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.

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.

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.

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.

A single dose of fentanyl and midazolam prior to Cesarean section have no adverse neonatal effects.

PURPOSE: Analgesia and sedation, routinely used as adjunct medications for regional anesthesia, are rarely used in the pregnant patient because of concerns about adverse neonatal effects. In an effort to obtain more information about maternal analgesia and sedation we studied neonatal and maternal effects of iv fentanyl and midazolam prior to spinal anesthesia for elective Cesarean section. METHODS: In this double-blinded, randomized, placebo-controlled trial, 60 healthy women received either a combination of 1 microg x kg(-1) fentanyl and 0.02 mg x kg(-1) midazolam intravenously or an equal volume of iv saline at the time of their skin preparation for a bupivacaine spinal anesthetic. Sample size was based on a non-parametric power analysis (power > 0.80 and alpha = 0.05) for clinically important differences in Apgar scores. Fetal outcome measures included Apgar scores, continuous pulse oximetry for three hours, and neurobehavioural scores. Maternal outcomes included catecholamine levels, and recall of anesthesia and delivery. RESULTS: There were no between-group differences of neonatal outcome variables (Apgar score, neurobehavioural scores, continuous oxygen saturation). Mothers in both groups showed no difference in their ability to recall the birth of their babies. CONCLUSIONS: Maternal analgesia and sedation with fentanyl (1 microg x kg(-1)) and midazolam (0.02 mg x kg(-1)) immediately prior to spinal anesthesia is not associated with adverse neonatal effects.

Laryngeal muscle activities with cerebral hypoxia-ischemia in newborn lambs.

This study tested the hypotheses that (1) acute cerebral hypoxia-ischemia changes laryngeal adductor, laryngeal abductor, and diaphragmatic activities, resulting in central apnea with laryngeal closure; and (2) these laryngeal muscle activities act to maintain absolute lung volume. The respiratory pattern was determined in three asphyxiated, awake preterm lambs after cesarean section birth and in 12 awake, term lambs, with normal lung function, after induction of acute cerebral hypoxia-ischemia by occlusion of the brachiocephalic artery. Electrocorticogram activity, flow, volume, electromyograms of laryngeal abductor and adductor muscles and diaphragm, and, in the term lambs, trans-upper airway pressure and carotid blood flow were recorded. With either preterm birth asphyxia or induced acute cerebral hypoxia-ischemia, minute ventilation initially increased, and then hypopnea occurred. During the hypopnea, laryngeal adductor activity was prominent, accompanied by an increased upper airway pressure and a maintained/raised absolute lung volume. Thus, when acute hypoxia-ischemia limited to the upper body is induced in lambs with normal lung function, expiratory laryngeal adduction with closure of the upper airway occurs and likely functions to aid autoresuscitation.