Background: In the latest decades some compelling evidence confirmed the substantial benefits of ... more Background: In the latest decades some compelling evidence confirmed the substantial benefits of using human milk, especially for preterm infants [1-5]. Donor human milk is a valid alternative. Objective: This survey aimed to evaluate the activity of the human milk banks in Italy, analysing several items. Methods: The Italian Association of Donor Human Milk Banks (Associazione Italiana Banche del Latte Umano Donato, AIBLUD) was founded in 2005. It currently consists of 35 human milk banks (Figure 1), whose management should follow the Italian Guidelines. Among the goals of the association, scientific work plays a major role. After publication of the Italian Guidelines, the 2012 survey on Italian human milk banks also led to a nationwide improvement: some banks were established, others that were considered inactive were shut down [11]. In 2013 the Italian Ministry of Health published the national recommendations, based on the Italian Guidelines [12]. Results: 91% of the banks (32/35) responded to this second survey. Table 2 shows the average number of hours per week dedicated to the milk bank activity. This data varies greatly among the banks, as it did in 2012. The majority of the banks keeps having approximately 6 hours a day of work Conclusion: This second survey gave AIBLUD and the Italian Ministry of Health important information on the Italian human milk banks, overcoming their difficulties and correcting some negative aspects.
Background Preterm birth is a major global health challenge, the leading cause of death in childr... more Background Preterm birth is a major global health challenge, the leading cause of death in children under 5 years of age, and a key measure of a population's general health and nutritional status. Current clinical methods of estimating fetal gestational age are often inaccurate. For example, between 20 and 30 weeks of gestation, the width of the 95% prediction interval around the actual gestational age is estimated to be 18-36 days, even when the best ultrasound estimates are used. The aims of this study are to improve estimates of fetal gestational age and provide personalised predictions of future growth. Methods Using ultrasound-derived, fetal biometric data, we developed a machine learning approach to accurately estimate gestational age. The accuracy of the method is determined by reference to exactly known facts pertaining to each fetus-specifically, intervals between ultrasound visits-rather than the date of the mother's last menstrual period. The data stem from a sample of healthy, well-nourished participants in a large, multicentre, population-based study, the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). The generalisability of the algorithm is shown with data from a different and more heterogeneous population (INTERBIO-21st Fetal Study). Findings In the context of two large datasets, we estimated gestational age between 20 and 30 weeks of gestation with 95% confidence to within 3 days, using measurements made in a 10-week window spanning the second and third trimesters. Fetal gestational age can thus be estimated in the 20-30 weeks gestational age window with a prediction interval 3-5 times better than with any previous algorithm. This will enable improved management of individual pregnancies. 6-week forecasts of the growth trajectory for a given fetus are accurate to within 7 days. This will help identify at-risk fetuses more accurately than currently possible. At population level, the higher accuracy is expected to improve fetal growth charts and population health assessments. Interpretation Machine learning can circumvent long-standing limitations in determining fetal gestational age and future growth trajectory, without recourse to often inaccurately known information, such as the date of the mother's last menstrual period. Using this algorithm in clinical practice could facilitate the management of individual pregnancies and improve population-level health. Upon publication of this study, the algorithm for gestational age estimates will be provided for research purposes free of charge via a web portal.
Ultrasound in Obstetrics & Gynecology, Mar 5, 2017
Objective Estimated fetal weight (EFW) and fetal biometry are complementary measures used to scre... more 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-21 st 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-21 st Fetal Study (FS), two components of the INTERGROWTH-21 st 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
Accurate estimation of gestational age is an essential component of good obstetric care and infor... more Accurate estimation of gestational age is an essential component of good obstetric care and informs clinical decision-making throughout pregnancy. As the date of the last menstrual period is often unknown or uncertain, ultrasound measurement of fetal size is currently the best method for estimating gestational age. The calculation assumes an average fetal size at each gestational age. The method is accurate in the first trimester, but less so in the second and third trimesters as growth deviates from the average and variation in fetal size increases. Consequently, fetal ultrasound late in pregnancy has a wide margin of error of at least ±2 weeks’ gestation. Here, we utilise state-of-the-art machine learning methods to estimate gestational age using only image analysis of standard ultrasound planes, without any measurement information. The machine learning model is based on ultrasound images from two independent datasets: one for training and internal validation, and another for exte...
Mother’s own milk (MOM) is the first choice in preterm infant feeding, and when it is not availab... more Mother’s own milk (MOM) is the first choice in preterm infant feeding, and when it is not available or is insufficient, donor human milk (DHM) is recommended. It has been shown that feeding preterm infants with human milk is less related to major morbidities, enhances feeding tolerance and prevents metabolic syndrome in childhood. As The Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) states, specific guidelines for Human Milk Banks (HMB) are needed to guarantee the best possible compromise between microbiological safety and nutritional/biological quality of human milk (HM). Currently, Holder pasteurization (HoP: pasteurization process at 62.5-63°C for 30 minutes) is recommended by all international guidelines: this method inactivates bacterial and viral pathogens but it also affects some nutritional and biological properties of human milk. New methods to ameliorate the biological quality and safety of DHM are under ...
Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth ... more Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth failure of very preterm infants. Wide heterogeneity is found in definitions and anthropometric charts used to describe EUGR. Aim: We aim to compare two traditional definitions of EUGR with a newly proposed one, based on a longitudinal evaluation, that takes into account the physiological period of fluid loss after birth. We also wish to detect which definition could better predict neurodevelopmental impairment at 24 months of corrected age (CA). Methods: A total of 195 infants with GA < 30 were included. EUGR was calculated both for weight and head circumference (HC). Cross-sectional EUGR was defined as measurements < 10th percentile at discharge; longitudinal EUGR was defined as z-score < −1 between birth and discharge measurements. The new longitudinal "post-loss" EUGR definition was proposed as z-score < −1 between measurements taken at 14-21 days of life and at discharge. Longitudinal postnatal Intergrowth-21st charts specifically built on preterm infants were used. Association with major and minor neurodevelopmental impairment at 24-month CA was assessed for each definition. K coefficient and ROC curve were evaluated. Results: Longitudinal "post-loss" definition of EUGR for HC is the one predicting minor neurodevelopmental impairment at the multivariate analysis (OR = 3.94), and it is also associated with a worse General Quotient. The chosen cutoff (z-score < −1) is the proper one. Maiocco et al. Neurodevelopmental Outcomes of EUGR Preterm Infants Conclusion: HC in-hospital growth could be a more accurate tool than weight to predict neurodevelopmental outcomes and especially minor neurological impairment. Longitudinal "post-loss" definition of EUGR assessed on longitudinal charts for preterm infants could be the most appropriate definition from the methodological, clinical, and prognostic point of view.
Background: Anaemia in pregnancy is a global health problem with associated morbidity and mortali... more Background: Anaemia in pregnancy is a global health problem with associated morbidity and mortality. Methods: A secondary analysis of prospective, population-based study from 2009 to 2016 to generate maternal haemoglobin normative centiles in uncomplicated pregnancies in women receiving optimal antenatal care. Pregnant women were enrolled <14 weeks' gestation in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21 st Project which involved eight geographically diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, United Kingdom and United States. At each 5 § 1 weekly visit until delivery, information was collected about the pregnancy, as well as the results of blood tests taken as part of routine antenatal care that complemented the study's requirements, including haemoglobin values. Findings: A total of 3502 (81%) of 4321 women who delivered a live, singleton newborn with no visible congenital anomalies, contributed at least one haemoglobin value. Median haemoglobin concentrations ranged from 114.6 to 121.4 g/L, 94 to 103 g/L at the 3 rd centile, and from 135 to 141 g/L at the 97 th centile. The lowest values were seen between 31 and 32 weeks' gestation, representing a mean drop of 6.8 g/L compared to 14 weeks' gestation. The percentage variation in maternal haemoglobin within-site was 47% of the total variance compared to 13% between sites. Interpretation: We have generated International, gestational age-specific, smoothed centiles for maternal haemoglobin concentration compatible with better pregnancy outcomes, as well as adequate neonatal and early childhood morbidity, growth and development up to 2 years of age. Funding: Bill & Melinda Gates Foundation Grant number 49038.
We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) f... more We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) from Brazil, India, Italy, Kenya and the UK participating in the INTERGROWTH-21st Project. There was a positive independent relationship of duration of exclusive breastfeeding (EBF) and age at weaning with gross motor development, vision and autonomic physical activities, most evident if children were exclusively breastfed for ≥7 months or weaned at ≥7 months. There was no association with cognition, language or behaviour. Children exclusively breastfed from birth to <5 months or weaned at >6 months had, in a dose-effect pattern, adjusting for confounding factors, higher scores for “emotional reactivity”. The positive effect of EBF and age at weaning on gross motor, running and climbing scores was strongest among children with the highest scores in maternal closeness proxy indicators. EBF, late weaning and maternal closeness, associated with advanced motor and vision maturation, ind...
American Journal of Obstetrics and Gynecology, 2020
BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess f... more BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess fetal well-being. However, many studies that have produced reference charts have important methodologic limitations, and these result in significant heterogeneity of reported reference ranges. OBJECTIVES: To produce international gestational age-specific centiles for umbilical artery Doppler indices based on longitudinal data and the same rigorous methodology used in the original Fetal Growth Longitudinal Study of the INTERGROWTH-21 st Project. STUDY DESIGN: In Phase II of the INTERGROWTH-21 st Project (the INTERBIO-21st Study), we prospectively continued enrolling pregnant women according to the same protocol from 3 of the original populations in Pelotas (Brazil), Nairobi (Kenya), and Oxford (United Kingdom) that had participated in the Fetal Growth Longitudinal Study. Women with a singleton pregnancy were recruited at <14 weeks' gestation, confirmed by ultrasound measurement of crownerump length, and then underwent standardized ultrasound every 5AE1 weeks until delivery. From 22 weeks of gestation umbilical artery indices (pulsatility index, resistance index, and systolic/diastolic ratio) were measured in a blinded fashion, using identical equipment and a rigorously standardized protocol. Newborn size at birth was assessed using the international INTERGROWTH-21 st Standards, and infants had detailed assessment of growth, nutrition, morbidity, and motor development at 1 and 2 years of age. The appropriateness of pooling data from the 3 study sites was assessed using variance component analysis and standardized site differences. Umbilical artery indices were modeled as functions of the gestational age using an exponential, normal distribution with second-degree fractional polynomial smoothing; goodness of fit for the overall models was assessed. RESULTS: Of the women enrolled at the 3 sites, 1629 were eligible for this study; 431 (27%) met the entry criteria for the construction of normative centiles, similar to the proportion seen in the original fetal growth longitudinal study. They contributed a total of 1243 Doppler measures to the analysis; 74% had 3 measures or more. The healthy lowrisk status of the population was confirmed by the low rates of preterm birth (4.9%) and preeclampsia (0.7%). There were no neonatal deaths and satisfactory growth, health, and motor development of the infants at 1 and 2 years of age were documented. Only a very small proportion (2.8% e6.5%) of the variance of Doppler indices was due to between-site differences; in addition, standardized site difference estimates were marginally outside this threshold in only 1 of 27 comparisons, and this supported the decision to pool data from the 3 study sites. All 3 Doppler indices decreased with advancing gestational age. The 3rd, 5th 10th, 50th, 90th, 95th, and 97th centiles according to gestational age for each of the 3 indices are provided, as well as equations to allow calculation of any value as a centile and z scores. The mean pulsatility index according to gestational age ¼ 1.02944 þ 77.7456*(gestational age) e2 e 0.000004455*gestational age 3. CONCLUSION: We present here international gestational agespecific normative centiles for umbilical artery Doppler indices produced by studying healthy, low-risk pregnant women living in environments with minimal constraints on fetal growth. The centiles complement the existing INTERGROWTH-21 st Standards for assessment of fetal well-being.
It is unclear whether early child development is, like skeletal growth, similar across diverse re... more It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and univer...
Objectives There are no international standards for relating fetal crown-rump length (CRL) to ges... more 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.
BJOG: An International Journal of Obstetrics & Gynaecology, 2013
Impaired fetal growth and preterm birth are the leading causes of neonatal and infant mortality w... more 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‐21st 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 t...
International Journal of Immunopathology and Pharmacology, 2008
The benefits of human milk have been confirmed for preterm infants, due to its nutritional aspect... more The benefits of human milk have been confirmed for preterm infants, due to its nutritional aspects and to its biologically active compounds. Oligosaccharides play an emerging leading role among these compounds. Mother's milk can sometimes be lacking for preterm infants; pasteurized donor milk represents therefore an important alternative. The aim of this study is to evaluate the effects of Holder pasteurization on the concentration and pattern of oligosaccharides in preterm human milk. Our results indicate that pasteurization does not affect the concentration or pattern of analyzed oligosaccharides.
ObjectivesTo describe the construction of the international INTERGROWTH-21st Neurodevelopment Ass... more ObjectivesTo describe the construction of the international INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) standards for child development at 2 years by reporting the cognitive, language, motor and behaviour outcomes in optimally healthy and nourished children in the INTERGROWTH-21st Project.DesignPopulation-based cohort study, the INTERGROWTH-21st Project.SettingBrazil, India, Italy, Kenya and the UK.Participants1181 children prospectively recruited from early fetal life according to the prescriptive WHO approach, and confirmed to be at low risk of adverse perinatal and postnatal outcomes.Primary measuresScaled INTER-NDA domain scores for cognition, language, fine and gross motor skills and behaviour; vision outcomes measured on the Cardiff tests; attentional problems and emotional reactivity measured on the respective subscales of the preschool Child Behaviour Checklist; and the age of acquisition of the WHO gross motor milestones.ResultsScaled INTER-NDA domain scores ar...
Mediterranean Diet and FA Milk for MDS = 4, and 45.24 ± 5.22% of fats for MDS = 5-8 points; p ANO... more Mediterranean Diet and FA Milk for MDS = 4, and 45.24 ± 5.22% of fats for MDS = 5-8 points; p ANOVA and p for trend < 0.01), ω-3 FA (1.07 ± 0.25 for MDS = 0-3, 1.22 ± 0.49 for MDS = 4, and 1.31 ± 0.51% of fats for MDS = 5-8 points; p ANOVA and p for trend < 0.01), and the major types of ω-3 FA (i.e., α-linolenic acid-ALA, eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA, docosapentaenoic acid-DPA). These associations were mainly driven by the adherence to the vegetables, MUFA/SFA, fish, and dairy products components of the Mediterranean diet. Conclusion: A high adherence to the Mediterranean diet was associated with human milk showing a lower content of SFA and higher content of MUFA and ω-3 FA, including DHA. The Mediterranean diet may contribute in human milk production with higher content of specific FA which is directly involved in infant's neural and visual development, as reported by previous studies.
2. Tully MR, ed. Guidelines for the Establishment and Operation of a Donor Human Milk Bank. 9th e... more 2. Tully MR, ed. Guidelines for the Establishment and Operation of a Donor Human Milk Bank. 9th ed. Raleigh, NC: Human Milk Banking Association of North America; 2000. 3. Arslanoglu S, Corpeleijn W, Moro G, et al; ESPGHAN Committee on Nutrition. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr. 2013;57:535-542. 4. Tully DB. Donor milk: what’s in it and what’s not. J Hum Lact. 2001;17(2):152-155. 5. Ogundele MO. Techniques for the storage of human breast milk: implications for anti-microbial functions and safety of stored milk. Eur J Pediatr. 2000;159(11):793-797. 6. García-Lara NR, Vieco DE, De la Cruz-Bértolo J, et al. Effect of holder pasteurization and frozen storage on macronutrients and energy content of breast milk. J Pediatr Gastroenterol Nutr. 2013;57(3):377-382. 7. Evans TJ, Ryley HC, Neale LM, et al. Effect of storage and heat on antimicrobial proteins in human milk. Arch Dis Child. 1978;53:239-241. 8. Christen L, Lai CT, Hartmann B, et al. The effect of UV-C pasteurization on bacteriostatic properties and immunological proteins of donor human milk. PLoS ONE. 2013;8(12):e85867. 9. Braga LP, Palhares DB. Effect of evaporation and pasteurization in the biochemical and immunological composition of human milk. J Pediatr (Rio J). 2007;83(1):59-63. 10. da Costa RS, do Carmo MG, Saunders C, et al. Characterization of iron, copper and zinc levels in the colostrum of mothers of term and preterm infants before and after pasteurization. Int J Food Sci Nutr. 2003;54(2):111-117. 11. Akinbi H, Meinzen-Derr J, Auer C, et al. Alterations in the host defense properties of human milk following prolonged storage or pasteurization. JPGN. 2010;51(3):347-352. 12. Elisia I, Kitts DD. Quantification of hexanal as an index of lipid oxidation in human milk and association with antioxidant components. J Clin Biochem Nutr. 2011;49(3):147-152. 13. Gibbs JH, Fisher C, Bhattacharya S, et al. Drip breast milk: its composition, collection and pasteurization. Early Hum Dev. 1977;1(3):227-245.
Background: Fortification of human milk is a standard practice for feeding very low birth weight ... more Background: Fortification of human milk is a standard practice for feeding very low birth weight infants. However, preterm infants often still experience suboptimal growth and feeding intolerance. New fortification strategies and different commercially available fortifiers have been developed. Commercially available fortifiers are constituted by a blend of ingredients from different sources, including plant oils and bovine milk proteins, thus presenting remarkable differences in the quality of macronutrients with respect to human milk. Based on the consideration that donkey milk has been suggested as a valid alternative for children allergic to cow's milk proteins, due to its biochemical similarity to human milk, we hypothesized that donkey milk could be a suitable ingredient for developing an innovative human milk fortifier. The aim of the study is to evaluate feeding tolerance, growth and clinical short and long-term outcomes in a population of preterm infants fed with a novel multi-component fortifier and a protein concentrate derived from donkey milk, in comparison to an analogous population fed with traditional fortifier and protein supplement containing bovine milk proteins. Methods: The study has been designed as a randomized, controlled, single-blind clinical trial. Infants born <1500 g and <32 weeks of gestational age were randomized to receive for 21 days either a combination of control bovine milk-based multicomponent fortifier and protein supplement, or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The fortification protocol followed is the same for the two groups, and the two diets were designed to be isoproteic and isocaloric. Weight, length and head circumference are measured; feeding tolerance is assessed by a standardized protocol. The occurrence of sepsis, necrotizing enterocolitis and adverse effects are monitored. Discussion: This is the first clinical study investigating the use of a human milk fortifier derived from donkey milk for the nutrition of preterm infants. If donkey milk derived products will be shown to improve the feeding tolerance or either of the clinical, metabolic, neurological or auxological outcomes of preterm infants, it would be an absolute innovation in the field of feeding practices for preterm infants.
Innovative Food Science and Emerging Technologies, Aug 1, 2016
(AAM) is copyrighted and published by Elsevier. It is posted here by agreement between Elsevier a... more (AAM) is copyrighted and published by Elsevier. It is posted here by agreement between Elsevier and the University of Turin. Changes resulting from the publishing process-such as editing, corrections, structural formatting, and other quality control mechanisms-may not be reflected in this version of the text. The definitive version of the text was subsequently published in INNOVATIVE FOOD SCIENCE & EMERGING TECHNOLOGIES,
Background: In the latest decades some compelling evidence confirmed the substantial benefits of ... more Background: In the latest decades some compelling evidence confirmed the substantial benefits of using human milk, especially for preterm infants [1-5]. Donor human milk is a valid alternative. Objective: This survey aimed to evaluate the activity of the human milk banks in Italy, analysing several items. Methods: The Italian Association of Donor Human Milk Banks (Associazione Italiana Banche del Latte Umano Donato, AIBLUD) was founded in 2005. It currently consists of 35 human milk banks (Figure 1), whose management should follow the Italian Guidelines. Among the goals of the association, scientific work plays a major role. After publication of the Italian Guidelines, the 2012 survey on Italian human milk banks also led to a nationwide improvement: some banks were established, others that were considered inactive were shut down [11]. In 2013 the Italian Ministry of Health published the national recommendations, based on the Italian Guidelines [12]. Results: 91% of the banks (32/35) responded to this second survey. Table 2 shows the average number of hours per week dedicated to the milk bank activity. This data varies greatly among the banks, as it did in 2012. The majority of the banks keeps having approximately 6 hours a day of work Conclusion: This second survey gave AIBLUD and the Italian Ministry of Health important information on the Italian human milk banks, overcoming their difficulties and correcting some negative aspects.
Background Preterm birth is a major global health challenge, the leading cause of death in childr... more Background Preterm birth is a major global health challenge, the leading cause of death in children under 5 years of age, and a key measure of a population's general health and nutritional status. Current clinical methods of estimating fetal gestational age are often inaccurate. For example, between 20 and 30 weeks of gestation, the width of the 95% prediction interval around the actual gestational age is estimated to be 18-36 days, even when the best ultrasound estimates are used. The aims of this study are to improve estimates of fetal gestational age and provide personalised predictions of future growth. Methods Using ultrasound-derived, fetal biometric data, we developed a machine learning approach to accurately estimate gestational age. The accuracy of the method is determined by reference to exactly known facts pertaining to each fetus-specifically, intervals between ultrasound visits-rather than the date of the mother's last menstrual period. The data stem from a sample of healthy, well-nourished participants in a large, multicentre, population-based study, the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). The generalisability of the algorithm is shown with data from a different and more heterogeneous population (INTERBIO-21st Fetal Study). Findings In the context of two large datasets, we estimated gestational age between 20 and 30 weeks of gestation with 95% confidence to within 3 days, using measurements made in a 10-week window spanning the second and third trimesters. Fetal gestational age can thus be estimated in the 20-30 weeks gestational age window with a prediction interval 3-5 times better than with any previous algorithm. This will enable improved management of individual pregnancies. 6-week forecasts of the growth trajectory for a given fetus are accurate to within 7 days. This will help identify at-risk fetuses more accurately than currently possible. At population level, the higher accuracy is expected to improve fetal growth charts and population health assessments. Interpretation Machine learning can circumvent long-standing limitations in determining fetal gestational age and future growth trajectory, without recourse to often inaccurately known information, such as the date of the mother's last menstrual period. Using this algorithm in clinical practice could facilitate the management of individual pregnancies and improve population-level health. Upon publication of this study, the algorithm for gestational age estimates will be provided for research purposes free of charge via a web portal.
Ultrasound in Obstetrics & Gynecology, Mar 5, 2017
Objective Estimated fetal weight (EFW) and fetal biometry are complementary measures used to scre... more 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-21 st 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-21 st Fetal Study (FS), two components of the INTERGROWTH-21 st 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
Accurate estimation of gestational age is an essential component of good obstetric care and infor... more Accurate estimation of gestational age is an essential component of good obstetric care and informs clinical decision-making throughout pregnancy. As the date of the last menstrual period is often unknown or uncertain, ultrasound measurement of fetal size is currently the best method for estimating gestational age. The calculation assumes an average fetal size at each gestational age. The method is accurate in the first trimester, but less so in the second and third trimesters as growth deviates from the average and variation in fetal size increases. Consequently, fetal ultrasound late in pregnancy has a wide margin of error of at least ±2 weeks’ gestation. Here, we utilise state-of-the-art machine learning methods to estimate gestational age using only image analysis of standard ultrasound planes, without any measurement information. The machine learning model is based on ultrasound images from two independent datasets: one for training and internal validation, and another for exte...
Mother’s own milk (MOM) is the first choice in preterm infant feeding, and when it is not availab... more Mother’s own milk (MOM) is the first choice in preterm infant feeding, and when it is not available or is insufficient, donor human milk (DHM) is recommended. It has been shown that feeding preterm infants with human milk is less related to major morbidities, enhances feeding tolerance and prevents metabolic syndrome in childhood. As The Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) states, specific guidelines for Human Milk Banks (HMB) are needed to guarantee the best possible compromise between microbiological safety and nutritional/biological quality of human milk (HM). Currently, Holder pasteurization (HoP: pasteurization process at 62.5-63°C for 30 minutes) is recommended by all international guidelines: this method inactivates bacterial and viral pathogens but it also affects some nutritional and biological properties of human milk. New methods to ameliorate the biological quality and safety of DHM are under ...
Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth ... more Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth failure of very preterm infants. Wide heterogeneity is found in definitions and anthropometric charts used to describe EUGR. Aim: We aim to compare two traditional definitions of EUGR with a newly proposed one, based on a longitudinal evaluation, that takes into account the physiological period of fluid loss after birth. We also wish to detect which definition could better predict neurodevelopmental impairment at 24 months of corrected age (CA). Methods: A total of 195 infants with GA < 30 were included. EUGR was calculated both for weight and head circumference (HC). Cross-sectional EUGR was defined as measurements < 10th percentile at discharge; longitudinal EUGR was defined as z-score < −1 between birth and discharge measurements. The new longitudinal "post-loss" EUGR definition was proposed as z-score < −1 between measurements taken at 14-21 days of life and at discharge. Longitudinal postnatal Intergrowth-21st charts specifically built on preterm infants were used. Association with major and minor neurodevelopmental impairment at 24-month CA was assessed for each definition. K coefficient and ROC curve were evaluated. Results: Longitudinal "post-loss" definition of EUGR for HC is the one predicting minor neurodevelopmental impairment at the multivariate analysis (OR = 3.94), and it is also associated with a worse General Quotient. The chosen cutoff (z-score < −1) is the proper one. Maiocco et al. Neurodevelopmental Outcomes of EUGR Preterm Infants Conclusion: HC in-hospital growth could be a more accurate tool than weight to predict neurodevelopmental outcomes and especially minor neurological impairment. Longitudinal "post-loss" definition of EUGR assessed on longitudinal charts for preterm infants could be the most appropriate definition from the methodological, clinical, and prognostic point of view.
Background: Anaemia in pregnancy is a global health problem with associated morbidity and mortali... more Background: Anaemia in pregnancy is a global health problem with associated morbidity and mortality. Methods: A secondary analysis of prospective, population-based study from 2009 to 2016 to generate maternal haemoglobin normative centiles in uncomplicated pregnancies in women receiving optimal antenatal care. Pregnant women were enrolled <14 weeks' gestation in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21 st Project which involved eight geographically diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, United Kingdom and United States. At each 5 § 1 weekly visit until delivery, information was collected about the pregnancy, as well as the results of blood tests taken as part of routine antenatal care that complemented the study's requirements, including haemoglobin values. Findings: A total of 3502 (81%) of 4321 women who delivered a live, singleton newborn with no visible congenital anomalies, contributed at least one haemoglobin value. Median haemoglobin concentrations ranged from 114.6 to 121.4 g/L, 94 to 103 g/L at the 3 rd centile, and from 135 to 141 g/L at the 97 th centile. The lowest values were seen between 31 and 32 weeks' gestation, representing a mean drop of 6.8 g/L compared to 14 weeks' gestation. The percentage variation in maternal haemoglobin within-site was 47% of the total variance compared to 13% between sites. Interpretation: We have generated International, gestational age-specific, smoothed centiles for maternal haemoglobin concentration compatible with better pregnancy outcomes, as well as adequate neonatal and early childhood morbidity, growth and development up to 2 years of age. Funding: Bill & Melinda Gates Foundation Grant number 49038.
We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) f... more We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) from Brazil, India, Italy, Kenya and the UK participating in the INTERGROWTH-21st Project. There was a positive independent relationship of duration of exclusive breastfeeding (EBF) and age at weaning with gross motor development, vision and autonomic physical activities, most evident if children were exclusively breastfed for ≥7 months or weaned at ≥7 months. There was no association with cognition, language or behaviour. Children exclusively breastfed from birth to <5 months or weaned at >6 months had, in a dose-effect pattern, adjusting for confounding factors, higher scores for “emotional reactivity”. The positive effect of EBF and age at weaning on gross motor, running and climbing scores was strongest among children with the highest scores in maternal closeness proxy indicators. EBF, late weaning and maternal closeness, associated with advanced motor and vision maturation, ind...
American Journal of Obstetrics and Gynecology, 2020
BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess f... more BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess fetal well-being. However, many studies that have produced reference charts have important methodologic limitations, and these result in significant heterogeneity of reported reference ranges. OBJECTIVES: To produce international gestational age-specific centiles for umbilical artery Doppler indices based on longitudinal data and the same rigorous methodology used in the original Fetal Growth Longitudinal Study of the INTERGROWTH-21 st Project. STUDY DESIGN: In Phase II of the INTERGROWTH-21 st Project (the INTERBIO-21st Study), we prospectively continued enrolling pregnant women according to the same protocol from 3 of the original populations in Pelotas (Brazil), Nairobi (Kenya), and Oxford (United Kingdom) that had participated in the Fetal Growth Longitudinal Study. Women with a singleton pregnancy were recruited at <14 weeks' gestation, confirmed by ultrasound measurement of crownerump length, and then underwent standardized ultrasound every 5AE1 weeks until delivery. From 22 weeks of gestation umbilical artery indices (pulsatility index, resistance index, and systolic/diastolic ratio) were measured in a blinded fashion, using identical equipment and a rigorously standardized protocol. Newborn size at birth was assessed using the international INTERGROWTH-21 st Standards, and infants had detailed assessment of growth, nutrition, morbidity, and motor development at 1 and 2 years of age. The appropriateness of pooling data from the 3 study sites was assessed using variance component analysis and standardized site differences. Umbilical artery indices were modeled as functions of the gestational age using an exponential, normal distribution with second-degree fractional polynomial smoothing; goodness of fit for the overall models was assessed. RESULTS: Of the women enrolled at the 3 sites, 1629 were eligible for this study; 431 (27%) met the entry criteria for the construction of normative centiles, similar to the proportion seen in the original fetal growth longitudinal study. They contributed a total of 1243 Doppler measures to the analysis; 74% had 3 measures or more. The healthy lowrisk status of the population was confirmed by the low rates of preterm birth (4.9%) and preeclampsia (0.7%). There were no neonatal deaths and satisfactory growth, health, and motor development of the infants at 1 and 2 years of age were documented. Only a very small proportion (2.8% e6.5%) of the variance of Doppler indices was due to between-site differences; in addition, standardized site difference estimates were marginally outside this threshold in only 1 of 27 comparisons, and this supported the decision to pool data from the 3 study sites. All 3 Doppler indices decreased with advancing gestational age. The 3rd, 5th 10th, 50th, 90th, 95th, and 97th centiles according to gestational age for each of the 3 indices are provided, as well as equations to allow calculation of any value as a centile and z scores. The mean pulsatility index according to gestational age ¼ 1.02944 þ 77.7456*(gestational age) e2 e 0.000004455*gestational age 3. CONCLUSION: We present here international gestational agespecific normative centiles for umbilical artery Doppler indices produced by studying healthy, low-risk pregnant women living in environments with minimal constraints on fetal growth. The centiles complement the existing INTERGROWTH-21 st Standards for assessment of fetal well-being.
It is unclear whether early child development is, like skeletal growth, similar across diverse re... more It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and univer...
Objectives There are no international standards for relating fetal crown-rump length (CRL) to ges... more 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.
BJOG: An International Journal of Obstetrics & Gynaecology, 2013
Impaired fetal growth and preterm birth are the leading causes of neonatal and infant mortality w... more 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‐21st 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 t...
International Journal of Immunopathology and Pharmacology, 2008
The benefits of human milk have been confirmed for preterm infants, due to its nutritional aspect... more The benefits of human milk have been confirmed for preterm infants, due to its nutritional aspects and to its biologically active compounds. Oligosaccharides play an emerging leading role among these compounds. Mother's milk can sometimes be lacking for preterm infants; pasteurized donor milk represents therefore an important alternative. The aim of this study is to evaluate the effects of Holder pasteurization on the concentration and pattern of oligosaccharides in preterm human milk. Our results indicate that pasteurization does not affect the concentration or pattern of analyzed oligosaccharides.
ObjectivesTo describe the construction of the international INTERGROWTH-21st Neurodevelopment Ass... more ObjectivesTo describe the construction of the international INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) standards for child development at 2 years by reporting the cognitive, language, motor and behaviour outcomes in optimally healthy and nourished children in the INTERGROWTH-21st Project.DesignPopulation-based cohort study, the INTERGROWTH-21st Project.SettingBrazil, India, Italy, Kenya and the UK.Participants1181 children prospectively recruited from early fetal life according to the prescriptive WHO approach, and confirmed to be at low risk of adverse perinatal and postnatal outcomes.Primary measuresScaled INTER-NDA domain scores for cognition, language, fine and gross motor skills and behaviour; vision outcomes measured on the Cardiff tests; attentional problems and emotional reactivity measured on the respective subscales of the preschool Child Behaviour Checklist; and the age of acquisition of the WHO gross motor milestones.ResultsScaled INTER-NDA domain scores ar...
Mediterranean Diet and FA Milk for MDS = 4, and 45.24 ± 5.22% of fats for MDS = 5-8 points; p ANO... more Mediterranean Diet and FA Milk for MDS = 4, and 45.24 ± 5.22% of fats for MDS = 5-8 points; p ANOVA and p for trend < 0.01), ω-3 FA (1.07 ± 0.25 for MDS = 0-3, 1.22 ± 0.49 for MDS = 4, and 1.31 ± 0.51% of fats for MDS = 5-8 points; p ANOVA and p for trend < 0.01), and the major types of ω-3 FA (i.e., α-linolenic acid-ALA, eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA, docosapentaenoic acid-DPA). These associations were mainly driven by the adherence to the vegetables, MUFA/SFA, fish, and dairy products components of the Mediterranean diet. Conclusion: A high adherence to the Mediterranean diet was associated with human milk showing a lower content of SFA and higher content of MUFA and ω-3 FA, including DHA. The Mediterranean diet may contribute in human milk production with higher content of specific FA which is directly involved in infant's neural and visual development, as reported by previous studies.
2. Tully MR, ed. Guidelines for the Establishment and Operation of a Donor Human Milk Bank. 9th e... more 2. Tully MR, ed. Guidelines for the Establishment and Operation of a Donor Human Milk Bank. 9th ed. Raleigh, NC: Human Milk Banking Association of North America; 2000. 3. Arslanoglu S, Corpeleijn W, Moro G, et al; ESPGHAN Committee on Nutrition. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr. 2013;57:535-542. 4. Tully DB. Donor milk: what’s in it and what’s not. J Hum Lact. 2001;17(2):152-155. 5. Ogundele MO. Techniques for the storage of human breast milk: implications for anti-microbial functions and safety of stored milk. Eur J Pediatr. 2000;159(11):793-797. 6. García-Lara NR, Vieco DE, De la Cruz-Bértolo J, et al. Effect of holder pasteurization and frozen storage on macronutrients and energy content of breast milk. J Pediatr Gastroenterol Nutr. 2013;57(3):377-382. 7. Evans TJ, Ryley HC, Neale LM, et al. Effect of storage and heat on antimicrobial proteins in human milk. Arch Dis Child. 1978;53:239-241. 8. Christen L, Lai CT, Hartmann B, et al. The effect of UV-C pasteurization on bacteriostatic properties and immunological proteins of donor human milk. PLoS ONE. 2013;8(12):e85867. 9. Braga LP, Palhares DB. Effect of evaporation and pasteurization in the biochemical and immunological composition of human milk. J Pediatr (Rio J). 2007;83(1):59-63. 10. da Costa RS, do Carmo MG, Saunders C, et al. Characterization of iron, copper and zinc levels in the colostrum of mothers of term and preterm infants before and after pasteurization. Int J Food Sci Nutr. 2003;54(2):111-117. 11. Akinbi H, Meinzen-Derr J, Auer C, et al. Alterations in the host defense properties of human milk following prolonged storage or pasteurization. JPGN. 2010;51(3):347-352. 12. Elisia I, Kitts DD. Quantification of hexanal as an index of lipid oxidation in human milk and association with antioxidant components. J Clin Biochem Nutr. 2011;49(3):147-152. 13. Gibbs JH, Fisher C, Bhattacharya S, et al. Drip breast milk: its composition, collection and pasteurization. Early Hum Dev. 1977;1(3):227-245.
Background: Fortification of human milk is a standard practice for feeding very low birth weight ... more Background: Fortification of human milk is a standard practice for feeding very low birth weight infants. However, preterm infants often still experience suboptimal growth and feeding intolerance. New fortification strategies and different commercially available fortifiers have been developed. Commercially available fortifiers are constituted by a blend of ingredients from different sources, including plant oils and bovine milk proteins, thus presenting remarkable differences in the quality of macronutrients with respect to human milk. Based on the consideration that donkey milk has been suggested as a valid alternative for children allergic to cow's milk proteins, due to its biochemical similarity to human milk, we hypothesized that donkey milk could be a suitable ingredient for developing an innovative human milk fortifier. The aim of the study is to evaluate feeding tolerance, growth and clinical short and long-term outcomes in a population of preterm infants fed with a novel multi-component fortifier and a protein concentrate derived from donkey milk, in comparison to an analogous population fed with traditional fortifier and protein supplement containing bovine milk proteins. Methods: The study has been designed as a randomized, controlled, single-blind clinical trial. Infants born <1500 g and <32 weeks of gestational age were randomized to receive for 21 days either a combination of control bovine milk-based multicomponent fortifier and protein supplement, or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The fortification protocol followed is the same for the two groups, and the two diets were designed to be isoproteic and isocaloric. Weight, length and head circumference are measured; feeding tolerance is assessed by a standardized protocol. The occurrence of sepsis, necrotizing enterocolitis and adverse effects are monitored. Discussion: This is the first clinical study investigating the use of a human milk fortifier derived from donkey milk for the nutrition of preterm infants. If donkey milk derived products will be shown to improve the feeding tolerance or either of the clinical, metabolic, neurological or auxological outcomes of preterm infants, it would be an absolute innovation in the field of feeding practices for preterm infants.
Innovative Food Science and Emerging Technologies, Aug 1, 2016
(AAM) is copyrighted and published by Elsevier. It is posted here by agreement between Elsevier a... more (AAM) is copyrighted and published by Elsevier. It is posted here by agreement between Elsevier and the University of Turin. Changes resulting from the publishing process-such as editing, corrections, structural formatting, and other quality control mechanisms-may not be reflected in this version of the text. The definitive version of the text was subsequently published in INNOVATIVE FOOD SCIENCE & EMERGING TECHNOLOGIES,
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Papers by Enrico Bertino