Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project.

BACKGROUND: We describe our experience from a multi-national application of a European Union-funded research-driven paediatric trial (DEEP-2, EudraCT 2012-000353-31; NCT01825512). This paper aims to evaluate the impact of the local and national rules on the trial authorisation process in European and non-European countries. National/local provisions and procedures, number of Ethics Committees and Competent Authorities to be addressed, documentation required, special provisions for the paediatric population, timelines for completing the authorisation process and queries received were collected; compliance with the European provisions were evaluated. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model analysis were used to determine factors potentially influencing the timelines. The Cluster Analysis procedure was used to identify homogenous groups of cases. RESULT: The authorisation process was completed in 7.7 to 53.8 months in European countries and in 17.1 to 27.1 months in non-European countries. The main factors influencing these timelines were the requests for changes/clarifications in European countries and the different national legislations in non-European countries. CONCLUSION: This work confirms that the procedures and requirements for the clinical trial application of a paediatric trial are different. In the European Union, the timeframes for submission were generally harmonised but longer. In non-European countries, delays were caused by national dispositions but the entire authorisation process resulted faster with less requests from ECs/CAs. The upcoming application of Regulation (EU) 536/2014 is expected to harmonise practices in Europe and possibly outside. Networks on paediatric research acting at international level will be crucial in this effort.

The ethical framework for performing research with rare inherited neurometabolic disease patients.

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families. CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied.

Severe anaemia associated with Plasmodium falciparum infection in children: consequences for additional blood sampling for research.

BACKGROUND: Plasmodium falciparum infection may cause severe anaemia, particularly in children. When planning a diagnostic study on children suspected of severe malaria in sub-Saharan Africa, it was questioned how much blood could be safely sampled; intended blood volumes (blood cultures and EDTA blood) were 6 mL (children aged <6 years) and 10 mL (6-12 years). A previous review [Bull World Health Organ. 89: 46-53. 2011] recommended not to exceed 3.8 % of total blood volume (TBV). In a simulation exercise using data of children previously enrolled in a study about severe malaria and bacteraemia in Burkina Faso, the impact of this 3.8 % safety guideline was evaluated. METHODS: For a total of 666 children aged >2 months to <12 years, data of age, weight and haemoglobin value (Hb) were available. For each child, the estimated TBV (TBVe) (mL) was calculated by multiplying the body weight (kg) by the factor 80 (ml/kg). Next, TBVe was corrected for the degree of anaemia to obtain the functional TBV (TBVf). The correction factor consisted of the rate 'Hb of the child divided by the reference Hb'; both the lowest ('best case') and highest ('worst case') reference Hb values were used. Next, the exact volume that a 3.8 % proportion of this TBVf would present was calculated and this volume was compared to the blood volumes that were intended to be sampled. RESULTS: When applied to the Burkina Faso cohort, the simulation exercise pointed out that in 5.3 % (best case) and 11.4 % (worst case) of children the blood volume intended to be sampled would exceed the volume as defined by the 3.8 % safety guideline. Highest proportions would be in the age groups 2-6 months (19.0 %; worst scenario) and 6 months-2 years (15.7 %; worst case scenario). A positive rapid diagnostic test for P. falciparum was associated with an increased risk of violating the safety guideline in the worst case scenario (p = 0.016). CONCLUSIONS: Blood sampling in children for research in P. falciparum endemic settings may easily violate the proposed safety guideline when applied to TBVf. Ethical committees and researchers should be wary of this and take appropriate precautions.

Microbiological, clinical and molecular findings of non-typhoidal Salmonella bloodstream infections associated with malaria, Oriental Province, Democratic Republic of the Congo.

BACKGROUND: In sub-Saharan Africa, non-typhoidal Salmonella (NTS) can cause bloodstream infections, referred to as invasive non-typhoidal Salmonella disease (iNTS disease); it can occur in outbreaks and is often preceded by malaria. Data from Central Africa is limited. METHODS: Clinical, microbiological and molecular findings of NTS recovered in a blood culture surveillance project (2009-2014) were analyzed. RESULTS: In March-July 2012 there was an epidemic increase in malaria infections in the Oriental Province of the Democratic Republic of the Congo (DRC). In one referral hospital, overall hospital admissions in June 2012 were 2.6 times higher as compared to the same period in the years before and after (336 versus an average of 128 respectively); numbers of malaria cases and blood transfusions were nearly three- and five-fold higher respectively (317 versus 112 and 250 versus 55). Case fatality rates (in-hospital deaths versus all admissions) peaked at 14.6 %. Salmonella Typhimurium and Salmonella Enteritidis together accounted for 88.9 % of pathogens isolated from blood cultures collected during an outreach visit to the affected districts in June 2012. Children infected with Salmonella Enteritidis (33 patient files available) tended to be co-infected with Plasmodium falciparum more often than children infected with Salmonella Typhimurium (40 patients files available) (81.8 % versus 62.5 %). Through the microbiological surveillance project (May 2009-May 2014) 113 unique NTS isolates were collected (28.5 % (113/396) of pathogens); most (95.3 %) were recovered from children < 15 years. Salmonella Typhimurium (n = 54) and Salmonella Enteritidis (n = 56) accounted for 47.8 % and of 49.6 % NTS isolates respectively. Multilocus variable-number tandem-repeat analysis (MLVA) revealed more heterogeneity for Salmonella Typhimurium than for Salmonella Enteritidis. Most (82/96, 85.4 %) NTS isolates that were available for antibiotic susceptibility testing were multidrug resistant. All isolates were susceptible to ceftriaxone and azithromycin. CONCLUSION: During the peak of an epidemic increase in malaria in the DRC in 2012, a high proportion of multidrug resistant Salmonella Typhimurium and Salmonella Enteritidis were isolated from blood cultures. Overall, the two serovars showed subtle differences in clinical presentation and genetic diversity.

Operational lessons learned in conducting an international study on pharmacovigilance in pregnancy in resource-constrained settings: The WHO Global Vaccine safety Multi-Country collaboration project.

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions.

Estimating baseline rates of adverse perinatal and neonatal outcomes using a facility-based surveillance approach: A prospective observational study from the WHO Global Vaccine Safety Multi-Country Collaboration on safety in pregnancy.

Background: Most perinatal and neonatal deaths occur in low- and middle-income countries (LMICs), yet, quality data on burden of adverse outcomes of pregnancy is limited in such countries. Methods: A network of 21 maternity units, across seven countries, undertook surveillance for low birthweight, preterm birth, small for gestational age (SGA), stillbirths, congenital microcephaly, in-hospital neonatal deaths, and neonatal infections in a cohort of over 85,000 births from May 2019 - August 2020. For each outcome, site-specific rates per 1,000 livebirths (or per 1,000 total births for stillbirth) and 95% confidence intervals (CI) were calculated. Descriptive sensitivity analysis was conducted to gain insight regarding underreporting of four outcomes at 16 sites. Findings: Estimated rates varied across countries and sites, ranging between 43·3-329·5 and 21·4-276·6/1000 livebirths for low birthweight and preterm birth respectively and 11·8-81/1,000 livebirths for SGA. No cases of congenital microcephaly were reported by three sites while the highest estimated rate was 13/1,000 livebirths. Neonatal infection and neonatal death rates varied between 1·8-73 and 0-59·9/1000 livebirths respectively while stillbirth rates ranged between 0-57·1/1000 total births across study sites. Results from the sensitivity analysis confirmed the underreporting of congenital microcephaly and SGA in our study. Interpretation: Our study establishes site-specific baseline rates for important adverse perinatal and neonatal outcomes and addresses a critical evidence gap towards improved monitoring of benefits and risks of emerging pregnancy and neonatal interventions. Funding: The study was sponsored by the World Health Organization with funding from the Bill and Melinda Gates Foundation.

WHO global vaccine safety multi-country collaboration project on safety in pregnancy: Assessing the level of diagnostic certainty using standardized case definitions for perinatal and neonatal outcomes and maternal immunization.

Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1-3 of BC diagnostic certainty). Over a one-year period (2019-2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies.

Trends in preterm births in Flanders, Belgium, from 1991 to 2002.

Changes in the preterm birth rate have been attributed predominantly to increases in multiple pregnancies, associated with advanced maternal age and assisted reproduction, and to obstetric intervention. We examined their contribution to the frequencies of preterm (<37 weeks), very preterm (<32 weeks) and severely preterm (<28 weeks) birth among 700 383 singleton and twin births in Flanders from 1991 to 2002. We examined changes across four 3-year periods (triennia) with confidence interval [CI] analysis and yearly incremental rates using linear and logistic regression analyses. Over the 12 years, twin pregnancies increased from 1.5% to 2.0%, averaging 1.6% [95% CI 1.54, 1.66] in 1991-93 and 1.9% [95% CI 1.81, 1.94] in 2000-02 (P < 0.001). The proportion of women aged 35 years or more increased from 6.8% [95% CI 6.69, 6.92] in 1991-93 to 11.3% [95% CI 11.2, 11.5] in 2000-02 (P < 0.001) and those aged under 20 from 1.9% [95% CI 1.81, 1.93] to 2.3% [95% CI 2.26, 2.41] (P < 0.001). Assisted reproduction increased from 2.6% [95% CI 2.48, 2.62] to 4.2% [95% CI 4.11, 4.30] (P < 0.001) and obstetric intervention to end pregnancy from 36.2% [95% CI 36.0, 36.4] to 40.3% [95% CI 40.1, 40.6] (P < 0.001). These increases related to an annual increase of 0.23% in the preterm birth rate from 5.5% [95% CI 5.4, 5.6] in 1991-93 to 7.2% [95% CI 7.1, 7.3] in 2000-02 (P < 0.001). The proportions of very and severely preterm births also increased by nearly a third, but their contribution to the total preterm birth rate remained stable at 15% and 5%, respectively. Odds ratios for the increases per year were 1.035 [95% CI 1.032, 1.038] for preterm birth, 1.024 [95% CI 1.018, 1.031] for very preterm and 1.028 [95% CI 1.017, 1.040] for severely preterm births after adjusting for other changes in the population. Overall, the data show, first, marked increases in the frequency of known contributors to the preterm birth rate, including twin pregnancies, advanced maternal age, assisted reproduction and obstetric intervention. Second, the preterm birth rate further increased significantly within subgroups of women with one or more of these characteristics. Third, the preterm birth rate also rose, from 4.4% [95% CI 4.2, 4.5] in 1991-93 to 5.6% [95% CI 5.5, 5.8] in 2000-02 (P < 0.001), in women with none of these contributing factors. This indicates that changes in the frequency of these known predictors are insufficient to explain the steady increase in preterm, very preterm and severely preterm births over more than a decade.

Vaccine safety surveillance in pregnancy in low- and middle-income countries using GAIA case definitions: A feasibility assessment.

BACKGROUND: Global efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination. METHODS: Candidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty. RESULTS: Fifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them. DISCUSSION: GAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy.

Dopamine is not an independent risk factor for reduced amikacin clearance in extremely low-birth-weight infants.

INTRODUCTION: Important inter-individual variability in amikacin clearance was observed in preterm infants, only in part explained by gestational age (GA), birth weight, or coadministration of nonselective cyclo-oxygenase (COX) inhibitor. We therefore evaluated whether dopamine had an additional effect on amikacin clearance. METHODS: Clinical characteristics (GA, weight, COX inhibitor, dopamine, prenatal betamethasone) and amikacin pharmacokinetics were retrospectively collected in a cohort of preterm infants (GA of <31 wks, early neonatal life on respiratory support, between January 1, 1999 and January 6, 2005). Pharmacokinetics were calculated by assuming a one-compartment model with instantaneous input and first-order output based on paired samples collected for therapeutic drug monitoring before and following second administration. Monovariate analysis (Spearman, Mann-Whitney U test) was used to study the impact of clinical characteristics on amikacin clearance, and logistic regression was used to assess their potential independent effect. RESULTS: Paired amikacin samples were available for 240 neonates (mean GA, 28 wks; birth weight, 1042 g). Amikacin clearance was 0.46 (range, 0.09-2.33) mL/kg/min and distribution volume was 0.54 (range, 0.17-2.31) L/kg. GA, birth weight, COX inhibitor, and dopamine had a significant effect on amikacin clearance. In a logistic regression model, dopamine was no longer a significant variable when GA, birth weight, or cotreatment of a nonselective COX inhibitor was entered as second variable. CONCLUSIONS: Dopamine is an indicator but not an independent marker of reduced amikacin clearance in early neonatal life in extremely low-birth-weight infants. Therefore, neither dose nor interval should be adapted when dopamine is prescribed, if GA and coadministration of nonselective COX inhibitors already have been taken into account.

Measurement of the liver tissue oxygenation by near-infrared spectroscopy.

OBJECTIVE: To study the relation between the liver tissue oxygenation index (TOI), transcutaneously measured with spatially resolved spectroscopy (a new method of near-infrared spectroscopy or NIRS), the mixed venous oxygen saturation and the blood flow in the different parts of the splanchnic circulation in newborn piglets. DESIGN: Tissue oxygenation index of the liver was measured in six newborn piglets at 33 degrees C, 35 degrees C, 37 degrees C and after a decrease in arterial carbon dioxide pressure (PaCO(2)). MEASUREMENTS: Mixed venous oxygen saturation, blood gas analysis and peripheral oxygen saturation were measured at each step. Gastric, proximal jejunal, midgut, distal ileal, splenic and hepatic arterial blood flow were measured by injection of coloured microspheres into the left atrium. NIRS optodes were attached to the skin over the liver and TOI was calculated. RESULTS: No significant changes of TOI of the liver were seen during the increase in temperature or change in PaCO(2). TOI correlated well with mixed venous oxygen saturation (r=0.85), the mid-ileal blood flow (r=0.57) and the distal ileal blood flow (r=0.72). CONCLUSIONS: Measurement of the TOI of the liver might be a non-invasive way to measure the distal ileal blood flow.

Massive lung collapse with partial resolution after several years: a case report.

BACKGROUND: Bronchitis obliterans is a severe and extremely rare complication of respiratory tract infections in children and is characterized by massive atelectasis and collapse of the affected lung. Of the rare cases reported in the literature all surviving children underwent surgical resection of the collapsed lung. CASE PRESENTATION: We report an infant with bronchitis obliterans that was treated conservatively. 5 years after the initial event, partial lung re-expansion was documented. CONCLUSION: This case therefore supports a conservative treatment whenever possible with pneumonectomy only as a last treatment option.

The flow-pressure plot: a new look on the patient-ventilator interaction in neonatal care.

Most modern neonatal ventilators have now a built-in flow sensor and, as a spin-off of their mechanical action, provide some information about lung function characteristics as compliance and resistance after computation of the flow and pressure signals. Additionally, respiratory graphics as volume-pressure and flow-volume plots can be displayed. In clinical practice, however, they are rarely used to refine the ventilator setting. A nonconventional flow-pressure plot is presented in this article, constructed from the volume or flow, and pressure outputs of a Babylog 8000 (Dräger, Lübeck, Germany). This flow-pressure diagram appears to be useful in the real-time computation of respiratory mechanics based on the Rahn's law of respiratory motion. Its major advantage, however, is the easy pattern recognition of subtle changes in infant-ventilator interaction, ie, excessive triggering, fighting against the ventilator, augmented breath, tube subobstruction. It may be useful to add the flow-pressure plot to the classical respiratory graphics allowing to monitor mechanical ventilation more accurately and to fine tune the ventilator setting accordingly.

Association of patent ductus arteriosus and severe hypothyroidism in term newborns: coincidence or causal?

We report on 3 term newborns with the association of patent ductus arteriosus (PDA) and severe hypothyroidism attributed to thyroid agenesis (n = 2) or feto-maternal pit-1 deficiency (n = 1). This association suggests that sufficient thyroid hormone availability is among the prerequisites for normal postnatal ductal closure. Unravelling the maturational effects of thyroid hormone on the ductus arteriosus might also be relevant in preterm infants as further studies of the perinatal thyroid axis may clarify the potential role of thyroid hormone in PDA closure in preterm infants. Based on our observation, hypothyroidism should be considered in term infants with PDA.

Nonlinear analysis of heart rate variability in infants with apparent life-threatening events.

Some studies have shown that neonates having experienced an Apparent Life-Threatening Event (ALTE) have an increased risk of dying of the Sudden Infant Death Syndrome (SIDS). In this study the heart rate variability in neonates has been analyzed through a study of the long range correlations and scale invariance (self-similarity) in their cardiac rhythm. The goal is to see whether it is possible to distinguish normal infants from infants with ALTEs using the previously mentioned nonlinear measures of the heart rate variability. Twelve ALTE infants are included in this study. To determine the degree to which these neonates suffer from ALTEs two examinations are performed: a polysomnography and home monitoring. Using the nonlinear measures obtained from the nonlinear analysis of the heart rate variability, the group suffering most from ALTEs can clearly be separated from the other neonates.

Measurement of tissue oxygenation index during the first three days in premature born infants.

No normal values of tissue oxygenation index (TOI) of the brain are known regarding premature born infants. We measured TOI, a measure for the cerebral hemoglobin oxygen saturation, on the head of 15 preterm infants with a median postmenstrual age of 28 weeks (interquartile range (IQR) between 26-29 weeks) with spatially resolved spectroscopy (NIRO 300, Hamamatsu) during the first three days of life. Infants with intra-ventricular hemorrhage or periventricular leucomalacia before the first measurement, as shown by ultrasound, were excluded. The first measurement was done within the first 6 hours of life, the second and third measurement at, respectively, 24 and 48 hours after this first measurement. The mean TOI was calculated if saturation did not change by more than 5% for at least 30 minutes. Other parameters measured were PaO2, PCO2, pH, mean arterial blood pressure, heart rate, hemoglobin, glycemia and peripheral oxygen saturation. There was a significant increase of TOI after 24 (p < 0.05) and 48 (p < 0.001) hours. The median TOI on the first day was 57% (95% CI: 54-65.7), 66.1% on the second day (95%CI: 61.9-82.3%) and 76.1% on the third day (95%CI 67.8-80.1%). No correlation was found between TOI and peripheral oxygen saturation, blood pressure, PaO2, PaCO2 and hemoglobin concentration after multiple regression analysis. TOI increases in the first three days in premature born babies. The increase of TOI is not due to an increase of oxygenation or mean arterial blood pressure. In our opinion, it reflects the increase in cerebral blood flow during the first three days.

Quantitation of the concordance between cerebral intravascular oxygenation and mean arterial blood pressure for the detection of impaired autoregulation.

Since some important forms of brain injury in premature infants are caused in considerable part by disturbances in cerebral blood flow (CBF), it is important to be able to detect whether the cerebrovascular autoregulation, the mechanism by which CBF is maintained constant despite alterations in mean arterial blood pressure (MAP), is working properly. A recent study suggested that concordant changes in MAP and cerebral intravascular oxygenation (HbD), measured non-invasively by near-infrared spectroscopy (NIRS) as the difference between the concentration changes of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (Hb), reflect impaired cerebrovascular autoregulation. Consequently, premature infants with impaired cerebrovascular autoregulation could be identified by simultaneous, continuous measurements of HbD and MAP. From several premature babies, MAP, HbD and arterial oxygen saturation (SaO2) were measured simultaneously at the University Hospital Leuven, Belgium. The concordance between MAP and HbD was quantitated using three different measures, among which a newly developed measure that looks for similarity of the dynamics between signals. Some preliminary results obtained from the measured data are given.

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.

Structural and functional outcome in infants treated with cryotherapy for threshold retinopathy between 1989 and 1999.

PURPOSE: To assess visual outcome, funduscopic appearance, and refraction for infants treated with cryotherapy for threshold retinopathy of prematurity (ROP) between 1989 and 1999. METHODS: Retrospective analysis of the medical records of premature infants with threshold ROP who were treated with cryotherapy. RESULTS: A total of 2,146 premature infants were screened for ROP during the study period. Of the 66 infants who were subsequently treated for threshold ROP with cryotherapy, 58 infants had at least 1 year of follow-up and comprised the study population. After correcting for improved survival, the overall incidence of treated infants with cryotherapy increased during the study period. Comparison of infants treated from 1989 through 1995 (group 1; n=26) and 1996 through 1999 (group 2; n=32) showed group 2 infants had improved visual outcome, better funduscopic anatomic appearance, and decreased myopia. CONCLUSION: Although the incidence of treated premature infants increased during the study period, visual outcome improved. The literature attributes improved visual and anatomical outcome to the use of the diode laser in the treatment of threshold ROP. In this study, the improved visual and anatomical results obtained with cryotherapy could be attributed in part to the development over the years of a milder type of retinopathy of prematurity and to earlier treatment of threshold ROP.