Bovine colostrum as a fortifier to human milk in very preterm infants - A randomized controlled trial (FortiColos).

BACKGROUND: Human milk for very preterm infants need fortification for optimal growth and development but the optimal fortification product remains to be identified. AIMS: To investigate feasibility, safety and preliminary efficacy on growth and blood biochemistry when using intact bovine colostrum (BC) as a fortifier to human milk in very preterm infants. METHODS: In an open-label, multicenter, randomized controlled pilot trial (infants 26-31 weeks' gestation), mother's own milk or donor human milk was fortified with powdered BC (n = 115) or a conventional fortifier (CF, bovine-milk-based, n = 117) until 35 weeks' postmenstrual age. Fortifiers and additional micronutrients were added to human milk according to local guidelines to achieve optimal growth (additional protein up to +1.4 g protein/100 mL human milk). Anthropometry was recorded weekly. Clinical morbidities including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) were recorded. Clinical biochemistry included plasma amino acid (AA) levels to assess protein metabolic responses to the new fortifier. RESULTS: A total of 232 infants, gestational age (GA) 28.5 ± 1.4 (weeks + days), fulfilled inclusion criteria. Birthweight, GA and delta Z scores from birth to end of intervention on weight, length or head circumference did not differ between groups, nor between the subgroups of small for gestational age infants. Likewise, incidence of NEC (BC: 3/115 vs. CF: 5/117, p = 0.72, unadjusted values), LOS (BC: 23/113 vs. CF: 14/116, p = 0.08) and other morbidities did not differ. BC infants received more protein than CF infants (+10%, p < 0.05) and showed several elevated AA levels (+10-40%, p < 0.05). CONCLUSION: Infants fortified with BC showed similar growth but received more protein and showed a moderate increase in plasma AA-levels, compared with CF. Adjustments in protein composition and micronutrients in BC-based fortifiers may be required to fully suit the needs for very preterm infants.

Extreme neonatal hyperbilirubinemia and kernicterus spectrum disorder in Denmark during the years 2000-2015.

OBJECTIVE: To determine the incidence and etiology of extreme neonatal hyperbilirubinemia, defined as total serum bilirubin (TSB) ≥450 µmol/L, and kernicterus spectrum disorder (KSD) in Denmark between 2000 and 2015. STUDY DESIGN: We identified all infants born between 01.01.2000 and 31.12.2015 with TSB ≥450 µmol/L, ratio of conjugated to TSB <0.30, gestational age ≥35 weeks, and postnatal age ≤4 weeks, using Danish hospitals' laboratory databases. RESULT: We included 408 infants. The incidence of extreme neonatal hyperbilirubinemia among infants with gestational age ≥35 weeks was 42/100,000 during the study period with a seemingly decreasing incidence between 2005 and 2015. Twelve of the 408 infants developed KSD, (incidence 1.2/100,000) Blood type ABO isohemolytic disease was the most common explanatory etiology. CONCLUSIONS: Our study stresses the importance of a systematic approach to neonatal jaundice and ongoing surveillance of extreme neonatal hyperbilirubinemia and KSD.

Follow-up of extreme neonatal hyperbilirubinaemia in 5- to 10-year-old children: a Danish population-based study.

AIM: To investigate whether infants with neonatal hyperbilirubinaemia but without intermediate or advanced bilirubin encephalopathy develop long-term sequelae, with impairment of motor development, executive function, or hearing. METHOD: This nested double-cohort study included 167 exposed children (107 males, 60 females) born in Denmark 2000 to 2005 at gestational age ≥35 weeks with a total serum bilirubin ≥450 µmol/L (26.3mg/dL) and 163 age-, sex-, and gestational age-matched unexposed children (103 males, 60 females). The children were examined at a mean age of 7.7 years (SD 1.7y) using the Movement Assessment Battery for Children-Second Edition (MABC-2), pure tone audiometry, and the Behavioural Regulation Inventory of Executive Function (BRIEF) questionnaire. RESULTS: The follow-up rate was 70% of the eligible infants in the exposed group and 45% in the unexposed group. Mean difference was -0.2 (95% confidence interval [CI] -1.1 to 0.8) in adjusted standard score for MABC-2 and 0.3 (95% CI -2.9 to 3.5) in adjusted BRIEF executive composite standard score. No children had significant hearing impairment or a diagnosis of cerebral palsy, attention-deficit-hyperactive disorder, or autism spectrum disorder recorded in national registries. INTERPRETATION: No evidence was found of an increased risk of deficits in motor development, executive function, or hearing in children with extreme hyperbilirubinaemia who did not have intermediate or advanced bilirubin encephalopathy.

Breastfeeding progression in preterm infants is influenced by factors in infants, mothers and clinical practice: the results of a national cohort study with high breastfeeding initiation rates.

BACKGROUND AND AIM: Many preterm infants are not capable of exclusive breastfeeding from birth. To guide mothers in breastfeeding, it is important to know when preterm infants can initiate breastfeeding and progress. The aim was to analyse postmenstrual age (PMA) at breastfeeding milestones in different preterm gestational age (GA) groups, to describe rates of breastfeeding duration at pre-defined times, as well as analyse factors associated with PMA at the establishment of exclusive breastfeeding. METHODS: The study was part of a prospective survey of a national Danish cohort of preterm infants based on questionnaires and structured telephone interviews, including 1,221 mothers and their 1,488 preterm infants with GA of 24-36 weeks. RESULTS: Of the preterm infants, 99% initiated breastfeeding and 68% were discharged exclusively breastfed. Breastfeeding milestones were generally reached at different PMAs for different GA groups, but preterm infants were able to initiate breastfeeding at early times, with some delay in infants less than GA 32 weeks. Very preterm infants had lowest mean PMA (35.5 weeks) at first complete breastfeed, and moderate preterm infants had lowest mean PMA at the establishment of exclusive breastfeeding (36.4 weeks). Admitting mothers to the NICU together with the infant and minimising the use of a pacifier during breastfeeding transition were associated with 1.6 (95% CI 0.4-2.8) and 1.2 days (95% CI 0.1-2.3) earlier establishment of exclusive breastfeeding respectively. Infants that were small for gestational age were associated with 5.6 days (95% CI 4.1-7.0) later establishment of exclusive breastfeeding. CONCLUSION: Breastfeeding competence is not developed at a fixed PMA, but is influenced by multiple factors in infants, mothers and clinical practice. Admitting mothers together with their infants to the NICU and minimising the use of pacifiers may contribute to earlier establishment of exclusive breastfeeding.

Factors associated with exclusive breastfeeding of preterm infants. Results from a prospective national cohort study.

BACKGROUND AND AIM: Evidence-based knowledge of how to guide the mothers of preterm infants in breastfeeding establishment is contradictive or sparse. The aim was to investigate the associations between pre-specified clinical practices for facilitating breastfeeding, and exclusive breastfeeding at discharge as well as adequate duration thereof. METHODS: A prospective survey based on questionnaires was conducted with a Danish national cohort, comprised of 1,221 mothers and their 1,488 preterm infants with a gestational age of 24-36 weeks. Adjusted for covariates, the pre-specified clinical practices were analysed by multiple logistic regression analyses. RESULTS: At discharge 68% of the preterm infants were exclusively breastfed and 17% partially. Test-weighing the infant, and minimizing the use of a pacifier, showed a protective effect to exclusive breastfeeding at discharge (OR 0.6 (95% CI 0.4-0.8) and 0.4 (95% CI 0.3-0.6), respectively). The use of nipple shields (OR 2.3 (95% CI 1.6-3.2)) and the initiation of breast milk expression later than 48 hours postpartum (OR 4.9 (95% CI 1.9-12.6)) were associated with failure of exclusive breastfeeding at discharge. The clinical practices associated with an inadequate breastfeeding duration were the initiation of breast milk expression at 12-24 hours (OR 1.6 (95% CI 1.0-2.4)) and 24-48 hours (OR 1.8 (95% CI 1.0-3.1)) vs. before six hours postpartum, and the use of nipple shields (OR 1.4 (95% CI 1.1-1.9)). CONCLUSION: Early initiation of breast milk pumping before 12 hours postpartum may increase breastfeeding rates, and it seems that the use of nipple shields should be restricted. The use of test-weighing and minimizing the use of a pacifier may promote the establishment of exclusive breastfeeding, but more research is needed regarding adequate support to the mother when test-weighing is ceased, as more of these mothers ceased exclusive breastfeeding at an early stage after discharge.

Dose-response relationship of phototherapy for hyperbilirubinemia.

BACKGROUND AND OBJECTIVE: Using light-emitting diodes during conventional phototherapy, it is possible to reduce the distance from light source to infant, thus increasing light irradiance. The objective of this study was to search for a "saturation point" (ie, an irradiation level above which there is no further decrease in total serum bilirubin [TsB]). This was a prospective randomized study performed in the NICU of Aalborg Hospital, Denmark. METHODS: One hundred fifty-one infants (gestational age ≥ 33 weeks) with uncomplicated hyperbilirubinemia were randomized to 1 of 4 distances from the phototherapy device to the mattress (20, 29, 38, and 47 cm). TsB was measured before and after 24 hours of phototherapy and irradiance every eighth hour. Main outcome was 24-hour decrease of TsB expressed in percent, ( TsB(0-24), difference between TsB(0) and TsB(24) [%]). RESULTS: A highly significant linear relation was seen between light irradiance and TsB(0-24) (%) (P < .001): when the irradiance increased from 20 to 55 µW/cm(2)/nm, TsB(0-24) (%) increased from approximately 30% to 50%. In addition, smooth regression showed no tendency for TsB(0-24) (%) to level off as irradiance increased. TsB(0-24) (%) was negatively correlated to birth weight and positively to formula volume. Average weight gain during phototherapy was 1%, independent of light irradiance. CONCLUSIONS: By using light-emitting diodes, we found a linear relation between light irradiance in the range of 20 to 55 µW/cm(2)/nm and a decrease in TsB after 24 hours of therapy, with no evidence of a saturation point.

Follow-up of neonates with total serum bilirubin levels ≥ 25 mg/dL: a Danish population-based study.

OBJECTIVE: To study if severe hyperbilirubinemia in infants with no or minor neurologic symptoms in the neonatal period affects children's development at the age of 1 to 5 years. METHODS: Controlled descriptive follow-up study of a national cohort of Danish children. The exposed group consisted of all live-born infants in Denmark from 2004 to 2007 with a gestational age ≥ 35 weeks and severe hyperbilirubinemia in the neonatal period, defined as at least 1 measure of total serum bilirubin level ≥ 25 mg/dL during the first 3 weeks of life. The exposed group of 206 children was matched with a control group of 208 children. The Ages and Stages Questionnaire (ASQ), a method of evaluating the child's development, was filled in by parents. Main outcome measure was effect size of ASQ total score. Statistical analyses comprised a matched analysis of 102 pairs and a nonmatched regression analysis of all participants. RESULTS: The response rate was 79% (n = 162 of 206) in the study group and 70% (n = 146 of 208) in the control group. Neither the matched nor the nonmatched analysis showed any statistically significant differences between the groups; the effect size of the total score was 0.04 (-0.24 to 0.32) and -0.04 (-0.26 to 0.19), respectively. CONCLUSIONS: Using the parent-completed ASQ, we found no evidence of developmental delay in children aged between 1 and 5 years with severe neonatal hyperbilirubinemia compared with a matched control group.

Measuring developmental deficit in children born at gestational age less than 26 weeks using a parent-completed developmental questionnaire.

AIM: To assess developmental deficit in children born at gestational age (GA) < 26 wk using a parental questionnaire and to use regression analysis to study a cohort born in 1999-2003. PATIENTS AND METHODS: Three groups were studied: group 1, GA < 26 wk; group 2, GA 26-27 wk; group 3, children born at term. The Ages & Stages Questionnaire (ASQ) was used. The parents of each child were mailed an age-specific questionnaire between November 2004 and April 2005. The term children were used as a reference to calculate a standard deviation score (ASQ-SDS) for each child in the two preterm groups. RESULTS: Seventy-five per cent of the questionnaires were returned (group 1: n=61; group 2: n=57; group 3: n=72). The age at scoring ranged from 12 to 60 mo (mean 32.8 mo). After correction for parental education, 22% of the children born at GA < 26 wk and 13% of those at GA 26-27 wk had an ASQ-SDS below -2. Chronic lung disease of prematurity was associated with developmental deficit (mean difference -1.1 ASQ-SDS, p=0.004). CONCLUSION: The ASQ identified a significant developmental deficit in the children born extremely preterm. The rate of 22%, however, in children born at GA < 26 wk is reassuring.