Silvia Maria Ibidi

Low Apgar scores at 5 minutes in a low risk population: maternal and obstetrical factors and postnatal outcome

OBJECTIVE To evaluate the association between Apgar scores of less than seven at five minutes (AS5min < 7) and antenatal factors and postnatal outcomes. METHODS A retrospective cohort and case-control study of 27,252 consecutive term newborns in a low risk obstetrical population between January 2003 and December 2010. Maternal and infant databases were reviewed from all cases with AS5min < 7 (n = 121; 0.4%) and 363 cases with AS5min > 7 at 5 minutes who were randomly selected by a computer program. The main outcomes were neonatal death, newborn respiratory distress, need for orotracheal intubation and neonatal intensive care unit (NICU), and hypoxic-ischemic-encephalopathy. RESULTS After multiple regression analysis, repeated late decelerations on cardiotocography (OR: 2.4; 95% CI: 1.4-4.1) and prolonged second stage of labor (OR: 3.3; 95% CI: 1.3-8.3) were associated with AS5min < 7, as well as neonatal respiratory distress (OR: 3.0; 95% CI: 1.3-6.9), orotracheal intubation (OR: 2.5; 95% CI: 1.2-4.8), need for NICU (OR: 9.5; 95% CI: 6.7-16.8), and hypoxic-ischemic-encephalopathy (OR: 14.1; 95% CI: 3.6-54.7). No other antenatal factors were associated with AS5min < 7 (p > 0.05). CONCLUSION Repeated late decelerations and prolonged second stage of labor in the low-risk population are predictors of AS5min < 7, a situation associated with increased risk of neonatal respiratory distress, need for mechanical ventilatory support and NICU, and hypoxic-ischemic-encephalopathy.

Maternal smoking during pregnancy: Impact on otoacoustic emissions in neonates

OBJECTIVES To determine the effect of maternal smoking during pregnancy on transient evoked otoacoustic emissions levels in neonates. METHODS This was a cross-sectional study investigating neonates in the maternity ward of a university hospital in the city of São Paulo, Brazil. A total of 418 term neonates without prenatal or perinatal complications were evaluated. The neonates were divided into two groups: a study group, which comprised 98 neonates born to mothers who had smoked during pregnancy; and a control group, which comprised 320 neonates born to mothers who had not. In order to compare the two ears and the two groups in terms of the mean overall response and the mean transient evoked otoacoustic emissions in response to acoustic stimuli delivered at different frequencies, we used analysis of variance with repeated measures. RESULTS The mean overall response and the mean frequency-specific response levels were lower in the neonates in the study group (p<0.001). The mean difference between the groups was 2.47 dB sound pressure level (95% confidence interval: 1.47-3.48). CONCLUSIONS Maternal smoking during pregnancy had a negative effect on cochlear function, as determined by otoacoustic emissions testing. Therefore, pregnant women should be warned of this additional hazard of smoking. It is important that smoking control be viewed as a public health priority and that strategies for treating tobacco dependence be devised.

Dietary transition difficulties in preterm infants: critical literature review

OBJECTIVE To analyze the scientific literature on dietary changes in preterm children during the first years of life. DATA SOURCE The PubMed database was used for article selection. The texts were analyzed according to their objectives, research design, and research group characteristics. The following were selected to comprise the criteria: (1) publications in the period from 1996 to 2014; (2) participation of infants and children from birth to 10 years of age; (3) development of oral motor skills necessary for feeding; (4) development of the feeding process; and (5) feeding difficulties during childhood. SUMMARY OF THE FINDINGS There were 282 studies identified, of which 17 were used in the review, and five more articles were identified through the reference list of selected articles, totaling 22 references. CONCLUSION Very low birth weight preterm newborns are more likely to have feeding problems in early postnatal stages and during childhood when compared with full-term infants. Monitoring the feeding of these infants after hospital discharge is strictly recommended in an early intervention program aiming at better development of feeding skills.

Efferent inhibition of otoacoustic emissions in preterm neonates

INTRODUCTION Abnormalities in auditory function of newborns may occur not only because of preterm birth, but also from the use of medications and from diseases related to prematurity. OBJECTIVE To analyze the inhibitory effect from stimulation of the olivocochlear efferent system on transient evoked otoacoustic emissions in preterm neonates, comparing these data with those from full-term neonates. METHODS This was a prospective, cross-sectional, contemporary cohort study with 125 neonates, pooled into two groups: full-term (72 full-term neonates, 36 females and 36 males, born at 37-41 weeks of gestational age); and preterm (53 neonates, 28 males and 25 females, born at ≤36 weeks of gestational age, evaluated at the corrected gestational age of 37-41 weeks). Otoacoustic emissions were recorded using linear and nonlinear click-evoked stimuli, with and without contralateral stimulation. RESULTS The inhibitory effect of the efferent pathway in otoacoustic emissions was different (p=0.012) between groups, and a mean reduction of 1.48dB SPL in full-term births and of 1.02dB SPL in preterm births was observed for the non-linear click-evoked stimulus. CONCLUSION The results suggest a reduced inhibitory effect of the olivocochlear efferent system on otoacoustic emissions in preterm neonates.

Middle ear muscle reflex measurement in neonates: Comparison between 1000 Hz and 226 Hz probe tones

INTRODUCTION Middle ear muscle reflex (MEMR) evaluation assists in diagnosing hearing problems because normal responses depend on preconditions of a healthy auditory system. Studies in neonates recording the acoustic reflex with 226Hz probes have described high rates of absence. Other studies using a high frequency probe have found higher rates of presence in normal neonates. However, few studies have compared results between low and high frequency probes in the same newborns. OBJECTIVE To comparatively assess the ipsilateral acoustic reflex recorded by 226Hz and 1000Hz probes in newborns. METHOD A total of 77 newborns, with the presence of transient otoacoustic emissions, underwent tympanometry, wideband acoustic immittance, and ipsilateral reflex investigations with 226Hz and 1000Hz tone probes. RESULTS The acoustic reflex was activated at a much lower intensity with all activating stimuli using the 1000Hz probe compared with the values of the 226Hz probe. There was a higher incidence of ipsilateral acoustic reflexes recorded by the 1000Hz tone probe compared to the 226Hz tone probe. There was no correlation between the acoustic reflex thresholds and otoacoustic emissions. CONCLUSION In newborns, the acoustic reflex measurements obtained with the 1000Hz probe showed advantages over the 226Hz probe.

Congenital generalized lymphangiectasia: a rare developmental disorder for non-immune fetal hydrops

Firstly described by Rudolf Virchow in the 19th century, congenital generalized lymphangiectasia is a rare entity characterized by dilation of lymphatic vessels, and was recently classified in primary or secondary lymphangiectasia. Generalized forms may be diagnosed during pre-natal follow-up with ultrasound examination, and, depending on its severity, the newborn outcome is very poor. The authors report the case of a female newborn with a previous diagnosis of fetal hydropsy who was born after a full-term gestation with respiratory failure due to bilateral voluminous pleural effusion and ascites. Physical examination also disclosed syndromic facies. Despite all efforts of the intensive supportive care, the patient died after 24 days of life. The autopsy findings were consistent with the diagnosis of congenital pulmonary lymphangiectasia. The authors call attention to this rare diagnosis in patients with cavitary effusion and respiratory insufficiency at birth.

Number needed to treat in fluconazole prophylaxis in the neonatal intensive care unit.

To the Editors: In a recent publication in this journal, Rueda et al conducted a study in a developing country and demonstrated that routine prophylactic use of fluconazole at birth versus placebo in 523 neonates less than 1250 g is associated with significant impact on the frequency of documented systemic Candida infection (CI). The control group developed CI in 21 (7.7%), whereas the treatment group had only 3 (1.1%) CI. The benefit of prophylactic fluconazole (PF) to prevent a systemic CI was represented by the number needed to treat (NNT) with a nominal value of 7 according to Rueda et al. This measure is calculated on the inverse of the absolute risk reduction. NNT of 7 means that it is necessary to treat 7 neonates with PF to prevent 1 CI. This NNT is calculated incorrectly. Considering the absolute risk reduction of 6.6% (7.7% 1.1%), the NNT should be 15.2 (calculated by 1/6.6%) instead of 7. Although this error does not change the statistical significance of the benefit of fluconazole in the study of Rueda et al (P 0.007), for pharmacoeconomic analysis studies, this error has an important impact. There is scant information from developing countries about PF in neonates, and the estimated NNT of 15.2 is acceptable. A broader view on the updated systematic review results of the Cochrane metaanalysis of 5 of 8 eligible trials on “systemic antifungal agents prophylatic in low birth weight infants,” issue 12, 2010, revealed that NNT for PF is in line with the confidence intervals of PF, with significant reduction in the risk of invasive fungal infection in the infants who received prophylaxis (NNT 11; 95% confidence interval, 7–33). Although it requires confirmation from future studies, the prophylactic use of fluconazole in premature infants of lower weight, with higher natural risk of systemic candidiasis (extremely low birth weight 1000 g), suggests a greater benefit: the calculated NNT is 2.68 for fungal colonization (22% PF 60% placebo) and NNT of 5 for systemic fungal infection (0% PF 20% placebo). Moreover, the systematic reviews still show a nonsignificant decrease in the risk of death before hospital discharge (typical relative risk, 0.74 95% confidence interval, 0.51–1.09 ). To date, the only untoward effects reported with fluconazole use in preterm infants are reversible elevations in hepatic enzymes or bilirubin, without sequelae.

Comparison of main trials of recombinant human activated protein C in sepsis-are we encouraging more bleeding in neonates?

To the Editor: Since the section in Pediatric Critical Care Medicine focused on neonatal intensive care was first announced in January 2006, we were pleasantly surprised by continued publication of high-quality manuscripts in this area, including the observational study of Beshlawy et al (1) about the physiologic coagulation inhibitors: proteins C, S, and antithrombin III. Regarding this study, we would like to make a few considerations. First, there was an unintentional oversight of aforementioned Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study(2), the most relevant published study about recombinant human activated protein C (rh-aPC), in the references. Since its publication in 2001, PROWESS (2, 3) has been counted with 2504 citations (ISI-Web.of.Science in April 22, 2010), and is the cornerstone for rh-aPC therapy in adults. In that study, an absolute decrease in mortality of 6% and a number-needed-to-treat of 16 were demonstrated (2, 3). Second, we noted the absence of mortality scores for comparison with the high reported mortality (57%) in septic fullterm neonates (shown in Beshlawy’s Table 3) (1) and intracranial hemorrhage rate (23.3%) (1), which is 11 times higher than the baseline risk of bleeding reported in PROWESS (2%) (2). Finally, the conclusion by Beshlawy’s group (1) encourages “further placebocontrolled clinical trials to investigate the role of activated protein C and antithrombin-III in severe neonatal sepsis, and specially, in the states of DIC [disseminated intravascular coagulation].” Such a conclusion seems controversial to us, for the reasons specified below. When a specific pharmacologic treatment is recommended, it should target clear advantages that outweigh the possible side effects. This is far from true for almost the totality of physiologic coagulation inhibitors studies. In Table 1 , we have compiled seven of the most relevant trials on physiologic coagulation inhibitors (2–4) (n 13,244 patients), alongside the study of Beshlawy et al (1) (n 60 patients). Randomized controlled trials which evaluated the use of rh-aPC in adults with Acute Physiology and Chronic Health Evaluation 25 (Administration of Drotrecogin Alfa [Activated] in Early Stage Severe Sepsis [ADDRESS]) (3) and in children (Safety and Efficacy of Ranibizumab in Diabetic Macular Edema With Center Involvement [RESOLVE]) (3) failed to show any benefit in mortality but demonstrated an increase in bleeding risks (3, 5) (Table 1). Similarly, randomized controlled trials on antithrombin III (High-Dose Antithrombin III in Severe Sepsis Trial) (4) and recombinant tissue factor pathway inhibitor (Tifacogin/ Optimized Phase 3 Tifacogin in Multicenter Sepsis Trial [OPTIMIST]) (6) showed no improvement in 28-day mortality. Interestingly, the Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) trial was a single arm study, and impact on mortality was determined by historical comparisons with PROWESS’s placebo. In contrast, analyzing the risk of hazard shows an increase in the number of bleeding and severe bleeding events (3.5% to 10%) (2–4) secondary to physiologic coagulation inhibitors treatments. The only randomized controlled trial (PROWESS, 1690 patients) showing a treatment benefit over placebo has also demonstrated more severe bleeding (3.5% 2.0%, p .06) and intracranial hemorrhage (2). An editorial published in 2009 (5) noticed that the prevalence of serious bleeding during infusion is lower in studies sponsored by the manufacturers (mean, 2.5% to 3.4% in PROWESS/ADDRESS/ ENHANCE/MERCURY/Xigris and Prophylactic Heparin Evaluation in Severe Sepsis Study [XPRESS]/Wheeler) (5) than in independent studies (mean, 7.2% in Gentry/Bertolini/Kanji/ Voluntary Health Association and University Health System Consortium) (5). We calculated that the number needed to harm for serious bleeding in PROWESS was 66, and it ranges from 22 (ENHANCE), 40 (RESOLVE-Intracranial hemorrhage), 58 (ADDRESS), 52 (XPRESS) sponsored trials (Table 1) to 9.7 (Gentry), 11 (Bertolini), 12 (Kanji), 37 (Voluntary Health Association and University Health System Consortium) independent trials . Studies with adequate statistical power and negative results have strongly suggested the nonindication of those lowefficacy treatments in low-risk adults (3) and in pediatric patients(3). Therefore, recommendations for further studies with rh-aPC, antithrombin III, and tifacogin (r-TFPI) in neonates—a wellknown high-risk population for severe bleeding (23.3%) (1)—should be cautious and, possibly, reconsidered. We thank Dr. Débora Cristina Raulik Shieh of Universidade Federal do Paraná for her assistance in the preparation of the manuscript. The authors have not disclosed any potential conflicts of interest.