Long-term safety assessment in children who received hydrolyzed protein formulas with Lactobacillus rhamnosus GG: a 5-year follow-up.

Extensively hydrolyzed (EH) formula with Lactobacillus rhamnosus GG (LGG) was demonstrated to alleviate cow's milk allergy (CMA) symptoms and promote faster acquisition of tolerance to cow's milk protein. We previously demonstrated that partially hydrolyzed (PH) and EH formulas with LGG supported normal growth in healthy-term infants through 120 days of age. The objective of the current study was to evaluate growth, development, and specific adverse events through 5 years of age in participants from that cohort who continued receiving study formula. Infants who completed a double-blind, randomized growth and tolerance study were eligible to continue receiving the assigned study formula through 1 year of age (control: EH casein formula, EHF, or one of two investigational formulas: EH casein formula with LGG (EHF-LGG) or a PH formula with LGG (PHF-LGG)) and participate in follow-up through 5 years of age. Anthropometric measures, behavior development, and specific adverse events were recorded. No significant differences in achieved weight and height or behavioral development outcomes at 3 or 5 years of age were observed among study groups. Few statistically significant differences in the incidence of specific infection-related events through years 3 or 5 were observed among study groups, none of which were considered clinically relevant. CONCLUSION: Extensively and partially hydrolyzed formulas with LGG were associated with normal growth and development and long-term safety through 5 years of age. What is Known: • Infants with cow's milk allergy often experience allergic manifestations that can lead to poor nutrition status and poor growth. • Providing partially hydrolyzed (PH) and EH formulas with or without LGG in infants can support normal growth in healthy-term infants. What is New: • This study provides long-term safety data for the first 5 years of life on the use of extensively and partially hydrolyzed formulas with LGG when fed through 1 year of age. • Extensively and partially hydrolyzed formulas with LGG are associated with normal growth, development, and long-term safety through 5 years of age.

The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up.

AIMS/HYPOTHESIS: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type 1 diabetes. METHODS: The study population comprises newborn infants who have first-degree relatives with type 1 diabetes and meet the increased risk HLA inclusion, but not exclusion criteria. The study is being performed in 15 countries in three continents. First-degree relatives of patients with type 1 diabetes were identified from diabetes clinics, diabetes registries, and from other endocrinology or obstetrics offices and websites. HLA typing was performed at birth from cord or heel stick blood, and the results sent to the study's Data Management Unit within 2 weeks for communication of eligibility to the clinical study centre. All mothers recruited were encouraged to breastfeed. The intervention lasted for 6 to 8 months, and weaning formulas based on hydrolysed casein and standard cow's milk were compared. RESULTS: TRIGR recruited 5,606 infants, of whom 2,160 were enrolled as eligible participants, 6% more than the target of 2,032. Of those enrolled, 80% were exposed to the study formula. The overall retention rate over the first 5 years is 87%, with protocol compliance at 94%. The randomisation code will be opened when the last recruited child turns 10 years of age, i.e. in 2017. CONCLUSIONS/INTERPRETATION: The TRIGR experience demonstrates the feasibility and successful implementation of an international dietary intervention study. TRIGR is the first ever primary prevention trial for type 1 diabetes and, if completed successfully, will provide a definite answer to the research question. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777 FUNDING: The study was funded by the National Institute of Child Health and Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (grant numbers HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International and the Commission of the European Communities (specific RTD programme 'Quality of Life and Management of Living Resources', contract number QLK1-2002-00372 'Diabetes Prevention'. Other funding came from the EFSD/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland, Dutch Diabetes Research Foundation and Finnish Diabetes Research Foundation).

Growth, tolerance, and DHA and ARA status of healthy term infants receiving formula with two different ARA concentrations: Double-blind, randomized, controlled trial.

Circulating docosahexaenoic acid (DHA) and arachidonic acid (ARA) in total red blood cells (RBC) are considered indicators of fatty acid status. In this study, healthy term infants received study formula through 120 days of age. All study formulas had 17 mg DHA/100 kcal. Investigational formulas had 1) 25 g ARA/100 kcal and no added prebiotic blend (ARA-25; n = 29) or 2) 34 mg ARA/100 kcal and a prebiotic blend (1:1 ratio; 4 g/L) of polydextrose and galactooligosaccharides (PDX/GOS; n = 20). The control formula had 34 mg ARA/100 kcal and no added prebiotic blend (Control: n = 31). Fatty acids in total RBCs and plasma phospholipids (PPLs) at 120 days and buccal epithelial PLs at 14 and 120 days of age were assessed by capillary column gas chromatography. The calculated 90% confidence interval (CI) of each investigational formula relative to the Control for total RBC ARA (ARA-25: 93-105%; PDX/GOS: 96-110%) and total RBC DHA (ARA-25: 95-113%; PDX/GOS: 94-113%) fell within the pre-specified equivalence limit (85-118%), establishing study formula equivalence with respect to ARA and DHA. At day 120, total RBC and buccal epithelia PL ARA (µg/ml) were not significantly correlated (r = 0.041; p = 0.732); correlation in total RBC and buccal epithelia PL DHA was low, albeit significant (r = 0.324; p = 0.006). Consequently, buccal epithelial may not provide a suitable substitute for RBC when assessing fatty acid status and availability. The present RBC data suggest availability of DHA for central nervous system development and function is equivalent among infants receiving formulas that had 34 or 25 mg/100 kcal ARA and 17 mg/100 kcal DHA.

Comparison of the gastrointestinal growth- promoting effects of rat colostrum and mature milk in newborn rats in vivo.

The purpose of this study was to compare the effects of rat colostrum and mature milk on newborn rat gastrointestinal growth under conditions that controlled the possible confounding effects of energy intake and mode of feeding. Newborn Sprague-Dawley rat pups were tubefed equicaloric amounts of rat colostrum or mature rat milk for 40 h before they were killed. Compared to littermates that were killed immediately after birth, both groups of fed rats demonstrated increases in the weights of stomach and intestine, but there was no organ weight difference detected between colostrum-fed and mature milk-fed rat pups. However, both the concentration of DNA and the rate of synthesis of DNA in the intestines were greater in rats fed colostrum than in those at birth or those mature milk. Although the pancreas exhibited no detectable increase in weight by 41 h, the DNA concentration and total DNA content increased and RNA/DNA ratio decreased in both fed groups, also without apparent difference between rats fed colostrum and those fed mature milk. The rate of 3H-thymidine incorporation into DNA in pancreas, however, was greater in colostrum-fed pups than in mature milk-fed pups. These differences at 40 h age in intestinal and pancreatic cell replication activity, but not organ weights, can be ascribed to feeding colostrum.

Slow infusion feedings enhance duodenal motor responses and gastric emptying in preterm infants.

It is unknown whether it is better to feed preterm infants intragastrically by bolus or continuous infusion. This study compared the effect of 2 feeding rates on antral and duodenal motor responses and gastric emptying. Continuous perfusion manometry with a low-compliance machine was performed in 22 infants given feedings at 2 infusion rates. Gastric emptying was also assessed by using a dye-dilution technique to determine whether changes in motor response were reflected by changes in function. The number of antral contractions with both feeding rates decreased from that seen during fasting. Duodenal motor responses increased when infants were fed by slow infusion and decreased when they were fed by rapid infusion. Infants emptied 12 mL/kg of a 20-mL/kg feeding by 20 min after completion of the feeding given by slow infusion concomitantly with the increase in duodenal motor activity but only 8 mL/kg by 20 min after completion of the bolus feeding, when duodenal motor activity decreased (P < 0.01). Two hours after completion of the feeding, volumes remaining in the stomach after slow infusion were one-ninth those remaining after bolus feeding. When preterm infants are fed by slow infusion over 120 min, their duodenal motor responses are more like those observed in adults and their gastric contents are emptied faster and more completely than when they are fed with a rapid bolus.

Postpartum changes in pattern of gastrointestinal regulatory peptides in human milk.

Concentrations of gastrointestinal neuropeptides in serial human milk samples from 28 women were determined over the first 6 postpartum mo. All gut neuropeptides were present during the first postpartum week. Gastric inhibitory peptide (GIP) concentration remained constant but the others decreased by 6 wk. Bombesin concentration in breast milk was threefold greater than concurrent plasma concentration (p less than 0.001); all other neuropeptides were at the same or lower concentrations in milk than in plasma. At 36 wk gestation plasma concentrations of GIP were lower and concentrations of vasoactive intestinal peptide were higher than concentrations in age-matched control subjects. Concentrations of gastrin and cholecystokinin, bombesin, peptide histidine methionine, peptide YY, and neurotensin in plasma were similar in pregnant and nonpregnant women. These gut neuropeptides in milk may be important for growth and maturation of the gastrointestinal system in neonates. Bombesin may contribute to neonatal hypergastrinemia.

Acute and chronic intestinal motor activity responses to two infant formulas.

OBJECTIVE: Preterm formulas are nutritionally better for preterm infants; however, it has been observed that these formulas cause more feeding intolerance than do regular formulas. Because intestinal motor activity is responsible for the aboral movement of intraluminal nutrients, the purpose of this study was to evaluate intestinal motor activity responses to two infant formulas: 84 and 100.8 J/oz. STUDY DESIGN AND RESULTS: Intestinal motor activity was recorded in 52 preterm infants who had never been fed and who were randomly assigned to receive small enteral feedings (24 mL/kg per day) for 10 days with one of two commonly used infant formulas. In a subset of 26 of these infants, acute motor responses to both formulas were also evaluated. At the end of the study period, motor activity during fasting did not differ between the two groups of infants. However, motor responses during feeding to the two formulas differed significantly. When infants were fed for the first time, their motor activity increased compared with fasting when they were fed the 84-J/oz formula but decreased when they were fed the 100.8-J/oz formula. These differences in motor responses to the two formulas were not present 10 days later. These differences in motor responses to the 100.8- and 84-J/oz formulas were even more pronounced among the 7 infants who subsequently developed feeding intolerance to the 100.8-J/oz formula during the 10-day study period. CONCLUSION: Inhibition of motor responses to calorically denser formulas during active feeding in a subset of preterm infants may underlie the feeding intolerance they experience when they are fed these formulas. However, this inhibitory response diminishes with age, suggesting that denser formulas can be reintroduced later in life to these infants.

Birth asphyxia alters neonatal intestinal motility in term neonates.

As an extension of an earlier study showing that manometry can identify preterm newborns at risk for feeding intolerance, the authors investigated whether abnormalities of intestinal motor activity underlie the feeding intolerance seen in asphyxiated newborns. Low-compliance perfusion manometry was recorded within the first postnatal week in 25 term neonates admitted consecutively for respiratory diseases. Eleven of these neonates were identified to have experienced birth asphyxia because three concurrent features were present: 1-minute Apgar score of less than 2; 5-minute Apgar score of less than 4; and recurrent seizures within the first 48 postnatal hours. The remaining 14 neonates, who did not have any of these three characteristics, were considered to be nonasphyxiated control neonates. Motor activity differed in nonasphyxiated and asphyxiated neonates during fasting and feeding. During fasting, asphyxiated neonates had less migrating activity than nonasphyxiated neonates. In addition, episodes of motor quiescence and clustered phasic activity were less well organized in asphyxiated neonates. Both groups of neonates displayed a change in motor activity in response to a feeding infusion; however, the response was initiated significantly sooner in asphyxiated than in control neonates. All of the 11 asphyxiated neonates were intolerant of enteral feedings during the first poststudy week, but no control neonate was feeding intolerant. Six of the asphyxiated neonates were reevaluated 1 to 2 weeks later. During this latter study, motor activity in these asphyxiated neonates was similar to that of nonasphyxiated neonates; 5 of 6 of these neonates subsequently tolerated enteral feedings. It is speculated that changes in motor activity underlie the feeding intolerance that asphyxiated neonates typically exhibit.(ABSTRACT TRUNCATED AT 250 WORDS)

Manometrics for preterm and term infants: a new tool for old questions.

OBJECTIVE: The purpose of this study was to use low-compliance, continuous-perfusion manometry to assess motor activity responses of preterm and term infants to three different methods of feeding commonly used in neonatal intensive care units. METHODS: All 48 infants who participated in this study were assigned to one of three feeding trials using a 20-calorie/oz formula. Trial 1 varied the mode of feeding, trial 2 varied the volume of feeding, and trial 3 varied the concentration of feeding. RESULTS: In trial 1, small intestinal motor activity changed similarly and significantly in response to intragastric (P < .005) and transpyloric feeding (P < .02). In trial 2, feeding containing a small volume (4 mL/kg) and a larger volume (10 mL/kg) elicited significant changes in motor activity compared to that seen during fasting (P < .005). In trial 3, motor activity differed in response to varying caloric density. Motor activity failed to change in response to feedings that contained one-third-concentration formula, but it did change in response to the feedings that contained two-thirds- and full-concentration formula (P < .02). Furthermore, the onset of the motor response to feeding was inversely related to the concentration of formula (P < .01), and the duration of the fed response also was related to the concentration of formula (P < .01). CONCLUSIONS: Gastric and transpyloric feedings are equally potent in eliciting an intestinal motor response to feeding. Furthermore, a volume as small as 4 mL/kg is sufficient to elicit such a response. However, preterm intestinal motility responses are affected significantly by changes in the caloric density of formula, suggesting that diluted formula may not provide an optimal stimulant for the preterm intestinal functional responses to feeding.

Continuing care for the preterm infant after dismissal from the neonatal intensive care unit.

As more low-birth-weight babies survive, primary-care physicians are facing the responsibility of providing continuing care for those who have been dismissed from neonatal intensive-care units. Premature infants often require outpatient care for bronchopulmonary dysplasia, apnea, retinopathy of prematurity, intraventricular hemorrhage, hearing loss, hypothyroxinemia, anemia, neurodevelopmental sequelae, assessment of growth and nutrition, immunizations, and psychosocial stress. In this review, we present guidelines for the primary-care physician for the management of these conditions in preterm infants.

Evaluating the effect of a human values seminar series on ethical attitudes toward resuscitation among pediatric residents.

A human values seminar series was designed to provide training in medical ethics for residents in pediatrics. Attitudes of residents toward resuscitation of children were surveyed before and after the seminar series. Nonpediatric residents rotating through pediatrics served as control subjects. Although both groups of residents demonstrated a significant change in attitude on six scales at the end of 1 year of training, pediatricians and nonpediatricians differed from each other with respect to only one of these scales. After the seminar series, pediatric residents expressed decreased willingness to resuscitate certain critically ill infants in the emergency room, whereas nonpediatricians expressed more willingness (P less than 0.009). Attitude change in decision making among pediatricians was significantly correlated with the consideration given to societal needs, sanctity of life, and anticipated poor morbidity (P less than 0.05). Among nonpediatricians, attitude change was significantly correlated with poor prognosis for survival (P less than 0.05), morbidity (P less than 0.05), or anticipated poor intellectual outcome (P less than 0.01). Attitude differences between the two groups of residents were unrelated to differences in preexisting attitudes or demographic factors. These findings show that attitudes about ethical decisions are influenced by both "maturation," or progression through a training program, and formal instruction. The finding that clinical attitudes change rapidly as residents progress through training confirms our previous findings and suggests that residency training programs should provide support and formal instruction in ethics during this time of change. The small change caused by this current method of instruction indicates that preliminary studies are needed to delineate the goals and the structure of future ethics courses.

Cessation of unsuccessful pediatric resuscitation--how long is too long?

Emergency teams asked to provide cardiopulmonary resuscitation for pediatric patients often consist of nurses and physicians from various pediatric and nonpediatric specialties. Team members should agree on the timing of termination of unsuccessful resuscitative efforts; however, no firm guidelines about such timing have been established. The purposes of this study were to determine (1) whether a consensus exists among health-care professionals about the optimal duration of unsuccessful resuscitation for pediatric patients and (2) whether attitudes are influenced by individual case prognosis, medical specialty, level of training, or certification in pediatric advanced life support (PALS). By random selection, 140 physicians, nurses, and medical students were asked to specify the duration that they would continue unsuccessful resuscitative efforts for each of two hypothetical cases: one patient with a good prognosis for survival and one with a poor prognosis. Although no clear consensus existed, all groups of health-care providers chose significantly briefer durations of resuscitation for the case with a poorer prognosis (P < 0.01). The specified durations of resuscitation were briefer for those who had PALS certification than for those who did not and for pediatricians than for nonpediatric physicians (P < 0.01). Furthermore, PALS certification (P < 0.01) and pediatric specialty (P < 0.05) contributed as independent variables in influencing the study participants' attitudes about duration of resuscitation, whereas level of training did not. We conclude that no consensus exists among the groups studied on the optimal duration of unsuccessful resuscitative efforts in pediatric patients. We speculate that the opinions might be more uniform if resuscitation of pediatric patients was provided primarily by pediatricians or PALS-certified physicians.

Duplication of part of chromosome 1q: clinical report and review of literature.

We report a male infant with a 47,XY, + der(22),t(1;22)(q32;q11)pat karyotype. Thus, he has duplication of chromosomes 1(q32----qter) and 22(pter----q11). Six patients with dup 1(q32----qter) and eight with dup 1(q42----qter) have been described. These two groups of patients share several manifestations, including postnatal growth retardation; relative macrocephaly with widely separated sutures or large fontanelles; prominent forehead; highly arched palate; micrognathia; downward slant of the palpebral fissures; broad, flat nasal bridge; and apparently low-set, malformed ears. Although many of these abnormalities are nonspecific, partial duplication of 1q should be considered in infants with relative macrocephaly, large fontanelles, and downward slant of the palpebral fissures. Our patient had duplication of the part of chromosome 22 that may be associated with the clinically variable cat-eye syndrome. Patients with dup 22(pter----q11) may also have downward slant of the palpebral fissures, micrognathia, and apparently low-set, malformed ears. The structural gene locus for beta-glucosidase has been mapped to chromosome 1. beta-Glucosidase activity in fibroblasts from our patient was normal, and his parents' activities were not significantly different from those of control individuals. Therefore, either the locus for this enzyme is not present on 1(q32----qter) or the enzyme does not consistently show a substantial gene-dose effect.

Gut motility and the pathogenesis of necrotizing enterocolitis.

Forward movement of intestinal nutrients is achieved by motor activity. Motor activity patterns are "abnormal" in adults as well as preterm infants who display intolerance to enteral feedings. Manometrics can be used diagnostically and prospectively to identify infants at risk for feeding intolerance.

Minimal enteral feedings.

The provision of early minimal enteral nutrition to the metabolically stable premature infant appears to result in multiple nutritional benefits and in a minimal risk of complications. Whereas benefits can be achieved with feeding volumes ranging from 0.1 to 4 mL/kg, future studies will need to address the responses of the immune system, the circulatory system, and motor activity of the intestine to various feeding regimens before pragmatic recommendations can be concluded.

Gastrointestinal motility in the neonate.

Many aspects of the forward propulsion of enteral nutrients are not fully mature in the preterm and term neonate. Because the regulation of motor activity in the gastrointestinal tract is complex and multifaceted, many levels of regulation of this activity are immature in the preterm infant; however, as neonatologists develop a better understanding of the physiologic mechanisms that underlie these dysfunctions as well as the interactions of nutrients, hormones, and pharmacologic agents with these regulatory mechanisms, better feeding strategies can be tailored for these infants. Moreover, current studies will permit the development of predictive and diagnostic tools as well as the refinement of pharmacologic interventions for these infants.

Assessment in intestinal motility as a guide in the feeding management of the newborn.

Coordinated contractions of the gastrointestinal muscle layers mix ingested nutrients with secretions and propel unused nutrients forward for expulsion. Manometry is the technique of measuring pressure changes inside the gut lumen to indirectly measure the presence of contractions in the muscle layers. The types of gastrointestinal motor patterns seen in preterm infants differ from those seen in the adult. Characteristics of these patterns change with age and the way in which babies are fed. This technique has been useful in identifying better ways to feed preterm babies.

Health status of children with special health care needs: measurement issues and instruments.

The methods for measuring health care outcomes and monitoring the health status of the child with a chronic health condition must be available, accessible, and meaningful. This review was evoked by this need to identify reliable and valid instruments for measuring the health status of children with special health care needs. The objectives are as follows: (1) to review the methodologic and substantive issues related to the selection of instruments and (2) to identify those instruments available currently for collecting data regarding health status of children with special health care needs. A Medline search of the literature published since 1966 through 1998 and restricted to human subjects and the English language was conducted. Indexing terms included health status, quality of life, outcome assessment, functional status, and patient satisfaction. Multiple reviewers selected instruments based on their usefulness in clinical settings as generic, disease nonspecific, child health status instruments. Few instruments were identified that can be used by pediatricians for tracking and monitoring the health status of children with special health care needs. In conclusion, to progress in the field of outcomes measurement of children with special health care needs, it will be necessary to develop new measurement tools. These instruments must (1) provide valid and reliable information on health status; (2) be useful in guiding the management of patients; and (3) not be a burden for physicians, patients, or patient's families.

Liquid human milk fortifier significantly improves docosahexaenoic and arachidonic acid status in preterm infants.

We report the fatty acid composition of mother׳s own human milk from one of the largest US cohorts of lactating mothers of preterm infants. Milk fatty acid data were used as a proxy for intake at enrollment in infants (n=150) who received human milk with a powder human milk fortifier (HMF; Control) or liquid HMF [LHMF; provided additional 12mg docosahexaenoic acid (DHA), 20mg arachidonic acid (ARA)/100mL human milk]. Mothers provided milk samples (n=129) and reported maternal DHA consumption (n=128). Infant blood samples were drawn at study completion (Study Day 28). Human milk and infant PPL fatty acids were analyzed using capillary column gas chromatography. DHA and ARA were within ranges previously published for US term and preterm human milk. Compared to Control HMF (providing no DHA or ARA), human milk fortified with LHMF significantly increased infant PPL DHA and ARA and improved preterm infant DHA and ARA status.