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Neurodevelopment in Children Born Small for Gestational Age: A Randomized Trial of Nutrient-Enriched Versus Standard Formula and Comparison With a Reference Breastfed Group
Abstract
Many studies have shown that children born small for gestational age (SGA) are at a neurodevelopmental disadvantage. We have shown that nutrient enrichment of formula fed to term SGA infants improves their growth and hypothesized that it also would improve their neurodevelopmental outcome.
A randomized, controlled trial of standard term-infant (n = 147) or nutrient-enriched (n = 152) formula for the first 9 months. A reference group of 175 breastfed SGA infants was also recruited.
Subjects were recruited in 5 maternity hospitals in Cambridge, Nottingham, and Leicester, all in the United Kingdom.
Healthy, term infants (gestation: > or =37 weeks) with birth weight <10th centile.
Bayley mental and psychomotor scores at 18 months (primary) and developmental scores from Knobloch, Pasamanick, and Sherrard's developmental screening inventory at 9 months (secondary).
There was no significant intergroup difference in Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) scores at 18 months. However, at 9 months, children fed the enriched formula had a significantly lower developmental quotient (99.5 vs 102.0; 95% confidence interval [CI] for difference: -4.6, -0.4). A significant disadvantage was seen in girls (-5.1; 95% CI: -7.8, -2.4) but not in boys (0.9; 95% CI: -2.4, 4.2). Breastfed infants had significantly higher MDI and PDI scores at 18 months than formula-fed infants. Confounding factors accounted for approximately 34% of the observed association between breastfeeding and MDI score and none of the association between breastfeeding and PDI score.
The previously reported enhanced linear growth in SGA children fed enriched formula was not matched by a neurodevelopmental advantage. At 9 months, girls fed the enriched formula had a significant developmental disadvantage, although this was not seen at 18 months. Later follow-up will determine any long-term effects on health or development. Meanwhile, use of enriched formula for term SGA children should not be promoted. It seems that breastfeeding may be especially beneficial for neurodevelopment in children born SGA.
... Multiple factors related to the postnatal environment, including childhood conditions, maternal mental health, and exposure to household cigarette smoking, among others, may be involved in this outcome [15]. Alterations in hippocampal formation and its related neural structures [17] as well as the type of early postnatal feeding (breast vs. formula) could also be implicated [18]. In the present study, we hypothesized that early modulation of NGF would relate to prenatal growth. ...
... At age 4 months, SGA-breastfed infants maintained significantly higher circulating levels of NGF, while in formula-fed SGA infants, NGF concentrations decreased within the range of AGA and LGA infants. These differences could account, at least in part, for a poorer developmental quotient in formula-fed as compared to SGA-breastfed infants [18]. Previous studies have reported higher concentrations of trophic factors in human milk than in other biological fluids at different periods of maturation [31]. ...
... Thus, it is tempting to speculate that, given the role of NGF in neurodevelopment, the elevated NGF levels in SGA-breastfed infants could reflect the presence of a higher amount of NGF in breast milk, acting as a compensatory mechanism aimed at preserving and/or improving the cognitive function in those children. Indeed, SGA-breastfed infants have been reported to show higher Bayley Mental Development Index and Psychomotor Development Index as compared to formula-fed SGA infants [18]. This compensatory mechanism would not be operational in those cases where prenatal growth restraint associates to maternal preeclampsia [32]. ...
Background
Nerve growth factor (NGF) plays a key role in neuroprotection and developmental maturity. We assessed longitudinally the circulating concentrations of NGF in term healthy human newborns and infants as well as their association with prenatal growth and early postnatal feeding patterns.
Methods
Circulating NGF and anthropometric measures (weight, length, body mass index, and ponderal index) were assessed longitudinally—at birth and at age 4 months—in 86 term infants born appropriate (AGA), small (SGA), or large for gestational age (LGA).
Results
Cord blood NGF levels in SGA newborns were higher than those in AGA newborns (1.41 ± 0.2 pg/mL vs. 0.66 ± 0.1 pg/mL; p = 0.02) and not different from those in LGA neonates (0.79 ± 0.2 pg/mL). At age 4 months, SGA-breastfed infants showed the highest NGF concentrations (p = 0.02 and p = 0.01 vs. AGA and SGA-formula-fed infants, respectively), while LGA infants depicted a marginal increase. NGF levels in cord blood correlated negatively with the ponderal index at birth (r = −0.36; p = 0.0008).
Conclusions
Circulating NGF is related to both prenatal growth and early postnatal nutrition. The maintenance of increased NGF concentrations in SGA-breastfed infants at age 4 months might be a potential mechanism to counterbalance potential risks for developing cognitive and psychomotor disadvantages.
... The link between deficient growth in infancy and later life cognitive performance degradation has been widely accepted [1][2][3]. Stunting and faltering during infancy, or early childhood, are associated with reduced cognitive ability in later age performance [4,5], and these growth patterns have been the subject of extensive investigation [6][7][8][9]. In most of the previous work, investigators have studied this association by examining single growth indicators, for example head circumference [10] or body weight [11]. ...
... where Z = (Z 1 , Z 2 ) > is a 2-vector consisting of the first two PC scores obtained from the PCA of ζ = (ζ [1] , ζ [2] , ζ [3] ) and Rð1 À aÞ is the (1 − α)-HDR of Z as in Eq (4). Also, ρ 1 and ρ 2 are the eigenvalues associated with the first two PC scores Z 1 and Z 2 , respectively. ...
... We demonstrate the finite sample performance of the proposed method to identify clusters of extreme subjects. For this purpose random trajectories X = (X [1] , X [2] , X [3] ) were generated such that The FPC score vectors ξ ½j� ¼ ðx ½j� 1 ; x ½j� 2 Þ > were generated with multivariate normal distributions with mean zero, sd(ξ [1] ) = diag(3.0, 2.5), sd(ξ [2] ) = diag(3.0, ...
For longitudinal studies with multivariate observations, we propose statistical methods to identify clusters of archetypal subjects by using techniques from functional data analysis and to relate longitudinal patterns to outcomes. We demonstrate how this approach can be applied to examine associations between multiple time-varying exposures and subsequent health outcomes, where the former are recorded sparsely and irregularly in time, with emphasis on the utility of multiple longitudinal observations in the framework of dimension reduction techniques. In applications to children’s growth data, we investigate archetypes of infant growth patterns and identify subgroups that are related to cognitive development in childhood. Specifically, “Stunting” and “Faltering” time-dynamic patterns of head circumference, body length and weight in the first 12 months are associated with lower levels of long-term cognitive development in comparison to “Generally Large” and “Catch-up” growth. Our findings provide evidence for the statistical association between multivariate growth patterns in infancy and long-term cognitive development.
... We included 34 papers on postnatal weight gain and growth in term infants born SGA (summarised in Tables 1 and 2): most of these (n = 31) described observational studies, with only three papers from the same group describing different outcomes from two intervention studies (20)(21)(22). With regard to study quality, the majority were rated as moderate or high quality. ...
... Only one randomised controlled trial (RCT) (20) promoted early growth in SGA infants using a nutrient-and energyenriched formulawith higher protein, lipids, carbohydrate and micronutrient contentsand reported neurocognitive outcomes. The enriched formula group had a lower developmental quotient than the standard formula group at the age of nine months and no difference in neurocognitive outcomes measured using the Bayley Mental Development and Psychomotor Development indexes at the age of 18 months (Table 1). ...
... This review of postnatal weight gain and growth in relation to neurocognitive and metabolic outcomes in term-born SGA children only found two RCTs that met the eligibility criteria. The same RCT was reported with differing outcomes in three papers (20)(21)(22), and a second RCT was also described by the Singhal et al. paper (22). These trials showed that nutrient-and energy-enriched formulas that promoted early growth increased fat mass and also demonstrated some increases in lean body mass and increased BP. ...
We systematically reviewed papers published in English between 1994 and October 2015 on how postnatal weight gain and growth affect neurodevelopment and metabolic outcomes in term-born small-for-gestational-age (SGA) infants. Two randomised trials reported that enriched infant formulas that promoted early growth also increased fat mass, lean mass and blood pressure (BP), but had no effect on early neurocognitive outcomes. Meanwhile, 31 observational studies reported consistent positive associations between postnatal weight gain and growth with neurocognitive outcomes, adiposity, insulin resistance and BP. : Few intervention studies exist, despite consistent positive associations between early growth and neurocognition in term-born SGA infants.
... We included 34 papers on postnatal weight gain and growth in term infants born SGA (summarised in Tables 1 and 2): most of these (n = 31) described observational studies, with only three papers from the same group describing different outcomes from two intervention studies (20)(21)(22). With regard to study quality, the majority were rated as moderate or high quality. ...
... Only one randomised controlled trial (RCT) (20) promoted early growth in SGA infants using a nutrient-and energyenriched formulawith higher protein, lipids, carbohydrate and micronutrient contentsand reported neurocognitive outcomes. The enriched formula group had a lower developmental quotient than the standard formula group at the age of nine months and no difference in neurocognitive outcomes measured using the Bayley Mental Development and Psychomotor Development indexes at the age of 18 months (Table 1). ...
... This review of postnatal weight gain and growth in relation to neurocognitive and metabolic outcomes in term-born SGA children only found two RCTs that met the eligibility criteria. The same RCT was reported with differing outcomes in three papers (20)(21)(22), and a second RCT was also described by the Singhal et al. paper (22). These trials showed that nutrient-and energy-enriched formulas that promoted early growth increased fat mass and also demonstrated some increases in lean body mass and increased BP. ...
We systematically reviewed papers published in English between 1994 and October 2015 on how postnatal weight gain and growth affect neurodevelopment and metabolic outcomes in term-born small-for-gestational-age (SGA) infants. Two randomised trials reported that enriched infant formulas that promoted early growth also increased fat mass, lean mass and blood pressure (BP), but had no effect on early neurocognitive outcomes. Meanwhile, 31 observational studies reported consistent positive associations between postnatal weight gain and growth with neurocognitive outcomes, adiposity, insulin resistance and BP.
Conclusion:
Few intervention studies exist, despite consistent positive associations between early growth and neurocognition in term-born SGA infants.
... This association is seen in term infants also. 10 Studies have consistently shown that hormonal changes associated with breastfeeding help recovery after childbirth and suppress maternal fertility. The extent of these changes is again dependent on the frequency, intensity and duration of breastfeeding. ...
... In addition to meet their nutrition requirements, infants should receive nutritionally adequate and safe complementary foods while breastfeeding continues for up to 2 years of age or beyond. [8][9][10][11][12][13][14][15][16][17][18][19][20] Early initiation of breastfeeding has been documented to improve neonatal survival, and protective against the infection specific mortality among newborn infants. The integral aspect of early initiation of breastfeeding helps to develop a bond between a mother and her baby; it also helps to establish a successful and sustained lactation by inactivating prolactin hence reducing the quantity of breast milk. ...
Children should not suffer from the lack of adequate knowledge or ignorance from their parents. Breastfeeding colostrum is extremely useful for the immunity and growth of the newborn, as it is having been documented to improve neonatal survival, and protective against the infection specific mortality among newborn and mothers. The secondary data presented in this paper was abstracted from well-known search engines performed in March 2022. Search engines like Pubmed and Google scholar. In Pubmed 8 articles were returned and Google scholar 11 articles/ key words related to breastfeeding and colostrum and first hour of birth in India. Includes 19 studies altogether, all papers were done within 2019 to 2022 and published in English. Study result showed several preventive diseases among the children and their mother. Spreading awareness about natural breastfeeding and the importance of colostrum among mothers is the key to successfully contribute towards reduction of child mortality. May be carried forward for public health intervention of further research to better informed information, education and counselling for pregnant women for sustainable future of our children according to the United Nations sustainable goals, no one should be left behind.
... Sobre a influência do AME no DNPM, contatouse que crianças amamentadas exclusivamente por 6 meses, tem um DNPM melhor, do que as amamentadas por um tempo menor. Nos últimos anos vários estudos demonstraram associação entre AM e o desenvolvimento da infância até a vida adulta 5,19 . Algumas fornecem evidências de que o leite materno é o alimento "padrão ouro" para o desenvolvimento do cérebro 8,18 . ...
... Morley et al. 19 em estudo realizado com crianças que ...
Introduction: Child development is a complex process influenced by several factors, among others is highlighted the practice of breastfeeding. Beyond the biological effects, breastfeeding has effects on the social dimension and the psychological apparatus of the actors directly involved. Objective: To analyse the influence of exclusive breastfeeding and associated factors on the neurodevelopment (ND) of children up to 36 months old. Methods: A cross-sectional, community-based study with individuated data of 99 children up to 36 months old, evaluated socio demographic, obstetric and neonatal variables and assessed ND through the Development Monitoring Instrument. The variables were analysed using descriptive statistics and regression testing. Data were considered significant when p <0.05. Results: Regarding ND, 70.71% of the children had achieved the motor milestones for their age, 98.99% of mothers breastfed, 37.38% of them had exclusive breastfed (EBF) for six months. Factors that positively influenced the ND were vaginal delivery when compared to children with other types of delivery, and EBF for 6 months when compared to children who had EBF less than six months. Conclusions: The practice of exclusive breastfeeding for less than six months is associated with a higher prevalence of lower psychomotor development of children from zero to 36 months old. Other factors associated with delay in development are instrumented vaginal delivery with forceps or caesarean delivery.
... 2001, pertambahan usia bayi menyebabkan penurunan pemberian ASI sebesar 1,3 kali. 1 Berbagai penelitian menunjukkan ASI terbukti bermanfaat pada semua aspek perkembangan kognitif, 2,3,4,5,6 dan berperan penting dalam perkembangan motorik kasar dan halus serta perkembangan personal-sosial. 5 Selain itu, pembentukan bonding (kelekatan ibu terhadap anak), dan attachment (kelekatan anak terhadap ibu), ditemukan berkorelasi erat dengan menyusui. ...
... 2001, pertambahan usia bayi menyebabkan penurunan pemberian ASI sebesar 1,3 kali. 1 Berbagai penelitian menunjukkan ASI terbukti bermanfaat pada semua aspek perkembangan kognitif, 2,3,4,5,6 dan berperan penting dalam perkembangan motorik kasar dan halus serta perkembangan personal-sosial. 5 Selain itu, pembentukan bonding (kelekatan ibu terhadap anak), dan attachment (kelekatan anak terhadap ibu), ditemukan berkorelasi erat dengan menyusui. 7,8 Disisi lain, problem perilaku anak terutama kenakalan semakin mengkhawatirkan. ...
Latar belakang. Penelitian menunjukkan keuntungan pemberian ASI pada perkembangan psiko-sosial anak. Selain itu ditemukan korelasi erat antara menyusui dengan pembentukan bonding dan attachment. Kegagalan pembentukan bonding dan attachment akan berpengaruh besar pada perilaku anak pada fase berikutnya. Salah satu bentuk gangguan perilaku anak yang perlu dicermati adalah kenakalan. Kenakalan pada anak berkecenderungan persisten dan berisiko membentuk perilaku kriminal. Untuk itu diperlukan penelitian lebih lanjut untuk mengetahui adakah hubungan antara kenakalan dengan menyusui.
Tujuan. Mengetahui pengaruh lama pemberian ASI sebagai faktor risiko kenakalan.
Metode. Penelitian ini merupakan studi kasus kontrol dengan stratifikasi sampel satu banding satu. Pengumpulan data menggunakan kuesioner dan lembar penilaian perilaku nakal yang diisi oleh orang tua murid sekolah dasar di Yogyakarta. Lembar penilaian ini diadaptasi dari item perilaku delinquent dan agresif CBCL (child behavior checklist). Kasus adalah anak yang dideteksi delinquent dan atau agresif.
Hasil. Validasi alat ukur menghasilkan validitas konstrak item-item antara 0,5649 - 0,8547, koefisien reliabilitas perilaku agresif 0,8549 dan delinquent 0,6281. Dari 768 responden didapatkan 69 (8,9%) kasus. Anak yang mendapatkan ASI 2 tahun.
Kesimpulan. Pemberian ASI
... The first 2 years of life is a period with significant brain plasticity [42] and may provide opportunity to improve neurodevelopment. Although an earlier trial involving term SGA failed to demonstrate that faster weight gain confers neurodevelopmental benefits [43], more recent evidence suggests there could be some benefits [38]. ...
Background
Birthweight centiles beyond the traditional thresholds for small or large babies are associated with adverse perinatal outcomes but there is a paucity of data about the relationship between birthweight centiles and childhood development among children born from 37 weeks of gestation. This study aims to establish the association between birthweight centiles across the whole distribution and early childhood development among children born from 37 weeks of gestation.
Methods and findings
This is a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation. The cohort was generated by linking pregnancy and delivery data from the Scottish Morbidity Records (2003 to 2015) and the child developmental assessment at age 2 to 3.5 years. The main outcomes were child’s fine motor, gross motor, communication, and social developmental concerns measured with the Ages and Stages Questionnaires—3 (ASQ-3) and Ages and Stages Questionnaire: Social & Emotional—2 (ASQ:SE-2), and for a subset of children with additional specialist tools such as the Modified Checklist for Autism in Toddlers (M-CHAT) if the ASQ3/SE indicate these are necessary. The ASQ score for each domain was categorised as “concern” and “no concern.”
We used multivariate cubic regression splines to model the associations between birthweight centiles and early childhood developmental concerns. We used multivariate Poisson regression models, with cluster robust errors, to estimate the relative risks (RRs) of developmental concerns below and above the established thresholds. We adjusted for maternal age, early pregnancy body mass index (BMI), parity, year of delivery, gestational age at delivery, smoking history, substance misuse in pregnancy, alcohol intake, ethnicity, residential area deprivation index, maternal clinical conditions in pregnancy (such as diabetes and pre-eclampsia), induction of labour, and child’s sex.
Babies born from 37 weeks of gestation with birthweight below the 25th centile, compared to those between the 25th and 74th centile, were at higher risk of developmental concerns. Those born between the 10th and 24th centile had an RR of 1.07 (95% CI: 1.03 to 1.12, p < 0.001), between the 3rd and 9th centile had an RR: 1.18 (95% CI: 1.12 to 1.25, p < 0.001), and <3rd centile had an RR of 1.37 (95% CI: 1.24 to 1.50, p < 0.001). There was no substantial increase in the risk of early childhood developmental concerns for larger birthweight categories of 75th to 89th (RR: 1.01; 95% CI: 0.97 to 1.05; p = 0.56), 90th to 96th (RR: 0.99; 95% CI: 0.94 to 1.05; p = 0.86), and ≥97th centiles (RR: 1.04; 95% CI: 0.97 to 1.12; p = 0.27), referent to birthweight between 25th and 74th centile.
The percentage of developmental concerns attributable to birthweight between the 10th and 24th centile was more than that of birthweight <3rd centile (p = 0.023) because this group includes more of the population. Approximately 2.50% (95% CI: 1.26 to 3.61) of social skills concerns and 3.00% (95% CI: 1.33 to 4.67) of fine motor developmental concerns were attributable to birthweight between the 10th and 24th centile compared to 0.90% (95% CI: 0.48 to 1.26) and 2.30% (95% CI: 1.73 to 2.67) respectively for birthweight <3rd centile. We acknowledge the limitation of ASQ as a screening tool, the subjective nature of developmental assessments (particularly for speech) among young children, and inability to control for early childhood illness and upbringing factors may have an impact on our findings.
Conclusions
We observed that from 37 weeks of gestation birthweight below the 25th centile was associated with child developmental concerns, with an association apparent at higher centiles above the conventional threshold defining small for gestational age (SGA, 3rd or 10th centile). Mild to moderate SGA is an unrecognised potentially important contributor to the prevalence of developmental concerns. Closer surveillance, appropriate parental counselling, and increased support during childhood may reduce the risks associated with lower birthweight centiles.
... Term formula can be offered to infants born from 35 weeks' gestational age, although growth should be monitored carefully as it may be nutritionally inadequate for some late preterm infants. However, there is some evidence that post-discharge formulas are not of benefit to term or near term infants that are small for gestational age (Morley et al, 2004;Singhal et al, 2007). ...
This article discusses the nutritional needs of moderate and late preterm infants (born between 32+0weeks and 36+6weeks' gestation) and makes recommendations for best practice both while these infants are in hospital and when they are discharged into the community. These recommendations were derived following a roundtable meeting of a group comprising two neonatologists, three paediatric dietitians, a health visitor/paediatric nurse and a midwife practitioner. The meeting and medical writing assistance was sponsored by Nutricia. None of the participants accepted honoraria for their contributions to the discussion.
... standard formula) during the first 9 months after birth failed to demonstrate neurodevelopmental benefits from induced faster weight gain at age 24 months. 6 Furthermore, multiple studies showing that rapid early weight gain increases later cardio-metabolic risks 7-10 underline the paradox of promoting excessive postnatal growth. 11 Reports of this dilemma call for better characterisation of the benefits of growth on neurodevelopment. ...
Background
Despite the limited evidence, accelerated early postnatal growth (EPG) is commonly believed to benefit neurodevelopment for term-born infants, especially those small for gestational age.
Objectives
To investigate the existence of critical time windows in the association of EPG with neurodevelopment, considering birth size groups.
Study design
In the French ELFE birth cohort, 12,854 term-born neonates were classified as small, appropriate or large for gestational age (SGA, AGA, LGA, respectively). Parents reported their child's development by using the Child Development Inventory (CDI-score) at age 12 months and the MacArthur-Bates Development Inventory (MAB-score; 100 score units) assessing language ability at age 24 months. Predictions of individual weight, body mass index (BMI), length, and head circumference (HC) from birth to age 24 months were obtained from repeated measurements fitted with the Jenss-Bayley mixed-effects model. For each infant, conditional gains (CG) in these growth parameters were generated at four-time points (3, 6, 12 and 24 months) representing specific variations in growth parameters during 0–3, 3–6, 6–12, 12–24 months, independent of previous measures. Using multivariable linear regression models, we provided the estimate differences of the neurodevelopmental scores according to variation of each growth parameter CG, by birth size group.
Results
For SGA infants, the MAB-score differed by 5.8 (95% confidence interval [CI] −0.2, 11.8), 6.7 (95% CI −0.1, 13.3), and 9.7 (95% CI 1.9, 17.5) score units when CG in BMI, weight, and HC at 3 months varied from −2 to 1 standard deviation, respectively. For all infants, MAB-score was linearly and positively associated with length conditional gains at 12 months, with stronger magnitude for SGA infants. Results for the CDI-score were overall consistent with those for MAB-score.
Conclusions
For term-born SGA infants, moderate catch-up in HC, BMI and weight within the first 3 months of life may benefit later neurodevelopment, which could guide clinicians to monitor EPG.
... Although the effect of prenatal development of vital organs such as lungs, kidneys, and the brain on the development of preoperative and postoperative complications has not been clarified yet, low gestational week and low birth weight are shown as risk factors in previous studies (10)(11)(12)(13)(14) . ...
Objectives: The Norwood operation performed for hypoplastic left heart syndrome (HLHS) in the neonatal period remains to be a high-risk and difficult surgical procedure. It is known that preterm birth often accompanied by low birth weight is associated with high mortality and morbidity in these patients.
Patients and Methods: The study included 54 patients who underwent the Norwood procedure in our clinic in the period between December 2012 and December 2019. Patient data were evaluated retrospectively; including gestational week, age, body weight, total bypass time, aortic cross-clamp time, extubation time, the length of stay in the intensive care unit, the length of hospital stay, and the preoperative and postoperative levels of urea, creatinine, ALT, AST, and platelet counts.
Results: The body weight of the patients ranged from 2350 to 4500 grams with an average of 3296.3±486.7 grams. The age of the patients at the time of operation ranged from 1 to 374 days with an average of 30.31±70.51 days. The comparison of patients by term pregnancies resulted in no statistically significant differences but the comparison by gestational weeks revealed a statistically significant result.
Conclusion: Preoperative risk factors affect prognosis more than the surgical technique and the treatment approach in patients with a functional single ventricle. When the gestational week was evaluated as a preoperative risk factor for its effects on the postoperative prognosis of stage 1 Norwood operation in our study, it was found that mortality decreased significantly after the 38.8th gestational week (272 gestational days).
... In all studies except for Lucas et al. (2001) and Morley et al. (2004) attrition of participants (as measured at the latest available cognitive outcome), was high ( "Because the number of enrolled infants was not stratified according to hospital, inter-hospital variations might have confounded the outcome". Furthermore, substantial between-group differences in baseline variables existed, and there were several possible outcome scales ("raw score" and "index score") without indication which one was the prespecified primary outcome scale. ...
Background Due to high attrition in randomised controlled trials (RCTs), cognitive effects of infant formula modifications remain uncertain. The aim of this thesis was to test a new method to minimise attrition and, through doing so, to compare differences in academic performance between children previously randomised to either nutritionally modified or standard infant formula. Methods Nine dormant infant formula RCTs conducted in England (1982-2001) were available for linkage to the National Pupil Database. Linkage was based on legal exemption from the need for participant consent. A trusted third party provided de-identified data for up to four candidate pupil matches per participant and agreement-metrics for all shared linkage variables. I completed the linkage of de-identified data, using auxiliary RCT variables and probabilistic methods. Six RCTs (n=1,563) were eligible for analysis, and a further three RCTs were used to assess linkage success and improve multiple imputation of missing data. Participant academic performance was measured using exam grades, with the primary outcome being General Certificate of Secondary Education (GCSE) Maths grades at age 16 years. Modified formula and standard formula groups were compared on an intention-to-treat basis, stratified by trial. Results Within the six trials eligible for analysis, primary outcome data was available for 86% of all participants. Available outcome data was substantially higher than the average of 22% above age 2 years in previous consent-based cognitive follow-ups of the trials. There was no evidence of benefit for GCSE Maths performance for any type of modified formula. Secondary academic outcomes provided weak evidence of harm for one of the formula modifications. Conclusions Unconsented linkage of dormant trials to administrative education data is feasible and leads to higher follow-up rates compared to traditional consented follow-up methods. None of the investigated nutritionally modified formula interventions improved academic performance.
... P = 2.703E-8, followed by post hoc Tukey's test analysis, *P < 0.05, **P < 0.01, ***P < 0.001. IUGR: intrauterine growth restriction; NSC: neural stem cell; GFAP: glial fibrillary acidic protein; DAPI: 4′,6diamidino-2-phenylindole IUGR not only reduces the number of NSCs that differentiate into neurons but also increases the number of glial cells, seriously affecting fetal central nervous development and inducing long-term neurodevelopmental problems (Morley et al. 2004;Rees et al. 2008;Marconi et al. 2009). Therefore, it is of great importance to take adequate measures to protect NSC differentiation in the prenatal period to reduce brain injury in IUGR fetuses. ...
Intrauterine growth restriction (IUGR) affects brain neural stem cell (NSC) differentiation. In the present study, we investigated whether taurine supplementation may improve NSC differentiation in IUGR fetal rats via the protein kinase A-cyclic adenosine monophosphate (cAMP) response element protein-brain derived neurotrophic factor (PKA-CREB-BDNF) signaling pathway. The IUGR fetal rat model was established with a low-protein diet. Fresh subventricular zone (SVZ) tissue from the fetuses on the 14th day of pregnancy was microdissected and dissociated into single-cell suspensions, then was cultured to form neurospheres. The neurospheres were divided into the control group, the IUGR group, the IUGR+taurine (taurine) group, the IUGR+H89 (H89) group and the IUGR+taurine+H89 (taurine+H89) group. The mRNA and protein expression levels of PKA, CREB and BDNF were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting (WB). Tuj-1-positive neurons and GFAP-positive glial cells were detected by immunofluorescence. The total number of proliferating NSCs and the percentage of Tuj-1-positive neurons in the IUGR group were lower than those in the control group, but the percentage of GFAP-positive cells was higher in the IUGR group than in the control group. Taurine supplementation increased the total number of neural cells and the percentage of Tuj-1-positive neurons, and reduced the percentage of GFAP-positive cells among differentiated NSCs after IUGR. H89 reduced the total number and percentage of Tuj-1-positive neurons and increased the percentage of GFAP-positive cells. The mRNA and protein levels of PKA, CREB, and BDNF were lower in the IUGR group. The mRNA and protein expression levels of these factors were increased by taurine supplementation but reduced by the addition of H89. Taurine supplementation increased the ratio of neurons to glial cells and prevented gliosis in the differentiation of NSCs in IUGR fetal rats by activating the PKA-CREB-BDNF signaling pathway.
... A study by Bier et al. found that the cognitive and motor scores of premature babies who were breastfed were higher than those of babies fed with formula [89]. In addition, Morley et al. found that at 18 months, breastfed babies had better mental and psychomotor development than babies who received formula [90]. The breastfeeding process is one of intimate contact between mother and child. ...
Introduction
Child emotional or behavioral problems and insufficient social development has been a heavy burden on family and society. However, currently large-scale studies on emotional and behavioral problems as well as social competence among school children in China are still lacking. This cross-sectional study analyzed the current status and risk factors of behavioral problems and social competences in Beijing students.
Method
A total of 9,295 students, with ages ranging from 6 to 16 years old, were enrolled in the study. The Child Behavior Checklist (CBCL) was used to screen emotional and behavioral problems, social competences of students. We then assessed significant predictors factors associated with children behavioral problems and social competences.
Results
The total detection rate of behavioral problems of this cohort was 16.7%. All kinds of social competence scores of boys were lower than girls (P <0.05). The scores of social and learning ability in children with behavioral problems were significantly lower than those without behavior problems (P <0.05). Gender, developmental delay, recent life events, negative relationships and negative child-rearing styles were the shared influencing factors for behavioral problems and social competence. In addition, age, macrosomia, threatened abortion, hospitalization for physical illness, physical illness, poor sleep were independent risk factors for children's emotional and behavioral problems, and non-breastfeeding was an independent risk factor for abnormal social competence.
Conclusion
The social competence, emotional and behavioral problems are serious among students in Beijing. More attention should be paid to mental health and effective intervention measures should be provided.
... Currently, neonatologists recommend nutrient-enriched formula for preterm as well as SGA babies. However, nutrient-enriched formula has been shown to improve head growth, but not neurodevelopment in SGA infants (8), and increases the risk of rapid weight gain and eventually obesity. There is much ongoing discussion related to the issue of undernutrition vs. overnutrition. ...
Children born small for gestational age (SGA) face an increased risk of health problems in later life, particularly persistent short stature, neurocognitive dysfunction, impaired renal and pulmonary function, decreased bone density, sensorineural hearing loss, premature adrenarche, and metabolic syndrome. Insulin resistance appears to be a key component underlying these metabolic complications. Long-term, continuous, GH treatments in short children born SGA lead to a normalization of height through childhood to adulthood. Recombinant human GH has been proven to be relatively safe. We recommend early surveillance in a growth clinic for children born SGA without catch-up growth. Obesity, insulin resistance, and the risk of metabolic syndrome increase with catch-up growth, but short stature and cognitive dysfunction increase without catch-up growth in children born SGA. A solution to this catch-up dilemma is breast feeding for a minimum of 6 to 12 mo. Because the overall prevalence of metabolic risk factors is very low, routine evaluation of metabolic parameters is not recommended for all children born SGA, but it may be useful to consider metabolic evaluations in overweight or obese children born SGA. Since children born SGA have many risk factors, long-term management from neonate to adulthood is very important.
... RCT [58]; BFR [85] VEP (16, 34 wk) Negative 4, 78, 181 Morley et al, 2004 (161) BF [175] versus FF [147] 12 A (18 mo); U (9 mo) Positive, adjusted (A) Mortensen et al, 2002 (171) BF duration, 1 to 9 mo [3253] BF duration, 0 to 6 mo [2393] 16 G (6 y) [1450]; H (8 y) [1375] Positive, adjusted (G) Quinn et al, 2001 (173) BF duration, 0 to 6 mo [3880] G (5 y) Positive, adjusted Rao et al, 2002 (177) BF duration, SGA [220]; AGA [299] A (13 mo); B (5 y) Positive, adjusted (B) Ribas-Fito et al, 2003 (174) BF duration, 2 wk to 16 wk [92] A, I (13 mo) Positive, adjusted 17 ...
This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely to result in altered brain concentrations of the n−3 fatty acid docosahexaenoic acid (DHA) during the perinatal period of “brain growth spurt.” Experimental designs reviewed include observational breastfeeding studies and randomized controlled trials in humans and studies in rodents and nonhuman primates. This review is based on a large number of expert reviews and commentaries and on some 50 recent studies in humans and animals that have not yet been included in published reviews. Expert opinion regarding the strengths and weaknesses of the major experimental systems and uncertainties associated with interpreting results is summarized. On the basis of our reading of this literature, we conclude that evidence from several types of studies, particularly studies in animals, suggests that, within the context of specific experimental designs, changes in brain concentrations of DHA are positively associated with changes in cognitive or behavioral performance. Additional experimental information required to conclude that a causal association exists is discussed, as are uncertainties associated with applying results from specific experimental designs to the question of whether infant formula should be supplemented with DHA.
... Long-term interventional studies in pregnancies at high risk of low-BW delivery as well as on postnatal growth of low-BW newborns are needed to determine which strategy would be the most feasible in practice [36]. Current nutritional strategies that promote CUG should include the monitoring of weightfor-length and adiposity, and future research should seek to define "healthy CUG" [37,38]. We based our study upon a previously described mouse model of IUGR and CUG [39]. ...
Background
Intrauterine growth restriction (IUGR) and rapid postnatal weight gain or catch up growth (CUG) increase the susceptibility to metabolic syndrome during adult life. Longitudinal studies have also revealed a high incidence of learning difficulties in children with IUGR. The aim of the present study was to investigate the effect of nutrition and CUG on learning memory in an IUGR animal model. We hypothesized that synaptic protein expression and transcription, an essential mechanism for memory consolidation, might be affected by intrauterine undernutrition.
Methods
IUGR was induced by 50% maternal caloric undernutrition throughout late gestation. During the suckling period, dams were either fed ad libitum or food restricted. The pups were divided into: Normal prenatal diet-Normal postnatal diet (NN), Restricted prenatal diet- Normal postnatal diet + catch up growth (RN+), Normal prenatal diet-Restricted postnatal diet (NR) and Restricted prenatal diet-Restricted postnatal diet (RR). At 4 weeks of age, memory was assessed via a water maze test. To evaluate synaptic function, 2 specific synaptic proteins (postsynaptic density-95 [PSD95], synaptophysin) as well as insulin receptors (IR) were tested by Western Blot and quantitative polymerase chain reaction (qPCR). Brain-derived neurotrophic factor and serum insulin levels were also studied.
Results and conclusions
The RN+ group presented a learning curve similar to the NN animals. The RR animals without CUG showed learning disabilities. PSD95 was lower in the RR group than in the NN and RN+ mice. In contrast, synaptophysin was similar in all groups. IR showed an inverse expression pattern to that of the PSD95. In conclusion, perinatal nutrition plays an important role in learning. CUG after a period of prenatal malnutrition seems to improve learning skills. The functional alterations observed might be related to lower PSD95 activity and a possible dysfunction in the hormone regulation of synaptic plasticity.
... 8,[67][68][69] This differential pattern of nutritional effects on boys and girls was also reported in preterm infants who were given preterm formula after discharge from hospital 70,71 as well as in infants born at term but small for gestational age who were given enriched formula for the first 6 months. 62,72 Future clinical trials of nutritional interventions need to be adequately powered to assess nutritional effects on boys and girls separately, detect sex-related interactions, and determine long-term metabolic and cardiovascular outcomes, body compo sition, and neurodevelopment. ...
Nutrition of newborn infants, particularly of those born preterm, has advanced substantially in recent years. Extremely preterm infants have high nutrient demands that are challenging to meet, such that growth faltering is common. Inadequate growth is associated with poor neurodevelopmental outcomes, and although improved early growth is associated with better cognitive outcomes, there might be a trade-off in terms of worse metabolic outcomes, although the contribution of early nutrition to these associations is not established. New developments include recommendations to increase protein supply, improve formulations of parenteral lipids, and provide mineral supplements while encouraging human milk feeding. However, high quality evidence of the risks and benefits of these developments is lacking. Clinical trials are also needed to assess the effect on preterm infants of experiencing the smell and taste of milk, to determine whether boys and girls should be fed differently, and to test effects of insulin and IGF-1 supplements on growth and developmental outcomes. Moderate-to-late preterm infants have neonatal nutritional challenges that are similar to those infants born at earlier gestations, but even less high quality evidence exists upon which to base clinical decisions. The focus of research in nutrition of infants born at term is largely directed at new formula products that will improve cognitive and metabolic outcomes. Providing the most effective nutrition to preterm infants should be prioritised as an important focus of neonatal care research to improve long-term metabolic and developmental outcomes.
... Fortifying human milk with energy, protein, mineral, vitamins AEDC and iron is essential in order to improve the infant's growth and its neurological development. It helps also to prevent infants from hyponatremia, hypophosphoremia, anemia and osteomalacia [4,5]. By addition of vitamin D in particular is crucial to the infant development. ...
... 24 They often consider preterm and growth-restricted neonates in the single category of low BW infants, although these pathological conditions are different. 25 A standard, albeit controversial, 26,27 goal for these babies has been weight catch-up by 1 year of age to improve neurological development. Instantaneous weight growth velocities provide a new way to study the catch-up phenomenon. ...
Physiological evidence suggests that birth weight (BW) and postnatal growth affect blood pressure (BP) level, independently or in interaction. Their respective roles are difficult to disentangle in epidemiological studies, however, especially when adjusting for final weight. We assessed the portion of the effect of BW on BP at 5 years that was not attributable to postnatal growth and investigated potential interactions between BW and postnatal growth velocity at different time points in the EDEN mother-child study. Collecting a median of 19 weight measurements for each of the 1119 children who completed follow-up enabled us to model instantaneous growth velocity at any age. After computing a BP SD-score at 5 years, adjusted for age, sex, current body mass index, and height, we used multiple linear regression to study its association with age- and sex-specific BW z score, adjusting for several maternal and pregnancy risk factors. We tested interactions between BW categories (small-, appropriate-, and large-for-gestational-age) and weight growth velocities at different ages. The BW z score was negatively and significantly correlated with the systolic BP SD-score at the age of 5 years (r=-0.07, P=0.02). Interactions were found between BW categories and weight growth velocities from 1 to 4 months (P from 0.002 to 0.08) but not at older ages; specifically, children born small for gestational age with a fast weight growth velocity in their first few months of life had the highest absolute systolic BP and SD score values at 5 years. They may need monitoring for cardiovascular risks.
... However, there are fewer studies investigating alterations of diet in term babies. One study of term babies born small for gestational age found neurodevelopmental outcomes were worse in girls in the supplemented group at 9 mo of age, despite a positive effect on growth, although developmental differences between groups did not appear to persist at later follow up (30). The mechanisms underlying these dimorphic responses remain unclear. ...
Background:
The nutritional plane and composition during fetal life can impact upon growth and epigenetic regulation of genes affecting pancreatic β-cell development and function. However, it is not clear whether β-cell development can be altered by nutritional factors or growth rate after birth. We therefore investigated the effect of neonatal nutritional supplements on growth, glucose tolerance and pancreatic development in lambs.
Methods:
Newborn lambs were randomised to daily nutritional supplements, calculated to increase macronutrient intake to a similar degree as human breast milk fortifier, or an equivalent volume of water, for two weeks while continuing to suckle ewe milk. Intravenous glucose tolerance test (IVGTT) was performed at 4 months of age, and pancreata collected for molecular analysis.
Results:
Supplemented lambs had slower weight gain than Controls. In supplemented lambs, insulin response to IVGTT was increased in males but decreased in females, compared to same sex controls, and was unrelated to growth rate. mRNA expression of key genes in β-cell development showed sexually dimorphic effects. Epigenetic change occurred in the promotor region of PDX1 gene with decreased suppression and increased activation marks in supplemented lambs of both sexes.
Conclusion:
Nutritional interventions in early life have long-term, sex-specific effects on pancreatic function.Pediatric Research (2016); doi:10.1038/pr.2016.168.
... 8,[67][68][69] This differential pattern of nutritional effects on boys and girls was also reported in preterm infants who were given preterm formula after discharge from hospital 70,71 as well as in infants born at term but small for gestational age who were given enriched formula for the first 6 months. 62,72 Future clinical trials of nutritional interventions need to be adequately powered to assess nutritional effects on boys and girls separately, detect sex-related interactions, and determine long-term metabolic and cardiovascular outcomes, body compo sition, and neurodevelopment. ...
Fetal nutrients are derived largely from the mother, and fetal nutrition is thus closely related to maternal nutrition. However, it is important to appreciate that maternal nutrition is not the same as fetal nutrition. Firstly, the mother has her own nutrient demands which may be in conflict with those of the fetus. For example, pregnant adolescent sheep deliver smaller fetuses, especially when the ewes are very well nourished and therefore growing well, and the growth restriction appears to be predominantly secondary to reduced placental growth.1-3 Human adolescents also tend to give birth to lighter infants, and birth weight has been reported to be less in offspring of adolescents with a higher dietary sugar intake.4, 5 Secondly, the fetus lies at the end of a long supply line which can be impaired at many points. Nutrients are used by the fetus predominantly for growth and metabolism, with little energy expenditure on other processes such as thermoregulation, movement and digestion. Fetal nutrients are in fact the main drivers of fetal growth, with genetic factors playing a much smaller role. Indeed, the genetic regulation of fetal growth itself appears to be under nutritional regulation, with levels of all the major hormones involved in fetal growth being regulated by circulating nutrient levels. The placenta is also a very metabolically active organ with its own nutrient demands and metabolic pathways. The demands of the fetus and placenta must be in close harmony, particularly in situations where the nutrient supply is precarious, as if the placenta is starved of nutrients and fails the fetus will also not survive. Therefore, in extreme cases the placenta may even consume substrates provided by the fetus. This chapter will attempt to describe the physiology of fetal nutrient supply as we currently understand it, and to relate some aspects of fetal nutrition to clinical data.
Motor development is the progress in the coordination capacity of the musculoskeletal system and is a major indicator of postnatal healthy child growth. Optimal neurodevelopment that includes cognitive and motor components is the keystone for healthy child growth and reflects central and peripheral nervous system maturation and it is known that neurodevelopmental rate is fastest in the first two years of life. This chapter will focus on effects of postnatal nutritional content and the type of feeding process on neurodevelopment of preterm and term infants.KeywordsBreastfeedingMotor development in infantsMotor development in preterm infantsBreast MilkNewborn
Evidence supports that growth trajectory during infancy has a major impact on body composition. We aimed to examine body composition in children born small for gestational age (SGA) or appropriate for gestational age (AGA) adjusted for postnatal growth velocity. We enrolled 365 children, 75 SGA and 290 AGA, aged 7 to 10 years, examining anthropometrics, skinfold thickness, and body composition using bioelectrical impedance analysis. Growth velocity was defined as rapid or slow (weight gain > or <0.67 z-scores, respectively). Gestational age, sex, delivery mode, gestational diabetes, hypertension, nutrition, exercise, parental body mass index (BMI), and socioeconomic status were considered. At a mean of 9 years of age, SGA compared with AGA-born children, had significantly lower lean mass. BMI was negatively associated with SGA status (beta = 0.80, P = .046), after adjusting for birth weight, delivery mode, and breastfeeding. The lean mass index was negatively associated with SGA status (beta = 0.39, P = .018), after adjusting for the same factors. SGA-born participants with slow growth velocity had significantly lower lean mass in comparison to AGA-born counterparts. SGA-born children with rapid compared with those with slow growth velocity had significantly higher absolute fat mass. BMI was negatively associated with a slow postnatal growth pattern (beta = 0.59, P = .023), and the lean mass index was negatively associated with a slow postnatal growth pattern (beta = 0.78, P = .006), after adjusting for the same factors. In conclusion, SGA-born children presented a lower lean mass in comparison to AGA-born counterparts, whereas BMI and lean mass index were negatively associated with slow postnatal growth velocity.
Background
Studies have shown that prenatal heat exposure may impact fetal growth, but few studies have examined the critical windows of susceptibility. As extreme heat events and within season temperature variability is expected to increase in frequency, it is important to understand how this may impact gestational growth.
Objectives
We investigated associations between various measures of weekly prenatal heat exposure (mean and standard deviation (SD) of temperature and heat index (HI), derived using temperature in °C and dew point) and term birthweight or odds of being born small for gestational age (SGA) to identify critical windows of susceptibility.
Methods
We analyzed data from mother-child dyads (n = 4442) in the Boston-based Children's HealthWatch cohort. Birthweights were collected from survey data and electronic health records. Daily temperature and HI values were obtained from 800 m gridded spatial climate datasets aggregated by the PRISM Climate Group. Distributed lag-nonlinear models were used to assess the effect of the four weekly heat metrics on measures of gestational growth (birthweight, SGA, and birthweight z-scores). Analyses were stratified by child sex and maternal homelessness status during pregnancy.
Results
HI variability was significantly associated with decreased term birthweight during gestational weeks 10–29 and with SGA for weeks 9–26. Cumulative effects for these time periods were −287.4 g (95% CI: −474.1 g, −100.8 g for birthweight and 4.7 (95% CI: 1.6, 14.1) for SGA. Temperature variability was also significantly associated with decreased birthweight between weeks 15 and 26. The effects for mean heat measures on term birthweight and SGA were not significant for any gestational week. Stratification by sex revealed a significant effect on term birthweight in females between weeks 23–28 and in males between weeks 9–26. Strongest effects of HI variability on term birthweight were found in children of mothers who experienced homelessness during pregnancy. Weekly HI variability was the heat metric most strongly associated with measures of gestational growth. The effects observed were largest in males and those who experienced homelessness during pregnancy.
Discussion
Given the impact of heat variability on birthweight and risk of SGA, it is important for future heat warnings to incorporate measure of heat index and temperature variability.
OBJECTIVES
We assessed the effect of feeding preterm or low birth weight infants with infant formula compared with mother’s own milk on mortality, morbidity, growth, neurodevelopment, and disability.
METHODS
We searched Medline (Ovid), Embase (Ovid), and Cochrane Central Register of Controlled Studies to October 1, 2021.
RESULTS
Forty-two studies enrolling 89 638 infants fulfilled the inclusion criteria. We did not find evidence of an effect on mortality (odds ratio [OR] 1.26, 95% confidence interval [CI] 0.91–1.76), infection (OR 1.52, 95% CI 0.98–2.37), cognitive neurodevelopment (standardized mean difference −1.30, 95% CI −3.53 to 0.93), or on growth parameters. Formula milk feeding increased the risk of necrotizing enterocolitis (OR 2.99, 95% CI 1.75–5.11). The Grading of Recommendations Assessment, Development, and Evaluation certainty of evidence was low for mortality and necrotizing enterocolitis, and very low for neurodevelopment and growth outcomes.
CONCLUSIONS
In preterm and low birth weight infants, low to very low-certainty evidence indicates that feeding with infant formula compared with mother’s own milk has little effect on all-cause mortality, infection, growth, or neurodevelopment, and a higher risk of developing necrotizing enterocolitis.
Objective
To compare differences in academic performance between adolescents who were randomised in infancy to modified or standard infant formula.
Design
Linkage of seven dormant randomised controlled trials to national education data.
Setting
Five hospitals in England, 11 August 1993 to 29 October 2001, and schools in England, September 2002 to August 2016.
Participants
1763 adolescents (425 born preterm, 299 born at term and small for gestational age, 1039 born at term) who took part in one of seven randomised controlled trials of infant formula in infancy.
Interventions
Nutrient enriched versus standard term formula (two trials), long chain polyunsaturated fatty acid (LCPUFA) supplemented versus unsupplemented formula (two trials), high versus low iron follow-on formula (one trial), high versus low sn-2 palmitate formula (one trial), and nucleotide supplemented versus unsupplemented formula (one trial).
Main outcome measures
The primary outcome, determined by linkage of trial data to school data, was the mean difference in standard deviation scores for mandated examinations in mathematics at age 16 years. Secondary outcomes included differences in standard deviation scores in English (16 and 11 years) and mathematics (11 years). Analysis was by intention to treat with multiple imputation for participants missing the primary outcome.
Results
1607 (91.2%) participants were linked to school records. No benefit was found for performance in mathematics examinations at age 16 years for any modified formula: nutrient enriched in preterm infants after discharge from hospital, standard deviation score 0.02 (95% confidence interval −0.22 to 0.27), and nutrient enriched in small for gestational age term infants −0.11 (−0.33 to 0.12); LCPUFA supplemented in preterm infants −0.19 (−0.46 to 0.08) and in term infants −0.14 (−0.36 to 0.08); iron follow-on formula in term infants −0.12 (−0.31 to 0.07); and sn-2 palmitate supplemented formula in term infants −0.09 (−0.37 to 0.19). Participants from the nucleotide trial were too young to have sat their General Certificate of Secondary Education (GCSE) examinations at the time of linkage to school data. Secondary outcomes did not differ for nutrient enriched, high iron, sn-2 palmitate, or nucleotide supplemented formulas, but at 11 years, preterm and term participants randomised to LCPUFA supplemented formula scored lower in English and mathematics.
Conclusions
Evidence from these randomised controlled trials indicated that the infant formula modifications did not promote long term cognitive benefit compared with standard infant formulas.
Men and women are significantly different in their body system, and this difference has been studied in various fields of medicine. Medical research has identified a substantial group of gender-specific adult diseases, but biological differences between sexes are evident even from the beginning of pregnancy. The evaluation of gender specifi-cities has been also extended to newborns, infants, children and adolescents. Gender-specific medicine deals with the differences between men and women both in health and diseases. Male and female fetuses react differently to the same intrau-terine environment, suggesting biological variation at cel-lular and molecular level. Male sex is a risk factor for adverse pregnancy outcomes. There are significant sex-related differences in relation to different outcomes in preterm newborns and in the neonatal age, as well as in the incidence of congenital malformations, response to drugs during infancy, neurological and respiratory diseases. The functional and structural development of the lungs occurs earlier in fema-les, especially in preterm newborns. In this narrative review, we describe how the sex of the fetus and the newborn can affect morbidity and mortality, both during pregnancy and after birth. Gender-related medicine can be applied to the neonatal age to evaluate disease-re-lated sex differences. This could possibly allow for the appli-cation of preventive strategies and/or specific treatments, with a great impact on public health. © 2021, Il Pensiero Scientifico Editore s.r.l.. All rights reserved.
Despite the introduction of early parenteral nutrition coupled with early enteral feeding, that improved growth in preterm infants, in most cases growth may not be optimal and many infants continue to be small for gestational age at hospital discharge. The increased risk for poor growth and nutritional challenges do not end after hospital discharge of preterm infants. The main objective of preterm infants’ nutrition is to reach the body composition and rate of growth of a normal fetus/infant of the same gestational age and to correct the nutritional deficit. The nutritional needs of preterm infants are higher than those of term infants, but the exact nutritional requirements are not yet fully known. Most nutritional guidelines provide recommendations for low and very low birth weight preterm newborn for early postnatal period. In clinical use there are two major strategies: multinutrient fortification of human breast milk and nutrient-enriched formulas. Several postdischarge nutritional strategies have been used, and recommendations and practices vary widely by country, by region and by neonatal unit. The optimal postdischarge enteral nutrition strategy able to provide the high requirements of rapidly growing preterm infants and to reduce the risk of potential adverse effects in adulthood is still on debate.
The study aimed to test whether or not milk fatty acid composition in mothers of small for gestational age (SGA) infants is similar to that in mothers of adequate for gestational age (AGA) infants. Thirty three mothers of SGA preterm infants and 66 mothers of AGA preterm infants were included. Milk and plasma fatty acids were analyzed using capillary gas chromatography. Milk DHA (0.68 ± 0.37 vs. 0.44 ± 0.24; p < 0.01) was higher and n-6:n-3 PUFA ratio (12.0 ± 4.64 vs. 16.0 ± 6.32; p < 0.05) was lower in mothers of SGA infants. Plasma ARA and DHA were increased in mothers of SGA infants and decreased in their infants. Milk ARA or DHA was positively related to the correspondent fatty acid in plasma (r = 0.374, p = 0.010 for ARA and r = 0.690, p < 0.001 for DHA). Breast milk in mothers of preterm infants born SGA is enriched in DHA and n-3 PUFA. Breastfeeding SGA preterm infant with own mother's milk is recommended.
Background
Clinicians’ interest in the long‐term effects of early postnatal growth (EPG) is growing. There is compelling evidence linking rapid EPG with later cardiovascular risk, but its neurodevelopmental benefits still remain hypothetical in individuals born moderately preterm (MP) or small for gestational at term (SGAT).
Methods
The objective was to perform a systematic review of the relationship between EPG before age 3 years and neurodevelopmental outcome for individuals born MP (32‐36 weeks’ gestational age) or SGAT. Following Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines, 3 independent investigators searched for articles published on this topic in the Web of Science, EMBASE and PubMed from database inception to July 1, 2017. A detailed quality scale was used to evaluate articles.
Results
We selected 19 articles relying on 12 distinct study populations; 7 articles from 3 study populations were considered at moderate or high quality. The lack of standardisation of growth analysis methods prevented performing a meta‐analysis. Overall, EPG was positively associated with neurodevelopmental outcome, especially Intelligence Quotient (IQ) when available. In this relationship, the first 6 months of life might be a critical period. Analysis of the few articles investigating the shape of the relationships revealed a non‐linear association, with a plateau for IQ with higher weight gain, which suggests a possible ceiling effect.
Conclusions
A positive association was generally found between EPG and neurodevelopmental outcome for individuals born MP or SGAT. Strategies for future epidemiological studies are suggested to improve the characterisation of this relationship.
Le retard de croissance intra-utérin (RCIU) est une anomalie dynamique de la croissance du foetus, avec deux facettes : le RCIU symétrique et le RCIU asymétrique. Nés proches du terme, ces enfants ne posent que peu de problèmes médicaux, mais leur devenir à moyen terme est peu connu. Nous avons mené une étude dont l'objectif principal a été d'évaluer la croissance à 9 mois d'enfants nés avec un RCIU en fonction de sa caractéristique symétrique ou asymétrique et de son étiologie. L'objectif secondaire de notre travail a été d'évaluer leur développement psychomoteur à 9 mois selon les mêmes modalités. Cette étude rétrospective, réalisée à la Maternité Régionale Universitaire de Nancy comportait 205 enfants, nés entre le 01/01/2009 et le 31/12/2010, après 32 semaines d'aménorrhée gravidiques, avec un RCIU inférieur au 5ème percentile. En anténatal, le RCIU n'a pas été évoqué dans la moitié des cas. A la naissance, 38,5% des enfants présentaient un RCIU symétrique et 61,5% un RCIU asymétrique. Dans plus de 50% des cas, il n'y a pas eu de diagnostic étiologique du RCIU évoqué en période anténatale ou post-natale. Nous avons pu le définir a posteriori dans 83% des cas. A 9 mois, 142 enfants ont pu être évalués. 76,7% des enfants présentaient un rattrapage de croissance. Les enfants du groupe symétrique avaient un périmètre crânien significativement plus faible à 9 mois que les enfants du groupe asymétrique, avec un RCIU d'étiologie principalement vasculaire. Parmi lesenfants nés avec un RCIU, 38% présentaient un retard de développement dans un ou plusieurs domaines, sans qu'il ne soit mis en évidence de différence entre les groupes symétrique et asymétrique. Cette étude permet d'insister sur l'intérêt d'un suivi de ces enfants nés avec un RCIU, qu'il soit symétrique ou asymétrique, non seulement centré sur leur rattrapage de croissance mais également sur leur développement psychomoteur
Infants with birth body weight less than 1500 g develop a postnatal growth failure in the vast majority of the cases. To limit this risk, enteral nutrition should be introduced appropriately, with respect to actual requirements of preterm neonates. Administration of enteral nutrition depends on postnatal age and clinical conditions. During the early adaptive period of life (from birth to approximately day 7), hemodynamic instability associated with immaturity of the gastrointestinal tract limit the use of enteral nutrition. Parenteral nutrition represents the main route of administration of nutrients in this period. However, enteral nutrition should be started since the first 1–2 days of life as minimal enteral feeding (10–30 ml/kg/day) and progressively increased (by 20–30 ml/kg/day) until full enteral feeding is reached (120 kcal/kg/day) and, contemporarily, parenteral nutrition could be stopped. In the stable growing period (from approximately day 7 to near term/discharge), all nutritional requirements, including macronutrients and micronutrients, should be reached only by enteral nutrition. Human milk is the preferred form of enteral nutrition for preterm babies; however, fortification with adequate amount of protein, carbohydrates, lipids, electrolytes, and micronutrients should be adopted to respect nutritional needs of these subjects. In this chapter, we focused on modalities to reach nutritional requirements by enteral nutrition.
Normal fetal growth can be altered by several pathological processes, including genetic diseases, infections, congenital anomalies, maternal hypoxia, and inadequate placental exchanges. The impossibility to reach the fetal genetic growth potential because of placental malfunction is defined intrauterine growth restriction (IUGR). IUGR causes slowing fetal growth, so that fetal biometry shifts from a higher to a significantly lower percentile during gestation, and it progressively leads to fetal hypoxia, acidemia, multiorgan damage, and death. Indeed, IUGR is associated with an excess of perinatal mortality and short- and long-term morbidity as well as metabolic syndrome in the adulthood. Prenatal diagnosis and appropriate timing of delivery improve neonatal outcomes.
When a fetus is found to be small for gestational age (SGA) at prenatal ultrasound, every effort has to be made to differentiate IUGR from other causes of impaired fetal growth. In case of IUGR, the clinical management is critically dependent on gestational age at onset. In early onset IUGR, the timing of delivery has to take into account the risks of prolonged intrauterine hypoxia versus the complications associated with preterm birth. In late onset IUGR, early induction of labor is probably the most cost-efficient method to prevent perinatal mortality and morbidity. In intermediate-onset IUGR there is a lack of clear evidence about the best tool to identify the fetuses that would benefit of timely delivery.
At birth, neonatal weight, length, and head circumference are indicators of the quality and quantity of intrauterine growth. SGA newborns, both preterm and term, have increased perinatal mortality risk and short-term complications such as birth asphyxia, infections, hypothermia, hypoglycemia, feeding difficulties, respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity, and necrotizing enterocolitis.
Even if most term children born SGA experience catch-up growth and achieve a normal adult height, approximately 10% of them remain shorter than peers born appropriate for gestational age. Preterm SGA infants can take four or more years to achieve heights in a normal range and the majority of them show a postnatal growth deficit at the time of hospital discharge (Extra Uterine Growth Restriction, EUGR).
Being born SGA is associated with long-term unfavorable outcomes such as learning difficulties, behavior problems, and development of metabolic syndrome.
The recognition of intrauterine malnutrition and the monitoring of early postnatal growth are of utmost importance for optimum survival and long-term outcomes of SGA infants.
Background:
To reach nutritional standards, human milk has to have 2g/dL of protein. In 2013, Lafeber stated that when human milk is fortified up to 2g/dL, it may increase its osmolality up to 500 mOsm/kg. He also warned that care must be taken when adding a drug or vitamins to human milk.
Aim:
We studied, for the first time, the impact of adding multivitamins (ADEC) on human fortified milk osmolality.
Method:
The osmolality of 36 pasteurized, fortified human milk samples was measured. The amount of milk required as a solvent to maintain osmolality below 500 mOsm/kg was then determined.
Results:
The osmolality of 2mL of fortified human milk reached up to 750 mOsm/kg when the multivitamins ADEC was added. The osmolality decreased proportionately as the solution was diluted and if vitamins are added in two half-doses each time. It is only with 20mL of milk that the osmolality lowers to its initial rate of 430 mOsm/kg. The stronger the milk's fortification is, the greater impact it has on the milk's osmolality.
Conclusion:
New nutritional recommendations for premature infants are needed. In the meantime, when the fortified milk intake is under 20mL, it is preferable to extend parenteral intakes with fat-soluble vitamins or reduce doses of vitamins in milk. Also, we should use enriched human milk as a fortifier and be cautious with indiscriminate fortification or when adding drugs and electrolyte solutions.
Babies born small for gestational age (SGA) are at risks of developing growth failure and impaired neurodevelopment as long-term outcomes when nutritional supply is inadequate during postnatal period. However, metabolic outcomes and cardiovascular risks later in life also do matter when excessive nutritional intake induces rapid catch-up growth after birth. Preterm infants born SGA and still small at hospital discharge need more nutrients than term infants to catch up within the first 2 years, whereas term infants born SGA should be cautious in gaining weight anytime. Therefore, nutritional strategies for optimal growth of SGA infants should be planned individually based on evidences.
The importance of breast-feeding (BF) for cognitive development has been researched widely over the past several decades. Although scholars agree that children who breast-feed are generally more intelligent, it is uncertain whether this advantage is due to BF effects or to other accompanying healthy characteristics of women who breast-feed. This is a problem in nearly every study, and even in studies controlling for known confounding variables, residual confounding remains a concern. This study tried a new approach, evaluating the relation between BF and cognitive development or ability in a population in which BF was inversely correlated with socioeconomic advantages and other healthy maternal behaviors. Normal birthweight (NBW, n = 1790) and low birthweight (LBW, n = 189) (< 2500 g) infants born in 1983-84 in Metropolitan Cebu, Philippines were followed from birth through middle childhood. Cognitive ability was assessed at ages 8.5 and 11.5 y with the Philippines Nonverbal Intelligence Test. Multivariable linear regressions were created to estimate crude and adjusted relations of various BF measures and later cognitive ability. After controlling for confounding variables, scores at 8.5 y were higher for infants breast-fed longer (1.6 points and 9.8 points higher among NBW and LBW infants, respectively, breast-fed for 12 to < 18 mo vs. < 6 mo). BF coefficients in both NBW and LBW 11.5-y models were attenuated but remained positive. This analysis highlights the importance of long-term BF after initial introduction of complementary foods, particularly in LBW infants born close to term.
Nutrition of preterm neonates is an important clinical issue and can be considered as an emergency procedure and a very crucial part of the complex neonatal care and treatment. Nutritional status has a great impact on the early adaptation of the breathing and lung function and on the general health condition later in life as well. The late consequences of early malnutrition are represented by neurocognitive and neurode-velopmental disorders, decreased intellectual capabilities, increased risk of cardio-vascular and metabolic morbidity. Inadequate nutrient intake and postnatal growth restriction of preterm neonates is a very common clinical situation. Most of the preemies are not able to achieve the fetal weight gain rate. It is very important to ensure early initiating of parenteral nutrition, minimal enteral or trophic feeding and later full oral feeding providing optimal protein and energy supply to the preterm neonates. The breast milk from the own mother or donor human milk has a lower protein content and is not adequate for the nutritional requirements of very low birth weight infants. The goal of human milk fortification is to add mainly protein and energy to the breast milk in order to provide optimal nutritional supply to these high risk infants. Different methods of human milk fortification are practiced-standard, target and adjustable fortification. In adjustable fortification extra protein is added to human milk with monitoring of blood urea nitrogen. This method has shown to be effective in achieving higher protein intakes and improved growth There are some important general guidelines, which can be used in the neonatal units for development of enteral feeding clinical protocols.
Preterm infants are vulnerable to the effects of malnutrition in both the pre- and post-discharge period. On-going illness and immaturity result in a delay in the establishment of adequate nutrition. During this period, cumulative nutrient deficits are accrued and growth is poor. The majority of preterm infants are discharged with a weight lower than their birth centile, indicative of poor growth. Nutrition has the potential to promote catch-up growth, although growth acceleration in some situations is associated with increased risk of metabolic problems in the longer term. Controlled trial data show that early nutrient intakes may 'programme' a range of long term metabolic outcomes. The Developmental Origins of Health and Disease (DOHaD) theory amalgamates many areas of scientific study and encompasses a wide range of diverse disciplines from epidemiology to molecular biology. The mechanisms linking early growth to later outcomes include permanent structural changes, accelerated cellular ageing and epigenetic mechanisms. There are data to link faster early growth with decreased insulin sensitivity in children born preterm, but many other long-term effects do not demonstrate consistent associations with early growth. Despite such potential metabolic concerns, the current data suggest that promoting improved nutrient intake and catch up growth in the pre- and post-discharge period is likely to result in better neurocognitive outcomes. © 2013 Springer Science+Business Media Dordrecht. All rights reserved.
Post-hospital nutrition of the preterm infant Precise nutrient requirements and achievable growth remainto bedefinedfor the premature infant post-hospital discharge. While fetal growth serves as the standard for the infant lessthan37weeks gestationandbreastfeedingmeets the needs of the healthy terminfant, neither goal meets the needs of the premie graduate. The graduate of the newborn intensive care unit (NICU) frequently enters into the home setting at a physical size which is significantly less than that of the fetus of the same postmenstrual age.1Nutrient need may be further altered by gender, ethnicity, hospital course and post hospital clinical status.2,3The limited number of investigations on nutrition posthospital discharge differ in their infant population, study diet, duration of study diet, and final results. Post discharge formulas have recently been developed and may meet the nutrient demands for selected premature infants. Continuedmonitoring of the infant’s dietary intake, anthropometricmeasurements, andclinical status willhelpto determine if the infant’s needs are met or if nutrient supplementation is indicated. Growth Prematureinfantscangrowatthefetal growthrateof at least 15 g kg-1day−1in the NICU.4This rate results in growth that parallels fetal growth, but because adequate weight gain commences only after 1-2weeks it does not result in catchup growth during the hospital stay.4,5Although most premature infants begin life appropriately grown, they are frequently discharged at a weight less than the 10th percentile for age.
Breastfeeding is the gold standard and strongly preferred method of feeding healthy term infants.1, 2 The American Academy of Pediatrics recommends human milk as the exclusive nutrient source for feeding full-term infants for the first 6 months after birth and indicates that it should be continued with the addition of solid foods, until 12 months of life.2 Likewise, the Canadian Pediatric Society recommends exclusive breastfeeding for a minimum of 4 months and suggests that it may continue for up to 2 years and beyond.1 Theduration of exclusive breastfeedingby the latter authoritative body is currently under review. Recently the World Health Organization made the recommendation that full-term infants be exclusively breastfed until the introduction of complementary foods at 6 months with continued breastfeeding thereafter.3 The scientific rationale for recommending breastfeeding as the preferred feeding choice is extensively reviewed elsewhere in this book. In the event that breastfeeding is contraindicated or a mother chooses not to breastfeed, a commercially prepared infant formula is the next best option. The American Academy of Pediatrics recommends that when breastfeeding is not initiated or is discontinued before an infant’s first birthday, a standard cow’s milk-based formula is the feeding of choice for term-born infants.2 Canadian Health officials recommenduse of cow’s milk-based, iron-fortified formulas until 9-12 months of age.1 Available data suggest that approximately 70% of North American women currently initiate breastfeeding.4, 5 At 6 months postpartum, however, only 32.5% of American women are still breastfeeding.
A large multicentre study on the short and long term clinical and developmental outcome of infants randomised to different diets is being undertaken. This report represents an interim analysis of the early postnatal growth performance of an unselected population of 194 preterm infants (gestation, mean (SD) 31 . 0 (2 . 9) weeks; birthweight, mean (SD) 1364 (294) g), both ill and well, examined in two (of four) parallel trials. One trial compared banked breast milk with a new preterm formula (primary trial); the other compared these diets as supplements to maternal milk (supplement trial). A major dietary effect on the number of days taken to regain birthweight and subsequent gains in weight, length, and head circumference was observed in the primary trial. Infants fed banked breast milk and weighing less than 1200 g at birth took a calculated additional three weeks to reach 2000 g compared with those fed on the preterm formula. A significant influence of diet on body proportions was seen in the relation between body weight, head circumference, and length. Similar though smaller differences in growth patterns were seen in the supplement trial. By the time they reach 2000 g, infants of birthweights 1200 to 1849 g fed on banked breast milk and infants below 1200 g fed on either banked breast milk or maternal milk supplemented (as necessary) with banked breast milk, fulfilled stringent criteria for failure to thrive (weight less than 2 SD below the mean for age). Only infants fed the preterm formula as their sole diet had maintained their birth centile by discharge from hospital. The misleading nature of comparisons between extrauterine and intrauterine steady state weight gains is emphasised.
Although the results of many clinical studies suggest that breast-fed children score higher on tests of cognitive function than do formula-fed children, some investigators have suggested that these differences are related to confounding covariables such as socioeconomic status or maternal education.
Our objective was to conduct a meta-analysis of observed differences in cognitive development between breast-fed and formula-fed children.
In this meta-analysis we defined the effect estimate as the mean difference in cognitive function between breast-fed and formula-fed groups and calculated average effects using fixed-effects and random-effects models.
Of 20 studies meeting initial inclusion criteria, 11 studies controlled for >/=5 covariates and presented unadjusted and adjusted results. An unadjusted benefit of 5.32 (95% CI: 4.51, 6.14) points in cognitive function was observed for breast-fed compared with formula-fed children. After adjustment for covariates, the increment in cognitive function was 3.16 (95% CI: 2.35, 3.98) points. This adjusted difference was significant and homogeneous. Significantly higher levels of cognitive function were seen in breast-fed than in formula-fed children at 6-23 mo of age and these differences were stable across successive ages. Low-birth-weight infants showed larger differences (5.18 points; 95% CI: 3.59, 6.77) than did normal-birth-weight infants (2.66 points; 95% CI: 2.15, 3.17) suggesting that premature infants derive more benefits in cognitive development from breast milk than do full-term infants. Finally, the cognitive developmental benefits of breast-feeding increased with duration.
This meta-analysis indicated that, after adjustment for appropriate key cofactors, breast-feeding was associated with significantly higher scores for cognitive development than was formula feeding.
Objective: To examine the association between birth weight and cognitive function in the normal population. Design: A longitudinal, population based, birth cohort study. Participants: 3900 males and females born in 1946. Main outcome measures: Cognitive function from childhood to middle life (measured at ages 8, 11, 15, 26, and 43 years). Results: Birth weight was significantly and positively associated with cognitive ability at age 8 (with an estimated standard deviation score of 0.44 (95% confidence interval 0.28 to 0.59)) between the lowest and highest birthweight categories after sex, father's social class, mother's education, and birth order were controlled for. This association was evident across the normal birthweight range (>2.5 kg) and so was not accounted for exclusively by low birth weight. The association was also observed at ages 11, 15, and 26, and weakly at age 43, although these associations were dependent on the association at age 8. Birth weight was also associated with education, with those of higher birth weight more likely to have achieved higher qualifications, and this effect was accounted for partly by cognitive function at age 8. Conclusions: Birth weight was associated with cognitive ability at age 8 in the general population, and in the normal birthweight range. The effect at this age largely explains associations between birth weight and cognitive function at subsequent ages. Similarly, the association between birth weight and education was accounted for partly by earlier cognitive scores.
Small-for-gestational-age (SGA) term infants are at risk of long-term growth deficits.
The objectives were to test the hypothesis that postnatal growth in SGA term infants can be altered by dietary intervention and to examine whether there is a critical window for nutritional programming of the growth trajectory during the first 9 mo postnatally.
Healthy term (gestation > or =37 wk) infants with birth weights below the 10th centile were randomly assigned to receive standard term formula (TF; n = 147) or nutrient-enriched formula (EF; n = 152) for the first 9 mo; 175 breast-fed SGA term infants formed a reference group. The main outcome measures were weight, length, and occipitofrontal head circumference (OFC) at 9 and 18 mo.
The infants fed the EF showed greater gains in length by 9 (1.1 cm; 95% CI: 0.38, 1.79) and 18 (1.0 cm; 0.25, 1.83) mo and in OFC by 9 (0.5 cm; 0.1, 0.9) and 18 (0.6 cm; 0.2, 1.1) mo than did infants fed the TF; the differences were larger in females. The dietary effects were independent of the pattern of growth retardation. Breast-fed infants showed greater gains in weight and OFC by 18 mo than did infants fed the TF; however, these differences disappeared after adjustment for age, parental size, and birth order.
Linear growth and OFC gains in SGA term infants improve after nutritional intervention during the first 9 mo of life and the effects persist for > or =9 mo beyond the intervention period. Further information on whether catch-up growth is beneficial or detrimental to long-term outcomes is required before public health interventions can be recommended.
Previous studies of growth and development in small-for-gestational-age (SGA) infants have been plagued by several methodologic defects, including a lack of control for socioeconomic status and parental height and an inability to distinguish among the effects of prematurity, neonatal asphyxia, and intrauterine growth retardation. An attempt has been made to overcome these defects in a study of 33 full-term, nonasphyxiated small-for-gestational-age neonates born between 1960 and 1966 and 33 matched control infants of normal birth weight. The infants were followed up and compared for physical growth and sexual, neurologic, and cognitive development at ages 13 to 19 years. Significant deficits in height, weight, and head circumference were found among the SGA cohort, even after statistical adjustment for differences in socioeconomic status and parental height. Sexual development and bone age were not delayed in the SGA group, however, indicating that the deficits in growth are permanent. On neurologic and cognitive testing, the SGA group had trends toward lower scores but scores were well within the normal range. It is concluded that full-term nonasphyxiated SGA infants have an impaired potential for physical growth, but a good prognosis for neurologic and cognitive development. Previous findings of more severe cognitive deficits are attributed to a failure to distinguish the effects of isolated intrauterine growth retardation from effects due to asphyxia.
Context Although studies have documented cognitive impairment in children who
were born small for gestational age (SGA), other studies have not demonstrated
differences in IQ or other cognitive scores. The need exists for long-term
studies of such children to assess functional outcomes not measurable with
standardized testing.
Objective To determine the long-term functional outcome of SGA infants.
Design Prospective cohort study.
Setting and Participants A total of 14,189 full-term infants born in the United Kingdom on April
5 through 11, 1970, were studied as part of the 1970 British Birth Cohort;
1064 were SGA (birth weight less than the fifth percentile for age at term).
Follow-up at 5, 10, 16, and 26 years was 93%, 80%, 72%, and 53%, respectively.
Main Outcome Measures School performance and achievement, assessed at 5, 10, and 16 years;
and years of education, occupational status, income, marital status, life
satisfaction, disability, and height, assessed at 26 years, comparing persons
born SGA with those who were not.
Results At 5, 10, and 16 years of age, those born SGA demonstrated small but
significant deficits in academic achievement. In addition, teachers were less
likely to rate those born SGA in the top 15th percentile of the class at 16
years (13% vs 20%; P<.01) and more likely to recommend
special education (4.9% vs 2.3%; P<.01) compared
with those born at normal birth weight (NBW). At age 26 years, adults who
were SGA did not demonstrate any differences in years of education, employment,
hours of work per week, marital status, or satisfaction with life. However,
adults who were SGA were less likely to have professional or managerial jobs
(8.7% vs 16.4%; P<.01) and reported significantly
lower levels of weekly income (mean [SD], 185 [91] vs 206 [102] £; P<.01) than adults who were NBW. Adults who were SGA
also reported significant height deficits compared with those who were NBW
(mean [SD] z score, −0.55 [0.98] vs 0.08 [1.02]; P<.001). Similar results were also obtained after adjusting
for social class, sex, region of birth, and the presence of fetal or neonatal
distress.
Conclusions In this cohort, adults who were born SGA had significant differences
in academic achievement and professional attainment compared with adults who
were NBW. However, there were no long-term social or emotional consequences
of being SGA: these adults were as likely to be employed, married, and satisfied
with life.
. Mortality, major neurological handicaps-including mental retardation, cerebral palsy and epilepsy-educational subnormality and height at 14 years of age were studied by birth weight percentiles in a birth cohort of 12000 children from northern Finland. Infant mortality was significantly higher below the mean -2 SD, 10th and 25th percentiles, than in the median class, from 25th to 75th percentiles, but mortality from one to 14 years only in the lowest weight class. Educational subnormality, including mental retardation ± some other handicap, was highly significantly more frequent in all the percentile classes lower than the median class but showed no significant tendency to be less frequent in the percentiles over the median. It was also highly significantly more frequent among the preterm than the term infant. The number of children with a major neurological handicap but normal school performance did not vary significantly by birth weight percentiles or by gestational age. Height at 14 years increased significantly by birth weight percentiles. The height of the boys with birth weight mean - and +2 SD was nevertheless within the 25th-75th percentiles for height at 14 years in general, while the height of the girls came close to these percentile limits. The preterm infants were significantly shorter than the term infants at 14 years.
The cognitive development and behaviour in the first six years of life of small for gestational age (SGA) babies born at term are reviewed. Differences in sample selection and confounding factors associated with socio-economic background, perinatal complications and biased follow-up make the interpretation of results and the comparison of studies difficult. Studies of infants (< 12 months) generally do not show any differences between SGA babies and controls. One study, carried out in Brazil and including comprehensive data on socio-economic background, parental literacy and infant stimulation, showed that low birth weight (LBW) babies were more vulnerable to effects of the environment than normal birth weight (NBW) babies, thus illustrating the importance of looking for interactions between covariates, rather than controlling for them. Deficits begin to appear in the second year of life, but are mainly found in high-risk subgroups. In all three studies of SGA children tested at 3 years of age, the SGA children had lower scores than NBW controls. SGA children tested between 4 and 7 years had generally lower scores than NBW, but differences were smaller and sometimes did no longer reach statistically significant levels. Some recommendations are made for future studies.
Among 12 468 legitimate single births in the first week of March 1946, 163 weighed 200 g or less (LBW group) and of these 80 survived to 18 years. 6 of the LBW survivors emigrated with their families and 5 have not been traced since birth. The remaining 69 were followed up to the age of 15 at which time two early school leavers were lost to the study. There is evidence that none of the survivors who emigrated or left the sample and serious physical or mental impairment. Compared with individually matched controls, the LBW children showed similar proportions with severe physical, mental, or behavioural handicaps. There are small and statistically nonsignificant differences in favour of the controls in ability and attainment scores at 15 years and in the level of academic qualifications gained by the age of 18. If the mean ability and attainment scores are expressed as an "intelligence quotient" with a mean of 100 and a standard deviation of 15, the LBW group has an average IQ of 93 and the controls of 97. Hospital stay after childbirth was much longer in 1946 than today and many LBW children spent more than 3 weeks in hospital. There is no evidence that long hospital stay was associated with problems of behaviour or learning in adolescence.
There is considerable controversy over whether nutrition in early life has a long-term influence on neurodevelopment. We have shown previously that, in preterm infants, mother's choice to provide breast milk was associated with higher developmental scores at 18 months. We now report data on intelligence quotient (IQ) in the same children seen at 7 1/2-8 years. IQ was assessed in 300 children with an abbreviated version of the Weschler Intelligence Scale for Children (revised Anglicised). Children who had consumed mother's milk in the early weeks of life had a significantly higher IQ at 7 1/2-8 years than did those who received no maternal milk. An 8.3 point advantage (over half a standard deviation) in IQ remained even after adjustment for differences between groups in mother's education and social class (p less than 0.0001). This advantage was associated with being fed mother's milk by tube rather than with the process of breastfeeding. There was a dose-response relation between the proportion of mother's milk in the diet and subsequent IQ. Children whose mothers chose to provide milk but failed to do so had the same IQ as those whose mothers elected not to provide breast milk. Although these results could be explained by differences between groups in parenting skills or genetic potential (even after adjustment for social and educational factors), our data point to a beneficial effect of human milk on neurodevelopment.
We examined the association of fetal and newborn complications, socioeconomic status, and home environment with learning deficits as assessed between 9 and 11 years of age.
A total of 218 high-risk newborns have been assessed at 1, 4, and 9 to 11 years of age. Fetal and newborn complications included 77 newborns with growth retardation. Socioeconomic variables included parental occupation and education. Outcome measures at 9 to 11 years included the Woodcock Reading Mastery Test and the Wide Range Achievement Test. Motor and cognitive development was assessed by a neurologic examination, the Bruininks-Oseretsky Test of Motor Proficiency, and the Wechsler Intelligence Scale for Children. Behavior was assessed with the Achenbach Child Behavior Check List and Connor's Teacher Rating Scale.
Learning deficits were identified in 77 of the 218 children (35%). Children with learning deficits had lower full-scale IQ scores and behavioral problems of inattention and anxiety. Both fetal growth retardation and the father's occupation score were independently associated with these learning deficits.
Fetal growth retardation, socioeconomic status, and behavioral characteristics of inattention and anxiety are associated with less favourable academic achievement at 9 to 11 years of age.
Undernutrition during early life is known to affect the morphology of the hippocampal formation. Recent advances in stereological techniques have made it possible to make relatively unbiased estimates of total cell numbers in well-defined brain regions. It was decided to use these methods to determine the effects of different levels of undernutrition during early postnatal life on the granule cells of the rat dentate gyrus.
Male hooded Long Evans rats were undernourished between the 16th day of gestation and 30 postnatal days of age to two different levels. The daily food intake of level-1 and level-2 rats represented about 60 and 40%, respectively, of that eaten by well-fed, age-matched controls. Nutritional rehabilitation of the rats was commenced when they had reached 30 days of age by placing them on an ad libitum diet. Groups of control and experimental rats were killed at 70 and 212 days of age. The Cavalieri principle was used to determine the granule cell layer volume within the dentate gyrus, and the “disector” method was used to determine numerical densities of these granule cells. These estimates were used to calculate the total numbers of granule cells.
There were between 260,000 and 320,000 granule cells within the dentate gyrus of 70-day-old control and experimental rats. By 212 days of age, well-fed controls had an average of about 834,000 granule cells. The level-1 and level-2 previously undernourished rats had about 515,000 and 595,000 granule cells, respectively. Two-way analysis of variance procedures showed significant main effects of nutrition and age as well as a significant interaction between them. These results provide strong evidence that a period of undernutrition during early life causes a long-term deficit in the total number of dentate gyrus granule cells.
The present study was based on data from a longitudinal research program. The cohort consisted of 12,079 children, born in the Stockholm area in 1953. There were 494 children born with low birth weight (LBW; 2500 g or less). The results of the present study showed, that the LBW children had significantly lower school marks and intelligence-test scores (numerical, verbal and logical abilities) at the age of 13 than the normal birth weight children (NBW). For girls reared in non-manual socio-economic status (SES), decreased school marks and IQ-test scores were related to birth weight, and this was especially pronounced for LBW girls born after pregnancy week 37. For boys, however, no decreased school marks and IQ-test scores were related to birth weight and gestational age, with the exception of verbal ability for LBW boys born after pregnancy week 37 reared in non-manual SES.
This paper provides an overview of problems in multivariate modeling of epidemiologic data, and examines some proposed solutions. Special attention is given to the task of model selection, which involves selection of the model form, selection of the variables to enter the model, and selection of the form of these variables in the model. Several conclusions are drawn, among them: a) model and variable forms should be selected based on regression diagnostic procedures, in addition to goodness-of-fit tests; b) variable-selection algorithms in current packaged programs, such as conventional stepwise regression, can easily lead to invalid estimates and tests of effect; and c) variable selection is better approached by direct estimation of the degree of confounding produced by each variable than by significance-testing algorithms. As a general rule, before using a model to estimate effects, one should evaluate the assumptions implied by the model against both the data and prior information.
The association between a mother's choice to provide breast milk and her baby's developmental status at 18 months post term was investigated in 771 low birthweight infants from five centres. Babies whose mothers chose to provide milk had an 8 point advantage in mean Bayley mental developmental index over infants of mothers choosing not to do so. A 4.3 point advantage remained after adjusting for demographic and perinatal factors. A similar finding was derived using a fundamentally different and questionnaire based test (academic scale of Developmental Profile II). Whether this significant residual developmental advantage relates to parental factors or to a beneficial effect of human milk itself on brain development has important implications for the nutritional management of premature babies.
137 small-for-gestational age (SGA) infants were examined in the neonatal period and at 2, 6 and 12 months. At each age a structured assessment was used for which a score denoting neurological maturation could be given. The SGA infants were significantly retarded compared with average-for-gestational age (AGA) infants from 2 months onwards. Within the SGA group the mean scores for boys, those who were first-born, breast-fed and/or born to mothers who smoked during pregnancy were in each case significantly higher than the rest at 6 and 12 months. Maternal smoking influenced all aspects of development at 12 months; whereas sex and method of infant feeding mainly affected the motor items, and birth order only those that were socially oriented. Positive associations were found between changes in somatic measures and changes in neurological scores from birth through to 6 months. Infants who grew faster also matured faster during this period of time, and vice versa. Positive correlations were found between size and scores at 2 and 6 months, but not at 12 months.
Mortality, major neurological handicaps--including mental retardation, cerebral palsy and epilepsy--educational subnormality and height at 14 years of age were studied by birth weight percentiles in a birth cohort of 12 000 children from northern Finland. Infant mortality was significantly higher below the mean -2 SD, 10th and 25th percentiles, than in the median class, from 25th to 75th percentiles, but mortality from one to 14 years only in the lowest weight class. Educational subnormality, including mental retardation +/- some other handicap, was highly significantly more frequent in all the percentile classes lower than the median class but showed no significant tendency to be less frequent in the percentiles over the median. It was also highly significantly more frequent among the preterm than the term infant. The number of children with a major neurological handicap but normal school performance did not vary significantly by birth weight percentiles or by gestational age. Height at 14 years increased significantly by birth weight percentiles. The height of the boys with birth weight mean - and +2 SD was nevertheless within the 25th-75th percentiles for height at 14 years in general, while the height of the girls came close to these percentile limits. The preterm infants were significantly shorter than the term infants at 14 years.
A controlled clinical trial was carried out to evaluate the effects of two different levels of protein intake on 304 infants with birth weights below 2,000 grams; the diets contained either 3.0 to 3.6 or 6.0 to 7.2 Gm. per kilogram per day of protein. The infants fed the higher intake had more fever, lethargy, and poor nipple feeding, but they had higher plasma protein levels and less edema than infants fed the lower intake.
PREDICTIVE diagnosis of development is possible because behavior matures in an orderly fashion, but it is not a simple matter. Unlike most other diagnostic problems in medicine, disturbances in neuropsychologic functioning involve integration on many different levels, from the biologic to the sociocultural. Analysis of something as complex as behavior thus is not without difficulties, and extensive training in making, and interpreting, observations is necessary for accurate diagnosis.
The number of children in whom abnormal development is suspected is enormous, the need for service great and the supply of specialists limited. Under these circumstances an adequate screening procedure which will detect infants in need of referral for a complete diagnostic evaluation is of great value. A number of devices and lists of behavior have been offered; when they have been tested at all it has not been for their correlation with an examination that has predictive ability. They have consisted for the most part of a few behavior patterns at widely separated ages and most have fallen into disuse because of their apparently unsatisfactory nature.
CRITERIA FOR AN ADEQUATE SCREENING DEVICE
In evaluating development one is concerned with both present and future functioning, and the complete examination from which the screening inventory is derived must be an adequate predictor of later abnormality. First, then, it must have validity. Since this predictive value can be determined only by longitudinal studies, such data must derive from follow-up correlations between complete infant examinations and those at later ages. Further, for prediction as well as for present management, intellectual defect and motor disability must be distinguished.
An 18-year follow-up examination on 56 male twins born in 1962-1963 was done by comparing birth records with the results of medical examinations at drafting for military service in 1981. Of the studied twins, 14.3% were unfit for military service compared with 6.2% of the total population of Norwegian conscripts in the same year. Preterm delivery rather than twinning per se is suggested as an explanation for this result. Vision was impaired in the preterm twins more often than in the total group of conscripts. The general intelligence, measured by standardized tests at the military medical board, did not differ significantly between the group of twins and the control conscripts.
To assess the cognitive and academic performance of adolescents who were born small for gestational age (SGA) at term.
A 17-year historical prospective study was done by matching neonatal data of 1758 infants to the results of the medical and intelligence assessment performed at age 17 years at the army draft board medical examination in Israel. The results of children born SGA (weight at term birth below the third percentile) were compared to those of children who were born appropriate for gestational age (AGA).
After adjustment by a multiple linear regression analysis, the mean (+/- standard error of the mean) intelligence test scores were 103.1 +/- 2.9 versus 105.8 +/- 1.5 (P = 0.3) for the males and 100.3 +/- 2.5 versus 104.7 +/- 1.6 (P < .03) for the females. Males born SGA at term were found to have lower educational achievements (having less than 12 years of schooling or attending a vocational school) compared with the AGA group. The odds ratio for this finding after adjustment by a logistic regression analysis was 2.40 (95% confidence interval 1.07-5.39; P < .03). Intranatal events were not found to have an effect on the measured neurodevelopmental outcome.
Infants born SGA at term have an increased risk for lower cognitive performance and schooling achievements than those born AGA; this result seems to be unrelated to their intranatal course.
To examine the effects on adolescents of being born small-for-gestational-age (SGA).
The sample are members of a cohort longitudinal study in which growth, cognitive development and behaviour are being studied into adulthood. Ninety-one SGA subjects were available for comparison with the rest of the sample (n = 1037) on measures of height, weight, head circumference, cognitive performance and behavioural variables to the age of 18 years old.
SGA subjects were shorter and lighter at 18 years of age than their appropriate-for-gestational-age (AGA) counterparts despite age of onset of menarche being the same in both groups. At age 13, SGA subjects scored significantly lower than the AGA group on the WISC-R scales. They were rated by parents as having more behaviour problems at age of 15.
SGA birth appears to be a potential problem which extends beyond childhood in its effects on growth, behaviour and cognitive performance.
Several studies show that children who were breastfed as babies gain higher scores on intelligence tests than those who were bottlefed. Although these findings suggest that breastfeeding in early life may promote cognitive development, their interpretation is complicated by the current association between breastfeeding and higher social class. We investigated the relation between method of feeding in infancy and adult intelligence in a setting where breastfeeding was not linked with socioeconomic advantage.
We followed up 994 men and women, born between 1920 and 1930 in Hertfordshire, UK, for whom information on infant feeding had been recorded by health visitors. Intelligence was measured by the AH4 IQ test, taken on a computer. Factors significantly linked with IQ were investigated by multivariate analysis.
Study participants who had been exclusively breastfed gained slightly higher scores on the IQ test than those who had been exclusively bottlefed, or fed with both breast and bottle. IQ was lower in participants who had used a dummy (pacifier) in infancy, in those whose fathers were in manual occupations at the time of their birth, and in those whose mothers were young at the time they were born. Scores on the IQ test fell as the number of older siblings increased. In multivariate analysis, after adjustment for the effect of all other variables, no association was found between adult intelligence and method of feeding. Dummy use in infancy, number of older siblings, maternal age at birth of the participant, and father's occupational class remained independent predictors of adult intelligence.
The mechanisms that link type of feeding in early life with later intelligence may have more to do with the child's social environment that with the nutritional qualities of the milk.
The World Health Organization (WHO) convened an Expert Committee to reevaluate the use of anthropometry at different ages for assessing health, nutrition, and social wellbeing. The Committee's task included identifying reference data for anthropometric indexes when appropriate, and providing guidelines on how the data should be used. For fetal growth, the Committee recommended an existing sex-specific multiracial reference. In view of the significant technical drawbacks of the current National Center for Health Statistics (NCHS)/WHO reference and its inadequacy for assessing the growth of breast-fed infants, the Committee recommended the development of a new reference concerning weight and length/height for infants and children, which will be a complex and costly undertaking. Proper interpretation of midupper arm circumference for preschoolers requires age-specific reference data. To evaluate adolescent height-for-age, the Committee recommended the current NCHS/WHO reference. Use of the NCHS body mass index (BMI) data, with their upper percentile elevations and skewness, is undesirable for setting health goals; however, these data were provisionally recommended for defining obesity based on a combination of elevated BMI and high subcutaneous fat. The NCHS values were provisionally recommended as reference data for subscapular and triceps skinfold thicknesses. Guidelines were also provided for adjusting adolescent anthropometric comparisons for maturational status. Currently, there is no need for adult reference data for BMI; interpretation should be based on pragmatic BMI cutoffs. Finally, the Committee noted that few normative anthropometric data exist for the elderly, especially for those > 80 y of age. Proper definitions of health status, function, and biologic age remain to be developed for this group.
Consistent data are available to suggest that children who have been breast fed are, on average, intellectually more able than their formula-fed contemporaries. This has been shown in eight of 10 population studies and all three studies of low birthweight infants. In general, the longer the child has been breast fed the more pronounced the effect. There is evidence that breast milk that has been pasteurised before feeding does not have this effect, but that fresh breast milk is effective whether the milk is delivered by tube or by the breast. However no studies have been able to have both sufficient statistical power and the ability to allow for other confounders such as parental ability, parental IQ and other factors that might explain these findings. Additional data from studies of visual acuity show an association between breast feeding and enhanced vision which is hypothesised to be due to the unique fatty acid composition of breast milk. The differences in intellectual development might also be related to these fatty acids. Alternative explanations for the effect on intellectual development concern the possible consequences of early infections, particularly gastroenteritis, which are more common in bottle-fed babies. In contrast with the many publications on cognitive function and breast feeding, there was only one on neurological dysfunction (showing a protective effect of breast feeding) and one on childhood behaviour (using the teacher's assessment no relationship with breast feeding was found). Further research is needed in both areas.
To determine whether perinatal nutrition influences cognitive function at 7 1/2 - 8 years in children born preterm.
Randomised, blinded nutritional intervention trial. Blinded follow up at 7 1/2 - 8 years.
Intervention phase in two neonatal units; follow up in a clinic or school setting.
424 preterm infants who weighed under 1850 g at birth; 360 of those who survived were tested at 7 1/2 - 8 years.
Standard infant formula versus nutrient enriched preterm formula randomly assigned as sole diet (trial A) or supplements to maternal milk (trial B) fed for a mean of 1 month.
Intelligence quotient (IQ) at 7 1/2 - 8 years with abbreviated Weschler intelligence scale for children (revised).
There was a major sex difference in the impact of diet. At 7 1/2 - 8 years boys previously fed standard versus preterm formula as sole diet had a 12.2 point disadvantage (95% confidence interval 3.7 to 20.6; P<0.01) in verbal IQ. In those with highest intakes of trial diets corresponding figures were 9.5 point disadvantage and 14.4 point disadvantage in overall IQ (1.2 to 17.7; P<0.05) and verbal IQ (5.7 to 23.2; P<0.01). Consequently, more infants fed term formula had low verbal IQ (<85): 31% versus 14% for both sexes (P=0.02) and 47% versus 13% in boys P=0.009). There was a higher incidence of cerebral palsy in those fed term formula; exclusion of such children did not alter the findings.
Preterm infants are vulnerable to suboptimal early nutrition in terms of their cognitive performance--notably, language based skills--at 7 1/2 - 8 years, when cognitive scores are highly predictive of adult ones. Our data on cerebral palsy generate a new hypothesis that suboptimal nutritional management during a critical or plastic early period of rapid brain growth could impair functional compensation in those sustaining an earlier brain insult. Cognitive function, notably in males, may be permanently impaired by suboptimal neonatal nutrition.
Preterm infants are frequently discharged from the hospital growth retarded and show reduced growth throughout childhood. In a large efficacy and safety trial, we tested the hypothesis that nutritional intervention in the first 9 months postterm would reverse postdischarge growth deficits and improve neurodevelopment without adverse safety outcomes.
Two hundred eighty-four infants (mean gestation: 30.9 weeks) were studied; 229 were randomly assigned a protein, energy, mineral, and micronutrient-enriched postdischarge formula (PDF; N = 113) or standard term formula (TF; N = 116) from discharge (mean 36.5 weeks' postmenstrual age). A reference group (N = 65) was breastfed until at least 6 weeks' postterm. Outcome measures. Anthropometry was performed at 6 weeks and 3, 6, 9, and 18 months. Development was measured at 9 months (Knobloch, Passamanick, and Sherrard's developmental screening inventory) and 18 months (Bayley Scales of Infant Development II; primary outcome) postterm.
At 9 months, compared with the TF group, those fed PDF were heavier (difference 370 g; 95% confidence interval [CI]: 84-660) and longer (difference 1.1 cm; 95% CI: 0.3-1.9); the difference in length persisted at 18 months (difference 0.82 cm; 95% CI: -0.04-1.7). There was no effect on head circumference. The effect of diet was greatest in males; at 9 months length deficit with TF was 1.5cm (95% CI: 0.3-2.7), and this remained at 18 months (1.5cm [95% CI: 0.3-2.7]). There was no significant difference in developmental scores at 9 or 18 months, although PDF infants had a 2.8 (-1.3-6.8) point advantage in Bayley motor score scales. At 6 weeks' postterm, exclusively breastfed infants were already 513 g (95% CI: 310-715) lighter and 1.6cm (95% CI: 0.8-2.3) shorter than the PDF group, and they remained smaller up to 9 months' postterm.
1) Improving postdischarge nutrition in the first 9 months may "reset" subsequent growth-at least until 18 months for body length. We intend to follow-up the children at older ages. The observed efficacy of PDF was not associated with adverse safety outcomes. 2) We cannot reject the hypothesis that postdischarge nutrition benefits motor development and this requires additional study. 3) Our data raise the possibility that breastfed postdischarge preterm infants may require nutritional supplementation, currently under investigation.
Later development of breast fed and artificially fed infants
- C Hoefer
- Hardy
- Mc
British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood
- T J Cole
- J V Freeman
- M A Preece