Veerle Cossey

Perinatal growth characteristics and associated risk of developing threshold retinopathy of prematurity.

PURPOSE To document perinatal growth characteristics in infants who developed threshold retinopathy of prematurity (ROP) in an attempt to describe prenatal and postnatal growth-related risk factors for threshold ROP. METHODS To document birth weight as well as absolute and relative weight gain (g/d and g/kg/d) in the first 6 weeks of life in infants who developed threshold ROP and who were admitted to a single tertiary neonatal intensive care unit between 1996 and 2000. These data were compared (case-control approach) with infants of the same gestational age (GA) who did not developed threshold ROP. RESULTS Small for gestational age (SGA; ie, weight <10th percentile for a given GA) and growth restriction (<25th percentile for a given GA) are risk factors for threshold ROP (relative risk = 3.7 and 4.5, respectively). Absolute weight gain (g/d) is also associated with an increased risk of developing threshold ROP (P<.05). In contrast, relative weight gain (g/kg/d) is not significantly different between threshold ROP infants and GA-matched controls. CONCLUSIONS SGA and a birth weight below the 25(th) percentile are risk factors for threshold ROP. Postnatal weight and absolute weight gain (g and g/d, respectively) in the first 6 weeks of life are statistically significant but of less clinical relevance because smaller infants at birth stay relatively smaller during the first 6 weeks of life. Even with normal (ie, same weight as control infants) postnatal relative weight gain (g/kg/d), growth retarded or restricted infants at birth still have an increased risk of developing threshold ROP.

Premature foetal closure of the arterial duct: clinical presentations and outcome

AIMS The prevalence of intra-uterine ductal dysfunction is unknown and the clinical consequences are poorly understood. The aim of this study was to investigate the echocardiographic (ECHO) abnormalities and outcomes of this rare phenomenon. METHODS AND RESULTS Retrospective analysis of foetal (n = 602) and neonatal ECHO databases (n = 1477) between 1998 and 2007. Clinical and imaging studies were reviewed for pathology due to or associated with premature closure of the duct. Twelve cases were identified. Eight (1.3%) were diagnosed pre-natally at a median gestational age of 29.0 weeks (range: 20.0-37.5 weeks). Four neonates (0.3%) with significant cyanosis and absence of the arterial duct were also included. The most common ECHO features were: excessive right ventricular (RV) hypertrophy (100%), more than expected tricuspid and pulmonary regurgitation (100% and 92%, respectively), and right atrial dilation (75%). Premature induction of delivery was advised for five patients. Neonatal therapy consisted of observation and oxygen administration (n = 7), ventilation with pulmonary vasodilators (n = 5), and one required extracorporeal membrane oxygenation. There were three deaths due to respiratory failure with severe pulmonary hypertension. During follow-up, two children required additional right heart procedures and one developed a non-compaction cardiomyopathy. CONCLUSION Foetal premature closure of the arterial duct causes stress at different foetal ages and many different levels of the right heart and pulmonary circulation, resulting in a wide range of secondary pathology. Disproportionate RV hypertrophy is the most common finding. Clinical outcomes range from mild symptomatology to lethal respiratory insufficiency.

Clinical Predictive Value of Real-Time PCR Quantification of Human Cytomegalovirus DNA in Amniotic Fluid Samples

The aim of this study was to evaluate the diagnostic reliability and prognostic significance of the quantification of cytomegalovirus (CMV) DNA in amniotic fluid (AF). We retrospectively reviewed the results for 282 amniotic fluid samples that had been tested for CMV by a quantitative real-time PCR. We observed three cases in which no CMV genomes were detected in the AF but in which the children were nevertheless congenitally infected. Hence, we conclude that a negative result by PCR for CMV in AF cannot rule out the possibility of congenital infection. No false-positive PCR results were observed. A correlation between the CMV viral load in AF and the fetal and neonatal outcomes could not be demonstrated in our study. Instead, a correlation was found between the CMV viral load and the gestational age at the time of amniocentesis.

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eighty-six 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r = −0.69 and −0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (F value 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R2 0.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivo ontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population.

Selecting neonates with congenital cytomegalovirus infection for ganciclovir therapy

ObjectiveThe objective of this study is to look for evidence based or scientific guidelines for selection of newborns with congenital cytomegalovirus (CMV) infection that might benefit from treatment with ganciclovir.Materials and methodsA literature search was conducted involving the MEDLINE database and the Cochrane Collaboration Library. Abstracts were reviewed to select pertinent articles dealing with ganciclovir therapy in neonates. References from selected articles as well as from reviews were screened for additional relevant articles. In total, 13 case reports (16 patients in all), three descriptive uncontrolled studies (20 patients in all), two randomized dose-comparative studies (54 patients in all) and one randomized controlled study (42 patients) were identified.ObservationsAll reported patients presented with central nervous system manifestation of CMV infection. Only the randomized controlled study showed a reduction of hearing deterioration in the treated group. Published predictors of hearing loss in congenitally CMV infected children allow identification of candidates that might benefit from treatment. Studies so far are promising but of insufficient number to make evidence based recommendations about indications for treatment of congenital CMV. As such, studies are very difficult to conduct and treatment of infants at high risk of hearing loss may appear justified. There is scientific data to help clinicians in selecting a subgroup of infants that is at higher risk of hearing deterioration and therefore might benefit the most from ganciclovir therapy.

Pasteurization of mother's own milk for preterm infants does not reduce the incidence of late-onset sepsis.

Background: Feeding preterm infants human milk has a beneficial effect on the risk of late-onset sepsis (LOS). Due to lack of microbiological standards, practices such as pasteurization of mother’s own milk differ widely among neonatal intensive care units worldwide. Objectives: To investigate whether pasteurization of mother’s own milk for very-low-birth-weight (VLBW) infants influences the incidence and severity of infection-related outcomes. Methods: In this randomized controlled trial, preterm infants (gestational age <32 weeks and/or birth weight <1,500 g) received either raw or pasteurized mother’s own milk during the first 8 weeks of life. The primary outcome was the incidence of proven LOS. A dose-response relation was verified, i.e. the dependence of the risk of sepsis on the actual and cumulative quantities of mother’s own milk. Results: This study included 303 VLBW infants (mean birth weight: 1,276 g; mean gestational age: 29 weeks) whose baseline and nutritional characteristics were similar. The incidence of laboratory-confirmed sepsis was not statistically different in infants fed raw milk compared to infants who received pasteurized milk: 22/151 (0.15, CI: 0.08–0.20) and 31/152 (0.20, CI: 0.14–0.27), respectively (RR: 0.71; 95% CI: 0.43–1.17). A significant dose-response relation was observed between the adjusted quantity of enteral feeding and the risk of LOS, regardless of the type of feeding. Conclusion: For preterm infants, pasteurization of mother’s own milk shows a trend towards an increase in infectious morbidity, although no statistical significance was reached. Practices should focus on collection, storage and labeling procedures to ensure the safety and quality of expressed milk.

Urinary propofol metabolites in early life after single intravenous bolus

BACKGROUND /st> Propofol clearance is lower in neonates than in adults and displays extensive interindividual variability, in part explained by postmenstrual age (PMA) and postnatal age (PNA). Since propofol is almost exclusively cleared metabolically, urinary propofol metabolites were determined in early life and compared with similar observations reported in adults. METHODS /st> Twenty-four hours urine collections were sampled after a single i.v. bolus of propofol (3 mg kg(-1)) in neonates undergoing procedural sedation. Clinical characteristics (PMA, PNA, weight, and cardiopathy) were recorded. Urine metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were quantified using high-pressure liquid chromatography. Urine recovery (% administered dose) and the contribution of PG and QG to urinary elimination were calculated. Data were reported by median and range, analysed by Mann-Whitney U or Spearmans rank. RESULTS /st> Eleven neonates (median PNA 11 days, PMA 38 weeks) were included. Median propofol metabolite recovery was 64% (range 34-98%). PG contributed 34% (range 8-67%) and QG 65% (range 33-92%). There was no significant correlation between either PMA, PNA, or cardiopathy and propofol metabolites. Compared with adults, the contribution of PG (34% vs 77%) was lower and the contribution of QG (65% vs 22%) was higher in neonates. CONCLUSIONS /st> Propofol metabolism in neonates differs from adults, reflecting the age-dependent limited glucuronidation capacity. Hydroxylation to quinol metabolites already contributes to propofol metabolism. These differences likely explain the PMA- and PNA-dependent reduced propofol clearance in neonates.

Ophthalmological findings in congenital cytomegalovirus infection: when to screen, when to treat?

Cytomegalovirus (CMV) is the leading cause of known congenital viral infections. Approximately 90% of congenitally infected newborns exhibit no clinical abnormalities at birth. In 5% to 15%, a wide spectrum of clinical signs is present at birth. Ophthalmological signs are seen in a large percentage of symptomatic patients but rarely in otherwise asymptomatic infants. Chorioretinitis, optic atrophy, and cortical visual impairment are the most frequent causes of visual problems in congenitally infected infants. There is no clear consensus in the literature on screening or treatment modalities concerning the ophthalmological aspects of congenital CMV. Further prospective studies are needed to set up guidelines for ophthalmological screening and treatment of infants with congenital CMV.

Expressed breast milk on a neonatal unit: a hazard analysis and critical control points approach.

With the increasing use of human milk and growing evidence of the benefits of mothers milk for preterm and ill newborns, guidelines to ensure its quality and safety are an important part of daily practice in neonatal intensive care units. Operating procedures based on hazard analysis and critical control points can standardize the handling of mothers expressed milk, thereby improving nutrition and minimizing the risk of breast milk-induced infection in susceptible newborns. Because breast milk is not sterile, microorganisms can multiply when the milk is not handled properly. Additional exogenous contamination should be prevented. Strict hygiene and careful temperature and time control are important during the expression, collection, transport, storage, and feeding of maternal milk. In contrast to formula milk, no legal standards exist for the use of expressed maternal milk. The need for additional measures, such as bacteriological screening or heat treatment, remains unresolved.

Prospective validation of neonatal vancomycin dosing regimens is urgently needed

Background Although vancomycin is frequently used to treat neonatal late-onset sepsis, there is no consensus on the optimal dosing regimen. Because many neonates needed dosing adaptation due to suboptimal trough values, the vancomycin dosing regimen in our neonatal department was changed during 2012. Objective We aimed to document the need for validation of neonatal vancomycin dosing by exploring serum trough levels achieved using 2 published dosing regimens (previous regimen: based on postmenstrual age and serum creatinine and new regimen: based on postmenstrual age and postnatal age) and to identify covariates associated with suboptimal vancomycin trough levels (<10 mg/L). Methods Routine therapeutic drug monitoring serum trough levels quantified after initiation of intravenous vancomycin therapy and clinical covariates were retrospectively collected. Median vancomycin trough levels of both dosing regimens were compared using the Mann-Whitney U test. The influence of continuous and dichotomous covariates on achieving a suboptimal trough level was explored using the Van Elteren test (stratified Mann-Whitney U test) and Mantel-Haenszel test (stratified χ2 test), respectively. Covariates significant in monovariate analysis were subsequently included in a logistic regression analysis. Results In total, 294 observations (median current weight 1870 g [range = 420–4863 g] and median postmenstrual age 35.07 weeks [range = 25.14–56.00 weeks]) were included. Using the previous and new dosing regimens, 66.3% and 76.2% of trough levels, respectively, were below 10 mg/L. Overall, suboptimal vancomycin trough values were significantly associated with lower weight (birth weight and current weight) and age (gestational age and postmenstrual age). Conclusions The majority of vancomycin trough levels in neonates achieved using 2 published dosing regimens did not reach the target of 10 mg/L. This illustrates the urgent need for prospective validation of neonatal vancomycin dosing regimens. We anticipate that dosing regimens integrating covariates reflecting general physiological maturation and renal maturation, as well as disease characteristics, could improve vancomycin exposure in neonates.