Jean Messer

Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection.

OBJECTIVE To evaluate plasma levels of interleukin-6 (IL-6) and soluble tumor necrosis factor receptors (sTNF-R) 55 and 75 in neonates as a contribution to the early diagnosis of infection. STUDY DESIGN We prospectively measured IL-6 and sTNF-R 55 and sTNF-R 75 plasma levels in 157 newborn infants admitted to our regional neonatal center in a 3-month period and in cord blood of 131 newborn infants delivered in our obstetrics unit. C-reactive protein was sequentially determined after admission. Newborn infants were classified into four groups: group 0, not infected; group 1, possibly infected; group 2a, infected (culture positive), and group 2b, probably infected (culture negative). We looked for the optimal cutoff point of these parameters, using the receiver operating characteristics (ROC) curve. RESULTS IL-6 levels were significantly higher in group 2 (n = 11; median level, 250 pg/ml; range, 0 to 81,000), group 2b (n = 25; median level, 750 pg/ml; range, 0 to 180,000), and group 1 (n = 35; median level, 160 pg/ml; range 0 to 10,000), in comparison with group 0 (n = 217; median level, 0 pg/ml; range, 0 to 3400). A cutoff value of 100 pg/ml or greater obtained by the ROC method gives a sensitivity of 83.3% and a specificity of 90.3%. For inborn infants (n = 220) sampled at birth, sensitivity is 100% and specificity 92.3%. This high sensitivity persists until the twelfth hour of life. The sTNF-R 55 levels are significantly higher in group 2a (median, 12.0 ng/ml; range, 3.2 to 24.4). In group 2b (median, 7.0 ng/ml; range, 3.0 to 25.2), and in group 1 (median, 7.0 ng/ml; range, 2.5 to 18.9) than in group 0 (median, 3.9 ng/ml; range, 1.5 to 15.0), and with a cutoff value of 6 ng/ml, sensitivity is 75% and specificity 69%. The sTNF-R 75 levels are significantly higher in group 2a (median, 17.0 ng/ml; range, 7.2 to 48.8). In group 2b (median, 11.2 ng/ ml; range, (2.0 to 31.3), and in group 1 (median, 10.6 ng/ml; range, 2.0 to 33.0); than in group 0 (median, 7.0 ng/ml; range, 1 to 23.0). With a cutoff value of 9 ng/ ml, sensitivity is 80% and specificity 67%. Sensitivity of C-reactive protein is low initially but improves with time. Combining IL-6 with C-reactive protein provides the possibility of identifying the majority of infected infants in the postnatal period. CONCLUSION A plasma IL-6 level of 100 pg/ml or greater, obtained before the twelfth hour of life, appears to be an ideal marker for detecting early-onset neonatal infection with a high degree of sensitivity and specificity. After the twelfth hour, the combined determination of IL-6 and C-reactive protein may be equally useful. The sTNF-R levels appear to be less useful in the early diagnosis of infection because of their smaller magnitude of variation.

Olfactory Stimulation Prevents Apnea in Premature Newborns

Objective. Methylxanthines and doxapram are currently used to treat apnea of prematurity but are not fully effective and often present undesirable side effects. The present study examines whether exposure to an odor known to modulate the infants respiratory rate could reduce the frequency of apneic spells. Method. Fourteen preterm newborns born at 24 to 28 gestational weeks presenting recurrent apnea despite caffeine and doxapram therapy were exposed to a pleasant odor diffused during 24 hours in the incubator. Efficiency of the olfactory treatment was judged by comparing frequency and severity of apneas occurring during the day of odorization with that observed the day before (baseline) and the day after (posttreatment control). Apnea was defined as any complete cessation of breathing movements for >20 seconds, or less if associated with hypoxia or bradycardia. Results. Concerning all types of apneas, a diminution of 36% was observed and seen in 12 of 14 infants. Apneas without bradycardia were reduced (44%) during the day with odorization, and this diminution affected all the infants. The frequency of apnea with moderate bradycardia (heart rate between 70 and 90 beats per minute) was maintained while the frequency of apnea associated with severe bradycardia (heart rate <70 beats per minute) decreased strongly (45%) and affected all the infants. No side effects were observed. Conclusion. The introduction of a pleasant odor in the incubator is of therapeutic value in the treatment of apneas unresponsive to caffeine and doxapram.

Incidence and distribution of pathogens in early-onset neonatal sepsis in the era of antenatal antibiotics.

In 2001 France issued a new set of guidelines for the use of antenatal antibiotics (AA). These guidelines recommended intrapartum antimicrobial prophylaxis (IAP) to prevent group B streptococcal (GBS) disease and AA to prolong pregnancy in the event of preterm premature rupture of membranes (AA for PPROM). This study aims to determine the effects of AA, recommended by national guidelines, on the incidence and distribution of pathogens in early-onset neonatal sepsis (EONS). We performed a population-based, prospective, observational study of level II and III perinatal centres throughout the region of Alsace, a northeastern area of France, between March 2004 and February 2005. The study population included all neonates with confirmed or probable EONS, who were treated with antibiotics for at least 5 days. We analysed exposure to AA, as well as clinical and microbiological data obtained from medical records. A total of 20 131 neonates were born during the study period, and 217 were included in the study. Of these, 24 subjects had confirmed sepsis, 140 had probable sepsis and 53 had possible EONS. The overall incidence of confirmed EONS was 1.19 per 1000 births. The infecting bacteria was GBS in 15 of 24 (62.5%) confirmed EONS cases (incidence: 0.75 per 1000 births) and in 81 of 140 (58%) probable sepsis cases. Escherichia coli was identified in 6 of 24 (25%) cases of confirmed EONS (incidence: 0.3 per 1000 births) and in 30 of 140 (21%) cases of clinical sepsis. Among E. coli infections (n= 36), amoxicillin resistance (n= 18) was statistically linked with AA use (P = 0.045). This link was significant in cases of PPROM (P = 0.015), but not when IAP was administered to prevent GBS disease (P = 0.264). IAP was not performed in 18 of 60 (30%) cases and 32 of 93 (34%) cases, despite positive screening or the presence of risk factors for EONS, respectively. Group B streptococcus remains the predominant pathogen in the era of AA. Aminopenicillin-resistant E. coli infections seem to be linked to prolonged AA in cases of PPROM and appear to preferentially affect preterm infants. Therefore, postnatal treatment strategies should consider this possible effect. Our data indicate that the current policy of GBS maternal prophylaxis is not associated with an excessive risk of pathogen resistance. Considering the high incidence of GBS EONS in our region, possible progress could result from better observance of guidelines. These results strengthen the need for continuation of surveillance.

Neonatal renal dysfunction and intrauterine exposure to prostaglandin synthesis inhibitors

Three cases of renal dysfunction at birth were observed in premature babies exposed in utero to prostaglandin synthetase inhibitors (PSI) and corticosteroids. Transient water and sodium retention with uraemia occurred in one patient, and severe acute renal failure with marked hyperkalaemia in twins. These findings may be due to impairment of prostaglandin (PG)-mediated renal adaptation to stress conditions after transplacental passage of PSI. Corticosteroids may also have affected PG synthesis inhibition.

A Multicenter, Randomized, Placebo-Controlled Trial of Prophylactic Recombinant Granulocyte-Colony Stimulating Factor in Preterm Neonates with Neutropenia

OBJECTIVE To test the hypothesis that prophylactic treatment of neutropenic premature neonates with recombinant granulocyte-colony stimulating factor (rG-CSF) would reduce the incidence of nosocomial infections (NIs). STUDY DESIGN A total of 25 neonatal intensive care units participated in this multicenter, randomized, double-blind, placebo-controlled trial. Premature infants of gestational age (GA) <or= 32 weeks were included if they had a peripheral blood count showing < 1500 neutrophils/mm(3) for at least 24 hours during the first 3 weeks of life. A total of 200 infants received either rG-CSF (10 microg/kg/day) or placebo for 3 days. Primary outcome was survival free of infection for 4 weeks after treatment, assessed in an intention-to-treat analysis. RESULTS A total of 102 infants received rG-CSF (mean GA, 29.2 weeks), and 98 received placebo (mean GA, 29.1 weeks). Survival free of confirmed infection for 4 weeks after treatment was 74/102 in the rG-CSF group and 66/98 in the placebo group (P = .42). However, during 2 weeks, there was a significant difference between groups (86/102 vs 70/98; P = .028). CONCLUSIONS In this population, prophylactic rG-CSF did not significantly increase survival free of infection at 4 weeks after treatment. The transient effect observed at 2 weeks in the most immature infants should be evaluated further.

Late-onset neonatal infections: incidences and pathogens in the era of antenatal antibiotics

Widespread use of intrapartum antimicrobial prophylaxis has significantly reduced the incidence of early-onset neonatal infection (EONI); however, little is known about the effects of increased maternal exposure to antibiotics on late-onset neonatal infection (LONI). This study aims to evaluate LONI epidemiology in our region after the application of French recommendations and to determine whether LONI-causing organisms and their antibiotic susceptibility are influenced by peripartum antibiotic exposure. We performed a prospective epidemiologic study of 139 confirmed and possible cases of bacterial LONI in patients treated with antibiotics for at least 5 days of the 22,458 infants born in our region in the year 2007. The overall incidence of LONI caused by all pathogens, Group B streptococcus (GBS) and Escherichia coli (E. coli) were 6.19, 0.36 and 2.72, respectively, per 1,000 live births. Our findings revealed three major types of LONI: E. coli-induced urinary tract infection (UTI) among term infants, coagulase negative Staphylococcus septicemia affecting preterm infants, and GBS infections with severe clinical presentation. Univariable analysis revealed that maternal antibiotic exposure was significantly associated with the risk of amoxicillin-resistant E. coli infection (p = 0.01). Postnatal antibiotic exposure was associated with an increased risk of E. coli LONI (p = 0.048). This link persisted upon multivariable analysis; however, no additional risk factors were identified for LONI caused by antibiotic-resistant E. coli. Conclusion Our findings confirm that despite the benefits of antenatal antibiotics, this treatment can increase the risk of antibiotic-resistant cases of LONI. National and international surveillance of LONI epidemiology is essential to assess benefits and potential negative consequences of perinatal antibiotic exposure.

Diagnostic approach to neonatal hypotonia: retrospective study on 144 neonates.

The objectives of our study were to determine the actual frequency of the different disorders causing neonatal hypotonia and to assess the reliability of the first physical examination as well as the contribution of the main standard diagnostic tests. One hundred and forty-four infants diagnosed with neonatal hypotonia between January 1st 1999 and June 30th 2005 in our tertiary care facility were retrospectively included in the study. Perinatal history, clinical type of hypotonia, results of standard diagnostic tests, final diagnosis and outcome were abstracted from the original charts. A final diagnosis was reached in 120 cases. Central (cerebral) causes represented 82% of the elucidated cases, mostly hypoxic and hemorrhagic lesions of the brain (34%), chromosomal aberrations and syndromic disorders (26%) and brain malformations (12%). Peripheral (neuromuscular) causes were mainly represented by spinal muscular atrophy (6%) and myotonic dystrophy (4%). Positive predictive value of the initial clinical examination was higher in central type hypotonia. Neuroimaging, karyotype analysis and DNA-based tests were the most helpful diagnostic tools. These recent clinical data can be used to improve our strategy in investigating neonatal hypotonia and a diagnostic algorithm is proposed based on our findings.

Exploring the olfactory environment of premature newborns: a French survey of health care and cleaning products used in neonatal units.

Aim:  To assess the main determinants of the newborn’s nosocomial olfactory environment.

Effects of antenatal antibiotics on the incidence and bacteriological profile of early-onset neonatal sepsis. A retrospective study over five years.

Background: Recommendations for the use of antenatal antibiotics have been widely implemented in the past few years, notably to prevent group B streptococcal disease or to prolong pregnancy in the case of preterm premature rupture of the membranes. Objectives: We designed a retrospective study to assess the potential effects of this increasing use of antibiotics on the incidence and bacteriological profile of early-onset neonatal sepsis (EONS). Methods: All neonates referred to our department for suspected EONS from January 1 1995 through December 31 1999 were included. Antenatal antibiotic exposure together with clinical and microbiological data from the neonatal period were gathered and analyzed on a yearly basis. Results: Of the 485 newborns who met the inclusion criteria, there were 101 cases of culture-confirmed sepsis; 339 cases of suspected sepsis and 69 cases of confirmed sepsis involved children born in the hospital, among a total of 16,627 live births registered in our center over the study period. The overall incidence of EONS dropped from 6.8 to 0.6/1,000 births between 1995 and 1999 (p < 0.001), but the rate of group B streptococcal infection decreased much more rapidly than that of non-group B streptococcal infection. We observed a trend towards the emergence of ampicillin-resistant Escherichia coli strains, which were isolated in seven cases. Among E. coli infections, ampicillin resistance was statistically linked with antenatal antibiotic use (p = 0.025). We also delineated several risk factors associated with these infections. Conclusion: In our center, antenatal antibiotic treatment was effective in reducing the incidence of EONS, but this benefit may come at the cost of favoring the emergence of ampicillin-resistant organisms causing severe neonatal infections. Antenatal and postnatal antibiotic treatment strategies should take this adverse effect into account.

Olfaction in Premature Human Newborns: Detection and Discrimination Abilities Two Months Before Gestational Term

It remains unclear at what stage during early ontogeny humans do have the ability to process olfactory information. Numerous studies have demonstrated olfactory detection, discrimination, preference and memory in full-term infants examined within hours or days after birth (see Schaal, 1988 for a review). Recent data have revealed that olfaction is functional before birth. Newborns evince selective responsiveness to complex or pure odorants, which they could only, or mainly contact in the prenatal environment (Marlier et al., 1998; Schaal et al., 1998, 2000).