An economic analysis of the cost of survival of micro preemies: A systematic review

ObjectiveThis study aimed to systematically review the current literature on the economic costs of micro preemie as well as evidence on the cost-effectiveness of interventions to improve outcomes for micro preemie babies with a birth weight of ≤500 g.MethodWe searched MEDLINE, CINAHL, Scopus, ECONLIT, Business Source Premier and Cochrane Library for studies reporting costs of micro preemie from January 2000. Costs were inflated to 2019 United States dollars (US$). All full-text articles were assessed for eligibility and a quality assessment of included articles was conducted using the Drummond and the Larg and Moss checklists.ResultsThe search identified three studies that met the inclusion criteria; two cost-of-illness studies and one cost-effectiveness study. Across studies, the mean healthcare spending per micro preemie survivor (in 2019 US$) ranged from US$61,310 (birth admission) to US$263,958 (inpatient and outpatient for the first six months of life). One modelling study reported exclusive human milk diet for micro preemies at birth was more cost-effective compared to the standard approach with cow milk diet from the third-party payer and societal perspectives.ConclusionDespite significant advances in perinatal care and expanded access to life-saving equipment to improve survival outcomes of micro preemie, there remains a paucity of research on economic costs associated with these babies. No study has utilised quality-adjusted life-years as an outcome measure. Given the chronic conditions and long-term neurologic disability associated with micro preemie survivors, an estimate of the lifetime cost to the individual, healthcare providers and society would provide a benchmark of the potential cost-savings that could accrue from cost-effective interventions to improve the survival rate of micro preemies.     

How to use... alkaline phosphatase in neonatology

Alkaline phosphatase (ALP) is regularly measured in clinical practice. Changes in serum levels are observed in a number of clinical conditions. In neonatology, it has been proposed as a useful marker for both a diagnosis and an indication of the severity of metabolic bone disease (MBD) in infants born preterm. Nutritional practices, aimed at reducing the occurrence or severity of MBD, have led to ALP being proposed as a stand-alone means of monitoring treatment. The current evidence does not support this use: ALP only achieves usefulness in a diagnostic and monitoring capacity when combined with other serum and imaging techniques.     

Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice

Current practice in relation to the prescribing, compounding and administration of parenteral nutrition for extremely preterm infants is inconsistent and based on largely historical evidence. Increasingly there are calls for more ‘aggressive’ nutritional interventions to prevent ‘postnatal growth failure’. However the evidence base for these recommendations is weak, and there are no long-term studies examining the impact of such practices. Here we summarise the evidence for preterm parenteral nutrition interventions. We suggest principles to guide practice based on evidence from a systematic search and review of evidence to date, and recommend actions necessary to advance the understanding of this important aspect of preterm care.     

Mechanical ventilation strategies

Although only a small proportion of full term and late preterm infants require invasive respiratory support, they are not immune from ventilator-associated lung injury. The process of lung damage from mechanical ventilation is multifactorial and cannot be linked to any single variable. Atelectrauma and volutrauma have been identified as the most important and potentially preventable elements of lung injury. Respiratory support strategies for full term and late preterm infants have not been as thoroughly studied as those for preterm infants; consequently, a strong evidence base on which to make recommendations is lacking. The choice of modalities of support and ventilation strategies should be guided by the specific underlying pathophysiologic considerations and the ventilatory approach must be individualized for each patient based on the predominant pathophysiology at the time.     

The implications of routine milk fortification for the short and long-term health of preterm babies

Fortification refers to the practice of enriching human milk feeds for very preterm babies with macronutrients, minerals and vitamins. Though standard of care in some parts of the world, adoption of fortification is not universal. Fortification entered into use on the assumption that human milk macronutrient content, principally protein, is insufficient to support the growth and development of very preterm babies. However, because of the substantial variability in human milk composition, routine fortification risks exposing some babies to very high protein intakes, which may be dangerous. Some clinicians fear fortification with cow-milk derived products will increase the risk of necrotising enterocolitis, leading them to favour commercial fortifiers made from pooled human milk over cow milk based products, a practice that has additional ethical implications. Randomised controlled trials of multi-nutrient fortification to-date are inadequate. No trial has had power to detect important functional effects; the majority are methodologically weak and focus primarily upon short-term growth. Evidence to guide practice is inadequate. There is an urgent need for collaboration to conduct high-quality research to end these long-standing uncertainties.     

Collection and storage of breast milk for very low birth weight infants: an overview of Italian practices

Methods of collection and storage of mothers' milk to feed premature infants who weigh less than 1500 g (very low birth weight infants) or who are under 32 weeks gestational age need to preserve the important factors in the milk and avoid infective contamination as much as possible. Mothers are directly involved and given responsibility for this practice, an involvement that requires adequate procedures and useful strategies. The aim of the study was to investigate and describe the procedures applied by Italian neonatal intensive care units (NICUs) regarding the collection and storage of the mothers' own milk for their preterm newborns. To do this, a questionnaire regarding the different aspects of collection and storage of breast milk for preterm newborns was sent out to 105 Italian level III NICUs. Ninety-two NICUs (87.6%) participated, and breast milk collection was possible in 87 of them (95%); 86% had an electric breast pump available as well as the components needed for breast milk collection and/or containers to store breast milk. In 41 (46%) of the hospitals where milk collection was possible, pump sets were loaned to the mother, either for 24 hours (10; 24%) or until discharge (25; 62%). Pump sets were disinfected/sterilised after each use in 75% of the NICUs, and every 24 hours in 18%. Sixty-four per cent of the hospitals did not pasteurise the milk. Refrigerated milk was used in 82% of NICUs, whereas only 58% administered fresh milk. Surplus breast milk was frozen in 79% of the centres. The procedures for collection and storage of mothers' own milk for very low birth weight infants in Italian NICUs were therefore shown in this study to be heterogeneous but (not far from the current evidence) more or less in line with current guidelines and standards of good clinical practice. Further investigations are needed to make this aspect of preterm infant care effective and safe.     

Fracture and fortified breast milk in an extremely preterm infant

Metabolic bone disease (MBD) in the newborn predominantly affects preterm infants. The risk of MBD is inversely proportional to gestational age and birthweight, and directly related to postnatal complications. Poor bone mineralization has been shown in 55% of infants born at less than 1000 g. Optimal nutrition for very preterm infants is thought to be mother's own milk but supplementation is required to meet dietary requirements. However, there is insufficient evidence to determine that supplementation of human milk with commercial fortifiers has an effect on bone mineral content. We report a case of severe MBD with fractures in an extremely preterm infant who was fed with fortified mother's milk.     

Increased epidermal growth factor levels in human milk of mothers with extremely premature infants

Maternal milk is the major source of nutrients and growth-promoting substances in the first weeks of life for the majority of neonates. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are trophic peptides present in human milk with significant healing effects on injured gastrointestinal mucosa. Decreasing gestational age of neonates is associated with higher risk of developing gastrointestinal disorders, and human milk provides better protection against these diseases compared with formula. The aim of this study was to evaluate the concentrations of EGF and TGF-alpha in human milk collected from mothers with infants born: extremely preterm, preterm, and full term. Milk samples were collected at the end of first, second, and fourth week postpartum from each mother of infants born in one of the three gestational age groups: extremely preterm (23-27 wk, n = 16), preterm (32-36 wk, n = 16), and full term (38-42 wk, n = 15). Milk concentrations of EGF and TGF-alpha were quantified with a homologous RIA in the milk aqueous fraction. Concentrations of EGF in human milk from the extremely preterm group (23-27 wk) were significantly higher compared with values from the preterm and full-term groups throughout the first month of lactation. A similar pattern was observed with human milk TGF-alpha; however, milk TGF-alpha levels were lower than EGF. In conclusion, we have found higher concentrations of EGF and TGF-alpha in human milk of mothers with extremely preterm babies. These data may indicate the potential importance of milk-borne EGF and TGF-alpha for the development of extremely premature infants.     

Are there interventions that improve breastfeeding and the use of breast milk in late preterm infants?

To answer the clinical question ‘Among late preterm infants are there any interventions that improve the rates of breastfeeding and the use of breast milk compared with current practice?’. MEDLINE via Ovid, Embase via Ovid, the Maternity and Infant Care Database and the Cochrane Library were searched for relevant articles. Articles were excluded if they did not discuss specific interventions to improve breastfeeding, for example, if they only commented on factors such as age, race and education. Articles were also excluded if they were not specific to the late preterm infant population. A total of 516 articles were found and screened by title and abstract independently by two reviewers. The full text of 17 articles was independently reviewed. The reference lists of these full‐text articles were screened, and 14 abstracts were subsequently reviewed. The final analysis included three studies. There is limited high‐quality research evidence for interventions to improve breastfeeding in late preterm infants. In the absence of robust academic research, clinical practice should be guided by clinical expertise and involve a multidisciplinary team, including qualified lactation consultants. While it seems reasonable for hospitals to support interventions that improve breastfeeding in term infants, managing late preterm infants as healthy term infants without additional specialist support may result in high breastfeeding failure rates among late preterm infants.     

采集母乳与母乳库母乳喂养对早产儿生长发育的影响

采集母乳与母乳库母乳可以作为早产儿在无法获得直接母乳喂养时可选择的一种喂养方式.目前文献提示,单纯以采集母乳与母乳库母乳喂养的早产儿生后短期内生长要慢于早产儿配方乳喂养,对早产儿远期生长的影响尚不明确;但采集母乳与母乳库母乳喂养可供给早产儿一定量的人乳特有成分,有利于早产儿神经发育,并减少坏死性小肠结肠炎、喂养不耐受等喂养相关并发症的发生.采集母乳与母乳库母乳的临床广泛应用还面临一些亟待解决的问题,将来的研究应更多关注于对早产儿远期生长发育的影响.     

Physician counselling practices and decision-making for extremely preterm infants in the Pacific Rim

OBJECTIVES: This study was undertaken to evaluate physician counselling practices and resuscitation decisions for extremely preterm infants in countries of the Pacific Rim. We sought to determine the degree to which physician beliefs, parents' opinion and medical resources influence decision-making for infants at the margin of viability. METHODS: A survey was administered to neonatologists and paediatricians who attend deliveries of preterm infants in Australia, Hong Kong, Japan, Malaysia, Taiwan and Singapore. Questions were asked regarding physician counselling practices, decision-making for extremely preterm infants and demographic information. RESULTS: Physicians counsel parents antenatally with increasing frequency as gestational age increases. Most physicians discuss infant mortality and morbidity with parents prior to delivery. Physicians less frequently discuss the option of no resuscitation of an extremely preterm infant, withdrawal of support at a later time, or financial costs to parents. Severe congenital malformations, perception of a poor future quality of life, parental wishes and a high probability of death for the infant are influential in limiting resuscitation in very preterm infants for a majority of physicians. Less influential factors are parent socioeconomic status, language barriers, financial costs for the family, allocation of national resources, moral or religious considerations, or fear of litigation. Physician thresholds for resuscitation of infants ranged between 22 and 25 weeks gestation and between 400 and 700 g birthweight. CONCLUSIONS: We report physician beliefs and practices regarding resuscitation and the counselling of parents of extremely preterm infants in Pacific Rim countries. While we find variation among countries, physician practices appear to be determined by ethical decision-making and medical factors rather than social or economic factors in each country.     

Outcome and cost of neonatal intensive care

The techniques required to provide life support and treatment for extremely preterm or otherwise sick babies are an emerging technology in health care. Twenty years ago, only tertiary referral centres provided such care, usually described as neonatal intensive care. However, it is now regarded as common practice in neonatal nurseries in richer countries. Because such care is very costly, and because of concern in most countries about health care budgets, the growth of neonatal care has raised questions about the corresponding benefits. In this paper, I shall summarise some evidence about changes in both outcomes and costs of caring for extremely sick newborn babies, and discuss how these data have been used in the debate about health care spending.     

Optimal protein and energy intakes in preterm infants

There is compelling evidence that current nutritional practice fails to provide sufficient dietary protein for preterm infants, especially extremely and very low birth weight infants. Nutrient requirements can be estimated by a variety of techniques, but most suggest that these infants will require a protein intake of 3.5-4.0 g/kg/d. Even when these infants are able to tolerate full enteral feeds, most currently available artificial milk formula or breast milk fortifiers will not ensure these protein requirements are met except when fed at high volumes. Energy requirements on the other hand may be currently met, and evidence from controlled studies suggests that intakes higher than 110-135 kcal/kg/d might not be beneficial. The data from studies on neonatal adiposity outcomes, and from studies examining relationship between early growth and later cardiovascular outcome, also suggest that excess nutrient intake might be harmful. In the light of this data, optimal intakes and protein-energy ratios require re-appraisal.     

Promoting growth for preterm infants following hospital discharge

Preterm infants, especially very preterm infants, are usually growth-restricted at the time of hospital discharge. Proposed interventions to promote catch-up growth following hospital discharge include multinutrient fortification of expressed breast milk for breastfed infants and nutrient-enriched formula milk for formula-fed infants. The current evidence to support these strategies is limited. Fortification of expressed breast milk may increase weight gain and skeletal and head growth during infancy, but more research is needed to define which nutrients confer most benefit, and which population of infants is likely to receive most benefit. Trials that have assessed feeding preterm infants with commercially available nutrient-enriched formula milk ('preterm' or 'postdischarge' formulae) compared with standard formula milk have not found consistent evidence of an effect on growth parameters or development, probably because ad libitum fed infants reduce their intake relative to the calorie-density of the milk. Future studies should focus on the effect of formulae enriched with protein and minerals rather than energy and assess the effect on lean mass and skeletal growth.     

Transmission of cytomegalovirus to extremely preterm infants through breast milk

AIM: To evaluate the rate and clinical expression of postnatal cytomegalovirus (CMV) infection transmitted through breast milk in extremely preterm infants. METHODS: Ten extremely preterm infants and their six mothers were included. Maternal CMV serology was determined. Breast milk samples and urine samples from the infants were screened for CMV. Symptoms and laboratory findings of CMV infected infants were documented. All infants received partly fresh and/or defrosted breast milk. RESULTS: CMV-DNA was found in breast milk in four of five CMV-seropositive mothers. Two infants were infected by CMV. They were the only infants fed with breast milk positive for viral culture. One infant developed hepatic affection concurrent with viral excretion in urine. This infant was later diagnosed with cystic fibrosis. CONCLUSION: This study supports that CMV transmission through breast milk can aggravate the clinical course in extremely preterm infants with preexisting hepatic conditions.     

Human milk banking; current evidence and future challenges

Human milk banks systematically collect, pasteurize, store, and distribute donated breast milk. In situations when a mother's own milk is insufficient or unavailable donor milk may be used as an alternative. There are a number of clinical groups who may benefit from donor milk; due to limitations in supply and evidence of benefit in term infants, most commonly donor milk is administered to preterm infants. Guidelines regarding the management of milk banks recommend potential donors are screened and tested and that milk is heat treated to minimize risk of transmission of infectious agents. Although essential to safety, pasteurization alters bioactive and nutritional properties of human milk. Pasteurized donor milk is lower in protein, calories and bioactive molecules compared with mother's own preterm milk produced in the first few weeks after delivery.Current evidence suggests that there are some health advantages for preterm infants to being fed pasteurized donor milk over preterm formula. There are challenges with regard to providing adequate nutrition with donor milk as well as logistical and ethical concerns. Formation of a national milk-bank network within the UK combined with standardized data collection would assist in the distribution and further evaluation of the potential benefits of this precious resource.     

Nutrition of preterm infants after hospital discharge

Growth failure in preterm infants remains extremely common despite advances in neonatal care. Many, or even a majority, leave the hospital with weights below the 10th centile for age. Because of this, the possibility of nutritional interventions to improve postdischarge growth has been considered. A variety of interventions have been tested in randomized controlled trials in formula-fed infants. Although the studies vary in design and in the intervention used, on balance the evidence supports the use of fortified formulas in formula-fed preterm infants after hospital discharge. Specially designed postdischarge formulas and preterm infant formulas seem equally efficacious. The situation for infants fed human milk is much less clear. Although the postdischarge growth in human milk-fed infants is not as good as in formula-fed infants, no interventions have been examined in human milk-fed infants in a randomized study, to our knowledge. We are unaware of any evidence that any of the commonly proposed nutritional interventions in human milk-fed infants after hospital discharge are either safe or efficacious. In the absence of such evidence, it seems prudent to avoid untested interventions in this population and to concentrate our efforts on the encouragement of breast-feeding after hospital discharge.     

Zinc deficiency in rapidly growing preterm infants

Symptomatic zinc deficiency was observed in a 24-week gestation, 640g birthweight infant fed exclusively with maternal breast milk. Our hypothesis was that subclinical Zn deficiency is not uncommon in very low birthweight infants because fortified human milk and preterm formula may contain little Zn. Zinc serum concentrations determined in 26 consecutive very low birthweight infants (gestational age 23-32, median 27 weeks), prior to discharge, at a chronological age of 37-121 (median 72) d, were found between 1.0 and 14.0 (median 6.4) μmol/l, in 14 infants they were below the normal range of 7.6-15.0μmol/l. Serum alkaline phosphatase and iron intake did not correlate with Zn concentrations. Nutritional supply of Zn and other trace elements by breast milk fortifiers and infant formulas currently used in Germany does not appear to meet the demands of rapidly growing extremely low birthweight infants during the first months of life.     

Calcium and phosphorus balance in extremely low birthweight infants in the first six weeks of life.

The absorption and retention of calcium and phosphorus in infants of 28 weeks'' gestation, or less, who were fed either breast milk or a preterm formula, were determined in 22 balance studies. Breast milk contained significantly lower amounts of calcium and phosphorus than the formula milk. The percentage absorption of calcium was similar in the two groups, but the infants fed breast milk had greater urinary calcium losses and significantly lower calcium retention than the group fed formula milk. The percentage phosphate absorption was also similar in the two groups but because of the higher phosphate intake in the formula milk this group retained a significantly greater amount of phosphate. The extremely low birthweight infants fed on breast milk were phosphorus depleted, with low plasma phosphate concentrations, and seemed to retain as much phosphate as possible. The hypophosphataemia may result in reduced deposition of calcium in bone and explain the calciuria in the breast fed infants. Substrate deficiency may be an important factor in the aetiology of rickets of prematurity and, particularly if breast milk is used, preterm infants may require calcium and phosphate supplements from an early age.     

Concentrations of IL-10 in preterm human milk and in milk from mothers of infants with necrotizing enterocolitis

BACKGROUND: Despite the protective effects of human milk against necrotizing enterocolitis, the incidence is highest in the extremely premature infant, and only minimally decreased with feeding human milk. This suggests that certain protective agents may be lower in milk from mothers delivering extremely premature infants. The anti-inflammatory cytokine IL-10 was one possibility. AIM: We hypothesized that low concentrations of IL-10 in preterm milk contribute to the development of necrotizing enterocolitis in extremely premature infants. METHODS: IL-10 in human milk collected at weeks 1, 2, and 4 postpartum was measured by ELISA in mothers of infants born extremely premature at 23-27 wk gestation (group EP), premature at 32-36 wk gestation (group P), and term at 38-42 wk gestation (group T). Single milk samples were collected from a separate group of mothers whose infants developed necrotizing enterocolitis. RESULTS: There were no significant differences in concentrations of milk IL-10 among groups EP, P, or T. Concentrations of IL-10 declined as lactation progressed (p < 0.001). IL-10 in milk was frequently undetected in all groups, but even more so in the milk of the group of women whose infants had necrotizing enterocolitis (86%) than in groups EP (40%) and P (27%) (p < 0.01). CONCLUSION: IL-10 was present in preterm milk from most women, and the concentrations in preterm and term milk were not significantly different. A paucity of IL-10 in human milk was found in certain mothers in each group, especially in those whose infants developed necrotizing enterocolitis.