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1. Cognitive Development in Preterm Infants 1

2. Breastfeeding is the best Start Breastfeeding ASAP, within first hour of birth. Exclusive breastfeeding till 6 months. Continue breastfeeding 2 years and beyond…..

3. Preterm birth: Born too soon Preterm birth: All births before 37 completed weeks of G estatio n Low birth weight premature infants : Birth weight <2500 grams 28 Quinn J-A et al. Vaccine. 2016 Dec 1; 34(49): 6047–6056 Extremely low birth weight (ELBW) Very low birth weight (VLBW) Low birth weight (LBW)

4. P reterm infants are physiologically im mature Preterm babies have highly vulnerable body surfaces and immature organ systems 2 1. Luu TM et al. CMAJ. 2016 Jul 12;188(10):736-746. 2. Humberg A et al. Seminars in Immunopathology (2020) 42:451–468.. 2

5. 5 Achieving appropriate growth and development is often difficult because of the special needs of the preterm infant As compared to Term infants, Preterm infants have: Difference in body composition 2 Low stores of liver glycogen 2 Low nutrients stores/ reserve 3 Reduced innate and adaptive immunity 4 Metabolic and gastrointestinal immaturity 1 Klein CJ. J Nutr . 2002 Jun;132(6 Suppl 1):1395S-577S. 2. Tudehope D et al. J Pediatr. 2013 Mar;162(3 Suppl):S72-80. 3. Czech- Kowalska J. Semin Fetal Neonatal Med. 2020 Feb;25(1):101071. 4. Melville JM, Moss TJM. Front Neurosci . 2013 May 21;7:79. Term Preterm Term gut Preterm gut Term Preterm Term Preterm Preterm

6. Infants born prematurely are predisposed to inferior outcomes Pados et al. BMC Pediatrics (2021) 21:110. Vaidya U et al. Indian J Nutri. 2017;4(1):151. Poor weight gain and body growth 2 Unmet nutritional needs in preterm infants leads to: Infection, sepsis, mortality Impaired neurodevelopment 42% of preterm infants present with problematic feeding 1

7. A ppropriate nutritional care of preterm infants can support early growth and neurodevelopment World Review of Nutrition and Dietetics, Vol. 110. Editor(s): Koletzko , B. (Munich). Better nutritional support Better neurodevelopmental outcomes Improved growth

8. Stages of nutrition support in preterm infants Su B-H. Pediatr Neonatol . 2014 Feb;55(1):5-13 HMF or appropriate milk alternative 3 2 1 Acute stage Early aggressive nutrition Growing care stage Post discharge stage

9. Preterm Infants: Immature Neurodevelopment 9 Breastmilk: The Gold Standard in Infant Nutrition. For view of Healthcare Professionals Only

10. 10 Third T rimester of Gestation is a Critical P eriod of Brain D evelopment 1. Newville J, Ortega M and Maxwell J (2018) Front. Young Minds. 6:20. doi : 10.3389/frym.2018.00020. 2. Bouyssi-Kobar M et al. Pediatrics 2016 Nov;138(5):e20161640. 3. Beke AM. Developments in Health Sciences 1(1), pp. 27–29 (2018). . Brain growth spurt Most sensitive period of brain development 3 5 months 6 months 7 months 8 months 9 months 18-21 weeks 22-26 weeks 27-30 weeks 31-35 weeks 36-40 weeks 22 weeks 25 weeks 4 times Increase in brain size occurs during the third trimester of gestation

11. 11 ` Placental transfer of fatty a cids to fetus Increased placental transfer of fatty acids occurs at later stages of pregnancy to meet the high demands of developing fetal brain Maternal side Fetal side Fetal Adipose tissue Increased fatty acids in fetal circulation DHA: 16 times higher ARA: >90 times higher than maternal fat tissues DHA= Docosahexaenoic acid ARA= Arachidonic acid Diet Absorbed Fatty acids Fetal Brain Fatty acids stored in fetal fat tissue 1. Bobiński R, Mikulska M. Acta Biochim Pol. 2015;62(3):499-507. 2. Martin CR et al. J Pediatr. 2011 November ; 159(5): 743–749.e1-2. Enables rapid development of brain

12. 12 DHA and ARA aid in neurodevelopment and neuroprotection in preterm infants Mother’s body reserves Stored in fetal cell membranes Multiplication and differentiation of brain cells Neurological and brain development ARA DHA Sambra V et al. Nutrients 2021, 13, 986 . Maternal diet Omega 6 fatty acid Omega 3 fatty acid DHA= Docosahexaenoic acid ARA= Arachidonic acid Fetal brain

13. 13 Rapid accumulation of both DHA and ARA occurs in the developing brain during the third trimester Basak S et al. Nutrients 2021,13, 2061 . DHA= Docosahexaenoic acid ARA= Arachidonic acid

14. DHA and ARA are crucial for the development of the nervous system Form components of nerve membranes Help in transmission of signals in brain Increase growth of brain cells ARA DHA J.P. Schuchardt , A. Hahn. https://doi.org/10.1533/9780857092922.1.32 . DHA= Docosahexaenoic acid ARA= Arachidonic acid DHA and ARA are the most abundant and important Long chain polyunsaturated fatty acids (LCPUFA) in brain

15. 15 Preterm Infants have deficit DHA stores due to early cessation of pregnancy Very preterm infants (<28 weeks gestation) Harris W, Baack M. J Perinatol . 2015 Jan; 35(1): 1–7. DHA deficiency persists or worsens Limited ability to convert precursor ALA to DHA Poor nutritional provision of preformed DHA and ARA Decreased adipose stores

16. 16 The DHA gap of Prematurity This difference provides a range of values in which the premature infant ideally should be maintained during the postnatal period Martin CR et al. J Pediatr. 2011 Nov; 159(5): 743–749.e1-2. Difference in DHA levels in term and preterm infants at birth

17. 17 Current preterm nutrition practices may increase the risk of post-natal DHA Deficiency Lapillonne A et al. Neonatology 2010;98:397–403 Deficiency of DHA increases from first to the end of the fourth week of life All preterm infants in the study exhibited a cumulative DHA deficit The smaller the infant, the larger the DHA deficit

18. 1. De Rooy . Clin Nutr . 2017 Dec;36(6):1593-1600 . 2. Koletzko. Am J Clin Nutr 2019;00:1–7 Extremely preterm infants receive insufficient intakes of ARA ESPGHAN & Koletzko recommendations: ARA contents in milk feed for infants should be at least equal to the contents of DHA 2 Cumulative ARA deficit increases from first to the end of the sixth week of life

19. Neurological benefits of DHA and ARA supplementation in Preterm infants Clinical evidences 19

20. 20 Preterm infants receiving standard care receive low levels of ARA and DHA Böckmann KA et al. European Journal of Nutrition (2021) 60:861–872 Less Arachidonic acid ( ARA ) Higher Linoleic acid ( LA ) Less Docosahexaenoic acid ( DHA ) Term infant Preterm infant versus Compared to Term infants, Preterm infants had: Parental nutrition is rich is linoleic acid which contributes to non-physiological fatty acid levels in preterm infants

21. 21 Higher DHA level in the first few weeks of life is associated with improved brain development in preterm infants Tam EWY et al. Pediatr Res. 2016 May ; 79(5): 723–730. F indings of brain injury on MRI scan An increase in postnatal DHA levels by 1% was associated with decreasing the risk of brain injury by 4.3 times *EPA= Eicosapentaenoic acid LA= Linoleic acid Red blood cell fatty acid composition (DHA, ARA, LA, EPA* level) was assessed DHA ARA LA EPA c ompared with

22. DHA and ARA supplementation is associated with higher problem-solving ability and long-term neurodevelopmental benefits Nonverbal cognitive and language development 2 Scores lower than 85 (out of 100) indicate neuro-impairment Evaluated using Ages and Stages Questionnaire at the 6-month follow-up evaluation Problem solving ability 1 Evaluated using Mental Development Index (MDI) 1. Henriksen C et al. Pediatrics. 2008 Jun;121(6):1137-45. 2. Fang et al. Chang Gung Med J. 2005 Oct;28(10):708-15 . Problem solving scores Mental Development Index (MDI) scores Group with DHA and ARA supplementation Control group p=0.02 p=0.02 DHA and ARA supplemented group showed significantly higher scores at 6 months

23. Lapillonne A et al. Annals of Nutrition and Metabolism . 2016; 69(Suppl 1), 36–44 .  DHA supplementation is associated with better mental development at 18 months to 2 years Improved Mental Development Index Improved Psychomotor Development Index Preterm infants fed various amounts of DHA Larger amounts of DHA supplements (≥ 0.50 % of total fatty acids) Mental development assessed at 18–20 months

24. 24 Adding DHA and ARA in alternate milk feed in balanced ratios raises DHA and ARA level Study assessing fatty acid composition of plasma and RBCs Preterm infants fed conventional milk feed Preterm infants fed DHA and ARA enriched milk feed Foreman-van Drongelen et al. British journal of nutrition (1996), 76, 64-61 Fatty acid level in plasma* DHA and ARA values of the supplemented group was similar to the level seen in breast fed preterm infants *Schematic representation

25. 25 M ilk feed with an ARA and DHA ratio of 2:1 had better psychomotor development Alshweki A et al. Nutr J. 2015;14:101. doi:10.1186/s12937-015-0091-3. Group A- ARA:DHA= 2:1 Group B- ARA:DHA= 1:1 1 child had Brunet Lézine score <85 6 children had Brunet Lézine score <85 An overall score ≥85 is considered normal Study assessing preterm child’s mental maturation level using Brunet Lezine scale 23 child had Brunet Lézine score ≥85 15 children had Brunet Lézine score ≥85 Group A with ARA:DHA ratio of 2:1 showed better mental development scores The Brunet Lezine scale provides an objective evaluation of a child’s maturation level in four areas: motor, coordination, language, and social

26. Key Take-aways 26