Mortality and severe morbidity of very preterm infants: comparison of two French cohort studies.

BACKGROUND: In Reunion Island, a French overseas department, the burden of preterm birth and perinatal mortality exceed those observed in mainland France, despite similar access to standard perinatal care. The purpose of the study was to compare the outcome of two cohorts of NICU-admitted very preterm infants born between 24 and 31 weeks of gestation (WG): the registry-based OGP (Observatoire de la Grande Prématurité, Reunion Island, 2008-2013) cohort, and the nationwide EPIPAGE-2 (mainland France, 2011) observational cohort. METHODS: The primary outcome was adverse neonatal outcomes defined as a composite indicator of in-hospital mortality or any of three following severe morbidities: bronchopulmonary dysplasia (BPD), necrotising enterocolitis, or severe neurological injury (periventricular leukomalacia or grade III-IV intraventricular haemorrhages). Logistic regression modelling adjusting for confounders was performed. RESULTS: A total of 1272 very preterm infants from the Reunionese OGP cohort and 3669 peers from the mainland EPIPAGE-2 cohort were compared. Adverse neonatal outcomes were more likely observed in the OGP cohort (32.6% versus 26.6%, p <  0.001), as result of both increased in-hospital mortality across all gestational age strata and increased BPD among the survivors of the 29-31 WG stratum. After adjusting for gestational age, gender and multiple perinatal factors, the risk of adverse neonatal outcomes was higher in the OGP cohort than in the EPIPAGE-2 cohort across all gestational age strata. CONCLUSIONS: Despite similar guidelines for standard perinatal care, very preterm infants born in Reunion Island have a higher risk for death or severe morbidity compared with those born in mainland France.

Low Renal Oxygen Saturation at Near-Infrared Spectroscopy on the First Day of Life Is Associated with Developing Acute Kidney Injury in Very Preterm Infants.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication in preterm infants, and the identification of early markers of renal hypoperfusion is a chief challenge in neonatal intensive care units. OBJECTIVES: To describe the association between early markers of cardiovascular function and renal perfusion with AKI occurrence in a cohort of preterm infants < 32 weeks' gestation. METHODS: 128 infants were prospectively included from birth to discharge. During the first day of life, we assessed cardiovascular function, systemic and organ blood flow by Doppler ultrasound, and monitored cerebral and renal regional oxygen saturation (rSO2) using near-infrared spectroscopy (NIRS). These measures were analyzed in relation to developing AKI and serum creatinine (SCr) peak from day 2 to 7 of life. RESULTS: 12 of 128 infants presented with AKI (9.4%). SCr peak was 155.3 ± 30.2 µmol/L in infants with AKI versus 82.0 ± 16.5 in non-AKI infants (p < 0.001). Among all measures of cardiovascular function and renal perfusion, low mean cerebral and renal rSO2 during the first day of life and a low resistive index at renal artery Doppler were significantly associated with developing AKI. After adjustment for possible confounding factors, low renal rSO2 on the first day of life remained associated with a high SCr peak from day 2 to 7 of life. CONCLUSION: Low renal rSO2 values during the first day of life correlate with developing AKI in preterm infants < 32 weeks' gestation. NIRS monitoring of renal function during adaptation seems promising, and its very early use after birth to detect kidney hemodynamic dysfunction deserves further investigations.

One-Year Outcome for Congenital Diaphragmatic Hernia: Results From the French National Register.

OBJECTIVE: To evaluate the status of congenital diaphragmatic hernia (CDH) management in France and to assess predictors of adverse outcomes. STUDY DESIGN: We reviewed the first-year outcome of all cases of CDH reported to the French National Register in 2011. RESULTS: A total of 158 cases were included. Of these, 83% (131) were prenatally diagnosed, with a mortality rate of 39% (44 of 112) for live born infants with a known outcome at hospital discharge. Mortality increased to 47% (60 of 128) including those with termination of pregnancy and fetal loss. This contrasts with the 7% (2 of 27) mortality rate of the patients diagnosed postnatally (P = .002). Mortality worsened with 1 prenatal marker of CDH severity (OR 3.38 [1.30-8.83] P = .013) and worsened further with 2 markers (OR 20.64 [5.29-80.62] P < .001). Classic postnatal risk factors of mortality such as side of hernia (nonleft P = .001), prematurity (P < .001), low birth weight (P = .002), and size of the defect (P < .001) were confirmed. Of the 141 live births (114 prenatal and 27 postnatal diagnosis) with known outcomes, 93 (67%) survived to hospital discharge, 68 (60%) with a prenatal diagnosis and 25 (93%) with a postnatal diagnosis. The median time to hospital discharge was 34 days (IQR, 19.25-62). Of these survivors, 71 (76%) were followed up for 1 year. CONCLUSIONS: Despite advances in management of CDH, mortality was high and associated with prenatal risk factors. Postnatally, severe persistent pulmonary hypertension was difficult to predict and presented persistent challenges in management.

Low Plasma Protein Levels at Birth Are Associated with Poor Cardiovascular Adaptation and Serious Adverse Outcome in Infants with Gestational Age <32 Weeks: The ProHémie Study.

BACKGROUND: Retrospective studies suggest that early hypoproteinemia has prognostic value for adverse outcome in preemies, but the underlying pathophysiology is unknown. We hypothesized that the prognostic relevance of hypoproteinemia could be related to its association with impaired cardiovascular function and organ perfusion during transition. OBJECTIVES: To describe the plasma protein status and the measures of cardiovascular function according to the outcome in infants <32 weeks' gestation. METHODS: One hundred and twenty-eight infants were prospectively included from birth to discharge. During the first 24 h of life, we assessed the cardiovascular function and systemic and organ blood flow by Doppler ultrasound, and monitored cerebral and renal regional oxygen saturation (cRSO2, rRSO2) using near-infrared spectroscopy. These measures were analyzed in relationship to hypoproteinemia (total plasma protein level <40 g/L at 12 h of life) and severe adverse outcome (death or survival with severe neurological injury). RESULTS: Hypoproteinemia was associated with a higher risk of a severe adverse outcome after adjustment of confounding variables (adjusted OR = 6.8; 95% CI 1.3-34). Compared to normoproteinemic infants and after adjustment for gestational age, hypoproteinemic ones had more significantly: hypotension (7 vs. 13%, p = 0.03), abnormal capillary refilling time (20 vs. 36%, p < 0.001), abnormal renal blood flow (resistive index 0.78 ± 0.11 vs. 0.85 ± 0.09, p = 0.04), lower rRSO2 (82.9 ± 9.2 vs. 73.6 ± 10.5%, p = 0.04), and lower systemic vascular resistance (0.155 ± 0.058 vs. 0.108 ± 0.037 mm Hg/L/kg; p = 0.04). The cRSO2 patterns were significantly decreased in infants with severe adverse outcome and independent from protein status. CONCLUSION: Hypoproteinemia is associated with impaired cardiovascular function. Further studies are required to elucidate the interplay between changes in protein levels, postnatal hemodynamics and clinical outcome.

Follow-up at two years of age and early predictors of non-compliance in a cohort of very preterm infants.

AIM: To examine the rates of follow-up at two years of age and perinatal factors associated with non-compliance in an observational population-based cohort of very preterm children enrolled in a routine follow-up program. METHOD: Data review of infants born between 2008 and 2012 in the Observatoire de La Grande Prématurité, Reunion Island cohort. All singletons born alive before 33weeks of gestational age and resident on the island at two years of age were included. Patients were considered compliant if they were timely evaluated between 20-28months of age, or non-compliant if they were not evaluated or evaluated after 28months of age. RESULTS: Of the 802 survivors (mean gestational age of 30.3±2.0months, mean birthweight of 1364±396g), 468 (58.4%) were examined between 20-28months, 119 (14.8%) after 28months of age, and 215 (26.8%) were never evaluated, respectively. In multivariate analysis, factors associated with non-compliance were higher parity (>2), past history of preterm delivery, maternal diabetes (preexisting or gestational), appropriate for gestational status, and centre of birth. CONCLUSION: Sustainable follow-up of vulnerable neonates remains a challenge in clinical practice. Early predictors of non-compliance can be used to define individualized and local follow-up strategies in these infants at high risk for developmental disabilities.

Diagnosis Accuracy of Transcutaneous Bilirubinometry in Very Preterm Newborns.

BACKGROUND: Transcutaneous bilirubin (TcB) is a validated test for systematic screening of neonatal hyperbilirubinemia and monitoring term and near-term infants under phototherapy. OBJECTIVES: To evaluate TcB diagnostic accuracy for very preterm neonates. METHODS: Total serum bilirubin (TSB) and TcB measurements were performed prospectively in a multicenter sample of newborns <30 weeks of gestational age (GA). TcB sensitivity, specificity, predictive values, and likelihood ratios for the detection of neonates requiring phototherapy were calculated over the first 15 days of life, with or without phototherapy, with the expectation of achieving a detection rate of hyperbilirubinemia of over 95%. The potential influence of neonatal characteristics on the discordance between TcB and TSB in very preterm newborns was analyzed using multivariate multilevel logistic regression analyses. RESULTS: Altogether, 481 measurements were analyzed in 167 preterm patients. Mean GA was 27.6 ± 1.6 weeks. The rates of newborns requiring phototherapy were 52% in the first 3 days, 16% from the 4th to the 7th day, and 2% during the second week. Diagnostic performance was similar among babies with or without phototherapy. TcB sensitivity decreased over time from 100% (93.9-100.0) to 50% (1.3-98.7). Specificity showed an inverse evolution from 14.8% (7.0-26.2) to 80.7% (72.2-89.2). The best performance was that of negative predictive values which varied from 95.5 to 100.0. False negatives were rare throughout the study (0.8% of measurements). In a multivariate analysis, the only factor significantly influencing discordance between TcB and TSB was postnatal age. We did not find any impact of GA and skin color. CONCLUSION: Among very preterm babies, TcB measurements might be useful for screening for neonatal jaundice in the first 2 weeks of life. In case of a TcB value below the phototherapy threshold, invasive TSB quantification could be unnecessary, with potential avoidance of blood drawing.

Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island.

BACKGROUND: Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection. METHODS: The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ ≤ 85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms. RESULTS: The mean DQ score was 86.3 (95%CI: 81.0-91.5) in infected children compared to 100.2 (95%CI: 98.0-102.5) in uninfected peers (P<0.001). Fifty-one percent (n = 17) of infected children had a GND compared to 15% (n = 21) of uninfected children (P<0.001). Specific neurocognitive delays in p-CHIKV-infected children were as follows: coordination and language (57%), sociability (36%), movement/posture (27%). After adjustment for maternal social situation, small for gestational age, and head circumference, p-CHIKV infection was found associated with GND (incidence rate ratio: 2.79, 95%CI: 1.45-5.34). Further adjustments on gestational age or breastfeeding did not change the independent effect of CHIKV infection on neurocognitive outcome. The mean DQ of p-CHIKV-infected children was lower in severe encephalopathic children than in non-severe children (77.6 versus 91.2, P<0.001). Of the 12 cases of CHIKV neonatal encephalopathy, five developed a microcephaly (head circumference <-2 standard deviations) and four matched the definition of cerebral palsy. MRI scans showed severe restrictions of white matter areas, predominant in the frontal lobes in these children. CONCLUSIONS: The neurocognitive outcome of children exposed to perinatal mother-to-child CHIKV infection is poor. Severe CHIKV neonatal encephalopathy is associated with an even poorer outcome.

Fryns syndrome without diaphragmatic hernia, DOOR syndrome or Fryns-like syndrome? Report on patients from Indian Ocean islands.

We report on six patients (five unpublished patients) from the Indian Ocean islands, with coarse face, cleft lip or palate, eye anomalies, brachytelephalangy, nail hypoplasia, various malformations (genitourinary or cerebral), abnormal electroencephalograms with impaired neurological examination and lethal outcome. Massive polyhydramnios was noted in the third trimester of pregnancy and neonatal growth was normal or excessive. The combination of the features is consistent with the diagnosis of Fryns syndrome (FS) without congenital diaphragmatic hernia. Besides chromosomal aberrations and microdeletion syndrome, differential diagnoses include conditions overlapping with FS such as Simpson-Golabi-Behmel, and conditions with hypoplasia/absence of the distal phalanges such as DOOR syndrome, Schinzel-Giedion syndrome, and Rudiger syndrome.

Antibody kinetics in infants exposed to Chikungunya virus infection during pregnancy reveals absence of congenital infection.

To search for serological evidence of congenital infection in apparently healthy neonates born to women infected with the Chikungunya virus (CHIKV) during pregnancy, monitoring for CHIKV-specific antibodies was performed within the CHIMERE cohort study (Reunion island, 2006-2008). CHIKV-specific antibody kinetics showed no evidence of asymptomatic congenital infection as neonates were tested negative for CHIKV-specific IgM antibodies at birth and 368 infants with CHIKV-specific IgG antibodies seroreversed completely (mean seroreversion time: 7.7 months). Seroreversion time of transplacental CHIKV IgG antibodies was inversely correlated with the stage of pregnancy at which exposure took place and end-term small for gestational infants seroreversed earlier.

Chikungunya virus infection during pregnancy, Reunion, France, 2006.

Mother-to-child transmission of chikungunya virus was reported during the 2005-2006 outbreak on Reunion Island, France. To determine the effects of this virus on pregnancy outcomes, we conducted a study of pregnant women in Reunion in 2006. The study population was composed of 1,400 pregnant women (628 uninfected, 658 infected during pregnancy, 27 infected before pregnancy, and 87 infected on unknown dates). We compared pregnancy outcomes for 655 (628 + 27) women not infected during pregnancy with 658 who were infected during pregnancy. Infection occurred during the first trimester for 15% of the infected women, the second for 59%, and the third for 26%. Only hospital admission during pregnancy differed between infected and uninfected women (40% vs. 29%). Other outcomes (cesarean deliveries, obstetric hemorrhaging, preterm births, stillbirths after 22 weeks, birthweight, congenital malformations, and newborn admissions) were similar. This virus had no observable effect on pregnancy outcomes.

Mother-to-child transmission of Chikungunya virus infection.

BACKGROUND: In 2005-2006 Reunion Island experienced a massive outbreak of chikungunya, a mosquito-borne alphavirus infection. During this epidemic, early neonatal cases were observed with a highly probable mother-to-child transmission. METHODS: A retrospective descriptive study was conducted in 5 neonatal medicine departments. Chikungunya virus infection was confirmed by reverse transcription-polymerase chain reaction or specific serology in mothers and their newborns. Mothers were screened if they presented signs at delivery or if their neonates became ill on the first days of life. RESULTS: Thirty-eight neonates were enrolled. All mothers, except 2 asymptomatic mothers, presented signs during the perinatal period (range, day(D) -4 to D+1). All neonates were symptomatic and presented symptoms on D3 to D7 (mean, D4). The mean interval between onset of maternal illness and onset of neonatal illness was 5 days (range, 3-9). The most frequent clinical signs in neonates were fever (79%), pain (100%), rash (82%), and peripheral edema (58%). Thrombocytopenia (76%), lymphopenia (47%), decreased prothrombin value (65%), and elevation of aspartate aminotransferase (77%) were detected. Complications included seizures (6), hemorrhagic syndrome (6), and hemodynamic disorders (10). Reverse transcription-polymerase chain reaction in cerebrospinal fluid was positive in 22 of 24 cases, and abnormal findings on brain magnetic resonance imaging (14 of 25) with white matter lesions or intraparenchymal hemorrhages or both were found. Echocardiography (16) showed myocardial hypertrophy (5), ventricular dysfunction (2), pericarditis (2), and coronary artery dilatation (6). One neonate died of necrotizing enterocolitis. CONCLUSIONS: The chikungunya epidemic that occurred on La Reunion Island revealed for the first time the possibility of mother-to-child transmission in the perinatal period with a high rate of morbidity.