Advances in Neonatal Infections.

Despite continued advances and developments in neonatal medicine, neonatal sepsis is the third leading cause of neonatal mortality and a major public health problem, especially in developing countries. Sepsis accounts for mortality for almost 50% of global children under 5 years of age.Over the past 50 years, there have been many advances in the diagnosis, prevention, and treatment of neonatal infections. The diagnostic advances include better culture techniques that permit more rapid confirmation of the diagnosis, advent of polymerase chain reaction (PCR) to rapidly diagnose viral infections, use of biologic markers indicating evidence of infection, and a better understanding of immunoglobulin markers of infection. From a therapeutic stand point, there have been a variety of antibiotics, antifungals, and antiviral agents, better approaches to prevent sepsis, specific immunotherapy, for example, respiratory syncytial virus (RSV); bundled approach to prevention of deep-line infection and better antibiotic stewardship, leading to earlier discontinuation of antibiotic therapy.Hand hygiene remains the benchmark and gold standard for late-onset sepsis prevention. The challenge has been that each decade, newer resistant bacteria dominate as the cause of sepsis and newer viruses emerge, for example, human immunodeficiency virus, zika virus, and novel coronavirus disease 2019.Future treatment options might include stem cell therapy, other antimicrobial protein and peptides, and targeting of pattern recognition receptors in an effort to prevent and/or treat sepsis in this vulnerable population. Also, the microbiome of premature infants has a smaller proportion of beneficial bacteria and higher numbers of pathogenic bacteria compared with term infants, likely owing to higher frequencies of cesarean sections, antibiotic use, exposure to the hospital environment, and feeding nonhuman milk products. Modifying the microbiome with more mother's milk and shorter duration of antibiotics in noninfected babies should be a goal. KEY POINTS: · Neonatal sepsis remains a leading cause of mortality.. · Challenges include bacterial resistance and newer viruses.. · Future treatments may include newer antibiotics/antivirals and stem cell therapy..

The ongoing quandary of defining the standard of care for neonates.

UNLABELLED: Despite extensive use of the term 'standard of care' (SOC), there is no such medical definition. How are neonatal therapies accepted as SOC with huge centre-to-centre variation? What defines SOC? We will consider paths to acceptance of multiple therapies (antenatal corticosteroids, preventing GBS, others). We conclude single-centre trials drive care, but are not consistently predictive for multicentre trials. Innovation/quality improvement initiatives also alter care, despite strong evidence practice changes take time. Furthermore, there are powerful medico-legal implications if a therapy is designated SOC. CONCLUSION: Defining SOC is a quandary with more legal implications than medical, but what's most critical is keeping current in a rapidly changing field.

Death or neurodevelopmental impairment at 18 to 22 months corrected age in a randomized trial of early dexamethasone to prevent death or chronic lung disease in extremely low birth weight infants.

OBJECTIVE: To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants. STUDY DESIGN: Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment. RESULTS: Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02). CONCLUSION: The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.

The preterm lung and airway: past, present, and future.

The tremendous advancement that has occurred in neonatal intensive care over the last 40-50 years can be largely attributed to greater understanding of developmental pathobiology in the newborn lung. Nonetheless, this improved survival from respiratory distress syndrome has been associated with continuing longer-term morbidity in the form of bronchopulmonary dysplasia (BPD). As a result, neonatal lung injury is a renewed focus of scientific interest. The onset of such an injury may begin in the delivery room, and this has generated interest in minimizing oxygen therapy and aggressive ventilatory support during the transition from fetal to neonatal lung. Fortunately, antenatal steroid therapy and selective use of surfactant therapy are now widely practiced, although fine tuning of this therapy for selected populations is ongoing. Newer therapeutic approaches address many aspects of BPD, including the pro-inflammatory component that characterizes this disorder. Finally, there is a greater need to understand the epidemiology and pathogenesis of the longer-term respiratory morbidity, most notably asthma, that persists in the preterm survivors of neonatal intensive care.

Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks' gestation.

CONTEXT: Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care. OBJECTIVE: To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10,541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables. MAIN OUTCOME MEASURES: Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age. RESULTS: Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]). CONCLUSION: Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

Cytokines and neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVE: To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants. STUDY DESIGN: Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1ß; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. RESULTS: IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-ß, soluble IL rα, macrophage inflammatory protein 1ß) were found to be altered on days 0-4 in infants who developed CP. CONCLUSIONS: CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

Predictive value of an early amplitude integrated electroencephalogram and neurologic examination.

OBJECTIVE: To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia. DESIGN: Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months. RESULTS: There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19). CONCLUSIONS: The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.

Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial.

It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.

Aggressive vs. conservative phototherapy for infants with extremely low birth weight.

BACKGROUND: It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). METHODS: We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. RESULTS: Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. CONCLUSIONS: Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

Trends in neonatal morbidity and mortality for very low birthweight infants.

OBJECTIVE: To document the mortality and morbidity of infants weighing 501-1500 g at birth according to gestational age, birthweight, and sex. STUDY DESIGN: Prospective collection of perinatal events and neonatal course to 120 days of life, discharge, or death from January 1990 through December 2002 for infants born at 16 participating centers of the National Institute of Child Health & Human Development Neonatal Research Network. RESULTS: Compared with 1995-1996, for 1997-2002 the survival of infants with birthweight of 501-1500 g increased by 1 percentage point (from 84% to 85%). Survival without major neonatal morbidity remained static, at 70%; this includes bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Survival increased for multiple births (26%, up from 22%), antenatal corticosteroid use (79%, up from 71%), and maternal antibiotics (70%, up from 62%) (P < .05). From 1997 to 2002, birthweight-specific survival was 55% for infants weighing 501-750 g, 88% for 751-1000 g, 94% for 1001-1250 g, and 96% for 1251-1500 g. More females survived. The incidence of NEC (7%), severe IVH (12%), and late-onset septicemia (22%) remained essentially unchanged, but BPD decreased slightly, from 23% to 22%. The use of postnatal corticosteroids declined from 20% in 1997-2000 to 12% in 2001-2002. Growth failure (weight <10th percentile) at 36 weeks' postmenstrual age decreased from 97% in 1995-1996 to 91% in 1997-2002. CONCLUSION: There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002. We speculate that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.

Short- and long-term consequences of hypotension in ELBW infants.

BACKGROUND: Hypotension affects close to half of all ELBW infants, yet an agreement on its definition is still lacking. Despite the fact that neonatal hypotension may be a risk factor for neurologic impairment, there is a paucity of data on the impact of low blood pressure (BP) in extremely low birth weight (ELBW) infants weighing below 1000 g on neuro-developmental outcome. OBJECTIVES: Explore the relationship between blood pressure in the first 72 hours of life, perinatal factors, morbidity, and mortality in ELBW infants. Compare neuro-sensory outcome in ELBW infants with and without symptomatic hypotension. METHODS: We reviewed the outcome for all 156 infants with a birth weight <1000 g admitted to the neonatal intensive care unit covering the time period 1998 to 1999. Infants who received fluid pushes and/or pressors during the first 72 hours of life in an attempt to increase blood pressure were regarded as "symptomatic" or "treated infants"; the others were designated "non-treated infants." Follow-up at 20 months corrected age included neurologic status, Bayley motor/mental evaluation, plus tests of vision and hearing. Statistical analysis was by SPSS 11.0. Univariate and multivariate analyses were conducted to determine morbidities associated with symptomatic hypotension. RESULTS: A total of 59 infants (mean BW 714 +/- 154 g; GA 24.9 +/- 1.7 weeks) required BP support; 97 infants (mean BW 768 +/- 141 g; GA 26.1 +/- 1.9 weeks) received no BP support. The groups had similar race, gender, delivery mode, and maternal socioeconomic status. Thirty-five (22%) infants died, including 20 who received BP support. There were more infants with severe IVH (grade III/IV), 19% versus 2%, and the mortality was greater, 34% versus 16%, in those infants who received BP support. Of the 121 survivors, 110 (91%) had complete follow-up evaluations. Multivariate analysis controlling for SES and neonatal morbidity revealed that symptomatic hypotension is associated with delayed motor development (-6.0; SE 3.1) and hearing loss (O.R. 8.9; CI 0.92-86.3). CONCLUSIONS: Symptomatic hypotension in ELBW infants in the first 72 hours of life is associated with significant short-term and long-term morbidity. Infants with symptomatic hypotension are more likely to have delayed motor development, hearing loss, and death.

Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants.

BACKGROUND: Neonatal hypotension may be a risk factor for neurologic impairment. Few studies have examined the impact of low blood pressure in extremely low birth weight (ELBW) infants weighing 400 to 999 g on neurodevelopmental outcome. OBJECTIVES: We set out to explore the relationship between treated hypotension in the first 72 hours of life and perinatal factors, morbidity, and mortality in ELBW infants and then to compare neurosensory outcome in ELBW infants with treated hypotension and those who never received treatment for hypotension. DESIGN/METHODS: We performed chart review of all 156 ELBW infants admitted to our level III NICU in 1998-1999. Infants had "treated hypotension" if they received fluid pushes, corticosteroids, and/or vasopressors during the first 72 hours of life in an attempt to increase blood pressure. Follow-up included neurologic examination, Bayley Scales of Infant Development, vision and hearing evaluation. Statistical analysis was performed by using SPSS 11.0. Univariate and multivariate analyses were conducted to determine morbidities associated with treated hypotension. RESULTS: Fifty-nine infants received treatment for hypotension. Ninety-seven infants did not. The groups had similar race, gender, delivery mode, chorioamnionitis, and maternal socioeconomic status. Thirty-eight (24%) infants expired, including 20 who received treatment for hypotension. Of the 156 infants in the study group, 110 underwent neurodevelopment testing, and 103 were able to undergo complete neurodevelopment testing and Bayley examination. Multivariate analysis controlling for socioeconomic status and neonatal morbidity revealed that treated hypotension is associated with delayed motor development and hearing loss. CONCLUSIONS: Treated hypotension in ELBW infants in the first 72 hours of life is associated with significant short-term and long-term morbidity. Infants with treated hypotension are more likely to have delayed motor development, hearing loss, and death.