Infant Milk Formula with Large, Milk Phospholipid-coated Lipid Droplets Enriched in Dairy Lipids Affects Body Mass Index Trajectories and Blood Pressure at School Age: Follow-up of a Randomized Controlled Trial.

BACKGROUND: Human milk comprises large fat globules enveloped by a native phospholipid membrane, whereas infant formulas contain small, protein-coated lipid droplets. Previous experimental studies indicated that mimicking the architecture of human milk lipid droplets in infant milk formula (IMF) alters lipid metabolism with lasting beneficial impact on later metabolic health. OBJECTIVES: To evaluate in a follow-up (FU) study of a randomized, controlled trial whether a Concept IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids beneficially impacts long-term body mass index (BMI in kg/m2) trajectories and blood pressure at school age. METHODS: Fully formula-fed infants were randomly assigned to Concept IMF (n = 115) or Control IMF with conventional, small lipid droplets containing vegetable oils (n = 108) for the first 4 mo of age. A group of 88 breastfed infants served as a reference. During FU, anthropometrics were collected at 1, 3, 4, and 5 y of age, and blood pressure only at the last visit. RESULTS: Compared to Control, Concept group children had consistently lower mean BMI values during FU, with the most marked difference at 1 y of age (difference in means -0.71 kg/m2, 95% confidence interval (CI): -1.13, -0.29; P = 0.001); mean values were close to the breastfed group (P > 0.05). Contrary, the mean BMI values of the Control group were higher compared with the breastfed group during FU from 1 to 5 y of age (differences in means from 0.59 to 0.96 kg/m2, respectively; P < 0.02). At 5 y of age, the Concept group had a lower mean diastolic and arterial blood pressure compared with the Control group; -4.3mm Hg (95% CI: -7.3, -1.3; P = 0.005) and -3.7 mm Hg (95% CI: -6.5, -0.9; P = 0.01), respectively. CONCLUSIONS: Early life feeding of an innovative IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids results in a BMI trajectory closer to breastfed infants and a lower blood pressure at school age. This trial was registered at the Dutch Trial Register as NTR3683 and NTR5538.

Perinatal Palliative Care Service: Developing a Comprehensive Care Package for Vulnerable Babies with Life Limiting Fetal Conditions.

Background: Perinatal Palliative Care provides comprehensive and holistic care for expectant and new parents, who receive a diagnosis of life-limiting fetal condition and opt to continue pregnancy and care for their newborn infant. Aim: To develop a service providing individually tailored holistic care during pregnancy, birth, postnatal and bereavement period. Methods: Following a baseline survey of neonatologists and discussions with key stakeholders we launched the Perinatal Palliative service at the KK Women's and Children's hospital, Singapore in January 2017. The multidisciplinary team, led by a Palliative care specialist comprised of Obstetricians, Neonatologists, nurses and medical social workers. The Birth defect clinic referred parents with antenatally diagnosed 'Lethal' fetal conditions. The team checked the understanding and the decision making process of parents and initiated and finalized advance care plans. The service also embraced deserving postnatal referrals upon request. Results: A total of 41 cases were seen from January 2017 to December 2019. Of these, 26/41(63%) were referred antenatally and had completed advance care plans. 18/41 (44%) died during or shortly after birth and 10/41(24%) continue to survive and are supported by the community palliative team. During this time a workflow was formulated and modified based on parent and team feedback. Conclusion: Awareness of the service has increased over the years and a clear workflow has been formulated. Advance care plans are prepared and documented before birth so as to enable service teams on board to provide well timed pertinent care. Feedbacks from parents about this service were positive.

The Test of Infant Motor Performance (TIMP) in very low birth weight infants and outcome at two years of age.

OBJECTIVE: To evaluate TIMP in preterm very low birth weight (VLBW) infants, analyze risk factors, for atypical TIMP (aTIMP) scores, and explore TIMP's predictive relationship with Bayley-III at 2 years. METHOD: A prospective study of 288 VLBW infants, with TIMP assessment between 34 weeks postmenstrual age and 16 weeks age, corrected for prematurity. RESULT: aTIMP scores were observed in 58/288(20%) infants, whose mean birth weight (BW) and gestational age were 1122 ± 257 g and 29.2 ± 2.12 weeks respectively. Risk factors included BW < 750 g (OR 4.8, 95% CI 1.3-17.7) and 750-1000 g (OR 2.9, 95% CI 1.2-6.9), presence of necrotizing enterocolitis ≥ stage 2; or focal intestinal perforation (OR 4.6, 95% CI 1.4-14.4), periventricular leukomalacia (OR 22.4,95% CI 2.0-246.2), and need for intensive resuscitation at birth (OR 2.7, 95% CI 1.3-5.5). aTIMP scores correlated with Bayley-III Score <85 in motor and cognitive domains with high specificity (80-82%) and negative predictive value (85-94%). CONCLUSION: Identification of the risk factors for aTIMP scores will enable targeted intervention to optimize resources and outcomes in VLBW infants.

New BPD-prevalence and risk factors for bronchopulmonary dysplasia/mortality in extremely low gestational age infants ≤28 weeks.

OBJECTIVE: To evaluate prevalence and risk factors of moderate-severe Bronchopulmonary dysplasia (BPD)/Death in extremely low gestation age neonates (ELGANs). STUDY DESIGN: Study of 266 ELGANs born at gestational age (GA) ≤ 28 weeks (w). Primary Outcome measure-composite outcome of moderate-severe BPD/Death using the National Institute of Child Health and Human Development NICHD's (2001) BPD definition. RESULT: Cohort's mean GA and birth-weight (BW) were 25.3 ± 1.4w and 724 ± 14 g respectively with an overall mortality of 19% and moderate-severe BPD of 67%. Prevalence of moderate-severe BPD/death decreased significantly with increasing GA (86-93%) at 23-24 w; to <60% at 27-28w (OR 0.63; 95% CI; 0.52-0.77). On univariate analysis, other risk factors included BW(OR 1.005; 95% CI; 1.003-1.007), Sepsis (OR 2.9; 95% CI, 1.3-6.4), PDA needing treatment (OR 2.2; 95% CI, 1.3-3.9); air leaks (OR 2.7; 95% CI; 1.02-7.3) FiO2 requirement >25%(OR 1.06; 95% CI; 1.01-1.11); and mechanical ventilation(MV) on Day7 (OR5.5; 95% CI; 2.8-10.8). Only need for Day7 MV was independently predictive of composite outcome (OR1.97; 95% CI; 1.3-3.1). CONCLUSION: Risk factor identification will enable initiatives to implement lung protective strategies and develop prospective models for BPD prediction and prognostication.

Causes, functional outcomes and healthcare utilisation of people with cerebral palsy in Singapore.

INTRODUCTION: A voluntary cerebral palsy (CP) registry was established in 2017 to describe the clinical characteristics and functional outcomes of CP in Singapore. METHODS: People with CP born after 1994 were recruited through KK Women's and Children's Hospital, National University Hospital and Cerebral Palsy Alliance Singapore. Patient-reported basic demographics, service utilisation and quality of life measures were collected with standardised questionnaires. Clinical information was obtained through hospital medical records. RESULTS: Between 1 September 2017 and 31 March 2020, 151 participants were recruited. A majority (n=135, 89%) acquired CP in the pre/perinatal period, where prematurity (n=102, 76%) and the need for emergency caesarean section (n=68, 50%) were leading risk factors. Sixteen (11%) of the total participants had post-neonatally acquired CP. For predominant CP motor types, 109 (72%) had a spastic motor type; 32% with spastic mono/hemiplegia, 41% diplegia, 6% triplegia and 21% quadriplegia. The remaining (42, 27.8%) had dyskinetic CP. Sixty-eight (45.0%) participants suffered significant functional impairment (Gross Motor Functional Classification System levels IV-V). Most participants (n=102, 67.5%) required frequent medical follow-up (≥4 times a year). CONCLUSION: Optimisation of pre- and perinatal care to prevent and manage prematurity could reduce the burden of CP and their overall healthcare utilisation.

Academic school readiness in children born very preterm and associated risk factors.

BACKGROUND AND AIMS: Although the intelligence quotient (IQ) test is useful to assess general cognitive function, it may miss more specific and subtle deficits of learning, working memory, attention and executive function. This study aims to evaluate cognitive performance and academic school readiness (SR) concepts in preterm very low birth weight (PT/VLBW) children, compared to typically developing term controls and to evaluate factors affecting basic (SR) concepts in children with IQ>85. METHODS: A prospective cohort study of 123 PT/VLBW survivors with birth weights ≤1250 g and 74 term controls born between 2007 and 2009 in Singapore were assessed for school readiness using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), Bracken School Readiness Assessment (BSRA-3) and Beery-Buktenica Developmental Test of Visual Motor Integration (VMI) at age 5.5 years. Social risk composite score (SRCS) was calculated based on ethnicity, parental education and family income and marital status. Uni- and multi-variable regressions were conducted to evaluate risk factors associated with poor academic SR in the entire cohort and in those with IQ >85. RESULTS: Mean gestational age and birth weight of the 123 PT/VLBW children were 27.8 (2.3) weeks and 939 (194) grams while that of the 74 term controls were 38.8 (1.2) weeks and 3165 (402) grams. PT/VLBW survivors had statistically significant lower full composite scores on WPPSI-III (97.0 vs 114), BSRA-3 (98.5 vs 112.3) and VMI (107.2 vs 112.9) compared to controls. The differences remained significant in preterm and children with higher SRCS even after adjustment. CONCLUSIONS: Prematurity and high social composite risk scores were risk factors affecting academic SR and this difference persisted in PT/VLBW children with normal cognitive scores with IQ >85.

Effectiveness of Palivizumab Against Respiratory Syncytial Virus Hospitalization Among Preterm Infants in a Setting With Year-Round Circulation.

BACKGROUND: The year-round respiratory syncytial virus (RSV) circulation in tropical regions leads to different transmission patterns and burden of disease among infants born very preterm. METHODS: We conducted a retrospective cohort study to estimate the effectiveness of palivizumab in preventing RSV hospitalization at 6 and 12 months after discharge, among infants born at <32 weeks' gestation in our tropical setting. RESULTS: A total of 109 infants (26.3%) received palivizumab at discharge, of 415 who were eligible. All patients received ≥4 doses, with 105 infants (96.3%) completing 5 doses. Within 1 year after discharge, there were 35 RSV-associated admissions (3 [2.8%] in the palivizumab vs 32 [10.5%] in the nonpalivizumab group; P = .02). After adjustment for confounders, the effectiveness of palivizumab against RSV hospitalization was estimated to be 90% (95% confidence interval, 10%-99%) up to 6 months after discharge. The median time to RSV hospitalization was shorter in the nonpalivizumab than in the palivizumab group (median [range], 155 [15-358] vs 287 [145-359] days, respectively; P = .11). Five infants (14.3%), all from the nonpalivizumab group, required admission to the intensive care unit. CONCLUSIONS: In our setting with year-round RSV circulation, palivizumab prophylaxis was effective in reducing RSV hospitalization among high-risk preterm infants of <32 weeks' gestation within the initial 6 months after discharge.

Evidence-Based Practices Reduce Necrotizing Enterocolitis and Improve Nutrition Outcomes in Very Low-Birth-Weight Infants.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants. Survivors may suffer both short- and long-term morbidities. Current evidence suggests that the incidence of NEC can be reduced by standardizing the care delivery in addressing key risk factors including an altered gut microbiome, use of formula milk, hyperosmolar feeds, and unrestricted use of high-risk medications METHODS: Since 2014, the department has a workgroup who analyzed all cases of NEC within a month of diagnosis to identify preventable risk factors. Existing evidence-based quality improvement strategies were revised and new ones were implemented sequentially over the next 4 years. These strategies include (1) a standardized feeding protocol, (2) early initiation of enteral feeding using human milk, (3) optimization of the osmolality of preterm milk feeds using standardized dilution guidelines for additives, and (4) promotion of healthy microbiome by use of probiotics, early oral care with colostrum and by restricting high-risk medications and prolonged use of empirical antibiotics RESULTS: Baseline characteristics of the patients including sex, gestational age, and birth weight were similar during the study period. After implementing the evidence-based practices successively over 4 years, the incidence of NEC in very- low birth-weight (VLBW) infants dropped from 7% in 2014 to 0% (P < .001) in 2018. The duration of parenteral nutrition, use of central line, and days to full feeds were also reduced significantly (P < .05) CONCLUSION: Adopting evidence-based best practices resulted in a significant decrease in the incidence of NEC and improved the nutrition outcomes in VLBW infants.

Emotional and Behavioural disorders in a cohort with Down syndrome using the Strengths and Difficulties Questionnaire: A pilot study.

BACKGROUND: Globally, mental health disorders and behavioural problems afflict persons with Down syndrome (DS) with a high prevalence reported in some studies. However, data on behavioural and emotional disorders in DS cohort in Asian countries are lacking. AIMS: To assess the mental health status of children and adults with DS, using the Strength and Difficulties Questionnaire (SDQ) and its impact on caregivers using the impact supplement. METHODS: The questionnaires were administered to caregivers of eligible participants aged ≥4 years. In addition, Down syndrome participant's ≥ 11 years old attempted the self-report. Scoring was done as per standard SDQ guidelines. RESULTS: The total difficulties score was observed to be at least borderline high in 30.6% (19/62) of the participants. Peer relationships and conduct subscale issues were rated high, with abnormal internalizing scores predominating over externalizing scores. From parents' perspective, behavioural issues impacted 41.9% (26/62) of participants' in areas of education, peer relationship and leisure. However, only 3.8% (1/26) of the caregivers whose children had behavioural issues perceived them as a burden. CONCLUSIONS: Mental health difficulties are a significant morbidity in our DS cohort. SDQ is a useful user-friendly tool for identification of behavioural problems enabling timely referral for intervention and therapy.

A novel Ser40Trp variant in IFITM5 in a family with osteogenesis imperfecta and review of the literature.

Osteogenesis imperfecta, is a genetically and clinically heterogeneous connective tissue disorder that disrupts bone architecture, making it fragile and more prone to fractures. While more than 85% of cases are due to variants in COL1A1 and COL1A2, variants in noncollagen genes have been identified in the remaining cases. The recurring heterozygous variant in IFITM5 (c.-14C>T) leads to osteogenesis imperfecta type V, a second missense variant in IFITM5 (c.119C>T, p.Ser40Leu) leads to phenotype resembling osteogenesis imperfecta type VI. In this report, we describe the first patient with Ser40Trp variant in IFITM5, who presented with multiple fractures in the prenatal period. She remained fracture free after birth (except for trauma-related fractures during puberty) with normal bone mineral densitometry. Her mother, who did not have a history of fracture, was noted to have somatogonadal mosaicism for this variant and became pregnant with a second child with multiple prenatal fractures, found to have the same variant. To our knowledge, this is the first case of somatogonadal mosaicism in IFITM5. In addition, we have summarized the literature on patients presenting with variant in codon 40 (serine) of IFTIM5 protein.

Randomised controlled trial of dexmedetomidine sedation vs general anaesthesia for inguinal hernia surgery on perioperative outcomes in infants.

BACKGROUND: Neonates and infants undergoing general anaesthesia for hernia surgery are at risk of perioperative cardiorespiratory adverse events. The use of regional anaesthesia with dexmedetomidine preserves airway tone and may potentially avoid these complications. This study compares the perioperative conditions and adverse events between dexmedetomidine sedation with caudal block and general anaesthesia with caudal block for inguinal hernia surgery in infants. METHODS: A randomised controlled trial was conducted in a tertiary hospital in Singapore involving 104 infants younger than 3 months, who were randomised to receive either dexmedetomidine sedation (DEX) with caudal block or general sevoflurane anaesthesia with tracheal intubation and caudal block (GA) for inguinal hernia surgery. Perioperative conditions, haemodynamics and adverse events were compared between groups. RESULTS: Fifty-one infants received DEX and 48 infants received GA. In the DEX group, 46 infants (90.2%) had their operations completed solely under this technique, two (3.9%) were converted to general anaesthesia with intubation, and three (5.9%) required brief administration of nitrous oxide or low-dose sevoflurane. Overall, 96.1% of infants in the DEX group did not require intubation. Perioperative conditions were similar in both groups. The DEX group had significantly lower heart rates and higher mean arterial pressures intraoperatively. Two infants in the DEX group (3.9%) required postoperative intensive care admission compared with six infants (12.5%) in the GA group. CONCLUSIONS: Dexmedetomidine sedation with caudal block provides a feasible alternative to general anaesthesia in infants undergoing hernia surgery. This technique avoids the need for tracheal intubation, which may be beneficial in neonates. CLINICAL TRIAL REGISTRATION: NCT02559102.

An infant formula with large, milk phospholipid-coated lipid droplets containing a mixture of dairy and vegetable lipids supports adequate growth and is well tolerated in healthy, term infants.

BACKGROUND: Lipid droplets in human milk have a mode diameter of ∼4 µm and are surrounded by a native phospholipid-rich membrane. Current infant milk formulas (IMFs) contain small lipid droplets (mode diameter ∼0.5 µm) primarily coated by proteins. A concept IMF was developed mimicking more closely the structure and composition of human milk lipid droplets. OBJECTIVES: This randomized, controlled, double-blind equivalence trial evaluates the safety and tolerance of a concept IMF with large, milk phospholipid-coated lipid droplets (mode diameter 3-5 µm) containing vegetable and dairy lipids in healthy, term infants. METHODS: Fully formula-fed infants were enrolled up to 35 d of age and randomly assigned to 1 of 2 formulas until 17 wk of age: 1) Control IMF with small lipid droplets containing vegetable oils (n = 108); or 2) Concept IMF with large, milk phospholipid-coated lipid droplets comprised of 48% dairy lipids (n = 115). A group of 88 breastfed infants served as reference. Primary outcome was daily weight gain during intervention. Additionally, number and type of adverse events, growth, and tolerance parameters were monitored. RESULTS: Equivalence of daily weight gain was demonstrated (Concept compared with Control IMF: -1.37 g/d; 90% CI: -2.71, -0.02; equivalence margin ± 3 g/d). No relevant group differences were observed in growth, tolerance and number, severity, or relatedness of adverse events. We did observe a higher prevalence of watery stools in the Concept than in the Control IMF group between 5 and 12 wk of age (P < 0.001), closer to the stool characteristics observed in the breastfed group. CONCLUSIONS: An infant formula with large, milk phospholipid-coated lipid droplets containing dairy lipids is safe, well tolerated, and supports an adequate growth in healthy infants. This trial was registered in the Dutch Trial Register (www.trialregister.nl) as NTR3683.

Factors affecting neurodevelopmental outcome at 2 years in very preterm infants below 1250 grams: a prospective study.

OBJECTIVE: To evaluate the neurodevelopmental outcomes of preterm very-low birth weight (PT/VLBW) infants at 2 years and identify risk factors associated with significant developmental delay or neurodevelopmental impairment (NDI). STUDY DESIGN: We evaluated 165 PT/VLBW infants born between January 2010 and December 2011, using the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III). NDI was defined as the presence of neurosensory impairment or significant delay with Bayley-III score < 70 in any domain and risk factors for delay/NDI were assessed using logistic regressions. RESULTS: Median Bayley-III composite scores in the cognitive, language and motor domains were 95, 89 and 94, respectively. NDI was present in 20% of the children, with 5-18% having significant delay in either cognitive, language or motor domain, seven (4%) children had cerebral palsy, three (2%) were deaf and none were blind. Regression models identified significant positive associations of delayed cognitive skills with male gender (Odds ratio (OR) 22.4, 95% confidence interval (CI) 1.5-341.1; P = 0.025), lack of anntenatal steroids (ANS) (OR 41.5, 95% CI 3.5-485.7; P = 0.003), and hypotension needing inotropes (OR 36.0, 95% CI 2.6-506.0; P = 0.008); delayed language skills with lower maternal education (OR 3.8, 95% CI 1.4-10.3; P = 0.10), lack of ANS (OR 2.8, 95% CI 1.1-7.4; P = 0.04), and 5 minute Apgar Score ≤ 5 (OR 7.4, 95% CI 1.4-38.4; P = 0.017) and delayed motor skills with chronic lung disease at 36 weeks (OR 38.3, 95% CI 2.4-603.4; P = 0.010). NDI was associated with lack of ANS (OR 2.91, 95% CI 1.21-7.00; P = 0.02) and use of postnatal steroids (OR 3.36, 95% CI 1.07-10.54; P = 0.0374). CONCLUSION: Risk factors for both NDI and individual domain delay were identified and will be helpful in planning of specific and targeted early intervention services.

Prospective evaluation of the Ages and Stages Questionnaire 3rd Edition in very-low-birthweight infants.

AIM: To evaluate the predictive and concurrent diagnostic agreement of the Ages and Stages Questionnaire 3rd Edition (ASQ-3) with the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) in infants born preterm and very-low-birthweight (PT/VLBW; ≤1250g). METHOD: We evaluated 141 PT/VLBW infants (68 males, 73 females) born at the KK Women's and Children's Hospital between January 2010 and December 2011, to determine predictive and concurrent diagnostic agreement between the ASQ-3 at 9, 12, 18, and 24 months corrected age and Bayley-III at 24 months. Cut-offs on the ASQ-3 at 24 months were estimated by receiver operating characteristic curves. RESULTS: Sixty (43%) and 25 (18%) failed in any domain of the ASQ-3 and Bayley-III (<70) respectively. A negative predictive value (NPV) >98% was achieved for the motor domain from 9 months, and >90% for the communication domain and the overall results at 24 months. Optimal referral ASQ-3 score at 24 months to achieve 100% NPV was 243. INTERPRETATION: In PT/VLBW infants, ASQ-3 screening at 24 months can reduce the need for costly psychometric assessments in children with normal results. Clinicians can be assured of normal motor development at 9 months using the ASQ-3, but should continue to screen children on other domains.