Feeding interval and use of donor breast milk for very low birthweight infants: A nationwide survey in Japan.

BACKGROUND: Enteral feeding is critical for postnatal growth of very low birthweight infants (VLBWI); however, a standard feeding strategy has not been established in Japan. A 2- or 3-h feeding interval is generally used, but no clear evidence supports either approach. Additionally, there is no nationwide breast milk bank in Japan and no consensus exists on the use of donor breast milk (DBM). To clarify the current feeding strategies for VLBWI in Japan, we undertook a nationwide survey. METHODS: We sent a questionnaire to the 382 NICUs included in the Neonatal Research Network in Japan. We sought information on NICU size, number of admissions, necrotizing enterocolitis (NEC) incidence, feeding interval, and use of DBM. RESULTS: We received responses from 217 NICUs (56.8%), including 76 tertiary centers and 140 regional centers. We only analyzed data obtained from tertiary perinatal centers with a high response rate (77.6%) owing to the insufficient response rate of lower-level facilities (<50%). Most NICUs (71.1%) used a 3-h feeding interval. Only 9.2% used a 2-h interval for all VLBWI. Most NICUs (64.5%) never used DBM, which is not routinely pasteurized. DBM was used in 27 NICUs (35.5%), with and without limitations. Data from 14,233 VLBWI were analyzed; 258 infants (1.8%) were diagnosed with NEC from 2011 to 2015. The incidence of NEC was higher in NICUs that used a 2-h interval (2.7%) than in others. No association was found between NEC and the use of DBM. The NEC incidence did not differ between centers using the most common strategy of a 3-h interval without DBM and those using other strategies. CONCLUSION: Most NICUs in Japan use a 3-h feeding interval and do not use DBM for VLBWI. Further prospective studies including multiple confounders are required to clarify the relationship between feeding strategy and the incidence of NEC.

Small for gestational age is a risk factor for the development of delayed thyrotropin elevation in infants weighing less than 2000 g.

OBJECTIVE: Delayed thyrotropin (TSH) elevation (dTSHe) is common in low birthweight infants. We aimed to clarify the risk factors for the development of dTSHe in infants weighing <2000 g at birth. PATIENTS AND METHODS: According to Japanese guidelines, infants with birthweight <2000 g underwent second capillary TSH screening within 30 days, either at 1 month of age; or when weight reached 2.5 kg; or at discharge. dTSHe was defined as TSH >20 mIU/L by venous sampling following a normal result (<15 mIU/L) at first screening aged 4-6 days. For each infant who developed dTHSe three babies without dTSHe were selected and matched for gestational age and birth year. Small for gestational age (SGA) was defined as a birthweight <10th percentile for the gestational age and sex. A multivariate analysis was performed to identify risk factors for the development of dTSHe. RESULTS: Among the 911 study infants, 17 infants (1.9%) had dTSHe. The median (range) birthweight in the dTSHe group (796 [388-1912] g) was significantly smaller than the comparison group (961 [408-1981] g) (P = 0.04). The number (%) of SGA infants was significantly higher in the dTSHe group (12 [71%]) than in the comparison group (13 [25%]) (P = 0.001). The multivariate analysis revealed that SGA was an independent risk factor for the development of dTSHe (adjusted odds ratio, 9.0; 95% confidence interval, 2.5-32.8; P = 0.001). CONCLUSIONS: Small for gestational age is an independent risk factor for the development of dTSHe in infants with a birthweight <2000 g. The influence of prematurity, a matching criterion for this study, on dTSHe requires additional study.

Probiotics and the development of very low birthweight infants: follow-up study of a randomised trial.

OBJECTIVE: To investigate the effect of Bifidobacterium bifidum OLB6378 on the development of very low birthweight (VLBW) infants at 18 months of corrected age. DESIGN: Long-term follow-up study of a cluster-randomised, placebo-controlled trial. PATIENTS: VLBW infants (birth weight <1500 g) born between January 2010 and March 2011 and managed at 19 neonatal intensive care unit facilities assigned to two groups to account for the effect of probiotic cross-contamination within facilities. INTERVENTIONS: For VLBW infants, administration of OLB6378 as a probiotic was started within 48 hours of birth and continued until the body weight reached 2000 g. MAIN OUTCOME MEASURES: At 18 months of corrected age, physical status and developmental quotient (DQ18) were assessed. The distribution of DQ18 scores was categorised into four levels of development: <70, significant developmental delay; 70-84, moderate developmental delay; 85-99, without developmental delay; ≥100, average development or better. RESULTS: Among 153 infants assigned to the OLB6378 administration group and 130 assigned to the placebo administration group, 102 and 105 infants, respectively, underwent the 18-month medical examination. The distribution of developmental levels (DQ18 scores <70, 70-84, 85-99 and ≥100) was significantly more favourable for OLB6378 administration (12, 12, 25 and 40 infants, respectively) than for placebo administration (15, 17, 23 and 24 infants, respectively) (ordered logistic regression analysis: partial correlation coefficient, 0.589; P value, 0.038). CONCLUSIONS: Although limited by assessment rates, result suggests that OLB6378 may have a beneficial effect on the psychological development in VLBW infants. CLINICAL TRIAL REGISTRATION: UMIN000002543.

Differences in mortality and morbidity according to gestational ages and birth weights in infants with trisomy 18.

The aim of this study was to clarify the effects of gestational age and birth weight on outcomes of the infants. Medical records of 36 infants with trisomy 18 admitted to Tokyo Women's Medical University Hospital from 1991 to 2012 were reviewed retrospectively. We compared clinical characteristics between term infants (n = 15) and preterm infants (n = 21). There were one very-low-birth-weight (VLBW) term infant (5%) and 12 VLBW preterm infants (80%). Although there were no significant differences in clinical characteristics and provided management between the two groups, none of the preterm infants achieved survival to discharge. On the other hand, 6 of 21 term infants (29%) achieved survival to discharge (P < 0.05). Similar results were obtained for comparisons between the VLBW infants and non-VLBW infants. Multiple logistic regression analysis revealed that shorter gestational age had a more negative impact than lower birth weight to survival to discharge in infants with trisomy 18. In both preterm and term groups, the infants who died before 30 days commonly died of respiratory failure or apnea. Whereas, the infants who survived more than 30 days mostly died of heart failure.

Bifidobacterium and enteral feeding in preterm infants: cluster-randomized trial.

BACKGROUND: This study evaluated the benefit of Bifidobacterium bifidum OLB6378 (B. bifidum) in very low-birthweight (VLBW) infants (birthweight <1500 g) for the acceleration of enteral feeding. METHODS: A cluster-randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals, divided into two groups: the B group (n = 10 hospitals; B. bifidum given to infants within 48 h of birth) and the P group (n = 9 hospitals; infants received a placebo). The primary outcome was establishment of enteral feeding after birth, defined as the postnatal day at which enteral feeding exceeded 100 mL/(kg/day). Secondary outcomes were defined as incidence of morbidity and somatic growth before discharge. RESULTS: Overall, 283 VLBW infants were enrolled in the study: B group, n = 153; and P group, n = 130. Enteral feeding was established within 21 days after birth in 233 infants, of whom 119 received B. bifidum and 114 received placebo until their bodyweight reached 2000 g. Enteral feeding was established significantly earlier in the B group, at 11.0 ± 3.6 days versus 12.1 ± 3.8 days in P group (P < 0.05). Infant growth during the stay in the neonatal intensive care unit was not different between groups, but the incidence of late-onset sepsis among all enrolled infants was significantly lower in the B group (3.9%, 6/153) than in the P group (10.0%, 13/130; P < 0.05). No differences were observed in the incidence of other adverse outcomes including mortality. CONCLUSIONS: B. bifidum in VLBW infants accelerated the establishment of enteral feeding after birth without increasing the incidence of adverse effects.

Identification of practices and morbidities affecting the mortality of very low birth weight infants using a multilevel logistic analysis: clinical trial or standardisation?

OBJECTIVES: To determine the feasibility of clinical trials of newly developed treatments or standardisation of existing practices to further improve outcomes among very low birth weight (VLBW) infants, a nationwide database was analysed with a two-dimensional approach using two multivariate logistic models. DESIGN: Retrospective observational analysis. SETTING: Level III perinatal centres in Japan. PARTICIPANTS: 15 920 VLBW infants admitted at 38 participating centres from 2003 through 2010. OUTCOME MEASURES: Clinical information for the infants was collected until discharge from the centres. A multivariate logistic model identified practices and morbidities associated with mortality. Then, those which were significantly associated with mortality were analysed using a multilevel logistic model. The residues calculated by the multilevel analysis were used as an indicator of centre variation. RESULTS: Among practices, antenatal steroids and intubation at birth showed relatively high centre variations (0.9 and 0.8) and favourable ORs (0.7 and 0.5) for mortality, while caesarean section showed a low centre variation (0.4) and a favourable OR (0.8). Sepsis and air leak showed high centre variations (0.4 and 0.4) and high ORs (3.8 and 3.4) among morbidities. Pulmonary haemorrhage, persistent pulmonary hypertension of the newborn, and intraventricular haemorrhage showed moderate variations (0.2, 0.3 and 0.2, respectively) and high ORs (5.6, 4.1 and 2.9, respectively). In contrast, necrotising enterocolitis showed the lowest variation (0.1) and a high OR (4.9). CONCLUSIONS: The two-dimensional approach has clearly demonstrated the importance of clinical trial or standardisation. The practices and morbidities with low centre variations and high ORs for mortality must be improved through clinical trials of newly introduced techniques, while standardisation must be considered for practices and morbidities with a high centre variation. TRIAL REGISTRATION: The database was registered as UMIN000006961.

Hemodynamic analysis in infants with late-onset circulatory collapse.

BACKGROUND: Late-onset circulatory collapse (LCC) is a disorder in which blood pressure decreases and oliguria suddenly occurs in preterm infants who have survived the acute stage, leading to shock, without contributing underlying factors. In order to evaluate hemodynamic changes during LCC, the correlation between myocardial functions and organ blood flow was investigated with echography. METHODS: Seven very-low-birthweight infants were given a diagnosis of LCC during the study period. Cardiovascular and organ flow parameters of the infants were recorded prospectively, once a week, and compared with eight control very-low-birthweight infants with matching gestational age. Echographic study was performed before LCC, at the onset of LCC, and after LCC among infants with LCC. RESULTS: A significant increase in ejection fraction and a significant decrease in end systolic wall stress were observed in infants with the LCC condition. At the same time, the mean blood flow velocity increased significantly in the superior mesenteric artery, while it decreased in the anterior cerebral artery. Systolic blood flow velocity increased and mean velocity was maintained in the renal artery during LCC. CONCLUSION: LCC is a distributive shock, characterized by a hyperdynamic state and decreased afterload. Echographic examination of organ flow during LCC is useful in understanding the pathophysiology of the disorder.

Trends in morbidity and mortality among very-low-birth-weight infants from 2003 to 2008 in Japan.

BACKGROUND: Although medical care for very-low-birth-weight (VLBW) infants has improved over time, it is unclear how this has affected mortality and morbidity. To characterize these trends, a network database was analyzed. METHODS: This is a cohort study of VLBW infants born from 2003 through 2008. RESULTS: Over the 6-y period, 19,344 infants were registered and analyzed. Crude mortality rates among the infants at discharge decreased significantly (from 10.8 to 8.7%) during the study period. The greatest improvement in mortality was observed among infants with birth weights between 501 and 750 g (25.6-17.7 %). The odds ratio (OR) of mortality over year adjusted for potential confounders by a logistic regression model was 0.94 (95% confidence interval 0.92-0.97). Significant increases were observed in some morbidities, including symptomatic patent ductus arteriosus with an OR of 1.11 (1.09-1.13); late-onset adrenal insufficiency, 1.21 (1.17-1.26); and necrotizing enterocolitis/intestinal perforation, 1.10 (1.01-1.12). However, the severe form of intraventricular hemorrhage, with an OR of 0.98 (0.92-0.99), decreased significantly. Risk-adjusted trends in other morbidities showed no significant change. CONCLUSION: Mortality of VLBW infants decreased significantly over the 6-y study period. Decreasing morbidity is essential for further improvement in the outcomes in VLBW infants.

Effect of Bifidobacterium administration on very-low-birthweight infants.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of early administration of Bifidobacterium bifidum OLB6378 (B. bifidum) on accelerating enteral feeding and bacterial colonization in very-low-birthweight (VLBW) infants. METHODS: We conducted a single-center prospective pilot study. Thirty-six VLBW infants were randomly divided into two groups: group E, wherein B. bifidum was supplemented within 48 h of birth, and group L, wherein it was supplemented more than 48 h after birth. RESULTS: Group E and group L reached a total feeding volume of 100 mL/(kg/day) after 10 [7-13] days and 11 [10-15] days, respectively (median [quartile]). The daily bodyweight gain in group E was significantly higher (21.4 ± 3.2 g/day vs 18.3 ± 4.0 g/day, P < 0.02; 11.1 ± 1.5 g/kg/day vs 10.4 ± 1.2 g/kg/day, P < 0.04). No significant differences were found in the fecal Bifidobacterium level between the groups quantitated with a real-time polymerase chain reaction assay at 1 and 4 weeks of age. However, the highest colonization rate of Bifidobacterium was observed when the supplementation started between 24 and 48 h after birth. The incidence of morbidities between the groups was similar. CONCLUSION: The early administration of B. bifidum to VLBW infants seems effective in promoting growth during the stay in the neonatal intensive care unit without increasing the incidence of morbidity. Furthermore, the preferable timing of starting the probiotic supplementation for VLBW infants is at latest less than 48 h after birth.

Hydrocortisone and long-term outcomes in very-low-birthweight infants.

BACKGROUND: The long-term effects of hydrocortisone (HDC) used for very-low-birthweight (VLBW) infants with chronic lung disease (CLD) are not fully understood. The aim of this study was to examine the short-term clinical effects and long-term impact of a physiological replacement dose of HDC on acute deterioration of CLD in VLBW infants. METHODS: This prospective case-control study included 110 of the 174 VLBW infants admitted to our facility between 2003 and 2006 who were followed up to a corrected age of 18 months. Infant deaths and infants with congenital deformities were excluded from the study. The infants were classified into the following three groups: infants with CLD and treated with HDC (1-2 mg/kg/dose) due to progressive deterioration in oxygenation (CLD treatment group; n = 24); infants with CLD but not treated with HDC (CLD untreated group; n = 40); and infants without CLD (non-CLD group; n = 46). RESULTS: The fraction of inspired oxygen (F(I) O(2) ) in the CLD treatment group improved significantly after treatment (P < 0.01). There were no significant differences among the three groups in terms of growth and neurodevelopmental quotient at the corrected age of 18 months following adjustment for birthweight, sex, and presence of light-for-date infants. There were also no significant intergroup differences in all three areas of developmental quotient. CONCLUSIONS: Physiological doses of HDC replacement are effective in treating acute deterioration in oxygenation in VLBW infants with CLD. Furthermore, this treatment modality did not adversely affect the growth and development of infants at the corrected age of 18 months.