Chapter 1. The Historical Roots of Paediatric Gastroenterology, Hepatology, and Nutrition.

The last 50 years have seen the establishment of paediatric gastroenterology, hepatology, and nutrition (PGHAN) as a well-recognised and thriving clinical specialty throughout most of Europe, and further afield. This has happened, in part, through the existence of the European Society for Paediatric Gastroenterology and Nutrition (ESPGHAN) as a forum for those interested in this branch of children's medicine. To illustrate the pan-European roots of PGHAN, some key scientific and medical events, discoveries, and inventions relevant to 3 common clinical problems-diarrhoea, jaundice, and infant-feeding-have been chosen to survey the historical development of the ways in which each was understood and treated within the changing thinking and practice of past times. Together they are used to trace the prehistory of ESPGHAN and provide a background against which to explain the genesis of the Society and how its spheres of clinical and scientific interest came to be defined.

Kinderheilkunde and continental connections in child health: the "Glasgow school revisited"--again.

The last two hundred years or so have seen the transformation of medical practice from a clinical art to the application of science to the diagnosis and treatment of disease. There has been a historical debate about how the use of technology and discoveries of the laboratory have become integrated within medical practice. In trying to understand the evolution of "scientific medicine," this has generally focused on the tensions between the differing cultures, persons, and professions of the "laboratory" and "clinic" and sought to explain how they were resolved within specific institutions. This paper looks again at the "Glasgow School" (the subject of a number of seminal papers on this subject) and the forces that shaped it, by exploring the career of Leonard Findlay, whose training in Glasgow, and in Berlin (where he worked in a department in which science and medicine were integrated), defined a style of clinical medicine that formed the model for a new sort of university department of medicine in which clinicians and scientists worked side by side, albeit under the leadership of the former. As a clinician exposed in Berlin to the emerging new sciences of nutrition, microbiology, and immunology, which were particularly relevant to the care of sick children, Findlay created in Glasgow a department of medical pediatrics, which owed less to local factors, figures, and forces and more to his experience in Germany.

Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity.

OBJECTIVE: Preterm infants show reduced retinal sensitivity at term corrected age compared with newborn term infants. We tested the hypothesis that retinal sensitivity in preterm infants is improved by early, high-dose vitamin A. STUDY DESIGN: We report a double-blind, randomized controlled trial of infants <32 weeks' gestation and/or <1501 g birth weight. Supplemented infants received additional intramuscular vitamin A 10 000 IU 3 times weekly from day 2 for a minimum of 2 weeks or until establishment of oral feeding. Hepatic stores were assessed by relative dose response (RDR). The primary outcome measure was cone-corrected dark-adapted retinal rod sensitivity measured by electroretinogram at 36 weeks' postmenstrual age (PMA). RESULTS: Eighty-nine infants (42 supplemented and 47 controls) were recruited. Plasma retinol was higher in supplemented infants at 7 and 28 days (median, 1.0 vs 0.5 µmol/L and 0.7 vs 0.6 µmol/L; P < .001 and .03, respectively). Neither plasma retinol nor RDR differed between groups at 36 weeks' PMA. Retinal sensitivity was greater in supplemented infants (-0.81 vs -0.61 log cd • s • m(-2); P < .03) and was not related to RDR. CONCLUSIONS: Early high-dose intramuscular vitamin A supplementation for infants at risk of retinopathy of prematurity improves retinal function at 36 weeks' PMA.

Use of stable isotopes to measure the metabolic activity of the human intestinal microbiota.

The human intestinal microbiota is a complex biological system comprising a vast repertoire of microbes with considerable metabolic activity relevant to both bacterial growth and host health. Greater strides have been made in the analysis of microbial diversity than in the measurement of functional activity, particularly in vivo. Stable isotope probing offers a new approach by coupling measurements of metabolic activity with microbial identification. Using a low-enrichment labeling strategy in vitro, this study has identified metabolically active bacterial groups via magnetic-bead capture methodology and stable isotope ratio analysis. Using five probes (EUB338, Bac303, Bif164, EREC482, and Clep866), changes in the activities of key intestinal microbial groups were successfully measured by exploiting tracers of de novo RNA synthesis. Perturbation of the nutrient source with oligofructose generated changes in the activity of bifidobacteria as expected, but also in the Bacteroides-Prevotella group, the Eubacterium rectale-Clostridium coccoides group, and the Clostridium leptum subgroup. Changes in activity were also observed in response to the medium type. This study suggests that changes in the functional activity of the gut microbiota can be assessed using tracers of de novo nucleic acid synthesis combined with measurement of low isotopic enrichment in 16S rRNA. Such tracers potentially limit substrate bias because they are universally available to bacteria. This low-enrichment labeling approach does not depend on the commercial availability of specific labeled substrates and can be easily translated to in vivo probing experiments of the functional activity of the microbiota in the human gut.

Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease.

BACKGROUND & AIMS: Childhood-onset inflammatory bowel disease (IBD) might be etiologically different from adult-onset IBD. We analyzed disease phenotypes and progression of childhood-onset disease and compared them with characteristics of adult-onset disease in patients in Scotland. METHODS: Anatomic locations and behaviors were assessed in 416 patients with childhood-onset (276 Crohn's disease [CD], 99 ulcerative colitis [UC], 41 IBD type unclassified [IBDU] diagnosed before seventeenth birthday) and 1297 patients with adult-onset (596 CD, 701 UC) IBD using the Montreal classification. RESULTS: At the time of diagnosis in children, CD involved small bowel and colon (L3) in 51% (138/273), colon (L2) in 36%, and ileum (L1) in 6%; the upper gastrointestinal (GI) tract (L4) was also affected in 51%. In 39%, the anatomic extent increased within 2 years. Behavioral characteristics progressed; 24% of children developed stricturing or penetrating complications within 4 years (vs 9% at diagnosis; P < .0001; odds ratio [OR], 3.32; 95% confidence interval [CI], 1.86-5.92). Compared with adults, childhood-onset disease was characterized by a "panenteric" phenotype (ileocolonic plus upper GI [L3+L4]; 43% vs 3%; P < .0001; OR, 23.36; 95% CI, 13.45-40.59) with less isolated ileal (L1; 2% vs 31%; P < .0001; OR, 0.06; 95% CI, 0.03-0.12) or colonic disease (L2; 15% vs 36%; P < .0001; OR, 0.31; 95% CI, 0.21-0.46). UC was extensive in 82% of the children at diagnosis, versus 48% of adults (P < .0001; OR, 5.08; 95% CI, 2.73-9.45); 46% of the children progressed to develop extensive colitis during follow-up. Forty-six percent of children with CD and 35% with UC required immunomodulatory therapy within 12 months of diagnosis. The median time to first surgery was longer in childhood-onset than adult-onset patients with CD (13.7 vs 7.8 years; P < .001); the reverse was true for UC. CONCLUSIONS: Childhood-onset IBD is characterized by extensive intestinal involvement and rapid early progression.

Helicobacter pylori isolates recovered from gastric biopsies of patients with gastro-duodenal pathologies in Cameroon: current status of antibiogram.

OBJECTIVE: To determine the prevalence of Helicobacter pylori in patients with gastro-duodenal pathologies and the susceptibility patterns of isolates to the currently recommended antibiotic treatment regimen used in Cameroon. METHODS: Consecutive dyspeptic patients referred to Douala General Hospital, Cameroon for endoscopy were recruited in the study. Gastric biopsies were collected from the patients and H. pylori isolated and identified following standard microbiology and biochemical techniques. Antibiotic susceptibility was determined by disk diffusion and agar dilution methods against clarithromycin, tetracycline, amoxicillin and metronidazole. Data were analysed using chi-square test and significance considered at P < 0.05. RESULTS: Seventy-one (92.2%) of the 77 patients (mean age 44.5 +/- 15.7, range 15-77 years) were positive for H. pylori. The antibiotic susceptibility rates were 56% for tetracycline, 55.3% for clarithromycin, 14.4% for amoxicillin and 6.8% for metronidazole. The prevalence of clarithromycin resistance in males vs. females was 42.1%vs. 46.7%, while for metronidazole it was 89.5%vs. 94.7% (P > 0.05). Antimicrobial susceptibility results also revealed 12 antibiotypes based on resistance to the antimicrobial agents investigated. The resistance pattern, amoxicillin and metronidazole (AMR(R) MET(R)) was the most common (23.7%) amongst the isolates. More than 60% of the isolates exhibited multi-drug resistance to three or four antibiotics. CONCLUSION: Multi-drug resistance is common against the current treatment regimen in Cameroon and, therefore, calls for urgent studies involving newer and broad spectrum antibiotics to address the problem.

What is the role of the metabolic activity of the gut microbiota in inflammatory bowel disease? Probing for answers with stable isotopes.

The pathogenesis of inflammatory bowel disease remains obscure. However, there has been increasing interest in the role of the gut microbiota, focusing in particular on the "unculturable majority" of luminal and mucosal bacteria, which until recently have been difficult to study owing to the technical challenges of identification and elucidating function. Bacterial components and metabolites have been implicated in signalling to host immune systems and regulating inflammatory responses. Although the rapid expansion in techniques of molecular microbiology has increased our understanding of bacterial diversity, the tools to assess bacterial metabolic activity, and to link the 2, lag behind. Stable isotope probing is a powerful technique to link the metabolic activity and diversity of "unculturable" bacteria through isotopic labelling of biomarkers such as DNA and RNA. Progression of current stable isotope probing methodology with high-resolution oligonucleotide 16s rRNA probe technology and high precision liquid chromatographic isotope ratio mass spectrometry may facilitate application in human microbial ecology. Progress towards stable isotope probing use in vivo, in concert with other advances in bacterial metabolome analysis, will lead to the development of a dynamic picture of the metabolic activity and diversity of intestinal bacteria in inflammatory bowel disease. Such insights will, over time, lead to fuller understanding of inflammatory bowel disease pathogenesis and the development of targeted therapies to reverse the "dysbiosis" that precedes disease relapse.

Probiotics for necrotizing enterocolitis: a systematic review.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most commonly acquired neonatal intraabdominal emergency and causes significant morbidity and mortality. A proposed strategy for the prevention of NEC is the administration of oral probiotics. Probiotics have been shown to reduce NEC in experimental rat models and have been used in clinical trials. The authors aimed to review the existing data on the use of oral probiotics for the prevention of NEC in preterm infants (age <33 weeks) and those with very low birth weight (VLBW). MATERIALS AND METHODS: Systematic review of randomized controlled trials (RCTs) and quasi-RCTs was performed to find outcome measures of incidence, severity, need for surgery, and mortality in NEC. Electronic searches were performed on Medline and CINAHL databases using key word and subject headings with combinations of the terms "infant, preterm"; "infant, VLBW"; "enterocolitis, necrotizing"; and "probiotics." In addition, citation searches were performed for all potential studies. RESULTS: Six potential RCTs were identified for inclusion, but there were no systematic or Cochrane database reviews identified. One study was discounted because of the use of historical controls, so 5 studies were selected for analysis. Cumulatively, 640 infants were treated with probiotics and 627 were used as control subjects. All of the studies showed a trend toward less NEC in the treatment group. The heterogeneity of probiotic formulations and the timing and methods of interventions in the identified studies made synthesis and comparison of data inappropriate. CONCLUSIONS: The data appear to lend support to the use of oral probiotics for the prevention of NEC in preterm infants and those with VLBW. However, the data are insufficient to comment on their short- and long-term safety. Type of probiotics used, as well as the timing and dosage, are still to be optimized. Further understanding of the pathogenesis of NEC and the mechanisms by which probiotics prevent it may lead to evidence-based treatment strategies.

Evaluation of 13C-urea breath test and fecal antigen immunoassay to detect Helicobacter pylori infection in Gambian infants.

Helicobacter pylori colonization was measured by [13C]-urea breath test in 198 Gambian infants and by fecal enzyme-linked immunosorbent assay in 52 of the 198 at ages 2, 5, and 12 months. By 12 months there was good concordance between tests; 33 of 44 (75%) test results were positive by enzyme-linked immunosorbent assay, and 29 of 44 (66%) test results were positive by urea breath test. H. pylori colonization is common among Gambian infants, and noninvasive tests can provide a reliable means of diagnosis.

Rapid growth in infancy: balancing the interests of the child.

Low birth weight is associated with a number of immediate adverse consequences, and it has been assumed that "catch-up" growth is a "good thing" because "better" nutritional status is associated with greater childhood health and survival. The same thinking applies to infants who suffer malnutrition and growth faltering during weaning. Recent studies suggest that the rapid postnatal growth of babies is associated with an enhanced risk for obesity, diabetes, hypertension, cardiovascular disease and osteopenia in later life. If this is true, it has implications for our recommendations for infant feeding. Insights from evolutionary biology, life cycle theory, animal husbandry, epidemiology and comparative zoology suggest that the energetic feeding of underweight infants should be considered in the context of the whole life cycle and balance the interests of the child with its likely fortunes in adulthood. Before we revise our current recommendations, we must consider the meaning of catch-up growth, what it involves in terms of tissues gained (fat, muscle and bone) and to what degree association represents causation. In the meantime, it will be prudent to balance the short- and long-term interests of the child by endeavoring to (1) optimize maternal nutrition and health, to avoid low birth weight, (2) breast-feed ideally, (3) consider birth weight, gestation and future "nutritional environment" when making decisions about infant feeding, (4) use appropriate growth charts, (5) avoid excessive postnatal weight gain, (6) think about the whole life span and (7) extrapolate from animal studies cautiously.

Acetate correction for postabsorption metabolism does not improve the [13C]mixed triacylglycerol breath test.

OBJECTIVE: The [C]mixed triacylglycerol (MTG) breath test is a noninvasive measure of fat digestion. After absorption and oxidation, C appears in breath CO2. Recovery is no more than 50% in healthy subjects because of sequestration of acetate in intermediary metabolism. The aims of this study were to investigate interindividual variation and postabsorptive metabolism of MTG using oral [1-C]acetate and to examine the use of correction factors to account for the "missing" label. PATIENTS AND METHODS: [C]mixed triacylglycerol and [1-C]acetate breath tests were performed on 8 healthy adults, 9 healthy children and 3 children with cystic fibrosis. Breath was sampled for 6 hours on each occasion. The enrichment of CO2 in breath was measured by isotope ratio mass spectrometry. Cumulative percentage dose recovered CO2 during the MTG test was corrected for label absorbed, but not completely oxidized using the cumulative percentage dose recovered during the acetate test. RESULTS: Mean recovery of C during the [C]MTG test with an acetate correction was close to 100% in healthy subjects: 103.1% (SD, 11.6%) in adults and 98.9% (SD, 30.3%) in children, but the wide variance indicated that some of the assumptions governing the use of acetate corrections with oral tracers may not be valid. CONCLUSION: The need to perform 2 tests, variation in physical activity between tests and differences in intermediary metabolism preclude the use of acetate correction factors when using [C]MTG to assess intraluminal fat digestion, especially in children.

Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN Committee on Nutrition.

Survival of small premature infants has markedly improved during the last few decades. These infants are discharged from hospital care with body weight below the usual birth weight of healthy term infants. Early nutrition support of preterm infants influences long-term health outcomes. Therefore, the ESPGHAN Committee on Nutrition has reviewed available evidence on feeding preterm infants after hospital discharge. Close monitoring of growth during hospital stay and after discharge is recommended to enable the provision of adequate nutrition support. Measurements of length and head circumference, in addition to weight, must be used to identify those preterm infants with poor growth that may need additional nutrition support. Infants with an appropriate weight for postconceptional age at discharge should be breast-fed when possible. When formula-fed, such infants should be fed regular infant formula with provision of long-chain polyunsaturated fatty acids. Infants discharged with a subnormal weight for postconceptional age are at increased risk of long-term growth failure, and the human milk they consume should be supplemented, for example, with a human milk fortifier to provide an adequate nutrient supply. If formula-fed, such infants should receive special postdischarge formula with high contents of protein, minerals and trace elements as well as an long-chain polyunsaturated fatty acid supply, at least until a postconceptional age of 40 weeks, but possibly until about 52 weeks postconceptional age. Continued growth monitoring is required to adapt feeding choices to the needs of individual infants and to avoid underfeeding or overfeeding.

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

INTRODUCTION: The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. PATIENTS AND METHODS: 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed. RESULTS: The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]). CONCLUSIONS: These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.

Specific immunoglobulin A antibodies in maternal milk and delayed Helicobacter pylori colonization in Gambian infants.

BACKGROUND: Immunoglobulin A (IgA) in maternal milk may protect Gambian infants from early Helicobacter pylori colonization. This study sought evidence that this protection could be due to specific IgA antibodies. METHODS: Sixty-five infants were screened from 12 weeks of age with [13C]-urea breath tests. Antibodies in maternal milk were measured to determine total IgA content and to detect specific IgA antibodies against crude whole-cell and recombinant H. pylori urease antigen preparations. RESULTS: Ten children (15%) had no evidence of early H. pylori colonization, 10 (15%) had early H. pylori colonization, and 43 (66%) had mixed results. Levels of maternal circulating specific immunoglobulin G, total milk IgA, and IgA directed against crude whole-cell H. pylori antigen preparation were not significantly associated with the rate of infant H. pylori colonization. However, mothers of infants with no evidence of early colonization produced significantly higher levels of anti-recombinant urease IgA antibodies in milk than did control mothers, particularly at 8, 16, and 20 weeks postpartum (P<.01). CONCLUSIONS: These observations support the hypothesis that antibodies in mother's milk directed against H. pylori urease can protect against colonization in human infancy.

Scotopic electroretinogram in term infants born of mothers supplemented with docosahexaenoic acid during pregnancy.

PURPOSE: To test the hypothesis that the supplementation of the diets of pregnant women with a fish oil rich in docosahexaenoic acid (DHA) enhances retinal development in their healthy term infants, as measured during the early postnatal period by the electroretinogram (ERG). METHODS: One hundred pregnant women were randomized to receive either a fish oil (n = 50) or a placebo oleic acid dietary supplement (n = 50) from 15 weeks of pregnancy until delivery. Total fatty acids in red blood cells (RBCs) and plasma were measured in mothers at 15 and 28 weeks of pregnancy and at delivery and in their infants in umbilical cord blood. Infant retinal development was assessed within the first week of life with full-field ERGs that included a scotopic blue intensity series (n = 41) and a bright white flash (2.0 log cd-s/m(2); n = 44). RESULTS: Infants born of mothers who received supplements did not differ at birth in weight, gestational age, or any other standard variable. Infant DHA status at birth, as measured from umbilical cord blood, did not differ significantly between maternal supplementation groups. ERG implicit times, amplitudes, and parameters of the stimulus-response function did not differ significantly between infants in the maternal supplemented and placebo groups. There was, however, a relationship between infant DHA status and maturity of the retina at birth, regardless of maternal supplementation group. A measure of retinal sensitivity (log sigma) correlated significantly (P < 0.005) with DHA status (as a percentage of total fatty acid; TFA) in infant cord blood. Infants in the highest quartile for cord blood DHA had higher retinal sensitivity compared with infants in the lowest quartile. Infants in the highest quartile for plasma DHA, both as a percentage of TFA and concentration, were born at a significantly later gestational age than were infants in the lower quartiles. CONCLUSIONS: These findings demonstrate an association between the DHA status of term infants and retinal sensitivity, suggesting an essential role of this long-chain polyunsaturated fatty acid (LCPUFA) in the development and function of the retina. However, maternal DHA status was not significantly associated with infant retinal sensitivity and no direct effect of maternal supplementation was observed.

Preparation and handling of powdered infant formula: a commentary by the ESPGHAN Committee on Nutrition.

Powdered infant formulae are not sterile and may contain pathogenic bacteria. In addition, milk products are excellent media for bacterial proliferation. Multiplication of Enterobacter sakazakii in prepared formula feeds can cause devastating sepsis, particularly in the first 2 months of life. In approximately 50 published case reports of severe infection, there are high rates of meningitis, brain abscesses and necrotizing enterocolitis, with an overall mortality from 33% to 80%. Breast feeding provides effective protection against infection, one of the many reasons why it deserves continued promotion and support. To minimize the risk of infection in infants not fully breastfed, recommendations are made for preparation and handling of powdered formulae for children younger than 2 months of age. In the home setting, powdered infant formulae should be freshly prepared for each feed. Any milk remaining should be discarded rather than used in the following feed. Infant feeds should never be kept warm in bottle heaters or thermoses. In hospitals and other institutions written guidelines for preparation and handling of infant formulae should be established and their implementation monitored. If formula needs to be prepared in advance, it should be prepared on a daily basis and kept at 4 degrees C or below. Manufacturers of infant formulae should make every effort to minimize bacterial contamination of powdered products.

Is there an advantage in normalising the results of the Helicobacter pylori [13C]urea breath test for CO2 production rate in children?

The urea breath test (UBT) is a non-invasive diagnostic test to detect the presence of Helicobacter pylori in the stomach, and is the simplest way to confirm eradication after treatment. The test is based on the capacity of H. pylori to secrete the enzyme urease, which hydrolyses urea to ammonia and carbon dioxide. The aim of this study was to determine whether there is an advantage in expressing the results of UBTs in terms of urea hydrolysis rate (UHR), rather than breath 13C enrichment alone. Retrospective analysis of data collected between 1995 and 2002 from 260 patients undergoing UBTs was performed. The cut-offs for positive tests using breath 30-minute enrichment (E30), UHR calculated using VCO2 estimated from height and weight (H/WT) and VCO2 estimated from weight only were determined using two-graph receiver operator characteristic (TG-ROC) analysis. The cut-off points were 3.5/1000 or 38.7 ppm 13C excess, 7.04 micromol/h and 7.08 micromol/h, respectively. There was no advantage in expressing the results as UHR (theta0, Theta-zero, where sensitivity = specificity = 0.97 (UHR H/WT), 0.98 (UHR WT) and 1.00 (E30)) rather than breath 13CO2 enrichment alone. Differences in the extent of H. pylori colonisation and urease activity are more important than variation in VCO2 in determining breath 13CO2 enrichment in the UBT.

State of the art of growth standards.

Growth charts have become widely used, if not universal, tools for the assessment of the growth and health of children. In 2006, the WHO published a set of charts designed to represent standards to which all the world's children should aspire. They were produced in response to the apparent variability in the patterns of child growth documented worldwide, and with the aim of creating a prescriptive standard based on best feeding advice. Our modern understanding and use of growth references arose out of the application of technology, mathematics and charting to the biology of growth in the 19th century. As means of summarizing normal development, modern growth standards have replaced Renaissance conceptions of human form based on idealized proportions in harmony with the cosmos, and the simple reference to key developmental milestones first noted by the ancients. The WHO growth standards are the culmination of a search for a human ideal based on 20th century biology. However, while they may be the 'best' standards based on contemporary feeding advice, they are 'provisional' because all developmental processes in biology, including body growth, are plastic and permit a flexibility of life course trajectories in response to epigenetic, nutritional and other environmental conditions.

Neonatal visual evoked potentials in infants born to mothers prescribed methadone.

OBJECTIVE: Drug misuse in pregnancy is associated with impaired infant visual development. Pilot data showed abnormal flash visual evoked potentials (VEPs) in neonates exposed to methadone in utero, but results were confounded by intrauterine growth restriction, gestation, and ongoing drug misuse. This large cohort study aimed to clarify the effects on neonatal flash VEPs of maternal drug misuse in pregnancy, including prescription of substitute methadone and subsequent development of neonatal abstinence syndrome. METHODS: This was a prospective cohort study. Flash VEPs were recorded within 3 days of birth from 100 healthy infants of drug-misusing mothers prescribed substitute methadone during pregnancy and 50 comparison infants matched for birth weight, gestation, and socioeconomic deprivation. VEP morphology was classified as mature, typical, or immature, and amplitudes and implicit times of the major waveform components measured. Drug exposure was determined by maternal history, maternal and infant urine, and meconium toxicology. RESULTS: VEPs from maternal drug-exposed infants were more likely to be of immature waveform (P < .001) and were smaller in overall amplitude (median 27 µV vs 39 µV, P < .001) compared with non-drug-exposed infants. Most infants were exposed to illicit drugs in addition to prescribed methadone; differences in VEP parameters were independently associated with maternal prescribed methadone and persisted after correcting for birth weight, cigarette smoking, and excess in utero alcohol exposure. CONCLUSIONS: In utero exposure to prescribed substitute methadone is associated with altered flash VEPs in the newborn period and these infants may warrant early clinical visual assessment.