LOS) in very low birth weight (VLBW) infants. STUDY DESIGN: In this double-blind, placebo-controlled study, infants with birth weights 500 to 1250 g were randomized to receive up to four doses of INH-A21 (Veronate) or placebo. The primary objective was to determine the safety and efficacy of INH-A21 versus placebo for prevention of S. aureus LOS in VLBW infants. RESULTS: A total of 1983 infants from 95 neonatal intensive care units were randomized, and received at least one dose of study drug. S. aureus LOS developed in 50 of 989 (5%) and 60 of 994 (6%) infants who received placebo or INH-A21, respectively (P = .34). No differences were found in the frequencies of LOS caused by coagulase-negative staphylococci (CoNS), Candida spp, or overall mortality. No adverse events were statistically significantly associated with INH-A21 infusions compared with placebo. CONCLUSION: INH-A21 failed to reduce the incidence of staphylococcal LOS or candidemia in premature infants.

Neonatal hypothalamic hamartoma: a differentiating nonlethal hamartoblastoma.

The authors report on a patient with a large hypothalamic hamartoma with a cleft lip and palate and seizures. Neuroimaging revealed a large extraaxial, intradural mass in the prepontine and interpeduncular cisterns with significant distortion of the brainstem. A stereotactic transfontanel needle biopsy revealed a cellular lesion that contained immature-appearing neuroepithelial cells consistent with prior descriptions of hypothalamic hamartoblastoma. While having a low level of proliferation by Ki67 (MIB-1) labeling, the lesion also contained evidence of neuronal maturation, with many cells expressing neuronal nuclear antigen as observed during immunohistochemical analysis. Further clinical evaluation revealed no other significant congenital abnormalities, and the patient was discharged home. Outpatient follow up has continued for 2 years and the patient has been doing well, requiring no further treatment. This case illustrates that, despite its immature and proliferative histological appearance, this rare neonatal mass can be regarded as a "differentiating" hypothalamic hamartoma and can have a favorable prognosis.

No place like home: telemonitoring can improve home care.

Effective use of telemonitoring equipment can reduce costs of providing home health care and increase revenues enough to ensure the fiscal health of this industry segment. Using telemonitoring as a basis, a home health agency can develop a disease management program, making itself more attractive to managed care organizations. Telemonitoring offers home health agencies a means to partner with hospitals to help reduce length of stay and recurrent hospitalizations of patients with chronic illness.

Costs and cost-effectiveness of periviable care.

With increasing concerns regarding rapidly expanding healthcare costs, cost-effectiveness analysis allows assessment of whether marginal gains from new technology are worth the increased costs. Particular methodologic issues related to cost and cost-effectiveness analysis in the area of neonatal and periviable care include how costs are estimated, such as the use of charges and whether long-term costs are included; the challenges of measuring utilities; and whether to use a maternal, neonatal, or dual perspective in such analyses. A number of studies over the past three decades have examined the costs and the cost-effectiveness of neonatal and periviable care. Broadly, while neonatal care is costly, it is also cost effective as it produces both life-years and quality-adjusted life-years (QALYs). However, as the gestational age of the neonate decreases, the costs increase and the cost-effectiveness threshold is harder to achieve. In the periviable range of gestational age (22-24 weeks of gestation), whether the care is cost effective is questionable and is dependent on the perspective. Understanding the methodology and salient issues of cost-effectiveness analysis is critical for researchers, editors, and clinicians to accurately interpret results of the growing body of cost-effectiveness studies related to the care of periviable pregnancies and neonates.

Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists.

This is an executive summary of a workshop on the management and counseling issues of women anticipated to deliver at a periviable gestation (broadly defined as 20 0/7 through 25 6/7 weeks of gestation), and the treatment options for the newborn. Upon review of the available literature, the workshop panel noted that the rates of neonatal survival and neurodevelopmental disabilities among the survivors vary greatly across the periviable gestations and are significantly influenced by the obstetric and neonatal management practices (eg, antenatal steroid, tocolytic agents, and antibiotic administration; cesarean birth; and local protocols for perinatal care, neonatal resuscitation, and intensive care support). These are, in turn, influenced by the variations in local and regional definitions of limits of viability. Because of the complexities in making difficult management decisions, obstetric and neonatal teams should confer prior to meeting with the family, when feasible. Family counseling should be coordinated with the goal of creating mutual trust, respect, and understanding and should incorporate evidence-based counseling methods. Since clinical circumstances can change rapidly with increasing gestational age, counseling should include discussion of the benefits and risks of various maternal and neonatal interventions at the time of counseling. There should be a plan for follow-up counseling as clinical circumstances evolve. The panel proposed a research agenda and recommended developing educational curricula on the care and counseling of families facing the birth of a periviable infant.

Treatment of presumed hypotension in very low birthweight neonates: effects on regional cerebral oxygenation.

CONTEXT: Previous studies have correlated poor neurological outcomes with hypotension. Treatment of hypotension in very low birthweight (VLBW) infants is common, and most often is based solely on the blood pressure measurement. Whether treatment improves cerebral oxygenation is unclear. OBJECTIVE: To determine if treatment of hypotension in VLBW neonates results in an increase in cerebral oxygenation. PATIENTS AND METHODS: In this single centre observational study, neonates <30 weeks and <1500 grams, blood pressure and regional cerebral oximetry (rCSO2) with near infrared spectroscopy were continuously monitored and digitally recorded. If patients were treated for hypotension during the first 3 days of life, effects of treatment on blood pressure and regional cerebral saturation were determined. RESULTS: Twenty-eight of 50 patients were treated by the medical team for hypotension, of which 22 had accurate data recorded for analysis. Both normal saline 10 ml/kg, and dopamine 2.5-5 mcg/kg per min significantly increased blood pressure, (saline 26.8±3.5 to 28.8±4.2 mm Hg, p<0.005; dopamine 27.6±1.9 to 29.5±3.2 mm Hg, p<0.02). Pre-treatment values of rCSO2 were similar to published normative values and treatment with either normal saline or dopamine had no effect on rCSO2. CONCLUSION: These results suggest that treating hypotension in VLBW neonates based solely on a blood pressure measurement of less than 30 mm Hg, while increasing blood pressure, may not increase cerebral oxygenation, possibly because many of these patients are in the autoregulatory zone for cerebral blood flow.

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections.

BACKGROUND: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. METHODS: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. RESULTS: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23-40) weeks and 21 (1-92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 µg/mL for 50% of the dose interval and >2 µg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5-148). CONCLUSIONS: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.