1. Please check and comment entries here.
Table of Contents

    Topic review

    Docosahexaenoic Acid and Neurodevelopment

    View times: 50
    Submitted by: Shweta Khandelwal


    There is a lot of interest in and buzz around improving brain potential (neurodevelopment) of our children. Various types of nutrition supplements are therefore advised/consumed to boost neurodevelopment, often without proper scientific evidence. India is one of the highest ranking countries in the world for the number of children suffering from malnutrition. The first 1000 days (conception to 2 years) are very critical for the growth and development of a child. Maternal nutrition during this time impacts the development of brain structure and function. Thus poor maternal diets (lacking in important nutrients) can result in delayed brain development and diseases in the offspring. Higher intake of a specific fat type known as long-chain omega-3 fatty acids (especially DHA) has been linked to better motor and mental development. The main dietary source of DHA is fatty fish and marine oils. Indian diets are largely DHA-deficient and the population levels of plasma DHA among Indians are reported to be very low. There are no harmful effects of consuming DHA during pregnancy or lactation. Thus we carried out a high quality rigorous randomized controlled trial (#DHANI trial*) supplementing 957 pregnant Indian women with either DHA or placebo capsules to examine how DHA impacts the brain development of the offspring. These capsules were given from <20 weeks of gestation to 6 months postpartum. The infants born to these supplemented mothers were tested using a standardized non-invasive tool called the Developmental Assessment Scale for Indian infants (DASII). This provides a developmental quotient (DQ) score taking the mental and motor development into consideration. Our published study* provides evidence that the maternal supplementation through pregnancy and lactation with DHA did not benefit their infant’s neurodevelopment at one year of age. Deeper insights into maternal dietary patterns, young child feeding practices, home environment, and the interactions amongst these factors are warranted to understand what shapes early neurodevelopment. Ongoing follow-up is needed, particularly given the ubiquity of DHA-supplemented health drinks, formulas and foods for children for touted cognitive enhancements in Indian markets.

    1. Introduction

    The first 1000 days are crucial for a child’s neurodevelopment [1]. The brain develops rapidly through neurogenesis, axonal and dendritic growth, synaptogenesis, synaptic pruning, myelination, and gliogenesis [2]. These events build on each other, such that even small perturbations can have long-term effects on the brain’s structural and functional capacity [3]. Maternal nutrition during this time influences both pre- and postnatal growth, and development of the offspring [4][5][6].

    It has been suggested that n-3 long-chain polyunsaturated fatty acids (LCPUFA) (especially docosahexaenoic acid [DHA]) levels enhance infant neurodevelopment [7][8][9][10][11]. The DHA is an important structural component of the human brain and retina. DHA accumulates in all of the brain regions and retinal photoreceptors [12]. These long-chain fatty acids regulate the fluidity of cell membranes as well as the activity of ion channels, enabling synaptic transmission and providing substrate binding to membrane receptors. The deposition of DHA in human brain phospholipids occurs primarily during the last trimester of pregnancy such as week 30 until the early postnatal periods continuing during the first two years of life [13][14][15]. Human fetuses and young infants have limited ability to synthesize n-3 LCPUFA de novo and are supplied via maternal (placental transfer, breast milk) or external (formula, dietary) sources [16][17]. Approximately 67 mg of DHA is accrued by the fetus per day [18]. Deprivation of n-3 LCPUFA, whether prenatally or after birth, has deleterious effects on learning abilities, memory, and visual grating acuity in monkeys, rats, and human infants [19][20].

    DHA can be obtained from marine algae, fatty fish, and marine oils. Endogenous synthesis of DHA is limited, especially in the presence of excess n-6 LCPUFA. The Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee recommends a diet with a 5–10:1 ratio of n-6/n-3 LCPUFA and 300 mg/day of preformed DHA during pregnancy [21][22]. Since cereal-based diets are rich in n-6 LCPUFA but largely deficient in DHA-rich sources, population levels of plasma DHA are low in India. Studies report [23][24] that mean DHA intake was lowest (11 mg) among Indian pregnant women in the third trimester [25] compared to pregnant women from other developing countries like Bangladesh, Burkina Faso, Chile, China, India, and Mexico.

    Studies conducted around the world to assess the association between intakes of DHA during pregnancy or lactation and neurodevelopmental outcomes in childhood have been inconsistent [[7][26][27][28][29][30][31][32][33][34][35]. Few studies have assessed the effect of both prenatal and postnatal intake of DHA [36][37]. There is a paucity of data on the potential benefits of maternal DHA supplementation in infants, especially in the Indian population. The present study examines the hypothesis whether 400 mg/d maternal DHA supplementation from ≤20 weeks through 6 months postpartum influences infant neurodevelopment at 12 months of age. The present study DHANI (Maternal DHA supplementation and offspring Neurodevelopment in India) is the first to examine the effects of maternal DHA supplementation from mid-pregnancy through six months postpartum on postnatal neurodevelopment in India.

    2. Discussion

    In this well designed and executed RCT, pre- and postnatal maternal supplementation with 400 mg/d DHA did not improve the infant’s development score as measured by DASII at 12 months of age. Our findings are in accordance with some other trials [38][39][40][41]. The reviews published so far in this field to understand the association between maternal DHA supplementation and infant neurodevelopment have also reported the evidence of a positive association between maternal DHA supplementation and infant neurodevelopment to be either too low or inconsistent, with a majority of the RCTs showing no positive effect [36]. Makrides et al. provided 800 mg/d and [42] showed no difference in children’s cognitive scores between the intervention and control group at 18 months. Similarly, Helland et al. [41] found no effect of prenatal supplementation with cod liver oil on cognitive development among 288 three-month-old children in Norway. On the other hand, the randomized trial of Colombo et al. [43] found that lower doses of DHA supplementation of the infants (4 to 9 months of age) showed better cognitive outcomes in terms of their attention span. Studies have reported maternal DHA status in pregnancy to be positively associated with infant’s brain volume at 1 month [44], improved infant’s attention [45], and enhanced problem-solving skills at 12 months [46]. Rees et al. [26] showed that the infants of mothers who had a higher dietary DHA intake during the second and third trimesters of their pregnancy performed better on cognitive assessment measures (habituation and sustained visual attention) at 4.5 and 9 months of age. However, it was also observed that the infants from the medium dietary DHA group [0.64% of fatty acids from DHA (34 mg/100 kcal)] performed significantly better than the low-DHA [0.32% (17 mg/100 kcal)] and high-DHA group [0.96% (51 mg/100 kcal)], with the latter showing the worst performance [26][43]. Additionally, some studies have reported improved cognition among older children whose mothers were supplemented with 400–600 mg/d DHA prenatally, after they turned four years old [27][30][35].

    The neurodevelopment in the current study was assessed with the help of the DASII test which is BSID’s adaptation. Although BSID is a global standardized test for assessing cognitive functioning and has been frequently utilized in neurodevelopment effects of LCPUFA in infants [47], its sensitivity to pick up some subtle differences in infant cognitive ability has been questioned [48]. Experts suggest that differences in intellectual functioning that are sensitive to pathways influenced by n-3 fatty acids may only be detected with more sensitive measures of neurodevelopment such as neuroimaging techniques [49], neuropsychological testing [50], distinct cognitive abilities, or executive functioning [51]. The suitability of these approaches for large field-based trials in low resource settings warrants further exploration.

    Few possible limitations of our single-center trial may include lack of details on home environment and detailed dietary data on the children which may have influenced the neurodevelopment in the first year of life. The measure of neurodevelopment used in the study (i.e., the DQ score) has not been validated against the functional magnetic resonance imaging (fMRI) which is currently considered the gold standard noninvasive hemodynamic-based neuroimaging technology. The fatty acid composition of the blood and breast milk collected from the enrolled women are not currently available. We also did not estimate dietary n-3 LCPUFA intakes in all the study subjects; however, the biomarker (RBC phospholipid DHA) is very responsive to intake and was measured at both enrollment and immediately after birth as an indicator of prior status and study DHA intake. Further, other fatty acids like AA and DHA:AA ratios may play a key role in neurodevelopment [52]. To the best of our knowledge, our study is the first one to examine the effects of in utero and early-life DHA exposure (through maternal supplementation from mid-pregnancy through six months postpartum) on postnatal neurodevelopment of Indian infants. Through a long supplementation phase and follow-up period, the participants of our trial reported good compliance and very low attrition. Genetic predisposition, prenatal and postnatal care and nutrition, and social and physical environment may all be critical in shaping the neurodevelopment of an infant. We collected maternal dietary data at baseline but not at later visits. Changes throughout the pregnancy with respect to not only n-3 LCPUFA but also other nutrients such as vitamin D or iron [53][54]] may affect offspring neurodevelopment.

    While DHA is a key intrinsic factor constituting more than 40% of brain polyunsaturated fatty acids [55][56], external factors like care and stimulation in the home environment also play a significant role in a child’s cognitive development [57][58]. Poor physical conditions of home and limited access to age-appropriate learning materials have been linked with social–emotional problems in children. Ramakrishnan et al. [38] indicated a possible attenuating effect of DHA on the positive association between home environment and psychomotor development. DHA may be especially helpful for children living in home environments characterized by reduced caregiver interactions and opportunities for early childhood stimulation [59]. It might have been useful to have these data in the present study. Further, the mean DQ score of girl children in the placebo group was higher. This inconsistency may be due to chance. Some studies also attribute gender-related differences in neurodevelopment to sex hormones [60] and/or social context [61], but since these were not assessed in our trial, we cannot be certain of this.

    In summary, supplementing mothers through pregnancy and lactation with 400 mg/d DHA (vs. placebo) did not benefit offspring neurodevelopment at one year of age in this Indian setting. Deeper insights into maternal dietary patterns, young child feeding practices, home environment, and the interactions amongst these factors are warranted to understand what shapes early neurodevelopment.

    The entry is from 10.3390/nu12103041


    1. Grantham-McGregor, S.; Cheung, Y.B.; Cueto, S.; Glewwe, P.; Richter, L.; Strupp, B. International Child Development Steering Group. Developmental potential in the first 5 years for children in developing countries. Lancet 2007, 369, 60–70.
    2. Jiang, X.; Nardelli, J. Cellular and molecular introduction to brain development. Neurobiol. Dis. 2016, 92 Pt A, 3–17.
    3. Cusick, S.; Georgieff, M.K. The Role of Nutrition in Brain Development: The Golden Opportunity of the “First 1000 Days”. J. Pediatr. 2016, 175, 16–21.
    4. Costello, A.M.D.L.; Osrin, D. Micronutrient Status during Pregnancy and Outcomes for Newborn Infants in Developing Countries. J. Nutr. 2003, 133 (Suppl. 2), 1757S–1764S.
    5. Larqué, E.; Demmelmair, H.; Koletzko, B. Perinatal supply and metabolism of long-chain polyunsaturated fatty acids: Importance for the early development of the nervous system. Ann. New York Acad. Sci. 2002, 967, 299–310.
    6. Rahmanifar, A.; Kirksey, A.; Wachs, T.D.; McCabe, G.P.; Bishry, Z.; Galal, O.M.; Harrison, G.G.; Jerome, N.W. Diet during lactation associated with infant behavior and caregiver-infant interaction in a semirural Egyptian village. J. Nutr. 1993, 123, 164–175.
    7. Meldrum, S.; Karen, S. Docosahexaenoic Acid and Neurodevelopmental Outcomes of Term Infants. Ann. Nutr. Metab. 2016, 69 (Suppl. 1), 22–28.
    8. Makrides, M. DHA supplementation during the perinatal period and neurodevelopment: Do some babies benefit more than others? Prostaglandins Leukot. Essent. Fat. Acids 2013, 88, 87–90.
    9. Ryan, A.S.; Astwood, J.D.; Gautier, S.; Kuratko, C.N.; Nelson, E.B.; Salem, N. Effects of long-chain polyunsaturated fatty acid supplementation on neurodevelopment in childhood: A review of human studies. Prostaglandins Leukot. Essent. Fat. Acids 2010, 82, 305–314. [Google Scholar] [CrossRef]
    10. Makrides, M.; Smithers, L.G.; Gibson, R. Role of Long-Chain Polyunsaturated Fatty Acids in Neurodevelopment and Growth. Nestle Nutr. Workshop Ser. Pediatr Program 2010, 65, 123–136.
    11. Hibbeln, J.R.; Davis, J.M.; Steer, C.; Emmett, P.; Rogers, I.; Williams, C.; Golding, J. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): An observational cohort study. Lancet 2007, 369, 578–585.
    12. Docosahexaenoic acid (DHA). Monograph. Altern. Med. Rev. 2009, 14, 391–399.
    13. Lauritzen, L.; Brambilla, P.; Mazzocchi, A.; Harsløf, L.B.S.; Ciappolino, V.; Agostoni, C. DHA Effects in Brain Development and Function. Nutrents 2016, 8, 6.
    14. Carlson, S.E. Docosahexaenoic acid supplementation in pregnancy and lactation. Am. J. Clin. Nutr. 2009, 89, 678s–684s.
    15. Makrides, M.; Gibson, R. Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation. Am. J. Clin. Nutr. 2000, 71 (Suppl. 1), 307S–311S.
    16. Koletzko, B.; Boey, C.C.; Campoy, C.; Carlson, S.E.; Chang, N.; Guillermo-Tuazon, M.A.; Joshi, S.; Prell, C.; Quak, S.H.; Sjarif, D.R.; et al. Current Information and Asian Perspectives on Long-Chain Polyunsaturated Fatty Acids in Pregnancy, Lactation, and Infancy: Systematic Review and Practice Recommendations from an Early Nutrition Academy Workshop. Ann. Nutr. Metab. 2014, 65, 49–80.
    17. Weiser, M.J.; Butt, C.M.; Mohajeri, M.H. Docosahexaenoic Acid and Cognition throughout the Lifespan. Nutrients 2016, 8, 99.
    18. Garg, P.; Pejaver, R.K.; Sukhija, M.; Ahuja, A. Role of DHA, ARA, & phospholipids in brain development: An Indian perspective. Clin. Epidemiology Glob. Health 2017, 5, 155–162.
    19. Brenna, J.T. Animal studies of the functional consequences of suboptimal polyunsaturated fatty acid status during pregnancy, lactation and early post-natal life. Matern. Child Nutr. 2011, 7 (Suppl. 2), 59–79.
    20. Wadhwani, N.; Patil, V.; Joshi, S.R. Maternal long chain polyunsaturated fatty acid status and pregnancy complications. Prostaglandins Leukot. Essent. Fat. Acids 2018, 136, 143–152.
    21. Wierzejska, R.; Jarosz, M.; Wojda, B.; Siuba-Strzelińska, M. Dietary intake of DHA during pregnancy: A significant gap between the actual intake and current nutritional recommendations. Roczniki Państwowego Zakładu Higieny 2018, 69, 381–386.
    22. Kris-Etherton, P.M.; Grieger, J.A.; Etherton, T.D. Dietary reference intakes for DHA and EPA. Prostaglandins Leukot. Essent. Fat. Acids 2009, 81, 99–104.
    23. Huffman, S.L.; Harika, R.K.; Eilander, A.; Osendarp, S.J. Essential fats: How do they affect growth and development of infants and young children in developing countries? A literature review. Matern. Child Nutr. 2011, 7 (Suppl. 3), 44–65.
    24. Shrimpton, R.; Huffman, S.L.; Zehner, E.R.; Darnton-Hill, I.; Dalmiya, N. Multiple Micronutrient Supplementation during Pregnancy in Developing-Country Settings: Policy and Program Implications of the Results of a Meta-Analysis. Food Nutr. Bull. 2009, 30 (Suppl. 4), S556–S573.
    25. Muthayya, S.; Dwarkanath, P.; Thomas, T.; Ramprakash, S.; Mehra, R.; Mhaskar, A.; Mhaskar, R.; Thomas, A.; Bhat, S.; Vaz, M.; et al. The effect of fish and ω-3 LCPUFA intake on low birth weight in Indian pregnant women. Eur. J. Clin. Nutr. 2009, 63, 340–346.
    26. Rees, A.; Sirois, S.; Wearden, A. Prenatal maternal docosahexaenoic acid intake and infant information processing at 4.5mo and 9mo: A longitudinal study. PLoS ONE 2019, 14, e0210984.
    27. Colombo, J.; Shaddy, D.J.; Gustafson, K.M.; Gajewski, B.J.; Thodosoff, J.M.; Kerling, E.H.; Carlson, S.E. The Kansas University DHA Outcomes Study (KUDOS) clinical trial: Long-term behavioral follow-up of the effects of prenatal DHA supplementation. Am. J. Clin. Nutr. 2019, 109, 1380–1392.
    28. Argaw, A.; Huybregts, L.; Wondafrash, M.; Kolsteren, P.; Belachew, T.; Worku, B.N.; Abessa, T.G.; Bouckaert, K.P. Neither n-3 Long-Chain PUFA Supplementation of Mothers through Lactation nor of Offspring in a Complementary Food Affects Child. Overall or Social-Emotional Development: A 2 × 2 Factorial Randomized Controlled Trial in Rural Ethiopia. J. Nutr. 2019, 149, 505–512.
    29. Gould, J.F.; Yelland, L.N.; Smithers, L.G.; Makrides, M.; Treyvaud, K.; Anderson, V.; McPhee, A. Seven-Year Follow-up of Children Born to Women in a Randomized Trial of Prenatal DHA Supplementation. JAMA 2017, 317, 1173–1175.
    30. Ramakrishnan, U.; Gonzalez-Casanova, I.; Schnaas, L.; DiGirolamo, A.; Quezada, A.D.; Pallo, B.C.; Hao, W.; Neufeld, L.M.; Rivera, J.A.; Stein, A.D.; et al. Prenatal supplementation with DHA improves attention at 5 y of age: A randomized controlled trial. Am. J. Clin. Nutr. 2016, 104, 1075–1082.
    31. Makrides, M.; Gould, J.F.; Gawlik, N.R.; Yelland, L.N.; Smithers, L.G.; Anderson, P.J.; Gibson, R.A. Four-Year Follow-up of Children Born to Women in a Randomized Trial of Prenatal DHA Supplementation. JAMA 2014, 311, 1802–1804.
    32. Carlson, S.E.; Colombo, J.; Gajewski, B.J.; Gustafson, K.M.; Mundy, D.; Yeast, J.; Georgieff, M.K.; Markley, L.A.; Kerling, E.H.; Shaddy, D.J. DHA supplementation and pregnancy outcomes. Am. J. Clin. Nutr. 2013, 97, 808–815.
    33. Escolano-Margarit, M.V.; Ramos, R.; Beyer, J.; Csábi, G.; Parrilla-Roure, M.; Cruz, F.; Pérez-García, M.; Hadders-Algra, M.; Gil, Á; Decsi, T.; et al. Prenatal DHA Status and Neurological Outcome in Children at Age 5.5 Years Are Positively Associated. J. Nutr. 2011, 141, 1216–1223.
    34. Ramakrishnan, U.; Stein, A.D.; Parra-Cabrera, S.; Wang, M.; Imhoff-Kunsch, B.; Juárez-Márquez, S.; Rivera, J.; Martorell, R. Effects of Docosahexaenoic Acid Supplementation During Pregnancy on Gestational Age and Size at Birth: Randomized, Double-Blind, Placebo-Controlled Trial in Mexico. Food Nutr. Bull. 2010, 31, S108–S116.
    35. Gustafson, K.M.; Liao, K.; Mathis, N.B.; Shaddy, D.J.; Kerling, E.H.; Christifano, D.N.; Colombo, J.; Carlson, S.E. Prenatal docosahexaenoic acid supplementation has long-term effects on childhood behavioral and brain responses during performance on an inhibitory task. Nutr. Neurosci. 2020, 1–11.
    36. Newberry, S.J.; Chung, M.; Booth, M.; Maglione, M.A.; Tang, A.M.; O’Hanlon, C.E.; Wang, D.D.; Okunogbe, A.; Huang, C.; Motala, A.; et al. Omega-3 Fatty Acids and Maternal and Child Health: An Updated Systematic Review. Évid. Rep. Assess. 2016, 2016, 1–826.
    37. Bergmann, R.L.; Haschke-Becher, E.; Klassen-Wigger, P.; Bergmann, K.E.; Richter, R.; Dudenhausen, J.W.; Grathwohl, D.; Haschke, F. Supplementation with 200 mg/day docosahexaenoic acid from mid-pregnancy through lactation improves the docosahexaenoic acid status of mothers with a habitually low fish intake and of their infants. Ann. Nutr. Metab. 2008, 52, 157–166.
    38. Ramakrishnan, U.; Stinger, A.; DiGirolamo, A.M.; Martorell, R.; Neufeld, L.M.; Rivera, J.A.; Schnaas, L.; Stein, A.D.; Wang, M. Prenatal Docosahexaenoic Acid Supplementation and Offspring Development at 18 Months: Randomized Controlled Trial. PLoS ONE 2015, 10, e0120065.
    39. Van Der Merwe, L.F.; Moore, S.E.; Fulford, A.J.; Halliday, K.E.; Drammeh, S.; Young, S.; Prentice, A.M. Long-chain PUFA supplementation in rural African infants: A randomized controlled trial of effects on gut integrity, growth, and cognitive development. Am. J. Clin. Nutr. 2013, 97, 45–57.
    40. Van Goor, S.A.; Dijck-Brouwer, D.J.; Erwich, J.J.H.; Schaafsma, A.; Hadders-Algra, M. The influence of supplemental docosahexaenoic and arachidonic acids during pregnancy and lactation on neurodevelopment at eighteen months. Prostaglandins Leukot. Essent. Fat. Acids 2011, 84, 139–146.
    41. Helland, I.B.; Smith, L.; Sareem, K.; Saugstad, O.D.; Drevon, C.A. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics 2003, 111, e39–e44.
    42. Makrides, M.; Gibson, R.; McPhee, A.J.; Yelland, L.; Quinlivan, J.; Ryan, P. Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children. JAMA 2010, 304, 1675–1683.
    43. Colombo, J.; Carlson, S.E.; Cheatham, C.L.; Gustafson, K.M.; Kepler, A.; Doty, T. Long-chain polyunsaturated fatty acid supplementation in infancy reduces heart rate and positively affects distribution of attention. Pediatr. Res. 2011, 70, 406–410.
    44. Morton, S.U.; Vyas, R.; Gagoski, B.; Vu, C.; Litt, J.; Larsen, R.J.; Kuchan, M.J.; Lasekan, J.B.; Sutton, B.P.; Grant, P.E.; et al. Maternal Dietary Intake of Omega-3 Fatty Acids Correlates Positively with Regional Brain Volumes in 1-Month-Old Term Infants. Cereb. Cortex 2020, 30, 2057–2069.
    45. Colombo, J.; Gustafson, K.M.; Gajewski, B.J.; Shaddy, D.J.; Kerling, E.H.; Thodosoff, J.M.; Doty, T.; Brez, C.C.; Carlson, S.E. Prenatal DHA supplementation and infant attention. Pediatr. Res. 2016, 80, 656–662.
    46. Braarud, H.C.; Markhus, M.W.; Skotheim, S.; Stormark, K.M.; Frøyland, L.; Graff, I.E.; Kjellevold, M. Maternal DHA Status during Pregnancy Has a Positive Impact on Infant Problem Solving: A Norwegian Prospective Observation Study. Nutrients 2018, 10, 529.
    47. Gould, J.F.; Smithers, L.G.; Makrides, M. The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development: A systematic review and meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2013, 97, 531–544.
    48. Colombo, J.; Carlson, S.E. Is the measure the message: The BSID and nutritional interventions. Pediatrics 2012, 129, 1166–1167.
    49. Jensen, C.L.; Voigt, R.G.; Llorente, A.M.; Peters, S.U.; Prager, T.C.; Zou, Y.L.; Rozelle, J.C.; Turcich, M.R.; Fraley, J.K.; Anderson, R.E.; et al. Effects of Early Maternal Docosahexaenoic Acid Intake on Neuropsychological Status and Visual Acuity at Five Years of Age of Breast-Fed Term Infants. J. Pediatr. 2010, 157, 900–905.
    50. Bradshaw, J.L. Developmental Disorders of the Frontostriatal System: Neuropsychological, Neuropsychiatric and Evolutionary Perspectives. Developmental Disorders of the Frontostriatal System: Neuropsychological, Neuropsychiatric and Evolutionary Perspectives; Psychology Press: New York, NY, USA, 2001.
    51. Cheatham, C.L.; Colombo, J.; Carlson, S.E. N-3 fatty acids and cognitive and visual acuity development: Methodologic and conceptual considerations. Am. J. Clin. Nutr. 2006, 83, 1458S–1466S.
    52. Klevebro, S.; Juul, S.E.; Wood, T.R. A More Comprehensive Approach to the Neuroprotective Potential of Long-Chain Polyunsaturated Fatty Acids in Preterm Infants Is Needed—Should We Consider Maternal Diet and the n-6:n-3 Fatty Acid Ratio? Front. Pediatr. 2020, 7.
    53. Santos, D.C.C.; Angulo-Barroso, R.; Li, M.; Bian, Y.; Sturza, J.; Richards, B.; Lozoff, B. Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months. Eur. J. Clin. Nutr. 2018, 72, 332–341.
    54. Morse, N.L. Benefits of Docosahexaenoic Acid, Folic Acid, Vitamin D and Iodine on Foetal and Infant Brain Development and Function Following Maternal Supplementation during Pregnancy and Lactation. Nutrents 2012, 4, 799–840.
    55. Singh, M. Essential fatty acids, DHA and human brain. Indian J. Pediatr. 2005, 72, 239–242.
    56. Dyall, S.C. Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA. Front. Aging Neurosci. 2015, 7, 52.
    57. Ferguson, K.T.; Cassells, R.C.; MacAllister, J.W.; Evans, G.W. The physical environment and child development: An international review. Int. J. Psychol. 2013, 48, 437–468.
    58. Susane, A.A.; Santos, D.N.; Bastos, A.C.; Pedromonico, M.R.M.; de Almeida-Filho, N.; Barreto, M.L. Family environment and child’s cognitive development: An epidemiological approach. Rev. Saude Publica 2005, 39, 1–6.
    59. Nguyen, P.H.; DiGirolamo, A.M.; Young, M.; Kim, N.; Nguyen, S.; Martorell, R.; Ramakrishnan, U.; Gonzalez-Casanova, I. Influences of early child nutritional status and home learning environment on child development in Vietnam. Matern. Child Nutr. 2018, 14, e12468.
    60. Pinares-Garcia, P.; Stratikopoulos, M.; Zagato, A.; Loke, H.; Lee, J. Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders. Brain Sci. 2018, 8, 154.
    61. Lemmers-Jansen, I.L.J.; Krabbendam, L.; Veltman, D.J.; Fett, A.-K.J. Boys vs. girls: Gender differences in the neural development of trust and reciprocity depend on social context. Dev. Cogn. Neurosci. 2017, 25, 235–245.