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1.  Brief Parenteral Nutrition Accelerates Weight Gain, Head Growth Even in Healthy VLBWs 
PLoS ONE  2014;9(2):e88392.
Whether parenteral nutrition benefits growth of very low birth weight (VLBW) preterm infants in the setting of rapid enteral feeding advancement is unclear. Our aim was to examine this issue using data from Japan, where enteral feeding typically advances at a rapid rate.
We studied 4005 hospitalized VLBW, very preterm (23–32 weeks' gestation) infants who reached full enteral feeding (100 ml/kg/day) by day 14, from 75 institutions in the Neonatal Research Network Japan (2003–2007). Main outcomes were weight gain, head growth, and extra-uterine growth restriction (EUGR, measurement <10th percentile for postmenstrual age) at discharge.
40% of infants received parenteral nutrition. Adjusting for maternal, infant, and institutional characteristics, infants who received parenteral nutrition had greater weight gain [0.09 standard deviation (SD), 95% CI: 0.02, 0.16] and head growth (0.16 SD, 95% CI: 0.05, 0.28); lower odds of EUGR by head circumference (OR 0.66, 95% CI: 0.49, 0.88). No statistically significant difference was seen in the proportion of infants with EUGR at discharge. SGA infants and infants who took more than a week until full feeding had larger estimates.
Even in infants who are able to establish enteral nutrition within 2 weeks, deprivation of parenteral nutrition in the first weeks of life could lead to under nutrition, but infants who reached full feeding within one week benefit least. It is important to predict which infants are likely or not likely to advance on enteral feedings within a week and balance enteral and parenteral nutrition for these infants.
PMCID: PMC3929530  PMID: 24586323
2.  Nutrient needs and feeding of premature infants. Nutrition Committee, Canadian Paediatric Society. 
OBJECTIVE: To recommend appropriate intake of nutrients, food sources and feeding practices for premature infants. OPTIONS: Unfortified milk from the premature infant's own mother, fortified milk from the premature infant's own mother, formula designed for preterm infants and parenteral nutrition. OUTCOMES: From birth to 7 days, the minimum achievable goal is the provision of sufficient nutrients to prevent deficiencies and catabolism of nutrient substrate in premature infants; from 7 days to discharge from the neonatal intensive care unit, growth and nutrient retention at a rate similar to that which would have been achieved had the infant remained in utero; and for 1 year following discharge, nutrient intake to achieve catch-up growth. EVIDENCE: Few randomized clinical trials of feeding infants specific nutrients or of feeding choices have been conducted. On the basis of a MEDLINE search of the literature, committee members prepared reviews of the available information on each nutrient and feeding choice. The reviews were critically appraised by the committee. Recommendations were based on the consensus of the committee. VALUES: Whenever possible, the evidence was weighed in favour of randomized controlled trials. If such trials were unavailable, cohort studies were considered. If trials of either kind were unavailable, published data were reviewed and recommendations were based on consensus opinion. BENEFITS, HARMS AND COSTS: The advantages of feeding premature infants unfortified milk from their own mothers are psychologic benefits for the mother as well as anti-infective benefits and possibly improved intellectual development for the infant. However, unfortified milk from the infant's own mother is inadequate as a sole source of nutrients. The use of fortified milk from the mother results in faster growth as well as having the other benefits of mother's milk. When formulas designed for premature infants are given in adequate volumes, they provide an intake of nutrients that allows the infant to duplicate intrauterine growth without undue metabolic stress. RECOMMENDATIONS: The preferred food for premature infants is fortified milk from the infant's own mother or alternatively, formula designed for premature infants. This recommendation applies to infants with birth weights of a minimum of 500 g to a maximum of 1800 to 2000 g, or with a gestational age at birth of a minimum of 24 weeks to a maximum of 34 to 38 weeks (until the infant is able to nurse effectively). VALIDATION: These guidelines are in line with, but not identical to, recent guidelines by the Committee on Nutrition of the American Academy of Pediatrics and the Committee on Nutrition of the Preterm Infant of the European Society of Paediatric Gastroenterology and Nutrition. SPONSOR: The preparation of these guidelines was sponsored and funded by the Canadian Paediatric Society.
PMCID: PMC1337975  PMID: 7773894
3.  Nutrition for healthy term infants 
Paediatrics & Child Health  1998;3(2):109-112.
Nutrition for Healthy Term Infants is the new national statement on nutrition for infants from birth to 24 months, developed collaboratively by the Canadian Paediatric Society, Dietitians of Canada and Health Canada.
The document summarizes the existing scientific literature on infant nutrition and presents principles and recommendations to help health care professionals promote optimal, evidence-based nutritional care for infants in Canada. Collaboration between the three key organizations involved in infant nutrition has produced unified messages for health professionals to deliver to the public.
For the first year of life four major topics are discussed: Breastfeeding, Alternate Milks, Other Fluids in Infant Feeding and Transition to Solid Foods. Safety Issues Around Feeding is presented next, followed by Nutrition in the Second Year of Life. The final section covers Other Issues in Infant Nutrition, and includes topics such as food allergies, colic, constipation, dietary fat, dental caries, gastroenteritis, diabetes, iron deficiency anemia and vegetarian diets. An extensive reference list of more than 200 citations is provided.
The Summary of Principles and Recommendations will be published in the official journals of the Canadian Paediatric Society (Paediatrics & Child Health, March/April 1998) and Dietitians of Canada (Canadian Journal of Dietetic Practice and Research, June 1998). The complete document can be downloaded from all three of the collaborating organizations’ web sites or a hard copy of the Statement, in either official language, can be obtained from the Canadian Paediatric Society, Dietitians of Canada or Health Canada.
Nutrition for Healthy Term Infants offers multidisciplinary health professionals the most current scientific tool for advising parents and positively influencing the nutritional environment provided to infants in Canada.
PMCID: PMC2851281  PMID: 20401210
Guidelines; Infants; Nutrition
4.  Strategies for Feeding the Preterm Infant 
Neonatology  2008;94(4):245-254.
According to many experts in neonatal nutrition, the goal for nutrition of the preterm infant should be to achieve a postnatal growth rate approximating that of the normal fetus of the same gestational age. Unfortunately, most preterm infants, especially those born very preterm with extremely low birth weight, are not fed sufficient amounts of nutrients to produce normal fetal rates of growth and, as a result, end up growth-restricted during their hospital period after birth. Growth restriction is a significant problem, as numerous studies have shown definitively that under nutrition, especially of protein, at critical stages of development produces long-term short stature, organ growth failure, and both neuronal deficits of number and dendritic connections as well as later behavioral and cognitive outcomes. Furthermore, clinical follow-up studies have shown that among infants fed formulas, the nutrient content of the formula is directly and positively related to mental and motor outcomes later in life. Nutritional requirements do not stop at birth. Thus, delaying nutrition after birth ‘until the infant is stable’ ignores the fundamental point that without nutrition starting immediately after birth, the infant enters a catabolic condition, and catabolism does not contribute to normal development and growth. Oxygen is necessary for all metabolic processes. Recent trends to limit oxygen supply to prevent oxygen toxicity have the potential, particularly when the blood hemoglobin concentration falls to less than 8 g/dl, to develop growth failure. Glucose should be provided at 6–8 mg/min/kg as soon after birth as possible and adjusted according to frequent measurements of plasma glucose to achieve and maintain concentrations > 45 mg/dl but < 120 mg/dl to avoid the frequent problems of hyperglycemia and hypoglycemia. Similarly, lipid is required to provide at least 0.5 g/kg/day to prevent essential fatty acid deficiency. However, the high rate of carbohydrate and lipid supply that preterm infants often get, based on the incomplete assumption that this is necessary to promote protein growth, tends to produce increased fat in organs like the liver and heart as well as adipose tissue. More and better essential fatty acid nutrition is valuable, but more organ and adipose fat has no known benefit and many problems. Amino acids and protein are essential not only for body growth but for metabolic signaling, protein synthesis, and protein accretion. 3.5–4.0 g/kg/day are necessary to produce normal protein balance and growth in very preterm infants. Attempts to promote protein growth with insulin has many problems – it is ineffective while contributing to even further organ and adipose tissue fat deposition. Enteral feeding always is indicated and to date nearly all studies have shown that minimal enteral feeding approaches (e.g., ‘trophic feeds’) promote the capacity to feed enterally. Milk has distinct advantages over formulas in avoiding necrotizing enterocolitis (NEC), and while feeding is associated with NEC, minimal enteral feeding regimens produce less NEC than those geared towards more aggressive introduction of enteral feeding. Finally, overfeeding has the definite potential to produce adipose tissue, or obesity, which then leads to insulin resistance, glucose intolerance, and diabetes. This scenario occurs more commonly as infants are fed more and gain weight more rapidly after birth, regardless of their birth weight. Infants with IUGR and postnatal growth failure may be uniquely ‘set up’ for this outcome, while infants with in utero obesity, such as infants of diabetic mothers, already are well along this adverse outcome pathway
PMCID: PMC2912291  PMID: 18836284
Nutrition; Feeding; Preterm infant; Oxygen; Glucose; Amino acids; Lipids; Insulin; Minimal enteral nutrition; Intravenous feeding; Intrauterine growth restriction
5.  Cognitive and Motor Development Among Small-for-Gestational-Age Infants: Impact of Zinc Supplementation, Birth Weight, and Caregiving Practices 
Pediatrics  2004;113(5):1297-1305.
Infants who are born small for gestational age (SGA) are at risk for developmental delays, which may be related to deficiencies in zinc, an essential trace metal, or to deficiencies in their ability to elicit caregiver responsiveness (functional isolation hypothesis). The objective of this study was to evaluate at 6 and 10 months of age the impact of a 9-month supplementation trial of 5 mg of zinc on the development and behavior of infants who were born SGA and to evaluate infants’ ability to elicit responsive caregiver behavior.
A randomized, controlled trial of zinc supplementation was conducted among 200 infants in a low-income, urban community in Delhi, India. Infants were recruited when they were full term (>36 weeks) and SGA (birth weight <10th percentile weight-for-gestational age). Infants were randomized to receive daily supplements of a micronutrient mix (folate, iron, calcium, phosphorus, and riboflavin) with or without 5 mg of zinc sulfate. The supplement was administered by field workers daily from 30 days to 9 months of age. At 6 and 10 months, infant development and behavior were measured in a clinical setting using the Bayley Scales of Infant Development II. Caregiver responsiveness, observed on an Indian version of the Home Observation for Measurement of the Environment scale, was measured during a home visit at 10 months. During both the clinic and home visits, caregivers reported on their infant’s temperament.
There were no direct effects of zinc supplementation on the infants’ development or behavior at either 6 or 10 months. In a subgroup analysis among the zinc-supplemented infants, lower birth weight infants were perceived to be more temperamentally difficult than higher weight infants; in the control group, birth weight was not associated with temperament. Heavier birth weight infants had better scores on all measures of development and behavior at 6 months and on changes in mental and motor development from 6 to 10 months, compared with lighter birth weight infants. Boys had better weight gain and higher scores on mental development and emotional regulation than girls. Infants who were from families of higher socioeconomic status (indexed by parental education, house size, and home ownership) had higher scores on mental development and orientation/engagement (exploratory behavior) than infants who were from families of lower socioeconomic status. In keeping with the functional isolation hypothesis, caregiver responsiveness was associated with infant irritability, controlling for socioeconomic status, gender, birth weight, and weight gain. Responsive mothers were more likely to perceive their infants to be temperamentally easy than less responsive mothers.
Possible explanations for the lack of effects of zinc supplementation on infant development and behavior include 1) subtle effects of zinc supplementation that may not have been detected by the Bayley Scales, 2) interference with other nutritional deficiencies, or 3) no impact of zinc deficiency on infants’ development and behavior. The link between birth weight and irritability among infants in the zinc supplementation group suggests that the response to zinc supplementation may differ by birth weight, with irritability occurring among the most vulnerable infants. Longer term follow-up studies among zinc-supplemented infants are needed to examine whether early supplementation leads to developmental or behavioral changes that have an impact on school-age performance. The relationship between infant irritability and low maternal responsiveness lends support to the functional isolation hypothesis and the importance of asking caregivers about infant temperament.
PMCID: PMC3140639  PMID: 15121945
zinc deficiency; cognitive development; mental development; motor development; behavior; temperament; maternal responsiveness
6.  Patterned orocutaneous therapy improves sucking and oral feeding in preterm infants 
To determine whether NTrainer patterned orocutaneous therapy affects preterm infants' non-nutritive suck and/or oral feeding success.
Thirty-one preterm infants (mean gestational age 29.3 weeks) who demonstrated minimal non-nutritive suck output and delayed transition to oral feeds at 34 weeks post-menstrual age.
NTrainer treatment was provided to 21 infants. The NTrainer promotes non-nutritive suck output by providing patterned orocutaneous stimulation through a silicone pacifier that mimics the temporal organization of suck.
Infants' non-nutritive suck pressure signals were digitized in the NICU before and after NTrainer therapy and compared to matched controls. Non-nutritive suck motor pattern stability was calculated based on infants' time- and amplitude-normalized digital suck pressure signals, producing a single value termed the Non-Nutritive Suck Spatiotemporal Index. Percent oral feeding was the other outcome of interest, and revealed the NTrainer's ability to advance the infant from gavage to oral feeding.
Multilevel regression analyses revealed that treated infants manifest a disproportionate increase in suck pattern stability and percent oral feeding, beyond that attributed to maturational effects alone.
The NTrainer patterned orocutaneous therapy effectively accelerates non-nutritive suck development and oral feeding success in preterm infants who are at risk for oromotor dysfunction.
PMCID: PMC2562454  PMID: 18462468
Feeding therapy; Non-nutritive suck; Oromotor control; Suck central pattern generator; Suck spatiotemporal variability
7.  Nutritional management of newborn infants: Practical guidelines 
The requirements of growth and organ development create a challenge in nutritional management of newborn infants, especially premature newborn and intestinal-failure infants. Since their feeding may increase the risk of necrotizing enterocolitis, some high-risk infants receive a small volume of feeding or parenteral nutrition (PN) without enteral feeding. This review summarizes the current research progress in the nutritional management of newborn infants. Searches of MEDLINE (1998-2007), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2007), abstracts and conference proceedings, references from relevant publications in the English language were performed, showing that breast milk is the preferred source of nutrients for enteral feeding of newborn infants. The number of nutrients found in human milk was recommended as a guideline in establishing the minimum and maximum levels in infant formulas. The fear of necrotizing enterocolitis and feeding intolerance are the major factors limiting the use of the enteral route as the primary means of nourishing premature infants. PN may help to meet many of the nutritional needs of these infants, but has significant detrimental side effects. Trophic feedings (small volume of feeding given at the same rate for at least 5 d) during PN are a strategy to enhance the feeding tolerance and decrease the side effects of PN and the time to achieve full feeding. Human milk is a key component of any strategy for enteral nutrition of all infants. However, the amounts of calcium, phosphorus, zinc and other nutrients are inadequate to meet the needs of the very low birth weight (VLBW) infants during growth. Therefore, safe and effective means to fortify human milk are essential to the care of VLBW infants.
PMCID: PMC2761573  PMID: 18985802
Breast milk; Infant formula; Trophic feeding; Parenteral nutrition
8.  Randomised trial of early diet in preterm babies and later intelligence quotient 
BMJ : British Medical Journal  1998;317(7171):1481-1487.
To determine whether perinatal nutrition influences cognitive function at 7½-8 years in children born preterm.
Randomised, blinded nutritional intervention trial. Blinded follow up at 7½-8 years.
Intervention phase in two neonatal units; follow up in a clinic or school setting.
424 preterm infants who weighed under 1850 g at birth; 360 of those who survived were tested at 7½-8 years.
Standard infant formula versus nutrient enriched preterm formula randomly assigned as sole diet (trial A) or supplements to maternal milk (trial B) fed for a mean of 1 month.
Main outcome measures
Intelligence quotient (IQ) at 7½-8 years with abbreviated Weschler intelligence scale for children (revised).
There was a major sex difference in the impact of diet. At 7½-8 years boys previously fed standard versus preterm formula as sole diet had a 12.2 point disadvantage (95% confidence interval 3.7 to 20.6; P<0.01) in verbal IQ. In those with highest intakes of trial diets corresponding figures were 9.5 point disadvantage and 14.4 point disadvantage in overall IQ (1.2 to 17.7; P<0.05) and verbal IQ (5.7 to 23.2; P<0.01). Consequently, more infants fed term formula had low verbal IQ (<85): 31% versus 14% for both sexes (P=0.02) and 47% versus 13% in boys P=0.009). There was a higher incidence of cerebral palsy in those fed term formula; exclusion of such children did not alter the findings.
Preterm infants are vulnerable to suboptimal early nutrition in terms of their cognitive performance—notably, language based skills—at 7½-8 years, when cognitive scores are highly predictive of adult ones. Our data on cerebral palsy generate a new hypothesis that suboptimal nutritional management during a critical or plastic early period of rapid brain growth could impair functional compensation in those sustaining an earlier brain insult. Cognitive function, notably in males, may be permanently impaired by suboptimal neonatal nutrition.
Key messagesSuboptimal nutrition during sensitive stages in early brain development may have long term effects on cognitive functionIn a randomised trial of early nutrition in preterm infants those fed standard rather than nutrient enriched preterm formula had reduced verbal IQ scores at 7½ to 8 years, at least in boysIn exploratory analyses on children of both sexes verbal IQ below 85 and cerebral palsy were more prevalent in the standard formula groupOur data show the potential vulnerability of the human brain to early suboptimal nutritionAvoidance of undernutrition in sick preterm infants seems important in optimising later neurodevelopmental outcomes
PMCID: PMC28727  PMID: 9831573
9.  Nutrition of the Fetus and Newborn 
Western Journal of Medicine  1987;147(4):435-448.
Both the successful development of healthy, long-term animal models to study fetal nutrition and metabolism and the improved survival of low-birth-weight, preterm infants have focused interest and research on fetal and neonatal nutrition and metabolism. Such a focus is important, given the recent emphasis on promoting neonatal growth in preterm infants at “normal” in utero growth rates. Estimates of nutrient requirements for growth in a human fetus remain ill defined, however. Body composition data appear biased toward thin infants. Animal data suggest that fetal nutrition proceeds according to species-specific growth rates, with variations in fat content largely dependent on placental fat permeability and on maternal nutrient supply as regulated by the placenta.
After birth, neonatal nutrition is affected primarily by food intake and the functional integrity and capacity of the gastrointestinal tract. Additionally, muscle activity, thermoregulation and stresses of various kinds and degrees modify a neonate's nutritional requirements. Functional deficits of the gastrointestinal tract have been circumvented by a more aggressive use of intravenous nutrition. Both intravenous and enteral nutrient mixtures have been substantially improved in the quantity of all nutrients and have been modified qualitatively toward compositions that are closer to those of human milk. These nutrient mixtures now produce plasma nutrient concentrations that approximate those of a healthy, breast-fed infant.
Although such efforts to improve the nutritional balance and growth of preterm infants have been successful, much remains to be learned about the nutritional requirements of sick infants.
PMCID: PMC1025905  PMID: 3318138
10.  Postgraduate education in nutrition in south Asia: a huge mismatch between investments and needs 
Despite decades of nutrition advocacy and programming, the nutrition situation in South Asian countries is alarming. We assume that modern training in nutrition at the post graduate level is an important contributor to building the capacity of individuals to think and act effectively when combating undernutrition. In this context, this paper presents a regional situation analysis of master’s level academic initiatives in nutrition with a special focus on the type of programme we think is most likely to be helpful in addressing undernutrition at the population level: Public Health Nutrition (PHN).
This situational analysis of Masters in nutrition across South Asian countries viz. India, Pakistan, Bangladesh, Sri Lanka, Afghanistan, Maldives, Nepal, Bhutan was conducted using an intensive and systematic Internet search. Further, detailed information was extracted from the individual institute websites and library visits.
Of the131 master’s degree programmes we identified one that was in PHN while another 15 had modules in PHN. Most of these universities and institutions were found in India with a few in Bangladesh and Sri Lanka. In the rest of the countries, neither nutrition nor PHN emerged as an academic discipline at the master’s level. In terms of eligibility Indian and Sri Lankan programmes were most inclusive, with the remaining countries restricting eligibility to those with health qualifications. On modules, no country had any on nutrition policy or on nutrition’s interactions with agriculture, social protection, water and sanitation or women’s empowerment.
If a strong focus on public health nutrition is key to reducing undernutrition, then the poor availability of such courses in the region is cause for concern. Nutrition master’s courses in general focus too little on the kinds of strategies highlighted in the recent Lancet series on nutrition. Governments seeking to accelerate declines in undernutrition should incentivize the delivery of postgraduate programmes in nutrition and Public Health Nutrition (PHN) that reflect the modern consensus on priority actions. In the absence of PHN type programmes, the competence to scale up nutrition capacity is likely to be impaired and the human potential of millions of infants will continue to be squandered.
PMCID: PMC3893432  PMID: 24397258
Public health nutrition; Higher Education; Capacity building; South Asia; Curriculum
11.  Infant feeding practices among HIV exposed infants using summary index in Sidama Zone, Southern Ethiopia: a cross sectional study 
BMC Pediatrics  2014;14:49.
Combining various aspects of child feeding into an age-specific summary index provides a first answer to the question of how best to deal with recommended feeding practices in the context of HIV pandemic. The objective of this study is to assess feeding practices of HIV exposed infants using summary index and its association with nutritional status in Southern Ethiopia.
Facility based cross-sectional study design with cluster random sampling technique was conducted in Sidama Zone, Southern Ethiopia. Bivariate and multivariable linear regression analyses were performed to assess the association between summary index (infant and child feeding index) (CS-ICFI) and nutritional status.
The mean (±standard deviation (SD)) cross-sectional infant and child feeding index (CS-ICFI) score of infants was 9.09 (±2.59), [95% CI: 8.69-9.49]). Thirty seven percent (36.6%) of HIV exposed infants fell in the high CS-ICFI category while 31.4% of them were found in poor feeding index tertile. About forty two percent (41.6%) of urban infants were found in the high index tertile but only 24% of the rural infants were found in high index tertile. Forty six percent (46%) of the rural infants were found in low (poor) feeding index category. The CS-ICFI has a statistically significant association with weight for age z score (WAZ) (ß = 0.168, p = 0.027) and length for age z score (LAZ) (ß = 0.183 p = 0.036). However CS-ICFI was not significantly associated with weight for height z score (WLZ) (p = 0.386).
Majority of HIV exposed infants had no optimum complementary feeding practices according to cross-sectional infant and child feeding index. CS-ICFI was statistically associated especially with chronic indicators of nutritional status (LAZ and WAZ). More rural infants were found in poor index tertile than urban infants. This may suggest that rural infants need more attention than urban infants while designing and implementing complementary feeding interventions.
PMCID: PMC3937064  PMID: 24548764
12.  Age-appropriate feeding practices and nutritional status of infants attending child welfare clinic at a Teaching Hospital in Nigeria 
Appropriate infant feeding is the key to optimum infant and child development and survival. This study investigates age-appropriate infant feeding practices and nutritional status of infants attending the immunization and child welfare clinic at Aminu Kano Teaching Hospital.
Materials and Methods:
Using a cross-sectional descriptive design, a sample of 300 sets of infants (age ≤12 months) and caregivers was systematically selected and studied. The data were analyzed using the MINITAB® 12.21 (USA) statistical software.
All the infants studied were still on breast milk. Most of the mothers demonstrated correct body positioning (89.9) and attachment (78.7%) during breastfeeding, and effective suckling was demonstrated in 77.0%. Interestingly, none of the infants was either exclusively breastfed for 6 months or currently on exclusive breastfeeding. Furthermore, only 64 (58.2%) of the 110 infants that were more than 6 months of age had appropriately been started on complementary feeding from 6 months of age. Overall, most caregivers (88.7%) had “fair” to “good” infant feeding practices. The practices were significantly associated with their level of education, and their relationship with the infants. Up to 40.0% and 73.7% of the infants had varying degrees of wasting and stunting respectively. Infant feeding practices and the age of the infants emerged as the only factors significantly associated with stunting, while both the caregivers’ practices and age of the infants emerged as significant predictors of wasting in the infants.
Conclusion and Recommendations:
Barely 3 years to the 2015 target of the millennium development goals (MDGs), infant feeding and nutritional status still poses a serious threat to the dream of realizing the MDG-4. The Ministry of Health and relevant developing partners in this region should as a matter of urgency, formulate and implement a strong community-based public health intervention program to improve the knowledge and practices of mothers on infant feeding.
PMCID: PMC3966099  PMID: 24696628
Age-appropriate feeding; infant feeding practices; Kano-Nigeria; nutritional status
13.  Cryptosporidium Prevalence and Risk Factors among Mothers and Infants 0 to 6 Months in Rural and Semi-Rural Northwest Tanzania: A Prospective Cohort Study 
Cryptosporidium epidemiology is poorly understood, but infection is suspected of contributing to childhood malnutrition and diarrhea-related mortality worldwide.
A prospective cohort of 108 women and their infants in rural/semi-rural Tanzania were followed from delivery through six months. Cryptosporidium infection was determined in feces using modified Ziehl-Neelsen staining. Breastfeeding/infant feeding practices were queried and anthropometry measured. Maternal Cryptosporidium infection remained high throughout the study (monthly proportion = 44 to 63%). Infection did not differ during lactation or by HIV-serostatus, except that a greater proportion of HIV-positive mothers were infected at Month 1. Infant Cryptosporidium infection remained undetected until Month 2 and uncommon through Month 3 however, by Month 6, 33% of infants were infected. There were no differences in infant infection by HIV-exposure. Overall, exclusive breastfeeding (EBF) was limited, but as the proportion of infants exclusively breastfed declined from 32% at Month 1 to 4% at Month 6, infant infection increased from 0% at Month 1 to 33% at Month 6. Maternal Cryptosporidium infection was associated with increased odds of infant infection (unadjusted OR = 3.18, 95% CI 1.01 to 9.99), while maternal hand washing prior to infant feeding was counterintuitively also associated with increased odds of infant infection (adjusted OR = 5.02, 95% CI = 1.11 to 22.78).
Both mothers and infants living in this setting suffer a high burden of Cryptosporidium infection, and the timing of first infant infection coincides with changes in breastfeeding practices. It is unknown whether this is due to breastfeeding practices reducing pathogen exposure through avoidance of contaminated food/water consumption; and/or breast milk providing important protective immune factors. Without a Cryptosporidium vaccine, and facing considerable diagnostic challenges and ineffective treatment in young infants, minimizing the overall environmental burden (e.g. contaminated water) and particularly, maternal Cryptosporidium infection burden as a means to protect against early infant infection needs prioritization.
Author Summary
Early infancy and childhood Cryptosporidium infection is associated with poor nutritional status, stunted growth, and cognitive deficits, yet minimal research is available regarding the burden and risk factors worldwide. Since there is no vaccine available, and because diagnostic challenges exist and treatment for children younger than one year is ineffective, prevention of early infancy infection through a better understanding of basic epidemiology is critical. This study was designed to investigate symptomatic and clinically silent infection amongst HIV-seropositive and HIV-seronegative mothers and their infants in a longitudinal cohort, and to indentify potential risk factors. Findings indicate that infants are living in a Cryptosporidium environment as demonstrated by the chronically high level of maternal infection throughout the 6-month post-partum period. Despite this, infant infection prevalence remains low until six months of age when it dramatically rises. The increase in infant infection corresponds to a reduction in exclusive breastfeeding. As expected, maternal infection is associated with increased infant infection, but unexpectedly, so is maternal hand washing prior to infant feeding. Since prevention may indeed be the “best medicine” for infants, investigation of beneficial breastfeeding practices, protective correlates in breast milk, and ways to reduce the maternal and environmental Cryptosporidium burden are needed.
PMCID: PMC4183438  PMID: 25275519
14.  Preterm nutritional intake and MRI phenotype at term age: a prospective observational study 
BMJ Open  2014;4(5):e005390.
To describe (1) the relationship between nutrition and the preterm-at-term infant phenotype, (2) phenotypic differences between preterm-at-term infants and healthy term born infants and (3) relationships between somatic and brain MRI outcomes.
Prospective observational study.
UK tertiary neonatal unit.
Preterm infants (<32 weeks gestation) (n=22) and healthy term infants (n=39)
Main outcome measures
Preterm nutrient intake; total and regional adipose tissue (AT) depot volumes; brain volume and proximal cerebral arterial vessel tortuosity (CAVT) in preterm infants and in term infants.
Preterm nutrition was deficient in protein and high in carbohydrate and fat. Preterm nutrition was not related to AT volumes, brain volume or proximal CAVT score; a positive association was noted between human milk intake and proximal CAVT score (r=0.44, p=0.05). In comparison to term infants, preterm infants had increased total adiposity, comparable brain volumes and reduced proximal CAVT scores. There was a significant negative correlation between deep subcutaneous abdominal AT volume and brain volume in preterm infants (r=−0.58, p=0.01).
Though there are significant phenotypic differences between preterm infants at term and term infants, preterm macronutrient intake does not appear to be a determinant. Our preliminary data suggest that (1) human milk may exert a beneficial effect on cerebral arterial vessel tortuosity and (2) there is a negative correlation between adiposity and brain volume in preterm infants at term. Further work is warranted to see if our findings can be replicated and to understand the causal mechanisms.
PMCID: PMC4039783  PMID: 24860004
15.  Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants 
AIMS—To improve energy intake in sick very low birthweight (VLBW) infants; to decrease growth problems, lessen pulmonary morbidity, shorten hospital stay, and avoid possible feeding related morbidity. Morbidity in VLBW infants thought to be associated with parenteral and enteral feeding includes bronchopulmonary dysplasia, necrotising enterocolitis, septicaemia, cholestasis and osteopenia of prematurity.
METHODS—A prospective randomised controlled trial (RCT) comparing two types of nutritional intervention was performed involving 125 sick VLBW infants in the setting of a regional neonatal intensive care unit. Babies were randomly allocated to either an aggressive nutritional regimen (group A) or a control group (group B). Babies in group B received a conservative nutritional regimen while group A received a package of more aggressive parenteral and enteral nutrition. Statistical analysis was done using Student's t test, the Mann-Whitney U test, the χ2 test and logistic regression.
RESULTS—There was an excess of sicker babies in group A, as measured by initial disease severity (P <0.01), but mean total energy intakes were significantly higher (P <0.001) in group A at days 3 to 42 while receiving total or partial parenteral nutrition. Survival and the incidences of bronchopulmonary dysplasia, septicaemia, cholestasis, osteopenia and necrotising enterocolitis were similar in both groups. Growth in early life and at discharge from hospital was significantly better in babies in group A. There were no decreases in pulmonary morbidity or hospital stay.
CONCLUSION—Nutritional intake in sick VLBW infants can be improved without increasing the risk of adverse clinical or metabolic sequelae. Improved nutritional intake resulted in better growth, both in the early neonatal period and at hospital discharge, but did not decrease pulmonary morbidity or shorten hospital stay.

 Keywords: very low birthweight infant; nutrition; bronchopulmonary dysplasia; necrotising enterocolitis
PMCID: PMC1720665  PMID: 9279175
16.  Nutritional practices and growth velocity in the first month of life in extremely low gestational age newborns 
Pediatrics  2009;124(2):649-657.
The goals of this study were to describe nutritional practices in the first month of life for a large cohort of extremely low gestational age newborns and to determine the impact of these nutritional practices on growth velocity over the same period.
The sample included 1187 infants born at 23 weeks to 27 weeks of gestation, at 14 institutions, between 2002 and 2004. Inclusion criteria included survival until day 28 and weight information for both day 7 and day 28. Growth velocity, expressed as grams per kilogram per day (g/kg/day), was calculated for the interval between days 7 and 28. Nutritional practices during the first week and on days 14, 21, and 28 were compared to current nutritional guidelines in the literature. Multivariable logistic regression models estimated the contribution of limited nutrition to limited growth velocity.
Protein and fat delivery approximated current nutritional recommendations while carbohydrate and total caloric delivery did not. Despite this, growth velocity of our study infants exceeded the current guideline of 15 g/kg/day. Nevertheless, we found extrauterine growth restriction (i.e., weight for gestational age below the 10th centile) in 75% of infants at 28 days, as compared to only 18% at birth. A growth velocity of 20-30 g/kg/day was associated with infants' maintaining or exceeding their birth weight Z-score, with rates in the upper range for the gestationally youngest infants. Early (day 7) nutritional practices were positively associated with growth velocity measured between days 7 and 28.
The early provision of nutrients is an important determinant of postnatal growth. Extrauterine growth restriction remains high in extremely premature infants even when they achieve a growth velocity rate within current guidelines.
PMCID: PMC2859427  PMID: 19651583
Infant, premature; nutrition; growth velocity
17.  A randomized trial to investigate the effects of pre-natal and infant nutritional supplementation on infant immune development in rural Gambia: the ENID trial: Early Nutrition and Immune Development 
Recent observational research indicates that immune development may be programmed by nutritional exposures early in life. Such findings require replication from trials specifically designed to assess the impact of nutritional intervention during pregnancy on infant immune development. The current trial seeks to establish: (a) which combination of protein-energy (PE) and multiple-micronutrient (MMN) supplements would be most effective; and (b) the most critical periods for intervention in pregnancy and infancy, for optimal immune development in infancy.
The ENID Trial is a 2 x 2 x 2 factorial randomized, partially blind trial to assess whether nutritional supplementation to pregnant women (from < 20 weeks gestation to term) and their infants (from 6 to 12 months of age) can enhance infant immune development. Eligible pregnant women from the West Kiang region of The Gambia (pregnancy dated by ultrasound examination) are randomized on entry to 4 intervention groups (Iron-folate (FeFol = standard care), multiple micronutrients (MMN), protein-energy (PE), PE + MMN). Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination, including ultrasound. At delivery, cord blood and placental samples are collected, with detailed infant anthropometry collected within 72 hours. Infants are visited weekly thereafter for a morbidity questionnaire. From 6 to 12 months of age, infants are further randomized to a lipid-based nutritional supplement, with or without additional MMN. The primary outcome measures of this study are thymic development during infancy, and antibody response to vaccination. Measures of cellular markers of immunity will be made in a selected sub-cohort. Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age.
The proposed trial is designed to test whether nutritional repletion can enhance early immune development and, if so, to help determine the most efficacious form of nutritional support. Where there is evidence of benefit from a specific intervention/combination of interventions, future research should focus on refining the supplements to achieve the optimal, most cost-effective balance of interventions for improved health outcomes.
Trial registration
PMCID: PMC3534399  PMID: 23057665
18.  Proteolysis and phenylalanine hydroxylation in response to parenteral nutrition in extremely premature and normal newborns. 
Journal of Clinical Investigation  1996;97(3):746-754.
To determine to what extent intravenous nutrition can reduce proteolysis in very immature and normal newborns, and to assess the capacity of preterm and normal newborns to convert phenylalanine to tyrosine, phenylalanine and leucine kinetics were measured under basal conditions and during parenteral nutrition in clinically stable, extremely premature (approximately 26 wk of gestation) infants and in normal term newborns. In response to parenteral nutrition, there was significantly less suppression (P < 0.001) of endogenous leucine and phenylalanine rate of appearance in extremely premature infants compared with term infants. Phenylalanine utilization for protein synthesis during parenteral nutrition increased significantly (P < 0.01) and by the same magnitude (approximately 15%) in both extremely premature and term infants. Phenylalanine was converted to tyrosine at substantial rates in both extremely premature and term infants; however, this conversion rate was significantly higher (P < 0.05) in extremely premature infants during both the basal and parenteral nutrition periods. These data provide clear evidence that there is no immaturity in the phenylalanine hydroxylation pathway. Furthermore, although parenteral nutrition appears to produce similar increases in protein synthesis in extremely premature and term infants, proteolysis is suppressed much less in extremely premature newborns. The factors responsible for this apparent resistance to suppression of proteolysis in the very immature newborn remain to be elucidated.
PMCID: PMC507112  PMID: 8609231
19.  Body Composition and Circulating High-Molecular-Weight Adiponectin and IGF-I in Infants Born Small for Gestational Age  
Diabetes  2012;61(8):1969-1973.
Prenatal growth restraint, if followed by postnatal overweight, confers risk for adult disease including diabetes. The mechanisms whereby neonatal nutrition may modulate such risk are poorly understood. We studied the effects of nutrition (breast-feeding [BRF] vs. formula-feeding [FOF]) on weight partitioning and endocrine state (as judged by high-molecular-weight [HMW] adiponectin and IGF-I) of infants born small for gestational age (SGA). Body composition (by absorptiometry), HMW adiponectin, and IGF-I were assessed at birth and 4 months in BRF infants born appropriate for gestational age (AGA; n = 72) and SGA infants receiving BRF (n = 46) or FOF (n = 56), the latter being randomized to receive a standard (FOF1) or protein-rich formula (FOF2). Compared with AGA-BRF infants, the catchup growth of SGA infants was confined to lean mass, independently of nutrition. Compared with AGA-BRF infants, SGA-BRF infants had normal HMW adiponectin and IGF-I levels at 4 months, whereas SGA-FOF infants had elevated levels of HMW adiponectin (particularly SGA-FOF1) and IGF-I (particularly SGA-FOF2). In conclusion, neonatal nutrition seems to influence endocrinology more readily than body composition of SGA infants. Follow-up will disclose whether the endocrine abnormalities in SGA-FOF infants can serve as early markers of an unfavorable metabolic course and whether they may contribute to design early interventions that prevent subsequent disease, including diabetes.
PMCID: PMC3402297  PMID: 22648385
20.  Clinical Factors Affecting Lipid Metabolism and Optimal Dose of Heparin in Preterm Infants on Parenteral Nutrition 
Preterm infants on parenteral nutrition are at a relatively high risk for hypertriglyceridemia because they have immature lipoprotein lipase activity. The purpose of this study was to analyze the clinical factors affecting lipid metabolism in preterm infants receiving parenteral nutrition and to evaluate the influence of intravenous heparin on serum triglycerides to determine the adequate heparin dose to prevent hypertriglyceridemia in preterm infants.
A single-center retrospective review was conducted among preterm infants receiving parenteral nutrition between January 2006 and February 2011. In 75 patients, 110 determinations were performed within 28 days postnatal age. Demographic and clinical data, including laboratory parameters, the dose and the duration of lipid administration, and the amount of intravenous heparin, were analyzed.
Serum triglycerides were higher in the small for gestational age (SGA) infants than in the appropriate for gestational age infants (185.5±134.9 mg/dL vs. 126.9±101.9 mg/dL, p=0.019). Birth weight, gestational age, and body weight were negatively correlated with serum triglyceride level (r=-0.289, p=0.002; r=-0.208, p=0.029; r=-0.287, p=0.002, respectively). The serum triglyceride level was statistically lower in preterm infants receiving 1 U/mL of heparin than in those receiving 0.5 U/mL heparin or no heparin.
Preterm infants receiving parenteral nutrition, particularly SGA and extremely low birth weight infants, tend to have hypertriglyceridemia. Thus, administration of 1 U/mL of heparin rather than 0.5 U/mL or none may be helpful to prevent hypertriglyceridemia in preterm infants.
PMCID: PMC3760703  PMID: 24010115
Lipids; Hypertriglyceridemia; Parenteral nutrition; Heparin; Preterm infant
21.  A critical review of methods for comparing estrogenic activity of endogenous and exogenous chemicals in human milk and infant formula. 
Environmental Health Perspectives  2003;111(8):1020-1036.
The two primary sources of nutrition for infants are human milk and infant formula. Both contain an array of endogenous and exogenous chemicals that may act through many separate hormonal mechanisms. The safety of infant nutrition sources has been questioned based on the possibility that exogenous chemicals may exert adverse effects on nursing or formula-fed infants through estrogen-mediated mechanisms. In response to these and other concerns, the National Research Council recommended assessing the estrogenic potency of natural and anthropogenic hormonally active agents. Furthermore, the Endocrine Disruptor Screening and Testing Advisory Committee of the U.S. Environmental Protection Agency specifically recommended testing chemicals present in human milk as a representative mixture to which large segments of the population are exposed. To date, no clinical or epidemiologic evidence demonstrates that levels of chemicals currently found in human milk or infant formulas cause adverse effects in infants. Nonetheless, the question is sufficiently important to warrant a consideration of how best to evaluate potential estrogenic risks. We reviewed the types of data available for measuring estrogenic potency as well as methods for estimating health risks from mixtures of chemicals in infant nutrition sources that act via estrogenic mechanisms. We conclude that the science is insufficiently developed at this time to allow a credible assessment of health risks to infants based on estimates of estrogenic potency or on an understanding of toxicologic effects mediated by estrogenic mechanisms. However, clinical and epidemiologic data for infant nutrition sources may provide insights about risks of such substances in human milk and infant formulas.
PMCID: PMC1241552  PMID: 12826475
22.  Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial 
Lancet  2012;379(9835):2449-2458.
In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks.
The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with, number NCT00164736.
676 mother–infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5–9) than in the maternal-antiretroviral (4%, 3–6; p=0·0273) or the infant-nevirapine (4%, 2–5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29–48 weeks than during the intervention phase (1·1 [95% CI 1·0–1·2] vs 0·7 [0·7–0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group).
In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity
US Centers for Disease Control and Prevention.
PMCID: PMC3661206  PMID: 22541418
23.  Maternal knowledge of infant feeding guidelines and label reading behaviours in a population of new mothers in San Francisco, California 
Maternal & child nutrition  2009;5(3):223-233.
The objective of this study was to evaluate the relationship between maternal nutrition knowledge and maternal socio-demographics including participation in the Special Supplemental Women, Infants and Children’s (WIC) Program. A cross-sectional study of new mothers at two San Francisco hospitals was conducted using some of the American Academy of Pediatrics’ guidelines in a structured questionnaire to assess maternal nutritional knowledge. Maternal nutritional attitudes towards product nutrient labels were also assessed in a questionnaire format. Logistic regression models were used to evaluate the odds of having high maternal nutrition knowledge and of infrequently reading nutrition labels. In multivariate logistic regression models, higher maternal nutrition knowledge (defined as answering all four nutrition questions correctly) was associated with higher income levels defined as ≥$25 000/year, odds ratio (OR) 10.03 95% confidence interval (CI) (1.51–66.74), and in linear models, higher nutritional knowledge was associated with having more children (P < 0.01), a higher income (P = 0.01) and not being a WIC participant (P < 0.01). Mothers with higher incomes were also more likely to read product nutritional labels OR 4.24, 95% CI (1.24–14.51), compared with mothers with lower incomes as were mothers with higher education levels OR 3.32, 95% CI (1.28–8.63). In San Francisco, lower income mothers are at greatest risk for low maternal nutrition knowledge and not reading product nutritional labels. Higher household income was independently associated with increased maternal nutrition knowledge and likelihood of reading nutritional labels. More comprehensive interventions need to target low-income mothers including current WIC participants to help close the nutritional advantages gap conferred by income and education.
PMCID: PMC3252047  PMID: 19888918
maternal nutrition knowledge; nutrient labels; WIC Program
24.  Exclusive breastfeeding and its effect on growth of Malawian infants: results from a cross-sectional study 
For the optimal nutrition of children under 2 years of age, it is considered important that they be exclusively breastfed for the first 6 months before being given complementary food.
Aims and Objectives:
A cross-sectional nutritional baseline survey was undertaken in 2011 in the Kasungu and Mzimba Districts of Malawi to assess the nutritional status of children under 2 years of age and its determinants in order to prepare a nutrition education intervention programme. The intention of this study was to assess the nutritional status of infants aged 0–<6 months with regard to food intake.
Interviews were conducted on randomly selected families with children under 2 years; anthropometric measurements were obtained from mothers and their children. Only infants between 0 and <6 months were selected for analysis (n  =  196). An ANCOVA test was performed on age of the infant with mothers’ height and weight as covariates.
Prevalence of stunting (infants’ length-for-age Z-score (LAZ) <−2SD) was 39%, wasting (WLZ <−2SD) 2%, and underweight (WAZ <−2SD) 13%. Of the infants under 6 months, 43% were exclusively breastfed. Predominant breastfeeding and mixed breastfeeding were less common (21% and 36%, respectively). The ANCOVA confirmed the association between exclusive breastfeeding and LAZ and WAZ: exclusively breastfed infants had a higher mean (SE) LAZ (−1·13, 0·12) and WAZ (−0·41, 0·13) than infants not being exclusively breastfed (−1·59, 0·11, and −0·97, 0·11, respectively). There was no overall significant association between breastfeeding practice and WLZ.
Exclusive breastfeeding of infants under 6 months is associated with higher mean LAZ and WAZ. Promotion of exclusive breastfeeding in low-income countries is important in preventing growth retardation.
PMCID: PMC4280265  PMID: 25005815
Exclusive breastfeeding; Child growth; LAZ; Malawi
25.  NT-Pro-B-Type Natriuretic Peptide Levels in Infants with Failure to Thrive due to Caloric Deprivation 
Background. Brain natriuretic peptide and its inactive fragment N-terminal pro-BNP (N-BNP) are reliable markers of ventricular dysfunction in adults and children. We analyzed the impact of nutritional state on N-BNP levels in infants with failure to thrive (FTT) and in infants with severe heart failure (HF). The purpose of this study was to compare N-BNP levels in infants with FTT with infants with severe HF and healthy controls. Methods. In a retrospective cohort study, we compared N-BNP levels from all consecutive infants with FTT and bodyweight below the tenth percentile (caloric deprivation (CD) group) to infants with severe HF. Reference values from infants between 2 and 12 month were taken from the literature and healthy infants. Results. Our results show that infants with FTT (n = 15) had significantly (P < .001) elevated N-BNP values compared with the healthy infants (n = 23), 530 (119–3150) pg/mL versus 115 (15–1121) pg/mL. N-BNP values in this CD group are comparable to the median value of infants with severe HF (n = 12) 673 (408–11310) pg/mL. There is no statistical significant difference in age. Conclusion. Nutritional state has an important impact on N-BNP levels in infants with FTT. We could show comparable levels of N-BNP in infants with FTT and infants with severe HF.
PMCID: PMC2864906  PMID: 20467454

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