Quality control of ultrasound for fetal biometry: results from the INTERGROWTH-21st Project.

OBJECTIVE: To assess a comprehensive package of ultrasound quality control in the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project, a large multicenter study of fetal growth. METHODS: Quality control (QC) measures were performed for 20 313 ultrasound scan images obtained prospectively from 4321 fetuses at 14-41 weeks' gestation in eight geographical locations. At the time of each ultrasound examination, three fetal biometric variables (head circumference (HC), abdominal circumference (AC) and femur length (FL)) were measured in triplicate on separately generated images. All measurements were taken in a blinded fashion. QC had two elements: (1) qualitative QC: visual assessment by sonographers at each study site of their images based on specific criteria, with 10% of images being re-assessed at the Oxford-based Ultrasound Quality Unit (compared using an adjusted kappa statistic); and (2) quantitative QC: assessment of measurement data by comparing the first, second and third measurements (intraobserver variability), remeasurement of caliper replacement in 10% (interobserver variability), both by Bland-Altman plots and plotting frequency histograms of the SD of triplicate measurements and assessing how many were above or below 2 SD of the expected distribution. The system allowed the sonographers' performances to be monitored regularly. RESULTS: A high level of agreement between self- and external scoring was demonstrated for all measurements (κ = 0.99 (95% CI, 0.98-0.99) for HC, 0.98 (95% CI, 0.97-0.99) for AC and 0.96 (95% CI, 0.95-0.98) for FL). Intraobserver 95% limits of agreement (LoA) of ultrasound measures for HC, AC and FL were ± 3.3%, ± 5.6% and ± 6.2%, respectively; the corresponding values for interobserver LoA were ± 4.4%, ± 6.0% and ± 5.6%. The SD distribution of triplicate measurements for all biometric variables showed excessive variability for three of 31 sonographers, allowing prompt identification and retraining. CONCLUSIONS: Qualitative and quantitative QC monitoring was feasible and highly reproducible in a large multicenter research study, which facilitated the production of high-quality ultrasound images. We recommend that the QC system we developed is implemented in future research studies and clinical practice. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

International estimated fetal weight standards of the INTERGROWTH-21st Project.

OBJECTIVE: Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH-21st Fetal Growth Standards that are available for use worldwide. METHODS: Women with an accurate gestational-age assessment, who were enrolled in the prospective, international, multicenter, population-based Fetal Growth Longitudinal Study (FGLS) and INTERBIO-21st Fetal Study (FS), two components of the INTERGROWTH-21st Project, had ultrasound scans every 5 weeks from 9-14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second-degree fractional polynomial models. RESULTS: Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0-14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 - 54.06633 × (AC/100)3 - 95.80076 × (AC/100)3 × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis-fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age-specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH-21st Newborn Size Standards but, at < 37 weeks' gestation, the EFW centiles were, as expected, higher than those of babies born preterm. Comparing EFW cross-sectional values with the INTERGROWTH-21st Preterm Postnatal Growth Standards confirmed that preterm postnatal growth is a different biological process from intrauterine growth. CONCLUSIONS: We provide an assessment of EFW, as an adjunct to routine ultrasound biometry, from 22 to 40 weeks' gestation. However, we strongly encourage clinicians to evaluate fetal growth using separate biometric measures such as HC and AC, as well as EFW, to avoid the minimalist approach of focusing on a single value. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound-based gestational-age estimation in late pregnancy.

OBJECTIVE: Accurate gestational-age (GA) estimation, preferably by ultrasound measurement of fetal crown-rump length before 14 weeks' gestation, is an important component of high-quality antenatal care. The objective of this study was to determine how GA can best be estimated by fetal ultrasound for women who present for the first time late in pregnancy with uncertain or unknown menstrual dates. METHODS: INTERGROWTH-21st was a large, prospective, multicenter, population-based project performed in eight geographically defined urban populations. One of its principal components, the Fetal Growth Longitudinal Study, aimed to develop international fetal growth standards. Each participant had their certain menstrual dates confirmed by first-trimester ultrasound examination. Fetal head circumference (HC), biparietal diameter (BPD), occipitofrontal diameter (OFD), abdominal circumference (AC) and femur length (FL) were measured every 5 weeks from 14 weeks' gestation until delivery. For each participant, a single, randomly selected ultrasound examination was used to explore all candidate biometric variables and permutations to build models to predict GA. Regression equations were ranked based upon minimization of the mean prediction error, goodness of fit and model complexity. An automated machine learning algorithm, the Genetic Algorithm, was adapted to evaluate > 64 000 potential polynomial equations as predictors. RESULTS: Of the 4607 eligible women, 4321 (94%) had a pregnancy without major complications and delivered a live singleton without congenital malformations. After other exclusions (missing measurements in GA window and outliers), the final sample comprised 4229 women. Two skeletal measures, HC and FL, produced the best GA prediction, given by the equation loge (GA) = 0.03243 × (loge (HC))2 + 0.001644 × FL × loge (HC) + 3.813. When FL was not available, the best equation based on HC alone was loge (GA) = 0.05970 × (loge (HC))2 + 0.000000006409 × (HC)3 + 3.3258. The estimated uncertainty of GA prediction (half width 95% interval) was 6-7 days at 14 weeks' gestation, 12-14 days at 26 weeks' gestation and > 14 days in the third trimester. The addition of FL to the HC model led to improved prediction intervals compared with using HC alone, but no further improvement in prediction was afforded by adding AC, BPD or OFD. Equations that included other measurements (BPD, OFD and AC) did not perform better. CONCLUSIONS: Among women initiating antenatal care late in pregnancy, a single set of ultrasound measurements combining HC and FL in the second trimester can be used to estimate GA with reasonable accuracy. We recommend this tool for underserved populations but considerable efforts should be implemented to improve early initiation of antenatal care worldwide. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy.

OBJECTIVES: There are no international standards for relating fetal crown-rump length (CRL) to gestational age (GA), and most existing charts have considerable methodological limitations. The INTERGROWTH-21(st) Project aimed to produce the first international standards for early fetal size and ultrasound dating of pregnancy based on CRL measurement. METHODS: Urban areas in eight geographically diverse countries that met strict eligibility criteria were selected for the prospective, population-based recruitment, between 9 + 0 and 13 + 6 weeks' gestation, of healthy well-nourished women with singleton pregnancies at low risk of fetal growth impairment. GA was calculated on the basis of a certain last menstrual period, regular menstrual cycle and lack of hormonal medication or breastfeeding in the preceding 2 months. CRL was measured using strict protocols and quality-control measures. All women were followed up throughout pregnancy until delivery and hospital discharge. Cases of neonatal and fetal death, severe pregnancy complications and congenital abnormalities were excluded from the study. RESULTS: A total of 4607 women were enrolled in the Fetal Growth Longitudinal Study, one of the three main components of the INTERGROWTH-21(st) Project, of whom 4321 had a live singleton birth in the absence of severe maternal conditions or congenital abnormalities detected by ultrasound or at birth. The CRL was measured in 56 women at < 9 + 0 weeks' gestation; these were excluded, resulting in 4265 women who contributed data to the final analysis. The mean CRL and SD increased with GA almost linearly, and their relationship to GA is given by the following two equations (in which GA is in days and CRL in mm): mean CRL = -50.6562 + (0.815118 × GA) + (0.00535302 × GA(2) ); and SD of CRL = -2.21626 + (0.0984894 × GA). GA estimation is carried out according to the two equations: GA = 40.9041 + (3.21585 × CRL(0.5) ) + (0.348956 × CRL); and SD of GA = 2.39102 + (0.0193474 × CRL). CONCLUSIONS: We have produced international prescriptive standards for early fetal linear size and ultrasound dating of pregnancy in the first trimester that can be used throughout the world.

Implementation of the INTERGROWTH-21st Project in Italy.

Turin, Italy, was one of the two European sites for the INTERGROWTH-21(st) Project. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two obstetric hospitals that together account for 79% of the city's approximately 12,000 births per year. Women were recruited for the Fetal Growth Longitudinal Study (FGLS) from ten antenatal clinics serving the city's largest obstetric hospital, Azienda Ospedaliera OIRM-S. Anna. Special activities to encourage participation and raise awareness of the project in this population included obtaining an endorsement from the coordinator of the city's antenatal care service, and disseminating information about the project to women through posters and leaflets in antenatal clinics. One of the major challenges at this site was the low recruitment rate in the early phase of FGLS because of the high prevalence of smoking and of women >35 years old in the population. The addition of six extra recruiting clinics served to increase the pool of potentially eligible women who could be screened and led to a marked improvement in the recruitment rate.

Standardisation of neonatal clinical practice.

The International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) is a large-scale, population-based, multicentre project involving health institutions from eight geographically diverse countries, which aims to assess fetal, newborn and preterm growth under optimal conditions. Given the multicentre nature of the project and the expected number of preterm births, it is vital that all centres follow the same standardised clinical care protocols to assess and manage preterm infants, so as to ensure maximum validity of the resulting standards as indicators of growth and nutrition with minimal confounding. Moreover, it is well known that evidence-based clinical practice guidelines can reduce the delivery of inappropriate care and support the introduction of new knowledge into clinical practice. The INTERGROWTH-21(st) Neonatal Group produced an operations manual, which reflects the consensus reached by members of the group regarding standardised definitions of neonatal morbidities and the minimum standards of care to be provided by all centres taking part in the project. The operational definitions and summary management protocols were developed by consensus through a Delphi process based on systematic reviews of relevant guidelines and management protocols by authoritative bodies. This paper describes the process of developing the Basic Neonatal Care Manual, as well as the morbidity definitions and standardised neonatal care protocols applied across all the INTERGROWTH-21(st) participating centres. Finally, thoughts about implementation strategies are presented.

The objectives, design and implementation of the INTERGROWTH-21st Project.

INTERGROWTH-21(st) is a multicentre, multiethnic, population-based project, being conducted in eight geographical areas (Brazil, China, India, Italy, Kenya, Oman, UK and USA), with technical support from four global specialised units, to study growth, health and nutrition from early pregnancy to infancy. It aims to produce prescriptive growth standards, which conceptually extend the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) to cover fetal and newborn life. The new international standards will describe: (1) fetal growth assessed by clinical and ultrasound measures; (2) postnatal growth of term and preterm infants up to 2 years of age; and (3) the relationship between birthweight, length and head circumference, gestational age and perinatal outcomes. As the project has selected healthy cohorts with no obvious risk factors for intrauterine growth restriction, these standards will describe how all fetuses and newborns should grow, as opposed to traditional charts that describe how some have grown at a given place and time. These growth patterns will be related to morbidity and mortality to identify levels of perinatal risk. Additional aims include phenotypic characterisation of the preterm and impaired fetal growth syndromes and development of a prediction model, based on multiple ultrasound measurements, to estimate gestational age for use in pregnant women without access to early/frequent antenatal care.

A rapid questionnaire assessment of environmental exposures to pregnant women in the INTERGROWTH-21st Project.

Impaired fetal growth and preterm birth are the leading causes of neonatal and infant mortality worldwide and there is a growing scientific literature suggesting that environmental exposures during pregnancy may play a causal role in these outcomes. Our purpose was to assess the environmental exposure of the Fetal Growth Longitudinal Study (FGLS) participants in the multinational INTERGROWTH-21(st) Project. First, we developed a tool that could be used internationally to screen pregnant women for such exposures and administered it in eight countries on a subsample (n = 987) of the FGLS participants. The FGLS is a study of fetal growth among healthy pregnant women living in relatively affluent areas, at low risk of adverse pregnancy outcomes and environmental exposures. We confirmed that most women were not exposed to major environmental hazards that could affect pregnancy outcomes according to the protocol's entry criteria. However, the instrument was able to identify some women that reported various environmental concerns in their homes such as peeling paint, high residential density (>1 person per room), presence of rodents or cockroaches (hence the use of pesticides), noise pollution and safety concerns. This screening tool was therefore useful for the purposes of the project and can be used to ascertain environmental exposures in studies in which the primary aim is not focused on environmental exposures. The instrument can be used to identify subpopulations for more in-depth assessment, (e.g. environmental and biological laboratory markers) to pinpoint areas requiring education, intervention or policy change.

Detection of bovine alpha-S1-casein in term and preterm human colostrum with proteomic techniques.

Due to increased social awareness of allergens and population hyper-sensitization, the reported incidence of allergic reactions to food allergens has increased over the past two decades. Cow's milk proteins (CMPs) are among the most common food allergens. The aim of this study was to use proteomics techniques to investigate cow's milk allergens in both full-term human colostrum and in preterm newborns mothers where both groups showed no prior allergen detection -- in order to understand whether cows milk allergens could be a cause of sensitization established through lactation. The most relevant finding was the detection of the intact bovine alpha-S1-casein in both term and preterm colostrum. Using techniques detailed in this paper and which allowed for direct protein identification, beta-lactoglobulin was not detected in any of the colostrum samples. According to our results, bovine alpha 1 casein is considered a major cow's milk allergen, is readily secreted in human milk, and so could be considered a possible cause of sensitization in exclusively breastfed infants.

A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations.

BACKGROUND: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest. PATIENTS AND METHODS: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual. RESULTS: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea. CONCLUSIONS: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations.

Early enteral feeding with human milk for VLBW infants.

In a NICU early enteral feeding is usually possible only when the newborn clinical conditions permit it. Because of the frequent need of umbilical/central catheters, they usually start with parenteral feeding and/or with minimal enteral feeding (trophic feeding). This kind of management is even more frequent in VLBWIs, in which the risk of NEC is very high. In this work we describe a model of early enteral exclusive feeding (EEEF) based on the use of banking human milk followed by mother milk. In the Centre of Neonatology of Trento, as in other Centers, the newborns weighing less than 750g or with a GE< 27 weeks, are treated with parenteral nutrition and minimal enteral feeding. The newborn weighing 750-1249g and with GE > 26 weeks define a group in which we find critical neonates, who can not be treated with enteral feeding, and neonates whose clinical conditions permit EEEF. In particular, in a period of 16 years (1994-2009) in Trento, 308 newborns weighing 750-1249 g and GE > than 26 weeks were admitted. The 90,9 % has been treated with prenatal steroids, the 91,9 % was inborn, the 96,1% survived. In the 59,1 % of the cases (175) we gave EEEF. We could continue with a complete EEEF in the 40,2 % of the total (119 cases). The characteristics of these neonates and our centre management, based mainly on early use of banking human milk and mother milk, are detailed described.

Higher protein intake strategies in human milk fortification for preterms infants feeding. Auxological and neurodevelopmental outcome.

Postnatal growth restriction and failure to thrive still remain a major problem in Extremely Low Birth Weight (ELBW) infants . The goal for the nutritional care of these infants is to achieve rate of growth similar to those of the fetus in utero at the equivalent gestational age. Human milk fortified remains the best food for all these preterms. Two groups of preterm of weight 580-1250 g and gestational age 23-32 wk, were fed with different protein intake in the human/maternal milk fortified ( 3,5 g Kg-1 per day and 4,8 g Kg-1 per day in the control and intervention group respectively).The feeding tolerance, intrahospital growth, neurological outcome and anthropometric data until 12 months of corrected age, were evaluated. The protein supplemented group (PSG) showed an intrahospital highter growth rate ( mostly in head circumference, p 0,02, and length growth, p 0,04) only in the preterms with 580-980 g and 23-30 wk. In the same preterms, Griffith Development Mental Score at 3 and 12 months corrected age showed higher score than in the control group in the Performance (p 0,04) and Hearing/Language (p 0,03) items. The auxological evaluation in the postdischarge period showed in the PSG group mean z-score values for length higher than those in the control group at 9 (p 0,04) months of corrected age.

Early neutral prebiotic oligosaccharide supplementation reduces the incidence of some allergic manifestations in the first 5 years of life.

BACKGROUND: A mixture of neutral prebiotic oligosaccharides has been shown to reduce the incidence of atopic dermatitis (AD) and allergy associated symptoms during the first 2 years of life. OBJECTIVE: To evaluate if this protective effect against allergy lasted beyond the intervention period until 5 y of age. METHODS: In a prospective, double blind, placebo-controlled fashion, healthy term infants at risk of atopy were fed either a prebiotic-supplemented (0.8 g/100 ml scGOS/lcFOS) or placebo-supplemented (0.8 g/100 ml maltodextrin) hypoallergenic formula during the first 6 mo of life. Following this intervention period, follow-up continued until 5 y of life. The present study evaluated (i) the cumulative incidence of allergic manifestations during 5 y, and (ii) the prevalence of allergic and persistent allergic manifestations at 5 y. Monitored allergic manifestations were AD, recurrent wheezing, allergic rhinoconjunctivitis and urticaria. RESULTS: Ninety-two children (50 in placebo group, 42 in intervention group) completed the 5-y follow-up. The 5-y cumulative incidences of any allergic manifestation and atopic dermatitis were significantly lower in the scGOS/lcFOS group (30.9, 19.1 %, respectively) compared to placebo group (66, 38 %, respectively) (p< 0.01 and< 0.05). Children in the scGOS/lcFOS group tended to have a lower incidence of allergic rhinoconjunctivitis, and allergic urticaria (4.8 vs 16% for both manifestations, p=0.08). There was no difference in the cumulative incidence of recurrent wheezing. With regard to the prevalences at 5 y, intervention group had significantly lower prevalence of any persistent allergic manifestation and rhinoconjunctivitis (4.8, 2.4 %, respectively) compared to placebo (26, 14 %, respectively) (p < 0.01 and =0.05). Prevalence of persistent AD tended to be lower in the intervention group (2.4 vs 12%, p= 0.09). Although intervention group had 75% reduction in the prevalence of persistent wheezing (4.8 vs 14 %), no significance was shown. CONCLUSION: Oligosaccharide prebiotics (scGOS/lcFOS), when started early in life have a protective effect against allergic manifestations in high risk infants. The protection lasts beyond infancy until 5 y of life, for AD and allergic rhinoconjunctivitis. Long-term follow-up studies in larger populations are warranted to evaluate the potential preventive effect of this mixture on asthma.

Update of adjustable fortification regimen for preterm infants: a new protocol.

Preterm infants fed fortified human milk in standard fashion receive less protein than they need due to customary assumptions. Protein is limiting for growth and neurocognitive development,and shortfalls of protein are not acceptable. Adjustable fortification regimen has been proven as an effective way to provide adequate protein intakes and appropriate growth in this group of infants. Italian Association of Human Milk Banks (AIBLUD) has promoted and implemented this Adjustable fortification regimen in neonatal intensive care units (NICUs) with success. This paper presents an update of Adjustable fortification regimen; a new protocol already utilized in several italian NICUs.

Biological, nutritional and clinical aspects of feeding preterm infants with human milk.

Benefits of breastfeeding are widely recognized, during the last decades human milk has been identified as the normative standard for infant feeding and nutrition. Recent evidence focused on specific bioactive and immunomodulatory factors, such as oligosaccharides, lactose, glycosaminoglycans of human milk and the variability of their concentrations during lactation in both term and preterm milk. Human milk should be fortified with proteins, minerals and vitamins to ensure optimal nutrient intake for preterm VLBWI infants. Best fortification strategies as well as the optimal composition of fortifiers are still object of research. Short and long-term clinical, metabolic, immunologic and neurodevelopmental advantages of breastfeeding ndividualizes fortification - particulary adjustable fortification- has proven to be effective when compared to formula are well documented. Moreover several non-experimental studies observed that clinical feeding tolerance is improved and the attainment of full enteral feeding is quicker by a diet of human milk. In addition, benefits of breastfeeding on psychological and relational aspects have to be considered. Mother’s own milk remains the first choice for all neonates, when it is not available or not sufficient despite significant lactation support, donor milk represents the second best alternative and although some nutritional elements are inactivated by the pasteurization process, it still has documented advantages compared to formula.

Donor human milk versus mother's own milk in preterm VLBWIs: a case control study.

As for term infants, over the past decades there has been increasing evidence of the benefits of human milk in the feeding of Very Low Birth Weight Infants (VLBWI), influencing not only short-term health outcomes but also long-term neurodevelopmental, metabolic outcomes, and growth. Mother's own milk is the first choice for all neonates including preterm infants, when it is unavailable or in short supply, pasteurized donor breast milk offers a safe alternative and is considered the next best choice. The main aim of this case-control retrospective analysis was to evaluate short term advantages of mother's own milk as a sole diet compared to donor milk as a sole diet, in terms of growth, antiinfectious properties, feeding tolerance, NEC and ROP prevention in a population of VLBWI born in a tertiary center. We did not find significant differences in clinical outcome from mother's own milk compared with pasteurized donor milk. Only a slight and statistically not significant difference in growth could be observed, in favour of maternal milk. We conclude that the maximum effort should always be put in supporting and promoting breastfeeding and donor milk used not only as an alternative to mother's milk but also as a breastfeeding promotion and support strategy.

Auxological evaluation of newborns.

Auxological evaluation of the newborn should be based on accurate anthropometry at birth and a reliable estimate of gestational age (GA). However, a comprehensive evaluation of the neonate should consider not only anthropometric traits at birth, but also fetal ultrasound biometry and Doppler velocimetry. Many charts have been proposed, but they are hardly comparable with each other, due to numerous methodological problems. The Italian Societies of Neonatology, of Pediatric Endocrinology and Diabetology and the Italian Society of Medical Statistics and Clinical Epidemiology promoted a multicenter survey with the aim to produce an Italian neonatal anthropometric reference (Italian Neonatal Study [INeS] charts) fulfilling the set of the criteria that a reliable neonatal chart should possess. In order to construct an international standard, an international project (INTERGROWTH-21st) has started a study aiming to create a prescriptive standard. Until an international standard is developed, the use of national updated reference charts is recommended.

Medication and breastfeeding.

It is well accepted that the best feeding method for infants is breastfeeding, due to its numerous biological and clinical effects on child and maternal health. The use of medication by the nursing mother and the physician's advice to stop nursing are the most common reasons for the cessation of breastfeeding. The physician plays an extremely delicate role and should be able to assess risks and benefits for both mother and child. The main factors that must be taken into account include pharmacokinetics, the duration of maternal therapy, the age of the infant and the general health of the infant. All physicians should have access to reliable and updated information on medication safety during breastfeeding (reference books, online medical literature). Few drugs have been demonstrated to be absolutely contraindicated during breastfeeding. Nevertheless clear, safe and reliable information is still lacking for most drugs and it would be desirable to improve the knowledge about mechanisms and consequences of infant exposure to drug present in milk.

Critical appraisal of different anthropometric charts to evaluate postnatal growth of preterm infants.

Preterm infants' survival has greatly increased in the last few decades thanks to the improvement in obstetrical and neonatal care. The correct evaluation of postnatal growth of these babies is nowadays of primary concern, although the definition of their optimal postnatal growth pattern is still controversial. Concerns have also been raised about the strategies to monitor their growth, specifically in relation to the charts used. At present, the charts available in clinical practice are fetal growth charts, neonatal anthropometric charts and postnatal growth charts for term infants. None of these, for different reasons, is suitable to correctly evaluate preterm infant growth. Recently, an international project has recently started aiming to create prescriptive standard for the evaluation of postnatal growth of preterm infants (INTERGROWTH-21st). Alternatively, at present, while specific charts for evaluating preterm infant postnatal growth are lacking, the best compromise is likely to be as follows: from birth to term neonatal anthropometric charts; International longitudinal charts WHO 2006 or CDC 2002 from term to childhood.

Amendment to 2010 Italian guidelines for the establishment and operation of a donor human milk bank.

The present paper is an amendment to the recent Italian Guidelines of human milk banking published in 2010. Working Group on Guidelines (Panel) of the Italian Association of Human Milk Banks (AIBLUD) states, in accordance with the European Union Comission's Amending Directive of January 2011, that the hard plastic feeding bottles used in the collection, storage and pasteurization of the human milk should be Bisphenol A (BPA) free. Until new evidence are available polycarbonate feeding bottles should not be used for collection, storage and pasteurization of human milk. The paper summarizes the former and current European Commission Directives and shows the related amending changes to the 2010 Italian Human Milk Banking Guidelines.