William E. Benitz

Serial Serum C-Reactive Protein Levels in the Diagnosis of Neonatal Infection

Objective. To evaluate serial serum C-reactive protein (CRP) levels for diagnosis of neonatal infection. Setting. A regional intensive care nursery and two community intensive care nurseries. Methods. All neonates treated for suspected bacterial infection were prospectively evaluated using a standardized clinical pathway. Infants were categorized as having proven sepsis (bacteria isolated from blood, cerebrospinal fluid, or urine culture), probable sepsis (clinical and laboratory findings consistent with bacterial infection without a positive culture), or no sepsis (findings not consistent with sepsis), without consideration of CRP levels. Infants whose blood cultures yielded skin flora but who demonstrated no other signs of bacterial infection were not considered to have sepsis. CRP levels were determined at the initial evaluation and on each of the next two mornings. Sensitivity, specificity, predictive values, and likelihood ratios were calculated for the first (CRP #1), second (CRP #2), higher of the second and third (CRP #2 and #3), or highest of all three CRP levels (CRP × 3). Results. Sepsis was suspected within the first 3 days after birth in 1002 infants (early-onset) and on 184 occasions in 134 older infants (late-onset). There were 20 early-onset and 53 late-onset episodes of proven sepsis, and 74 early-onset and 12 late-onset episodes of probable sepsis. CRP #1 had sensitivities of 39.4% and 64.6% for proven or probable sepsis and 35.0% and 61.5% for proven sepsis in early-onset and late-onset episodes, respectively. CRP levels on the morning after the initial evaluation (CRP #2) had higher sensitivities (92.9% and 85.0% for proven or probable sepsis and 78.9% and 84.4% for proven sepsis in early-onset and late-onset episodes, respectively), and normal results were associated with lower likelihoods of infection (likelihood ratios for normal results of 0.10 and 0.19 for proven or probable sepsis and 0.27 and 0.21 for proven sepsis, in early-onset and late-onset episodes, respectively). Three serial serum CRP levels had sensitivities of 97.8% and 98.1% for proven or probable sepsis and 88.9% and 97.5% for proven sepsis in early-onset and late-onset episodes, respectively. The negative predictive values for CRP × 3 were 99.7% and 98.7% for both proven or probable sepsis and for proven sepsis in early-onset and late-onset episodes, respectively. A CRP level obtained at the time of the initial evaluation can be omitted without significant loss of sensitivity or negative predictive value: the sensitivities of CRP #2 and #3 were 97.6% and 94.4% for proven or probable sepsis and 88.9% and 96.4% for proven sepsis in early-onset and late-onset episodes, respectively; negative predictive values were 99.7% both for proven and for proven or probable early-onset sepsis, 97.6% for proven or probable late-onset infection, and 98.8% for proven late-onset infection. Serial normal CRP levels were associated with a markedly reduced likelihood of infection as compared with that in the entire population before testing, with likelihood ratios ranging from 0.03 to 0.16 for the various subgroups. Maximum CRP levels >3 mg/dL had positive predictive values >20% for proven or probable early-onset infections and for proven or probable and proven late-onset infections, but only those >6 mg/dL had such a high positive predictive value for proven early-onset sepsis. Conclusions. Serial CRP levels are useful in the diagnostic evaluation of neonates with suspected infection. Two CRP levels <1 mg/dL obtained 24 hours apart, 8 to 48 hours after presentation, indicate that bacterial infection is unlikely. The sensitivity of a normal CRP at the initial evaluation is not sufficient to justify withholding antibiotic therapy. The positive predictive value of elevated CRP levels is low, especially for culture-proven early-onset infections.

Risk Factors for Early-onset Group B Streptococcal Sepsis: Estimation of Odds Ratios by Critical Literature Review

Objective. To identify and to establish the prevalence of ORs for factors associated with increased risk for early-onset group B streptococcal (EOGBS) infection in neonates. Study Design. Literature review and reanalysis of published data. Results. Risk factors for EOGBS infection include group B streptococcal (GBS)-positive vaginal culture at delivery (OR: 204), GBS-positive rectovaginal culture at 28 (OR: 9.64) or 36 weeks gestation (OR: 26.7), vaginal Strep B OIA test positive at delivery (OR: 15.4), birth weight ≤ 2500 g (OR: 7.37), gestation <37 weeks (OR: 4.83), gestation <28 weeks (OR: 21.7), prolonged rupture of membranes (PROM) >18 hours (OR: 7.28), intrapartum fever >37.5°C (OR: 4.05), intrapartum fever, PROM, or prematurity (OR: 9.74), intrapartum fever or PROM at term (OR: 11.5), chorioamnionitis (OR: 6.43). Chorioamnionitis is reported in most (88%) cases in which neonatal infection occurred despite intrapartum maternal antibiotic therapy. ORs could not be estimated for maternal GBS bacteriuria during pregnancy, with preterm premature rupture of membranes, or with a sibling or twin with invasive GBS disease, but these findings seem to be associated with a very high risk. Multiple gestation is not an independent risk factor for GBS infection. Conclusions. Mothers with GBS bacteriuria during pregnancy, with another child with GBS disease, or with chorioamnionitis should receive empirical intrapartum antibiotic treatment. Their infants should have complete diagnostic evaluations and receive empirical treatment until infection is excluded by observation and negative cultures because of their particularly high risk for EOGBS infection. Either screening with cultures at 28 weeks gestation or identification of clinical risk factors, ie, PROM, intrapartum fever, or prematurity, may identify parturients whose infants include 65% of those with EOGBS infection. Intrapartum screening using the Strep B OIA rapid test identifies more at-risk infants (75%) than any other method. These risk identifiers may permit judicious selection of patients for prophylactic interventions.

Levels of Neonatal Care

Provision of risk-appropriate care for newborn infants and mothers was first proposed in 1976. This updated policy statement provides a review of data supporting evidence for a tiered provision of care and reaffirms the need for uniform, nationally applicable definitions and consistent standards of service for public health to improve neonatal outcomes. Facilities that provide hospital care for newborn infants should be classified on the basis of functional capabilities, and these facilities should be organized within a regionalized system of perinatal care.

Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?

Medical and surgical interventions are widely used to close a persistently patent ductus arteriosus in preterm infants. Objective evidence to support these practices is lacking, causing some to question their usage. Emerging evidence suggests that treatments that close the patent ductus may be detrimental. This review examines the history of and evidence underlying these treatments. Neither individual trials, pooled data from groups of randomized-controlled trials, nor critical examination of the immediate consequences of treatment provide evidence that medical or surgical closure of the ductus is beneficial in preterm infants. These conclusions are supported by sufficient evidence. Neither continued routine use of these treatments nor additional clinical trials using similar designs seems to be justified. A definitive trial, comparing current standard management with novel strategies not primarily intended to achieve ductal closure, may be necessary to resolve doubts regarding the quality or conduct of prior studies.

Retinopathy of Prematurity and Pulse Oximetry: A National Survey of Recent Practices

OBJECTIVE: To determine if practices related to the use of pulse oximetry in the first 2 weeks following birth and after 2 weeks of age have a relationship to the rate of retinopathy of prematurity (ROP) and retinal ablation surgery in infants ≤1500 g.STUDY DESIGN: A questionnaire was mailed in July 2001 to 318 neonatal intensive care units (NICUs) in the United States and information was collected regarding SpO2 guidelines and the rate of both severe ROP and retinal ablation surgery.RESULTS: A total of 142 surveys were returned (45%). In all, 87% of the NICUs had SpO2 guidelines, and 60% of these centers maintained a different range of SpO2 for infants ≤ or >2 weeks of age. The range of SpO2 was 82 to 100% with an average minimum (min) and maximum (max) of 89 and 95%, respectively. In the NICUs with an SpO2 max of >98% in the first 2 weeks following birth, the rate of retinal ablation surgery was 5.5 vs 3% in those units with a max SpO2 >98% (p<0.05). After 2 weeks of age, the rate of retinal ablation surgery was 3.3% when max SpO2 was >92 vs 1.3% when the max SpO2 was ≤92% (p<0.00001). The rate of ≥stage 3 ROP after 2 weeks of age was 5.5% when max SpO2 was >92 vs 2.4% when max SpO2 was ≤92% (p<0.0005).CONCLUSION: NICUs in the US today have a wide range of SpO2 guidelines. The results of this survey show a “gradient of risk” towards less retinal ablation surgery when the max SpO2 is <98% in the first 2 weeks following birth (p<0.05). There was a statistically significant lower rate of ≥stage 3 ROP and retinal ablation surgery when the max SpO2 was ≤92% after the first 2 weeks of age. A randomized, controlled trial is needed to establish a safe upper limit of SpO2 in the premature infant at risk for developing ROP.

Hypothermia and neonatal encephalopathy.

Data from large randomized clinical trials indicate that therapeutic hypothermia, using either selective head cooling or systemic cooling, is an effective therapy for neonatal encephalopathy. Infants selected for cooling must meet the criteria outlined in published clinical trials. The implementation of cooling needs to be performed at centers that have the capability to manage medically complex infants. Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.

Combining hand techniques with electric pumping increases milk production in mothers of preterm infants.

Objective:Pump-dependent mothers of preterm infants commonly experience insufficient production. We observed additional milk could be expressed following pumping using hand techniques. We explored the effect on production of hand expression of colostrum and hands-on pumping (HOP) of mature milk.Study Design:A total of 67 mothers of infants <31 weeks gestation were enrolled and instructed on pumping, hand expression of colostrum and HOP. Expression records for 8 weeks and medical records were used to assess production variables.Result:Seventy-eight percent of the mothers completed the study. Mean daily volumes (MDV) rose to 820 ml per day by week 8 and 955 ml per day in mothers who hand expressed >5 per day in the first 3 days. Week 2 and/or week 8 MDV related to hand expression (P<0.005), maternal age, gestational age, pumping frequency, duration, longest interval between pumpings and HOP (P<0.003). Mothers taught HOP increased MDV (48%) despite pumping less.Conclusion:Mothers of preterm infants may avoid insufficient production by combining hand techniques with pumping.

Adjunct Laboratory Tests in the Diagnosis of Early-Onset Neonatal Sepsis

Early-onset sepsis remains a major diagnostic problem in neonatal medicine. Definitive diagnosis depends on cultures of blood or other normally sterile body fluids. Abnormal hematological counts, acute-phase reactants, and inflammatory cytokines are neither sensitive nor specific, especially at the onset of illness. Combinations of measurements improve diagnostic test performance, but the optimal selection of analytes has not been determined. The best-established use of these laboratory tests is for retrospective determination that an infant was not infected, based on failure to mount an acute-phase response over the following 24 to 48 hours.

Prevention and management of procedural pain in the neonate: An update

The prevention of pain in neonates should be the goal of all pediatricians and health care professionals who work with neonates, not only because it is ethical but also because repeated painful exposures have the potential for deleterious consequences. Neonates at greatest risk of neurodevelopmental impairment as a result of preterm birth (ie, the smallest and sickest) are also those most likely to be exposed to the greatest number of painful stimuli in the NICU. Although there are major gaps in knowledge regarding the most effective way to prevent and relieve pain in neonates, proven and safe therapies are currently underused for routine minor, yet painful procedures. Therefore, every health care facility caring for neonates should implement (1) a pain-prevention program that includes strategies for minimizing the number of painful procedures performed and (2) a pain assessment and management plan that includes routine assessment of pain, pharmacologic and nonpharmacologic therapies for the prevention of pain associated with routine minor procedures, and measures for minimizing pain associated with surgery and other major procedures.

Respiratory support in preterm infants at birth.

Current practice guidelines recommend administration of surfactant at or soon after birth in preterm infants with respiratory distress syndrome. However, recent multicenter randomized controlled trials indicate that early use of continuous positive airway pressure with subsequent selective surfactant administration in extremely preterm infants results in lower rates of bronchopulmonary dysplasia/death when compared with treatment with prophylactic or early surfactant therapy. Continuous positive airway pressure started at or soon after birth with subsequent selective surfactant administration may be considered as an alternative to routine intubation with prophylactic or early surfactant administration in preterm infants.