Effect of Maternal Docosahexaenoic Acid (DHA) Supplementation on Offspring Neurodevelopment at 12 Months in India: A Randomized Controlled Trial

Shweta Khandelwal, Dimple Kondal, Monica Chaudhry, Kamal Patil, Mallaiah Kenchaveeraiah Swamy, Deepa Metgud, Sandesh Jogalekar, Mahesh Kamate, Gauri Divan, Ruby Gupta, Dorairaj Prabhakaran, Nikhil Tandon, Usha Ramakrishnan, Aryeh D Stein, Shweta Khandelwal, Dimple Kondal, Monica Chaudhry, Kamal Patil, Mallaiah Kenchaveeraiah Swamy, Deepa Metgud, Sandesh Jogalekar, Mahesh Kamate, Gauri Divan, Ruby Gupta, Dorairaj Prabhakaran, Nikhil Tandon, Usha Ramakrishnan, Aryeh D Stein

Abstract

Intake of dietary docosahexaenoic acid (DHA 22:6n-3) is very low among Indian pregnant women. Maternal supplementation during pregnancy and lactation may benefit offspring neurodevelopment. We conducted a double-blind, randomized, placebo-controlled trial to test the effectiveness of supplementing pregnant Indian women (singleton gestation) from ≤20 weeks through 6 months postpartum with 400 mg/d algal DHA compared to placebo on neurodevelopment of their offspring at 12 months. Of 3379 women screened, 1131 were found eligible; 957 were randomized. The primary outcome was infant neurodevelopment at 12 months, assessed using the Development Assessment Scale for Indian Infants (DASII). Both groups were well balanced on sociodemographic variables at baseline. More than 72% of women took >90% of their assigned treatment. Twenty-five serious adverse events (SAEs), none related to the intervention, (DHA group = 16; placebo = 9) were noted. Of 902 live births, 878 were followed up to 12 months; the DASII was administered to 863 infants. At 12 months, the mean development quotient (DQ) scores in the DHA and placebo groups were not statistically significant (96.6 ± 12.2 vs. 97.1 ± 13.0, p = 0.60). Supplementing mothers through pregnancy and lactation with 400 mg/d DHA did not impact offspring neurodevelopment at 12 months of age in this setting.

Keywords: India; docosahexaenoic acid (DHA); lactation; maternal supplementation; neurodevelopment; pregnancy; randomized controlled trial (RCT).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Consort. # Reasons for exclusion: gestational diabetes (n = 69); Hb < 7 gm% (n = 46); gestational age >20 weeks (n = 673); high-risk pregnancies (n = 118); chronic conditions (n = 246); under any other trial (n = 4); delivery plan other than PK (n = 835); missing/wrong contact information (n = 257). * Others included: abortion (n = 1); abruptio placenta (n = 1); fresh stillbirth (n = 4); macerated stillbirth (n = 3); neonatal death (n = 2); maternal death (n = 1); congenital anomalies (n = 1); infant death (n = 2) in DHA group. ** Others included: fresh stillbirth (n = 4); macerated stillbirth (n = 2); medical termination (n = 1) in Placebo group.
Figure 2
Figure 2
Subgroup analysis. Difference: Placebo minus DHA; Difference in mean DQ score between DHA and placebo group at 12 months was calculated using two-sample t-test for each subgroup; p-value for interaction calculated using linear regression model including interaction term for characteristic of interest and treatment group.

References

    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. doi: 10.1016/s0140-6736(07)60032-4.
    1. Jiang X., Nardelli J. Cellular and molecular introduction to brain development. Pt ANeurobiol. Dis. 2016;92:3–17. doi: 10.1016/j.nbd.2015.07.007.
    1. 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. doi: 10.1016/j.jpeds.2016.05.013.
    1. 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. doi: 10.1093/jn/133.5.1757s.
    1. 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.
    1. 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.
    1. Meldrum S., Karen S. Docosahexaenoic Acid and Neurodevelopmental Outcomes of Term Infants. Ann. Nutr. Metab. 2016;69(Suppl. 1):22–28. doi: 10.1159/000448271.
    1. 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. doi: 10.1016/j.plefa.2012.05.004.
    1. 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. doi: 10.1016/j.plefa.2010.02.007.
    1. 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.
    1. 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. doi: 10.1016/S0140-6736(07)60277-3.
    1. Docosahexaenoic acid (DHA) Monograph. Altern. Med. Rev. 2009;14:391–399.
    1. 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. doi: 10.3390/nu8010006.
    1. Carlson S.E. Docosahexaenoic acid supplementation in pregnancy and lactation. Am. J. Clin. Nutr. 2009;89:678s–684s. doi: 10.3945/ajcn.2008.26811E.
    1. Makrides M., Gibson R. Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation. Am. J. Clin. Nutr. 2000;71(Suppl. 1):307S–311S. doi: 10.1093/ajcn/71.1.307S.
    1. 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. doi: 10.1159/000365767.
    1. Weiser M.J., Butt C.M., Mohajeri M.H. Docosahexaenoic Acid and Cognition throughout the Lifespan. Nutrients. 2016;8:99. doi: 10.3390/nu8020099.
    1. 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. doi: 10.1016/j.cegh.2017.09.003.
    1. 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. doi: 10.1111/j.1740-8709.2011.00301.x.
    1. 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. doi: 10.1016/j.plefa.2017.08.002.
    1. 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. doi: 10.32394/rpzh.2018.0044.
    1. 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. doi: 10.1016/j.plefa.2009.05.011.
    1. 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. doi: 10.1111/j.1740-8709.2011.00356.x.
    1. 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. doi: 10.1177/15648265090304S410.
    1. 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. doi: 10.1038/sj.ejcn.1602933.
    1. 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. doi: 10.1371/journal.pone.0210984.
    1. 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. doi: 10.1093/ajcn/nqz018.
    1. 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. doi: 10.1093/jn/nxy202.
    1. 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. doi: 10.1001/jama.2016.21303.
    1. 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. doi: 10.3945/ajcn.114.101071.
    1. 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. doi: 10.1001/jama.2014.2194.
    1. 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. doi: 10.3945/ajcn.112.050021.
    1. 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. doi: 10.3945/jn.110.129635.
    1. 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. doi: 10.1177/15648265100312s203.
    1. 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. doi: 10.1080/1028415x.2020.1712535.
    1. 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. doi: 10.23970/ahrqepcerta224.
    1. 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. doi: 10.1159/000129651.
    1. Khandelwal S., Swamy M.K., Patil K., Kondal D., Chaudhry M., Gupta R., Divan G., Kamate M., Ramakrishnan L., Bellad M.B., et al. The impact of DocosaHexaenoic Acid supplementation during pregnancy and lactation on Neurodevelopment of the offspring in India (DHANI): Trial protocol. BMC Pediatr. 2018;18:261. doi: 10.1186/s12887-018-1225-5.
    1. Longvah T., Bhaskarachary K., Venkaiah K., Longvah T., Aṉantaṉ I. Indian food Composition Tables. National Institute of Nutrition; Telangana, India: 2017.
    1. Patni B. Developmental Assessment Scales for Indian Infants (DASII) Ind. J. Prac. Pediatr. 2012;14:409–412.
    1. Ferreri C., Masi A., Sansone A., Giacometti G., LaRocca A.V., Menounou G., Scanferlato R., Tortorella S., Rota D., Conti M., et al. Fatty Acids in Membranes as Homeostatic, Metabolic and Nutritional Biomarkers: Recent Advancements in Analytics and Diagnostics. Diagnostics. 2016;7:1. doi: 10.3390/diagnostics7010001.
    1. Matthan N.R., Ooi E.M., Van Horn L., Neuhouser M.L., Woodman R., Lichtenstein A.H. Plasma Phospholipid Fatty Acid Biomarkers of Dietary Fat Quality and Endogenous Metabolism Predict Coronary Heart Disease Risk: A Nested Case-Control Study Within the Women’s Health Initiative Observational Study. J. Am. Hear. Assoc. 2014;3:e000764. doi: 10.1161/jaha.113.000764.
    1. Rose H.G., Oklander M. Improved Procedure for The Extraction of Lipids from Human Erythrocytes. J. Lipid Res. 1965;6:428–431.
    1. Lepage G., Roy C.C. Direct transesterification of all classes of lipids in a one-step reaction. J. Lipid Res. 1986;27:114–120.
    1. Finley D.A., Lönnerdal B., Dewey K.G., E Grivetti L. Breast milk composition: Fat content and fatty acid composition in vegetarians and non-vegetarians. Am. J. Clin. Nutr. 1985;41:787–800. doi: 10.1093/ajcn/41.4.787.
    1. 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. doi: 10.1371/journal.pone.0120065.
    1. 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. doi: 10.3945/ajcn.112.042267.
    1. 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. doi: 10.1016/j.plefa.2011.01.002.
    1. 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.
    1. 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. doi: 10.1001/jama.2010.1507.
    1. 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. doi: 10.1203/PDR.0b013e31822a59f5.
    1. 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. doi: 10.1093/cercor/bhz222.
    1. 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. doi: 10.1038/pr.2016.134.
    1. 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. doi: 10.3390/nu10050529.
    1. 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. doi: 10.3945/ajcn.112.045781.
    1. Colombo J., Carlson S.E. Is the measure the message: The BSID and nutritional interventions. Pediatrics. 2012;129:1166–1167. doi: 10.1542/peds.2012-0934.
    1. 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. doi: 10.1016/j.jpeds.2010.06.006.
    1. 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.
    1. 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. doi: 10.1093/ajcn/83.6.1458s.
    1. 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 doi: 10.3389/fped.2019.00533.
    1. 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. doi: 10.1038/s41430-017-0015-8.
    1. 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. doi: 10.3390/nu4070799.
    1. Singh M. Essential fatty acids, DHA and human brain. Indian J. Pediatr. 2005;72:239–242. doi: 10.1007/BF02859265.
    1. 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. doi: 10.3389/fnagi.2015.00052.
    1. 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. doi: 10.1080/00207594.2013.804190.
    1. 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.
    1. 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. doi: 10.1111/mcn.12468.
    1. 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. doi: 10.3390/brainsci8080154.
    1. 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. doi: 10.1016/j.dcn.2017.02.001.

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