The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy
Abstract
:1. Introduction
1.1. Behavioral and Emotional Functioning
1.2. The Link between DHA and Behavior
2. Materials and Methods
2.1. Search Strategy
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction and Synthesis
- (a)
- Diagnosed behavioral problems (such as by a psychologist, psychiatrist or pediatrician) or use of prescription medication for a behavioral problem,
- (b)
- Clinician-administered general behavior measures and/or behavioral sub-scores of other measures,
- (c)
- Teacher-rated behavior measures,
- (d)
- Parent-rated behavior measures,
- (e)
- Self-reported behavior measures, and
- (f)
- Sensitivity and/or subgroup analyses.
3. Results
3.1. Characteristics of Included Studies
3.2. Sample and DHA Supplementation Details
3.2.1. Maternal Interventions during Pregnancy
3.2.2. Interventions for Neonates Born Preterm
3.2.3. Postnatal Interventions for Breastfeeding Mothers
3.2.4. Postnatal Interventions Directly to Infants or Toddlers
3.3. Assessments of Behavioral Functioning and Behavior Problems
- (a)
- Diagnosed behavioral problems (such as by a psychologist, psychiatrist or pediatrician) or use of prescription medication for a behavioral problem
- (b)
- Clinician-administered general behavior measures and/or behavioral sub-scores of other measures
- (c)
- Teacher-rated behavior measures
- (d)
- Parent-rated behavior measures
- (e)
- Self-reported behavior measures
- (f)
- Sensitivity and/or subgroup analyses
3.4. Effect of DHA Intervention of Behavioral Functioning
3.4.1. Maternal Interventions during Pregnancy
- (a)
- Diagnosed behavioral problems (such as by a psychologist, psychiatrist or pediatrician) or use of prescription medication for a behavioral problem
- (b)
- Clinician-administered general behavior measures and/or behavioral sub-scores of other measures
- (c)
- Teacher-rated behavior measures
- (d)
- Parent-rated behavior measures
- (e)
- Self-reported behavior measures
- (f)
- Sensitivity and/or subgroup analyses
3.4.2. Interventions for Neonates Born Preterm
- (a)
- Diagnosed behavioral problems (such as by a psychologist, psychiatrist or pediatrician) or use of prescription medication for a behavioral problem
- (b)
- Clinician-administered general behavior measures and/or behavioral sub-scores of other measures
- (c)
- Teacher-rated behavior measures
- (d)
- Parent-rated behavior measures
- (e)
- Self-reported behavior measures
- (f)
- Sensitivity and/or subgroup analyses
3.4.3. Postnatal Interventions for Breastfeeding Mothers
- (a)
- Diagnosed behavioral problems (such as by a psychologist, psychiatrist or pediatrician) or use of prescription medication for a behavioral problem
- (b)
- Clinician-administered general behavior measures and/or behavioral sub-scores of other measures
- (c)
- Teacher-rated behavior measures
- (d)
- Parent-rated behavior measures
- (e)
- Self-reported behavior measures
- (f)
- Sensitivity and/or subgroup analyses
3.4.4. Postnatal Interventions Directly to Infants or Toddlers
- (a)
- Diagnosed behavioral problems (such as by a psychologist, psychiatrist or pediatrician) or use of prescription medication for a behavioral problem
- (b)
- Clinician-administered general behavior measures and/or behavioral sub-scores of other measures
- (c)
- Teacher-rated behavior measures
- (d)
- Parent-rated behavior measures
- (e)
- Self-reported behavior measures
- (f)
- Sensitivity and/or subgroup analyses
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Author and Reference | Setting Country; Place of Recruitment | Participants Sample Randomized Sample Characteristics | Intervention Duration, Form, Treatment and Control Intervention | Assessment Age, n Outcome Measure | Result |
---|---|---|---|---|---|
Maternal Prenatal Interventions | |||||
Tofail, 2006 [80] | Bangladesh; house-to-house survey | N enrolled: 400 Trt:200, ctrl:200 Third-world setting with endemic poverty, illiteracy, poor hygiene, overcrowding and poor housing | Duration: 25 week preg to birth Form: 4 capsules daily Trt: n-3 3000 mg/day, DHA 1200 mg/day Ctrl: soy oil | Age: 10 mo, n = 249 | |
Wolke | |||||
-scores: 5 | No diff | ||||
Judge, 2006 [81] | USA; hospital | N enrolled: 48 Trt:27, ctrl:21 | Duration: 24 week preg to birth Form: cereal bar Trt: n-3240 mg/bar, average DHA 240 mg/day Ctrl: corn oil | Age: 6 mo, n = 38 | |
ICQ | No diff | ||||
-sub-scores: 4 | No diff | ||||
Age 12 mo, n = 28 | |||||
RITQ | No diff | ||||
-sub-scores: 9 | No diff | ||||
Dunstan, 2008 [84]; Meldrum, 2015 [85] | Australia; antenatal clinic | N enrolled: 98 Trt:52, ctrl:46 All had allergic disease Excluded: normal diet includes >2 fish meals/week | Duration: 20 week preg to birth Form: 4 capsules daily Trt: n-3 3300 mg/day, DHA 2200 mg/day Ctrl: olive oil | Age: 2.5 years, n = 71 | |
GMDS | No diff | ||||
CBCL | No diff | ||||
-sub-scores: 2 | No diff | ||||
Age: 12 years, n = 50 | |||||
CBCL parent | No diff | ||||
-sub-scores: 3 | No diff | ||||
CBCL child | No diff | ||||
-sub-scores: 3 | No diff | ||||
Makrides, 2010 [86]; Makrides, 2014 [87]; Gould, 2017 [88] | Australia; antenatal clinic | N enrolled: 2399 Trt:1197, ctrl:1202 Singletons Subset for neurodevelopmental follow-up n = 726 (preterm and randomly selected term) | Duration: 18–21 week preg to birth Form: 3 capsules daily Trt: 800 mg DHA/day Ctrl: vegetable oil | Age: 18 mo, n = 726 | |
Bayley-III S-E | No diff | ||||
-subgroup: girls/boys | No diff | ||||
Bayley-III A-B | No diff | ||||
-subgroup: girls/boys | Trt girls worse | ||||
Age: 4 years, n = 646 | |||||
SDQ | Trt worse | ||||
-sub-scores: 6 | 1—Trt worse, 5—No diff | ||||
-subgroup: girls/boys | No diff | ||||
BRIEF-P | No diff | ||||
-sub-scores: 8 | 2—Trt worse, 6—No diff | ||||
-subgroup: girls/boys | No diff | ||||
Diagnoses | No diff | ||||
Age: 7 years, n = 543 | |||||
SDQ | Trt worse | ||||
BRIEF | Trt worse | ||||
-sub-scores: 2 | 2—Trt worse | ||||
Conners 3TM AI-P | Trt worse | ||||
Diagnoses | No diff | ||||
Ramakrishnan, 2010 [89]; Ramakrishnan, 2016 [90] | Mexico; antenatal clinic | N enrolled: 1094 Trt:547, ctrl:547 Medium–low SES Excluded: if taking n-3 | Duration: 18–22 weeks preg to birth Form: 2 capsules daily Trt: 400 mg/day DHA Ctrl: olive oil | Age: 5 years, n = 797 | |
BASC-2 | No diff | ||||
-scores: 4 | No diff | ||||
-sub-scores: 19 | No diff | ||||
-subgroup: girls/boys | No diff | ||||
-subgroup: maternal intelligence | No diff | ||||
-subgroup: SES | No diff | ||||
-subgroup: home environment | No diff | ||||
Carlson, 2013 [82]; Colombo, 2019 [83] | USA; antenatal clinics | N enrolled: 350 Trt:178, ctrl:172 Singleton, healthy, normal BMI | Duration: mean 14.5 weeks preg to birth Form: 3 daily capsules Trt: 600 mg/day DHA Ctrl: soy and corn oil | Age: 18 mo, n = 186 | |
Bayley-II BRS | No diff | ||||
Age: 36 mo, n = 141 | |||||
BASC-2 | |||||
-scores: 4 | No diff | ||||
Age: 48 mo, n = 140 | |||||
BASC-2 | |||||
-scores: 4 | No diff | ||||
Age: 60 mo, n = 140 | |||||
BASC-2 | |||||
-sub-scores: 4 | No diff | ||||
Age: 72 mo, n = 140 | |||||
BASC-2 | |||||
-sub-scores: 4 | No diff | ||||
Strom, 2013 [91] | Denmark; antenatal clinic | N enrolled: NR Trt:NR, ctrl:NR Singletons | Duration: NR Form: capsules Trt: 1 g DHA/day Ctrl: NR | Age: 14–20 years, n = 1051 | |
ADHD cases from registry | No diff | ||||
Miller, 2016 [92] | USA; antenatal clinic | N enrolled: 115 Trt:60, ctrl:55 Singletons | Duration: 24–28 weeks preg to 3 mo Form: capsules Trt: 300 mg DHA + 67 mg EPA/day Ctrl: sunflower oil | Age: 4 mo, n = 91 | |
Bayley-III S-E | No diff | ||||
-subgroup: girls/boys | No diff | ||||
Bayley-III A-B | No diff | ||||
-subgroup: girls/boys | No diff | ||||
Age: 12 mo, n = 83 | |||||
Bayley-III S-E | No diff | ||||
-subgroup: girls/boys | No diff | ||||
Bayley-III A-B | No diff | ||||
-subgroup: girls/boys | No diff | ||||
Ostradrahimi, 2017 [93] | Iran; health care centres | N enrolled: 150 Trt:75, ctrl: 75 | Duration: 20 weeks preg to 30 days Form: capsules Trt: 120 mg DHA + 180 mg EPA/day Ctrl: liquid paraffin | Age: 4 mo, n = 148 | |
ASQ S-P | No diff | ||||
Age: 6 mo, n = 146 | |||||
ASQ S-P | No diff | ||||
Brei, 2017 [94] | Germany; NR | N enrolled: 208 Trt:104, ctrl:104 | Duration: 15 weeks preg to 4 mo Form: capsules (+ dietary counselling to lower AA intake) Trt: 1020 mg DHA + 180 mg EPA/day Ctrl: general dietary information | Age: 4 years, n = 119 | |
CDI | No diff | ||||
Age: 5 years, n = 130 | |||||
CDI | No diff | ||||
Interventions for Preterm (Born <37 Weeks’ Gestation) Neonates | |||||
Fewtrell, 2002 [95] | UK; neonatal units | N enrolled: 195 Trt:95, ctrl:100 <37 week, birthweight <1750 g, FF | Duration: <10 days until discharge Form: formula Trt: LCPUFA formula Ctrl: standard formula | Age: 9 mo, n = 158 | |
KPSDSI | |||||
-score: 2 | No diff | ||||
Fewtrell, 2004 [96]; Isaacs, 2011 [97] | UK; neonatal units | N enrolled: 238 Trt:122, ctrl:116 <35 week, birthweight ≤ 2000 g FF | Duration: before discharge to 9 mo CA Form: formula Trt: LCPUFA formula Ctrl: standard formula | Age: 9 mo C,A n = 117 | |
KPSDSI | No diff | ||||
Age: 10years, n = 107 | |||||
BADSC | No diff | ||||
-subgroup: girls/boys | No diff | ||||
Henriksen, 2008 [103]; Westerberg, 2011 [104] | Norway; neonatal units | N enrolled: 141 Trt:68, ctrl:73 Birthweight<1500 g BF only | Duration: from enteral feeds to discharge from hospital or infant finished the 100 mL bottle of oil Form: oil added to breastmilk Trt: 32 mg DHA + 31 mg AA/100 mL breastmilk Ctrl: soy oil | Age: 6 mo CA, n = 105 | |
ASQ S-P | No diff | ||||
Age: 20 mo CA, n = 92 | |||||
ASQ S-P | No diff | ||||
Makrides, 2009 [98]; Smithers, 2010 [99]; Collins, 2015 [100] | Australia; neonatal units | N enrolled: 657 Trt:322, ctrl:335 Singletons and multiples <33 week Small subset for follow-up at 26 mo FF and BF | Duration: <5 days of starting full enteral feeds to term equivalent Form: preterm infant formula, 6 capsules daily to breastfeeding mothers Trt: formula 1% DHA Ctrl: formula 0.35% DHA | Age: 3–5 years CA, n = 125 | |
SDQ | No diff | ||||
-sub-scores: 5 | No diff | ||||
STSC | No diff | ||||
-sub-scores: 5 | 1—Trt worse, 5—No diff | ||||
Health care consultation | Trt worse | ||||
Prescription medication | No diff | ||||
Age: 7 years CA, n = 604 | |||||
SDQ | No diff | ||||
-sub-scores: 6 | No diff | ||||
-subgroup: girls/boys | 1—Trt girls worse, 5—No diff | ||||
-subgroup: birthweight <1250 g/≥1250 g | No diff | ||||
BRIEF | No diff | ||||
-sub-scores: 10 | No diff | ||||
-subgroup: girls/boys | 5—Trt girls worse, 6—No diff | ||||
-subgroup: birthweight <1250 g/≥1250 g | No diff | ||||
Conners 3TM AI-P | No diff | ||||
-subgroup: girls/boys | Trt girls worse | ||||
-subgroup: birthweight <1250 g/≥1250 g | No diff | ||||
Diagnoses | No diff | ||||
Prescription medication | No diff | ||||
Keim, 2018 [101,102] | USA; neonatal intensive care units | N enrolled: 377 Trt:189, ctrl:188 Singletons and multiples <35 week, no longer FF or BF | Duration: 10–16 mo CA for 6 mo Form: dissoluble powder Trt: 200 mg DHA + 200 mg AA/day Ctrl: 400 mg corn oil/day | Age: 16–22 mo, n = 377 | |
IBQ-R/ECBQ | |||||
-scores: 2 | No diff | ||||
-subgroup: higher household income | 1—Trt worse, 1—No diff | ||||
-subgroup: girls/boys | No diff | ||||
-subgroup: birthweight <1250 g/≥1250 g | No diff | ||||
BITSEA | |||||
-scores: 14 | No diff | ||||
-subgroup: girls/boys | No diff | ||||
PDDST-II | 13—No diff, 1—Trt girls better | ||||
-scores: 2 | 1—No diff, 1—Trt better | ||||
-subgroup: girls/boys | 1—No diff, 1—Trt boys better | ||||
Andrew, 2018 [105] | UK; neonatal units | N enrolled: 59 Trt:29, ctrl:30 Singletons <31 week/with risk of neurodevelopmental impairment (such as brain injury) | Duration: from full milk feeds for 2 years Form: sachet to mix with milk or food Trt: DHA 1% fatty acids Ctrl: no DHA | Age: 12 mo, n = 41 | |
VABS-II | No diff | ||||
Age: 24 mo, n = 41 | |||||
VABS-II | No diff | ||||
Postnatal Interventions for Breastfeeding Mothers | |||||
Cheatham, 2011 [107] | Denmark; antenatal GP visit (via Danish National Birth Cohort) | N enrolled: 175 Trt:62, ctrl:60, Ref:53 Healthy term infants BF Habitual fish intake below Danish median | Duration: <7days for 4 mo Form: muesli bars, cookies and capsules Trt: 4.5 g fish oil, 1.5 g LCPUFA Ctrl: olive oil Ref: high habitual fish intake | Age: 7 years, n = 98 | |
SDQ | No diff | ||||
-sub-score:5 | No diff | ||||
-subgroup: girls/boys | 5—No diff, 1—Trt boys worse | ||||
Argaw, 2018 [106] | Ethiopia; NR | N enrolled: 360 Trt1:90, Trt2:89, Trt3:90, ctrl:91 BF healthy singletons | Duration: 6–12 mo for 12 mo Form: mother—capsules, child—complimentary food supplements Trt1:mother—215 mg DHA + 285 mg EPA, child—169 mg DHA + 331 mg EPA Trt2:mother—215 mg DHA + 285 mg EPA Trt3: child—169 mg DHA + 331 mg EPA ctrl: mother—corn oil, child—corn + soy oil | Age: baseline, 6–12 mo, n = NR | |
Denver | No diff | ||||
ASQ S-E | No diff | ||||
Age: after 6 mo, 12–18 mo, n = 326 | |||||
Denver | No diff | ||||
ASQ S-E | No diff | ||||
Age: after 12 mo, 18–24 mo, n = 313 | |||||
Denver | No diff | ||||
ASQ S-E | No diff | ||||
Postnatal Interventions Directly to Infants and Toddlers | |||||
Auestad, 2001 [108] | USA; children’s hospital | N enrolled: 404 Trt1:82, Trt2:80, ctrl:77, BF:165 Healthy term born FF | Duration: <7 days to 12 mo Form: formula Trt1: 0.13% DHA—egg Trt2: 0.13% DHA—fish/fungal Ctrl: no LCPUFA BF: Trt1 and Trt2 formula if stopped BF | Age 6 mo, n = 239 | |
IBQ | |||||
-scores: 6 | 1—Trt worse, 5—No diff | ||||
Bayley-II BRS | No diff | ||||
Age 12 mo, n = 239 | |||||
IBQ | |||||
-scores: 6 | 1—Trt worse, 5—No diff | ||||
Bayley-II BRS | No diff | ||||
Lucas, 1999 [112] | UK; hospitals | N enrolled: 447 Trt:155, ctrl:154, BF:138 Term born FF | Duration: <7 days to 6 mo Form: formula Trt: 0.32% DHA Ctrl: no DHA | Age: 9 mo, n = 241 + BF = NR | |
KPSDSI | No diff | ||||
Birch, 2000 [109] | USA; hospitals | N enrolled: 119 Trt1:26, Trt2:27, ctrl:26, BF:40 Healthy term born FF | Duration: <5 days to 17 weeks Form: formula Trt1: 0.35% DHA Trt2: 0.36% DHA Ctrl: no DHA BF: no formula | Age: 18 mo, n = 76 | |
Bayley-II BRS | No diff | ||||
de Jong, 2012 [111] | Netherlands; antenatal clinics | N enrolled:474 Trt:145, ctrl:169, BF:160 Healthy term born FF | Duration: 2 mo to 6 mo Form: formula Trt: 0.3% DHA + 0.45% AA Ctrl: no DHA BF: Trt formula if stopped BF | Age: 9 years, n = 341 | |
CBCL-Parent | No diff | ||||
CBCL-Teacher | No diff | ||||
Drover, 2011 [110] | USA; hospitals | N enrolled: 159 Trt1:38, Trt2:39, Trt3:40, ctrl:42 Healthy full-term singletons Low SES FF | Duration: 1–9 days to 12 mo Form: formula Trt1: 0.32% DHA Trt2: 0.64% DHA Trt3: 0.96% DHA Ctrl: no DHA | Age: 18 mo, n = 92 | |
Bayley-II BRS | No diff | ||||
Phuka, 2012 [115] | Malawi; rural community with prevalent stunting | N enrolled: 182 Trt1:61, Trt2:61, Ctrl:60 | Duration: 6 mo to 18 mo Form: micronutrient complementary food Trt1: 50 g micronutrient-fortified lipid spread; DHA dose NR Trt2: 25 g micronutrient-fortified lipid spread, DHA dose NR Ctrl: micronutrient-fortified corn–soy flour | Age 18 mo, n = 163 | |
GMDS | No diff | ||||
Meldrum, 2012 [113]; Meldrum, 2020 [114] | Australia; antenatal clinic | N enrolled: 420 Trt:218, ctrl:202 All mothers had allergic disease FF and BF Excluded preterm | Duration: birth to 6 mo Form: oil capsules Trt: 250–280 mg/day DHA Ctrl: olive oil | Age:18 mo, n = 413 | |
Bayley-III S-E | No diff | ||||
-sub-score: 1 | No diff | ||||
Bayley-III A-B | No diff | ||||
CBCL (n = 269) | No diff | ||||
-sub-score: 13 | 12—No diff,1—Trt worse | ||||
Age: 6 years, n = 303 | |||||
AQ-Child | No diff | ||||
CBCL | No diff | ||||
-sub-scores: 3 | 2—No diff, 1—Trt worse | ||||
-subgroup: girls/boys | Trt boys worse | ||||
TRF | No diff | ||||
GRS, n = 66 | No diff |
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Gould, J.F.; Roberts, R.M.; Makrides, M. The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy. Nutrients 2021, 13, 415. https://doi.org/10.3390/nu13020415
Gould JF, Roberts RM, Makrides M. The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy. Nutrients. 2021; 13(2):415. https://doi.org/10.3390/nu13020415
Chicago/Turabian StyleGould, Jacqueline F., Rachel M. Roberts, and Maria Makrides. 2021. "The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy" Nutrients 13, no. 2: 415. https://doi.org/10.3390/nu13020415