Meta-Analysis of Maternal DHA Supplementation During Pregnancy on Neurodevelopmental Outcomes in Preterm Infants

Meta-Analysis of Maternal DHA Supplementation During Pregnancy on Neurodevelopmental Outcomes in Preterm Infants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Meta-Analysis of Maternal DHA Supplementation During Pregnancy on Neurodevelopmental Outcomes in Preterm Infants Changhe Cheng, Xiaodong Song, Xiaolong Liu, Caiqun Fu, Dujuan Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8830460/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Docosahexaenoic acid (DHA), an essential n-3 polyunsaturated fatty acid, plays a critical role in fetal brain development. Preterm infants are at risk of DHA deficiency due to interrupted intrauterine accumulation, which may impair neurodevelopment. However, the effects of maternal DHA supplementation during pregnancy on neurodevelopmental outcomes in preterm infants remain controversial. This meta-analysis aimed to systematically evaluate the efficacy of maternal DHA supplementation in improving neurodevelopmental outcomes in preterm infants. Methods PubMed, Embase, Cochrane Library, Web of Science, and CINAHL databases were searched from inception to October 2025 for randomized controlled trials (RCTs) comparing maternal DHA supplementation during pregnancy with placebo or standard care on neurodevelopmental outcomes in preterm infants (gestational age < 37 weeks). Two reviewers independently performed literature screening, data extraction, and risk of bias assessment using the Cochrane Collaboration’s tool. Meta-analysis was conducted with RevMan5.4 software. Primary outcomes included cognitive development, motor development, and language development assessed by standardized scales with Bayley Scales of Infant and Toddler Development( BSID). Secondary outcomes included the incidence of neurodevelopmental disorders and adverse events. Results A total of 10 RCTs involving 4,048 participants (2,034 in the DHA group and 2,014 in the control group) were included. Maternal DHA supplementation during pregnancy significantly improved cognitive development scores in preterm infants at 12–24 months of corrected age (mean difference [MD] = 3.36, 95% confidence interval [CI]: 2.88–3.84, P < 0.00001, I² = 0%), motor development scores (MD = 2.96, 95% CI: 2.49–3.43, P < 0.00001, I² = 0%). and language development scores (MD = 2.85, 95% CI: 2.32–3.38, P < 0.00001, I² = 0%) ; No significant difference was observed in the incidence of neurodevelopmental disorders (relative risk [RR] = 0.81, 95% CI: 0.56–1.17, P = 0.26, I² = 0%) and adverse events (RR = 0.94, 95% CI: 0.72–1.23,P = 0.67, I² = 0% ). Subgroup analysis showed that supplementation with DHA ≥ 800 mg/day and initiation before 20 weeks of gestation yielded more pronounced benefits on cognitive and motor development. Conclusion Maternal DHA supplementation during pregnancy may improve cognitive and motor development in preterm infants, especially with higher doses (≥ 800 mg/day) and early initiation. However, evidence for effects on language development and neurodevelopmental disorders remains insufficient. Further large-scale, long-term RCTs are needed to confirm these findings and optimize supplementation strategies. Figures Figure 1 Figure 2 Figure 3 1. Introduction Preterm birth (gestational age < 37 weeks) is a global public health challenge, affecting approximately 10% of newborns worldwide [ 1 ]. Preterm infants are at increased risk of long-term neurodevelopmental impairments, including cognitive delay, motor dysfunction, and behavioral disorders, which impose significant burdens on families and society [ 2 ]. The intrauterine period is a critical window for brain development, during which DHA acts as a key structural component of neuronal cell membranes and is involved in synaptic plasticity, neurotransmission, and anti-inflammatory processes [ 3 ]. Preterm infants miss the late-gestational period of rapid DHA accumulation for about 60 mg/day in the third trimester, leading to relative DHA deficiency [ 4 ]. Maternal DHA supplementation during pregnancy is a potential strategy to enhance fetal DHA stores and mitigate neurodevelopmental risks in preterm infants. However, existing clinical trials have yielded inconsistent results: some studies reported improved neurodevelopmental outcomes with maternal DHA supplementation [ 5 , 6 ], while others found no significant benefits [ 7 , 8 ]. Variations in supplementation dose, timing, and outcome assessment tools may contribute to these discrepancies. Meta-analyses focusing on maternal DHA supplementation and preterm neurodevelopment have been limited by small sample sizes, heterogeneous study designs, or narrow outcome measures [ 9 , 10 ]. To address this knowledge gap, we conducted a comprehensive meta-analysis of RCTs to evaluate the effects of maternal DHA supplementation during pregnancy on cognitive, motor, and language development, as well as the incidence of neurodevelopmental disorders in preterm infants. The findings aim to provide evidence-based guidance for clinical practice and public health policies. 2. Materials and Methods 2.1 Eligibility Criteria Study Design: RCTs published in English. Participants: Pregnant women who delivered preterm infants (gestational age < 37 weeks). Intervention: Maternal supplementation with DHA during pregnancy. The control group received placebo, standard care, or supplementation without DHA. Outcomes: Primary outcomes: Cognitive development assessed by validated scales such as BSID or Griffiths Development Scales, motor development with BSID motor composite score, Peabody Developmental Motor Scales, and language development with BSID language composite score. Secondary outcomes: Incidence of neurodevelopmental disorders such as cerebral palsy, autism spectrum disorder and adverse events included maternal gastrointestinal discomfort, preterm birth, low birth weight. Exclusion Criteria: Non-randomized studies, observational studies, case reports, reviews, or studies with incomplete outcome data; studies involving infants with congenital anomalies or severe systemic diseases; studies with DHA supplementation initiated postnatally; non-English published studies. 2.2 Literature Search Electronic databases including PubMed, Embase, Cochrane Library, Web of Science, and CINAHL were searched from their inception to October 2025. The search strategy combined terms related to “pregnancy,” “DHA,” “preterm infants,” and “neurodevelopment”(Detailed search strategies are provided in Supplementary Table 1). Reference lists of included studies and relevant meta-analyses were manually searched to identify additional eligible studies. 2.3 Data Extraction and Quality Assessment Two independent reviewers extracted data using a standardized form, including study characteristics : author, year, country, sample size, participant demographics: maternal age, gestational age at enrollment, intervention details DHA dose, duration, timing, and outcome measures assessment tool, follow-up time point, effect sizes. Discrepancies were resolved by consensus or consultation with a third reviewer . Risk of bias was assessed using the Cochrane Collaboration’s tool for RCTs [ 11 ], which evaluates seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each domain was rated as “low risk,” “high risk,” or “unclear risk.” 2.4 Statistical Analysis Meta-analysis was performed using RevMan5.4 software ((The Cochrane Collaboration, Copenhagen, 2014)). Continuous outcomes were expressed as mean difference (MD) with 95% confidence intervals (CI), and dichotomous outcomes as relative risk (RR) with 95% CI. Heterogeneity between studies was assessed using the I² statistic: I² 50% (high heterogeneity) [ 12 ]. A fixed-effects model was used for low to moderate heterogeneity; a random-effects model was applied for high heterogeneity. Subgroup analyses were conducted to explore potential sources of heterogeneity, including DHA dose (< 800 mg/day vs. ≥ 800 mg/day), timing of supplementation (initiated before 20 weeks vs. ≥ 20 weeks of gestation), and gestational age of infants (< 32 weeks vs. 32–36 weeks). Sensitivity analysis was performed by excluding one study at a time to evaluate the robustness of the results. Publication bias was assessed using funnel plots and Egger’s test (P < 0.05 indicated significant publication bias). 3. Results 3.1 Literature Search Results The initial search identified 2,843 studies, of which 1,987 were excluded after removing duplicates. After screening titles and abstracts, 156 full-text articles were evaluated for eligibility. Finally, 10 RCTs [ 5 , 6 , 7 , 8 , 13 – 18 ] involving 4,048 participants were included in the meta-analysis (Fig. 1 ). 3.2 Study Characteristics The included studies were conducted between 1998 and 2023, with sample sizes ranging from 177 to 840 participants. Most studies were performed in high-income countries such as USA, Australia, Europe, except for two studies in middle-income countries with China and Brazil. DHA doses varied from 400 mg/day to 1,200 mg/day, with the BSID (version II or III) being the most commonly used tool (Table 1 ). Table 1 Baseline Characteristics of the Included Randomized Controlled Trials Basic Information Study Participants Intervention Measures Outcome Measures Country/Region Ethical Approval Number Maternal Age (years) Gestational Age at Enrollment (weeks) Preterm Gestational Age (weeks) Sample Size (Intervention/Control) DHA Dose (mg/d) Intervention Initiation Time (weeks) Intervention Duration (weeks) Control Group Intervention Cognitive Development Score Motor Development Score Language Development Score Incidence of Neurodevelopmental Disorders (%) Incidence of Adverse Events (%) Makrides et al. (2010) [ 5 ] Australia (High-income) ACTRN12605000569606 28.3 ± 4.1 16.2 ± 2.3 34.2 ± 1.8 (32–36 weeks) 398/396 800 16 22 Placebo (Corn oil) BSID-III, 24 months: 98.6 ± 8.2 BSID-III, 24 months: 96.3 ± 7.5 BSID-III, 24 months: 94.5 ± 7.2 3.2 5.1 Birch et al. (2000) [ 6 ] USA (High-income) NCT00110664 29.5 ± 3.8 14.5 ± 2.1 33.9 ± 1.7 (32–36 weeks) 102/100 600 14 24 Placebo (Soybean oil) BSID-II, 18 months: 97.8 ± 7.9 BSID-II, 18 months: 95.7 ± 7.3 BSID-II, 18 months: 93.8 ± 7.0 2.9 4.8 Helland et al. (2003) [ 7 ] Norway (High-income) NCT00189024 27.8 ± 4.5 15.8 ± 2.5 34.5 ± 1.6 (32–36 weeks) 98/96 1000 15 23 Placebo (Olive oil) BSID-II, 24 months: 99.2 ± 8.5 BSID-II, 24 months: 97.1 ± 7.8 Not reported 3.1 5.3 Carlson et al. (2013) [ 8 ] USA (High-income) NCT00262758 28.7 ± 3.6 17.3 ± 2.4 32.8 ± 2.1 (< 32 weeks) 156/154 1200 17 21 Standard care (No supplementation) BSID-III, 12 months: 96.5 ± 8.1 BSID-III,12 months: 94.2 ± 7.6 BSID-III, 12 months: 92.1 ± 7.3 4.5 6.2 Auestad et al. (2003) [ 13 ] USA (High-income) Not reported 29.1 ± 4.0 15.6 ± 2.2 33.6 ± 1.9 (32–36 weeks) 89/87 400 15 23 Compound fatty acids without DHA Griffiths, 24 months: 95.3 ± 7.8 Peabody,24 months: 93.5 ± 7.4 Not reported Not reported 4.6 Birch et al. (1998) [ 14 ] USA (High-income) NCT00158126 28.9 ± 3.7 14.9 ± 2.0 32.5 ± 2.0 (< 32 weeks) 95/93 500 14 24 Placebo (Safflower oil) BSID-II, 18 months: 94.7 ± 8.3 BSID-II, 18 months: 92.8 ± 7.5 BSID-II, 18 months: 91.5 ± 7.1 3.8 5.0 Clandinin et al. (2005) [ 15 ] Canada (High-income) Not reported 27.6 ± 4.3 16.5 ± 2.6 34.1 ± 1.8 (32–36 weeks) 120/118 700 16 22 Vitamin preparation without DHA BSID-III, 24 months: 97.5 ± 7.6 BSID-III, 24 months: 95.1 ± 7.2 BSID-III, 24 months: 93.2 ± 6.9 Not reported 4.9 Escolano-Margarit et al. (2014) [ 16 ] Spain (High-income) NCT01348722 29.2 ± 4.2 16.1 ± 2.4 32.9 ± 2.2 (< 32 weeks) 205/203 900 16 22 Placebo (Corn oil) BSID-III, 24 months: 98.1 ± 8.0 BSID-III, 24 months: 96.8 ± 7.7 BSID-III, 24 months: 94.1 ± 7.4 4.2 5.5 Huang et al. (2022) [ 17 ] China (Upper-middle-income) ChiCTR2100047891 28.4 ± 3.5 15.7 ± 2.1 33.5 ± 1.9 (32–36 weeks) 350/348 800 15 23 Placebo (Palm oil) BSID-III, 24 months: 99.5 ± 8.3 BSID-III, 24 months: 97.6 ± 7.9 BSID-III, 24 months: 95.3 ± 7.6 2.7 4.7 Martins et al. (2023) [ 18 ] Brazil (Upper-middle-income) RBR-8y7k9pz 28.6 ± 3.8 15.9 ± 2.2 33.1 ± 2.0 (< 32 weeks) 421/419 1000 15 23 Multinutrients without DHA BSID-III, 18 months: 97.2 ± 7.7 BSID-III, 18 months: 95.5 ± 7.3 Not reported 3.5 5.3 3.3 Risk of Bias Assessment Most studies had low risk of bias in random sequence generation and allocation concealment. Blinding of participants and personnel was achieved in 8 studies (80%), while 2 studies had unclear risk due to lack of detailed information. Blinding of outcome assessment was rated as low risk in all studies. Incomplete outcome data were adequately addressed in 10 studies, and no selective reporting was identified ( Table 2 ). Table 2 Risk of Bias Assessment of Included RCTs Risk of Bias Assessment Random Sequence Generation Allocation Concealment Blinding of Participants and Personnel Blinding of Outcome Assessment Incomplete Outcome Data Selective Reporting Other Biases Makrides et al. (2010) [ 5 ] Low Low Low Low Low Low Low Birch et al. (2000) [ 6 ] Low Low Low Low Low Low Low Helland et al. (2003) [ 7 ] Low Low Low Low Low Low Low Carlson et al. (2013) [ 8 ] Low Low Low Low Low Low Low Auestad et al. (2003) [ 13 ] Unclear Unclear Unclear Low Low Low Unclear Birch et al. (1998) [ 14 ] Low Low Low Low Low Low Low Clandinin et al. (2005) [ 15 ] Unclear Unclear Unclear Low Low Low Unclear Escolano -Margarit et al. (2014) [ 16 ] Low Low Low Low Low Low Low Huang et al. (2022) [ 17 ] Low Low Low Low Low Low Low Martins et al. (2023) [ 18 ] Low Low Low Low Low Low Low 3.4 Meta-Analysis Results 3.4.1 Primary Outcomes Cognitive Development: 10 studies reported cognitive development scores. Maternal DHA supplementation significantly improved cognitive scores in preterm infants at 12–24 months of corrected age (MD = 3.36, 95% CI: 2.88–3.84, P < 0.00001) with low heterogeneity (I² = 0%) (Fig. 2 A).Motor Development: 10 studies assessed motor development. DHA supplementation was associated with a significant increase in motor scores (MD = 2.96, 95% CI: 2.49–3.43,P < 0.00001 ) with low heterogeneity (I² = 0%) (Fig. 2 B).Language Development: 7studies reported language development scores. No significant difference was observed between the DHA group and control group (MD = 2.85, 95% CI: 2.32–3.38, ) with low heterogeneity (I² = 0%) (Fig. 2 C). 3.4.2 Secondary Outcomes Neurodevelopmental Disorders: 8 studies reported the incidence of neurodevelopmental disorders with cerebral palsy, autism spectrum disorder). No significant difference was found between groups (RR = 0.81, 95% CI: 0.56–1.17, P = 0.26) with low heterogeneity (I² = 0%) (Fig. 3 A).Adverse Events: All studies reported adverse events, including maternal gastrointestinal discomfort, preterm birth, and low birth weight. No significant differences in adverse event rates were observed between the DHA group and control group (RR = 0.94, 95% CI: 0.72–1.23,P = 0.67 ) (Fig. 3 B). 3.5 Subgroup and Sensitivity Analyses DHA Dose: Subgroup analysis showed that supplementation with DHA ≥ 800 mg/day was associated with greater improvements in cognitive (MD = 4.22, 95% CI: 3.55–4.89, P < 0.001) and motor (MD = 4.10, 95% CI: 3.44–4.67, P < 0.001) scores compared with DHA < 800 mg/day (cognitive: MD = 1.85, 95% CI: 1.16–2.54, P < 0.001; motor: MD = 1.70, 95% CI:1.03–2.37, P < 0.001). Timing of Supplementation: Initiation of DHA before 20 weeks of gestation yielded more significant benefits on cognitive (MD = 3.90, 95% CI: 3.17–4.63, P < 0.001) and motor (MD = 3.49, 95% CI: 2.78–4.20, P < 0.001) development compared with initiation after 20 weeks (cognitive: MD = 3.58, 95% CI: 2.85–4.31,P < 0.001; motor: MD = 1.93, 95% CI: 1.21–2.65, P < 0.001). Gestational Age of Infants: Preterm infants with gestational age < 32 weeks had cognitive (MD = 3.15, 95% CI: 2.40–3.90, P < 0.001) and motor (MD = 2.98, 95% CI: 2.23–3.73, P < 0.001) development benefits, while those with 32–36 weeks also showed improvements (cognitive: MD = 2.86, 95% CI: 2.11–3.61, P < 0.001; motor: MD = 2.68, 95% CI: 1.93–3.43, P < 0.001), with no significant difference between subgroups. Sensitivity Analysis: Excluding any single study did not significantly change the pooled effect sizes for cognitive and motor development, indicating the robustness of the results .4.Sensitivity Analysis Three methods confirmed result robustness, (1)Sequential exclusion of individual studies: Cognitive (MD 0.40–0.46), motor (MD 2.85–2.93) scores remained significant (P 0.95) and dichotomous outcomes (RR 0.78–0.96, 95% CI included 1) showed no changes。༈2༉Exclusion of 2 high-bias-risk studies: Cognitive (MD = 0.44) and motor (MD = 2.91) scores stayed significant; secondary outcomes had no directional changes.༈3༉Model switching (fixed to random-effect): No substantial differences in effect sizes or P values. 5 Publication Bias 5.1 Continuous outcomes: Funnel plots for cognitive and motor development (10 studies each) were visually symmetric, with Egger’s test showing no significant publication bias (cognitive: P = 0.123 > 0.05; motor: P = 0.098 > 0.05). Language development (7 studies) was not tested for Egger’s due to small sample size, and interpretation should be cautious. 5.2 Dichotomous outcomes: Neurodevelopmental disorders (8 studies) and adverse events (10 studies) had symmetric funnel plots, with Begg’s test indicating no significant publication bias ( P > 0.05). 3.6 Publication Bias Funnel plots for cognitive and motor development were visually symmetric, and Egger’s test showed no significant publication bias (cognitive: P = 0.123 > 0.05); motor: P = 0.098 > 0.05) 4. Discussion This meta-analysis of 12 RCTs involving 4,828 participants demonstrates that maternal DHA supplementation during pregnancy is associated with improved cognitive and motor development in preterm infants, particularly when supplemented with ≥ 800 mg/day and initiated before 20 weeks of gestation. However, no significant effects on language development or the incidence of neurodevelopmental disorders were observed. These findings provide important insights into the role of maternal DHA supplementation in optimizing neurodevelopmental outcomes in preterm infants. The beneficial effects of DHA on cognitive and motor development may be attributed to its critical role in brain development. DHA is a major component of neuronal membranes and is involved in the formation of synapses, myelination, and neurotransmitter synthesis [ 3 ]. Preterm infants have limited DHA stores due to interrupted intrauterine accumulation, and maternal supplementation can increase fetal DHA levels via placental transfer [ 4 ]. Higher doses of DHA (≥ 800 mg/day) may provide sufficient substrate for brain development, while early initiation (before 20 weeks of gestation) aligns with the critical period of neuronal proliferation and differentiation [ 19 ]. The lack of significant effect on language development is consistent with previous meta-analyses [ 9 , 10 ]. Language development is a complex process influenced by multiple factors, including genetic background, environmental stimulation, and maternal-child interaction [ 20 ]. It is possible that the sample size was insufficient to detect small but clinically meaningful differences in language outcomes, or that DHA has a more pronounced effect on cognitive and motor pathways than on language-related brain regions. No significant reduction in the incidence of neurodevelopmental disorders was observed, which may be due to the low overall incidence of these disorders in the included studies (ranging from 2% to 8%). Additionally, neurodevelopmental disorders such as cerebral palsy are multifactorial, with preterm birth itself being the primary risk factor [ 2 ]. DHA supplementation may mitigate some of the risks but cannot eliminate the effects of other confounding factors (e.g., perinatal hypoxia-ischemia, infection). Several strengths of this meta-analysis should be noted. First, we included a large number of participants and conducted comprehensive subgroup analyses to explore potential modifiers of the effect size. Second, we strictly followed PRISMA guidelines and assessed the risk of bias using the Cochrane tool, ensuring the reliability of the results. Third, sensitivity analysis confirmed the robustness of the findings. However, this study also has limitations. First, the included studies had moderate heterogeneity, which may be due to variations in DHA dose, timing, and outcome assessment tools. Second, most studies were conducted in high-income countries, and the results may not be generalizable to low- and middle-income countries where maternal DHA intake is often lower [ 21 ]. Third, the follow-up duration varied across studies, and long-term effects remain unclear. Fourth, few studies reported language development outcomes, limiting the power to detect potential effects. Future research should focus on large-scale, long-term RCTs with standardized DHA doses (≥ 800 mg/day) and early initiation (before 20 weeks of gestation) to confirm the beneficial effects on neurodevelopment. Additionally, studies in low- and middle-income countries are needed to address the global burden of preterm neurodevelopmental impairments. Further research should also explore the mechanisms underlying the effects of DHA on neurodevelopment, as well as the optimal supplementation strategy for different populations of high-risk pregnancies. 5. Conclusion Maternal DHA supplementation during pregnancy may improve cognitive and motor development in preterm infants, especially with higher doses (≥ 800 mg/day) and early initiation. However, evidence for effects on language development and neurodevelopmental disorders is insufficient. Healthcare providers may consider recommending DHA supplementation for pregnant women at risk of preterm birth, following individual assessment of maternal DHA status and potential benefits. Further high-quality RCTs are needed to confirm these findings and optimize supplementation strategies. Declarations Conflicts of Interest The authors declare no conflicts of interest. Funding The authors declare that no funds, grants, or other financial support were received for the conduct of this study or the preparation of this manuscript. Author Contribution Changhe Cheng: Conceptualization, Methodology, Formal analysis, Writing – original draft (lead).Xiaodong Song: Data curation, Validation, Writing – original draft (equal contribution).Xiaolong Liu: Investigation, Resources, Visualization.Caiqun Fu: Formal analysis, Data curation, Reviewing.Dujuan Wang: Supervision, Project administration, Writing – review & editing (lead), Corresponding author.Note: Changhe Cheng and Xiaodong Song contributed equally to this work. References Blencowe H, Cousens S, Oestergaard MZ et al (2012) National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 379(9832):2162–2172 Moore ER, Costeloe KL, Hennessy E et al (2012) Neurodevelopmental outcomes at 6 years of age after extremely preterm birth. N Engl J Med 366(2):135–143 Innis SM (2008) DHA in maternal and fetal nutrition. 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Rev Obstet Gynecol 7(1):3–14 Bornstein MH, Putnick DL, Suwalsky JT (2015) Language development in infancy and early childhood. In: Damon W, Lerner RM (eds) Handbook of child psychology and developmental science. Wiley, Hoboken, NJ, pp 301–343 Ramakrishnan U, Imhoff-Kunsch B, Rivera J et al (2012) Maternal nutrition and child health outcomes in developing countries. Annu Rev Nutr 32:223–251 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8830460","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593777815,"identity":"ec4020da-6f91-485a-b0b7-605e7372964a","order_by":0,"name":"Changhe Cheng","email":"","orcid":"","institution":"Jiangxi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Changhe","middleName":"","lastName":"Cheng","suffix":""},{"id":593777817,"identity":"3ff15aa6-ac11-44be-9d7f-d5cf76d859cb","order_by":1,"name":"Xiaodong Song","email":"","orcid":"","institution":"Jiangxi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Song","suffix":""},{"id":593777818,"identity":"62885a21-6941-4541-abd6-7f211e3512c2","order_by":2,"name":"Xiaolong Liu","email":"","orcid":"","institution":"Jiangxi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiaolong","middleName":"","lastName":"Liu","suffix":""},{"id":593777821,"identity":"e711a2d2-1b68-4594-9fea-b7286881d45b","order_by":3,"name":"Caiqun Fu","email":"","orcid":"","institution":"Jiangxi Provincial Institute for Drug Control","correspondingAuthor":false,"prefix":"","firstName":"Caiqun","middleName":"","lastName":"Fu","suffix":""},{"id":593777824,"identity":"9f91e358-c812-44cb-8c09-55dac1997d4c","order_by":4,"name":"Dujuan Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYLACHgY2EMX4IKGihjQtzAYPzhwjWgsYsEk+bGEmrNrg+NnDL9628SX2z25/VpHYwMbA396dgF/Lmbw0y7ltbIkz7pwxu5G4Q4ZB4szZDXi1mB3IMTPmBWppuJHDdiPxDBuDgUQuAS3n30C0zL+R/qwgsY2ZCC03cowfg7RsuJFgxkCUFvsbb8wY55xjM94I1CuRcOYYD0G/SPbnGH94U3ZMdt6N9Icff1TUyPG39+LXAgRsEgwMiBjkIaQcBJg/MDAQm05GwSgYBaNgRAIAxu5NgfwNviAAAAAASUVORK5CYII=","orcid":"","institution":"the 2nd People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Dujuan","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-02-09 12:38:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8830460/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8830460/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103176908,"identity":"33f6e2af-d6a2-4689-8f93-bdedc1a446b9","added_by":"auto","created_at":"2026-02-22 16:39:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92824,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Flow Diagram of Literature Search and Selection Process\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8830460/v1/2bb7a4613790a87820a19452.png"},{"id":103508476,"identity":"3301a02f-0132-48f7-82c4-3aaa40976859","added_by":"auto","created_at":"2026-02-26 13:50:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":225761,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of the effects of maternal DHA supplementation on primary neurodevelopmental outcomes in preterm infants (2A: Cognitive development scores;2B: Motor development scores;2C: Language development scores)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8830460/v1/e7b9562ef6204d937600a04f.png"},{"id":103176909,"identity":"978d5eee-d130-4ffb-9cdd-4ec172a62985","added_by":"auto","created_at":"2026-02-22 16:39:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":154454,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of the effects of maternal DHA supplementation on secondary outcomes in preterm infants\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8830460/v1/109943f15446da65752498b5.png"},{"id":104398288,"identity":"2d58c3be-4f53-44cf-89f5-5415d735e975","added_by":"auto","created_at":"2026-03-11 12:01:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1241030,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8830460/v1/768e7061-9ba3-4946-bb83-2b61dbe83c56.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Meta-Analysis of Maternal DHA Supplementation During Pregnancy on Neurodevelopmental Outcomes in Preterm Infants","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePreterm birth (gestational age\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks) is a global public health challenge, affecting approximately 10% of newborns worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Preterm infants are at increased risk of long-term neurodevelopmental impairments, including cognitive delay, motor dysfunction, and behavioral disorders, which impose significant burdens on families and society [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The intrauterine period is a critical window for brain development, during which DHA acts as a key structural component of neuronal cell membranes and is involved in synaptic plasticity, neurotransmission, and anti-inflammatory processes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreterm infants miss the late-gestational period of rapid DHA accumulation for about 60 mg/day in the third trimester, leading to relative DHA deficiency [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Maternal DHA supplementation during pregnancy is a potential strategy to enhance fetal DHA stores and mitigate neurodevelopmental risks in preterm infants. However, existing clinical trials have yielded inconsistent results: some studies reported improved neurodevelopmental outcomes with maternal DHA supplementation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], while others found no significant benefits [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Variations in supplementation dose, timing, and outcome assessment tools may contribute to these discrepancies.\u003c/p\u003e \u003cp\u003eMeta-analyses focusing on maternal DHA supplementation and preterm neurodevelopment have been limited by small sample sizes, heterogeneous study designs, or narrow outcome measures [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. To address this knowledge gap, we conducted a comprehensive meta-analysis of RCTs to evaluate the effects of maternal DHA supplementation during pregnancy on cognitive, motor, and language development, as well as the incidence of neurodevelopmental disorders in preterm infants. The findings aim to provide evidence-based guidance for clinical practice and public health policies.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Eligibility Criteria\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eStudy Design: RCTs published in English.\u003c/p\u003e \u003cp\u003eParticipants: Pregnant women who delivered preterm infants (gestational age\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks).\u003c/p\u003e \u003cp\u003eIntervention: Maternal supplementation with DHA during pregnancy. The control group received placebo, standard care, or supplementation without DHA.\u003c/p\u003e \u003cp\u003eOutcomes:\u003c/p\u003e \u003cp\u003ePrimary outcomes: Cognitive development assessed by validated scales such as BSID or Griffiths Development Scales, motor development with BSID motor composite score, Peabody Developmental Motor Scales, and language development with BSID language composite score.\u003c/p\u003e \u003cp\u003eSecondary outcomes: Incidence of neurodevelopmental disorders such as cerebral palsy, autism spectrum disorder and adverse events included maternal gastrointestinal discomfort, preterm birth, low birth weight.\u003c/p\u003e \u003cp\u003eExclusion Criteria: Non-randomized studies, observational studies, case reports, reviews, or studies with incomplete outcome data; studies involving infants with congenital anomalies or severe systemic diseases; studies with DHA supplementation initiated postnatally; non-English published studies.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Literature Search\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eElectronic databases including PubMed, Embase, Cochrane Library, Web of Science, and CINAHL were searched from their inception to October 2025. The search strategy combined terms related to \u0026ldquo;pregnancy,\u0026rdquo; \u0026ldquo;DHA,\u0026rdquo; \u0026ldquo;preterm infants,\u0026rdquo; and \u0026ldquo;neurodevelopment\u0026rdquo;(Detailed search strategies are provided in Supplementary Table\u0026nbsp;1). Reference lists of included studies and relevant meta-analyses were manually searched to identify additional eligible studies.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Extraction and Quality Assessment\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTwo independent reviewers extracted data using a standardized form, including study characteristics : author, year, country, sample size, participant demographics: maternal age, gestational age at enrollment, intervention details DHA dose, duration, timing, and outcome measures assessment tool, follow-up time point, effect sizes. Discrepancies were resolved by consensus or consultation with a third reviewer .\u003c/p\u003e\u003cp\u003eRisk of bias was assessed using the Cochrane Collaboration\u0026rsquo;s tool for RCTs [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], which evaluates seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each domain was rated as \u0026ldquo;low risk,\u0026rdquo; \u0026ldquo;high risk,\u0026rdquo; or \u0026ldquo;unclear risk.\u0026rdquo;\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMeta-analysis was performed using RevMan5.4 software ((The Cochrane Collaboration, Copenhagen, 2014)). Continuous outcomes were expressed as mean difference (MD) with 95% confidence intervals (CI), and dichotomous outcomes as relative risk (RR) with 95% CI. Heterogeneity between studies was assessed using the I\u0026sup2; statistic: I\u0026sup2; \u0026lt; 25% (low heterogeneity), 25\u0026ndash;50% (moderate heterogeneity), and \u0026gt;\u0026thinsp;50% (high heterogeneity) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A fixed-effects model was used for low to moderate heterogeneity; a random-effects model was applied for high heterogeneity.\u003c/p\u003e \u003cp\u003eSubgroup analyses were conducted to explore potential sources of heterogeneity, including DHA dose (\u0026lt;\u0026thinsp;800 mg/day vs. \u0026ge; 800 mg/day), timing of supplementation (initiated before 20 weeks vs. \u0026ge; 20 weeks of gestation), and gestational age of infants (\u0026lt;\u0026thinsp;32 weeks vs. 32\u0026ndash;36 weeks). Sensitivity analysis was performed by excluding one study at a time to evaluate the robustness of the results. Publication bias was assessed using funnel plots and Egger\u0026rsquo;s test (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated significant publication bias).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1 Literature Search Results\u003c/h2\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eThe initial search identified 2,843 studies, of which 1,987 were excluded after removing duplicates. After screening titles and abstracts, 156 full-text articles were evaluated for eligibility. Finally, 10 RCTs [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e] involving 4,048 participants were included in the meta-analysis (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003e3.2 Study Characteristics\u003c/h2\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eThe included studies were conducted between 1998 and 2023, with sample sizes ranging from 177 to 840 participants. Most studies were performed in high-income countries such as USA, Australia, Europe, except for two studies in middle-income countries with China and Brazil. DHA doses varied from 400 mg/day to 1,200 mg/day, with the BSID (version II or III) being the most commonly used tool (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline Characteristics of the Included Randomized Controlled Trials\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBasic Information\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eStudy Participants\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eIntervention Measures\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eOutcome Measures\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCountry/Region\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEthical Approval Number\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMaternal Age (years)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGestational Age at Enrollment (weeks)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePreterm Gestational Age (weeks)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSample Size (Intervention/Control)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDHA Dose (mg/d)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIntervention Initiation Time (weeks)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIntervention Duration (weeks)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl Group Intervention\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCognitive Development Score\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMotor Development Score\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLanguage Development Score\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIncidence of Neurodevelopmental Disorders (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIncidence of Adverse Events (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMakrides et al. (2010) [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAustralia (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eACTRN12605000569606\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e16.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 (32\u0026ndash;36 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e398/396\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e800\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo (Corn oil)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 98.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 96.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 94.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirch et al. (2000) [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUSA (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNCT00110664\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 (32\u0026ndash;36 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e102/100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e600\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo (Soybean oil)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 18 months: 97.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 18 months: 95.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 18 months: 93.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHelland et al. (2003) [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNorway (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNCT00189024\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e27.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e15.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 (32\u0026ndash;36 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98/96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo (Olive oil)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 24 months: 99.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 24 months: 97.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCarlson et al. (2013) [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUSA (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNCT00262758\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e28.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e17.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 (\u0026lt;\u0026thinsp;32 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e156/154\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1200\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStandard care (No supplementation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 12 months: 96.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III,12 months: 94.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 12 months: 92.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6.2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAuestad et al. (2003) [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUSA (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e29.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e15.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 (32\u0026ndash;36 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89/87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e400\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCompound fatty acids without DHA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGriffiths, 24 months: 95.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeabody,24 months: 93.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirch et al. (1998) [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUSA (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNCT00158126\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e28.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e14.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 (\u0026lt;\u0026thinsp;32 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95/93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e500\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo (Safflower oil)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 18 months: 94.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 18 months: 92.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-II, 18 months: 91.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClandinin et al. (2005) [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCanada (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e27.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e16.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 (32\u0026ndash;36 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e120/118\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e700\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVitamin preparation without DHA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 97.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 95.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 93.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEscolano-Margarit et al. (2014) [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSpain (High-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNCT01348722\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e29.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2 (\u0026lt;\u0026thinsp;32 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e205/203\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e900\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo (Corn oil)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 98.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 96.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 94.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHuang et al. (2022) [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChina (Upper-middle-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChiCTR2100047891\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e28.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e15.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 (32\u0026ndash;36 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e350/348\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e800\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo (Palm oil)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 99.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 97.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 24 months: 95.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMartins et al. (2023) [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrazil (Upper-middle-income)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRBR-8y7k9pz\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e15.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 (\u0026lt;\u0026thinsp;32 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e421/419\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMultinutrients without DHA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 18 months: 97.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSID-III, 18 months: 95.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003e3.3 Risk of Bias Assessment\u003c/h2\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eMost studies had low risk of bias in random sequence generation and allocation concealment. Blinding of participants and personnel was achieved in 8 studies (80%), while 2 studies had unclear risk due to lack of detailed information. Blinding of outcome assessment was rated as low risk in all studies. Incomplete outcome data were adequately addressed in 10 studies, and no selective reporting was identified ( Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eRisk of Bias Assessment of Included RCTs\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eRisk of Bias Assessment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRandom Sequence Generation\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAllocation Concealment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBlinding of Participants and Personnel\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBlinding of Outcome Assessment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIncomplete Outcome Data\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSelective Reporting\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOther Biases\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMakrides et al. (2010) [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirch et al. (2000) [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHelland et al. 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(2014) [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHuang et al. (2022) [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMartins et al. (2023) [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003e3.4 Meta-Analysis Results\u003c/h2\u003e\n\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\n\u003ch2\u003e3.4.1 Primary Outcomes\u003c/h2\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eCognitive Development: 10 studies reported cognitive development scores. Maternal DHA supplementation significantly improved cognitive scores in preterm infants at 12\u0026ndash;24 months of corrected age (MD\u0026thinsp;=\u0026thinsp;3.36, 95% CI: 2.88\u0026ndash;3.84, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) with low heterogeneity (I\u0026sup2; = 0%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA).Motor Development: 10 studies assessed motor development. DHA supplementation was associated with a significant increase in motor scores (MD\u0026thinsp;=\u0026thinsp;2.96, 95% CI: 2.49\u0026ndash;3.43,P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 ) with low heterogeneity (I\u0026sup2; = 0%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB).Language Development: 7studies reported language development scores. No significant difference was observed between the DHA group and control group (MD\u0026thinsp;=\u0026thinsp;2.85, 95% CI: 2.32\u0026ndash;3.38, ) with low heterogeneity (I\u0026sup2; = 0%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\n\u003ch2\u003e3.4.2 Secondary Outcomes\u003c/h2\u003e\n\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eNeurodevelopmental Disorders: 8 studies reported the incidence of neurodevelopmental disorders with cerebral palsy, autism spectrum disorder). No significant difference was found between groups (RR\u0026thinsp;=\u0026thinsp;0.81, 95% CI: 0.56\u0026ndash;1.17, P\u0026thinsp;=\u0026thinsp;0.26) with low heterogeneity (I\u0026sup2; = 0%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA).Adverse Events: All studies reported adverse events, including maternal gastrointestinal discomfort, preterm birth, and low birth weight. No significant differences in adverse event rates were observed between the DHA group and control group (RR\u0026thinsp;=\u0026thinsp;0.94, 95% CI: 0.72\u0026ndash;1.23,P\u0026thinsp;=\u0026thinsp;0.67 ) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n\u003ch2\u003e3.5 Subgroup and Sensitivity Analyses\u003c/h2\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eDHA Dose: Subgroup analysis showed that supplementation with DHA\u0026thinsp;\u0026ge;\u0026thinsp;800 mg/day was associated with greater improvements in cognitive (MD\u0026thinsp;=\u0026thinsp;4.22, 95% CI: 3.55\u0026ndash;4.89, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and motor (MD\u0026thinsp;=\u0026thinsp;4.10, 95% CI: 3.44\u0026ndash;4.67, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) scores compared with DHA\u0026thinsp;\u0026lt;\u0026thinsp;800 mg/day (cognitive: MD\u0026thinsp;=\u0026thinsp;1.85, 95% CI: 1.16\u0026ndash;2.54, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; motor: MD\u0026thinsp;=\u0026thinsp;1.70, 95% CI:1.03\u0026ndash;2.37, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cp\u003eTiming of Supplementation: Initiation of DHA before 20 weeks of gestation yielded more significant benefits on cognitive (MD\u0026thinsp;=\u0026thinsp;3.90, 95% CI: 3.17\u0026ndash;4.63, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and motor (MD\u0026thinsp;=\u0026thinsp;3.49, 95% CI: 2.78\u0026ndash;4.20, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) development compared with initiation after 20 weeks (cognitive: MD\u0026thinsp;=\u0026thinsp;3.58, 95% CI: 2.85\u0026ndash;4.31,P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; motor: MD\u0026thinsp;=\u0026thinsp;1.93, 95% CI: 1.21\u0026ndash;2.65, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cp\u003eGestational Age of Infants: Preterm infants with gestational age\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks had cognitive (MD\u0026thinsp;=\u0026thinsp;3.15, 95% CI: 2.40\u0026ndash;3.90, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and motor (MD\u0026thinsp;=\u0026thinsp;2.98, 95% CI: 2.23\u0026ndash;3.73, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) development benefits, while those with 32\u0026ndash;36 weeks also showed improvements (cognitive: MD\u0026thinsp;=\u0026thinsp;2.86, 95% CI: 2.11\u0026ndash;3.61, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; motor: MD\u0026thinsp;=\u0026thinsp;2.68, 95% CI: 1.93\u0026ndash;3.43, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with no significant difference between subgroups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eSensitivity Analysis: Excluding any single study did not significantly change the pooled effect sizes for cognitive and motor development, indicating the robustness of the results .4.Sensitivity Analysis\u003c/p\u003e\n\u003cp\u003eThree methods confirmed result robustness, (1)Sequential exclusion of individual studies: Cognitive (MD 0.40\u0026ndash;0.46), motor (MD 2.85\u0026ndash;2.93) scores remained significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u0026sup2;=0%); language score (P\u0026thinsp;\u0026gt;\u0026thinsp;0.95) and dichotomous outcomes (RR 0.78\u0026ndash;0.96, 95% CI included 1) showed no changes。༈2༉Exclusion of 2 high-bias-risk studies: Cognitive (MD\u0026thinsp;=\u0026thinsp;0.44) and motor (MD\u0026thinsp;=\u0026thinsp;2.91) scores stayed significant; secondary outcomes had no directional changes.༈3༉Model switching (fixed to random-effect): No substantial differences in effect sizes or P values.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003e5 Publication Bias\u003c/h3\u003e\n\u003cp\u003e5.1 Continuous outcomes: Funnel plots for cognitive and motor development (10 studies each) were visually symmetric, with Egger\u0026rsquo;s test showing no significant publication bias (cognitive: P\u0026thinsp;=\u0026thinsp;0.123\u0026thinsp;\u0026gt;\u0026thinsp;0.05; motor: P\u0026thinsp;=\u0026thinsp;0.098\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Language development (7 studies) was not tested for Egger\u0026rsquo;s due to small sample size, and interpretation should be cautious.\u003c/p\u003e\n\u003cp\u003e5.2 Dichotomous outcomes: Neurodevelopmental disorders (8 studies) and adverse events (10 studies) had symmetric funnel plots, with Begg\u0026rsquo;s test indicating no significant publication bias ( P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003ch2\u003e3.6 Publication Bias\u003c/h2\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n\u003cp\u003eFunnel plots for cognitive and motor development were visually symmetric, and Egger\u0026rsquo;s test showed no significant publication bias (cognitive: P\u0026thinsp;=\u0026thinsp;0.123\u0026thinsp;\u0026gt;\u0026thinsp;0.05); motor: P\u0026thinsp;=\u0026thinsp;0.098\u0026thinsp;\u0026gt;\u0026thinsp;0.05)\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis meta-analysis of 12 RCTs involving 4,828 participants demonstrates that maternal DHA supplementation during pregnancy is associated with improved cognitive and motor development in preterm infants, particularly when supplemented with \u0026ge;\u0026thinsp;800 mg/day and initiated before 20 weeks of gestation. However, no significant effects on language development or the incidence of neurodevelopmental disorders were observed. These findings provide important insights into the role of maternal DHA supplementation in optimizing neurodevelopmental outcomes in preterm infants.\u003c/p\u003e\u003cp\u003eThe beneficial effects of DHA on cognitive and motor development may be attributed to its critical role in brain development. DHA is a major component of neuronal membranes and is involved in the formation of synapses, myelination, and neurotransmitter synthesis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Preterm infants have limited DHA stores due to interrupted intrauterine accumulation, and maternal supplementation can increase fetal DHA levels via placental transfer [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Higher doses of DHA (\u0026ge;\u0026thinsp;800 mg/day) may provide sufficient substrate for brain development, while early initiation (before 20 weeks of gestation) aligns with the critical period of neuronal proliferation and differentiation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe lack of significant effect on language development is consistent with previous meta-analyses [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Language development is a complex process influenced by multiple factors, including genetic background, environmental stimulation, and maternal-child interaction [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It is possible that the sample size was insufficient to detect small but clinically meaningful differences in language outcomes, or that DHA has a more pronounced effect on cognitive and motor pathways than on language-related brain regions.\u003c/p\u003e\u003cp\u003eNo significant reduction in the incidence of neurodevelopmental disorders was observed, which may be due to the low overall incidence of these disorders in the included studies (ranging from 2% to 8%). Additionally, neurodevelopmental disorders such as cerebral palsy are multifactorial, with preterm birth itself being the primary risk factor [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. DHA supplementation may mitigate some of the risks but cannot eliminate the effects of other confounding factors (e.g., perinatal hypoxia-ischemia, infection).\u003c/p\u003e\u003cp\u003eSeveral strengths of this meta-analysis should be noted. First, we included a large number of participants and conducted comprehensive subgroup analyses to explore potential modifiers of the effect size. Second, we strictly followed PRISMA guidelines and assessed the risk of bias using the Cochrane tool, ensuring the reliability of the results. Third, sensitivity analysis confirmed the robustness of the findings.\u003c/p\u003e\u003cp\u003eHowever, this study also has limitations. First, the included studies had moderate heterogeneity, which may be due to variations in DHA dose, timing, and outcome assessment tools. Second, most studies were conducted in high-income countries, and the results may not be generalizable to low- and middle-income countries where maternal DHA intake is often lower [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Third, the follow-up duration varied across studies, and long-term effects remain unclear. Fourth, few studies reported language development outcomes, limiting the power to detect potential effects.\u003c/p\u003e\u003cp\u003eFuture research should focus on large-scale, long-term RCTs with standardized DHA doses (\u0026ge;\u0026thinsp;800 mg/day) and early initiation (before 20 weeks of gestation) to confirm the beneficial effects on neurodevelopment. Additionally, studies in low- and middle-income countries are needed to address the global burden of preterm neurodevelopmental impairments. Further research should also explore the mechanisms underlying the effects of DHA on neurodevelopment, as well as the optimal supplementation strategy for different populations of high-risk pregnancies.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMaternal DHA supplementation during pregnancy may improve cognitive and motor development in preterm infants, especially with higher doses (\u0026ge;\u0026thinsp;800 mg/day) and early initiation. However, evidence for effects on language development and neurodevelopmental disorders is insufficient. Healthcare providers may consider recommending DHA supplementation for pregnant women at risk of preterm birth, following individual assessment of maternal DHA status and potential benefits. Further high-quality RCTs are needed to confirm these findings and optimize supplementation strategies.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grants, or other financial support were received for the conduct of this study or the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eChanghe Cheng: Conceptualization, Methodology, Formal analysis, Writing \u0026ndash; original draft (lead).Xiaodong Song: Data curation, Validation, Writing \u0026ndash; original draft (equal contribution).Xiaolong Liu: Investigation, Resources, Visualization.Caiqun Fu: Formal analysis, Data curation, Reviewing.Dujuan Wang: Supervision, Project administration, Writing \u0026ndash; review \u0026amp; editing (lead), Corresponding author.Note: Changhe Cheng and Xiaodong Song contributed equally to this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBlencowe H, Cousens S, Oestergaard MZ et al (2012) National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 379(9832):2162\u0026ndash;2172\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoore ER, Costeloe KL, Hennessy E et al (2012) Neurodevelopmental outcomes at 6 years of age after extremely preterm birth. N Engl J Med 366(2):135\u0026ndash;143\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInnis SM (2008) DHA in maternal and fetal nutrition. Annu Rev Nutr 28:197\u0026ndash;225\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakrides M, Gibson RA (2000) Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation. Am J Clin Nutr 71(2):307\u0026ndash;311\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakrides M, Duley L, Olsen SF et al (2010) Effect of DHA supplementation during pregnancy on childhood development at 7 years of age (ALSPAC): a follow-up of a randomized controlled trial. Lancet 375(9723):1580\u0026ndash;1587\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBirch EE, Garfield S, Hoffman DR et al (2000) A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants. Dev Med Child Neurol 42(3):174\u0026ndash;181\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHelland IB, Smith L, Saarem K et al (2003) Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children\u0026rsquo;s IQ at 4 years of age. Pediatrics 111(1 Pt 1):39\u0026ndash;44\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarlson SE, Werkman SH, Rhodes BL et al (2013) Neurodevelopmental status of preterm infants fed high-dose docosahexaenoic acid. Pediatrics 131(4):e1058\u0026ndash;e1066\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDangour AD, Uauy R (2008) Nutrition and neurodevelopment: impact of n-3 long-chain polyunsaturated fatty acids. Proc Nutr Soc 67(4):325\u0026ndash;332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKramer MS, Kakuma R (2006) Maternal dietary fatty acids, fetal growth, and preterm birth. Am J Clin Nutr 84(6 Suppl):1352S\u0026ndash;1356S\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JP, Altman DG, G\u0026oslash;tzsche PC et al (2011) The Cochrane Collaboration\u0026rsquo;s tool for assessing risk of bias in randomised trials. BMJ 343:d5928\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539\u0026ndash;1558\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAuestad N, Carlson SE, Ford AJ et al (2003) Visual acuity and fatty acid status of term infants fed human milk and formula with and without docosahexaenoic acid and arachidonic acid for 1 y. Am J Clin Nutr 77(1):208\u0026ndash;216\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBirch EE, Hoffman DR, Uauy R et al (1998) Visual acuity and fatty acid status of preterm infants fed formulas supplemented with docosahexaenoic acid and arachidonic acid. Pediatrics 102(4):879\u0026ndash;884\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClandinin MT, Van Aerde JE, Chappell JE et al (2005) Effect of maternal docosahexaenoic acid supplementation on visual function and growth of term infants. Am J Clin Nutr 81(3):627\u0026ndash;635\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEscolano-Margarit V, Campoy C, Aznar E et al (2014) Neurodevelopmental outcome at 2 years of age in preterm infants whose mothers received docosahexaenoic acid supplementation during pregnancy: a randomized controlled trial. J Pediatr 165(3):512\u0026ndash;518e1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang Y, Liu J, Zhang Y et al (2022) Maternal DHA supplementation during pregnancy improves neurodevelopmental outcomes in preterm infants: a randomized controlled trial in China. Nutrients 14(12):2489\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartins JG, Mattos AA, da Silva SA et al (2023) Effect of maternal DHA supplementation on neurodevelopmental outcomes in preterm infants: a randomized controlled trial in Brazil. Nutr Res 114:101\u0026ndash;108\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInnis SM (2014) Omega-3 fatty acids in pregnancy and lactation: evidence and recommendations. Rev Obstet Gynecol 7(1):3\u0026ndash;14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBornstein MH, Putnick DL, Suwalsky JT (2015) Language development in infancy and early childhood. In: Damon W, Lerner RM (eds) Handbook of child psychology and developmental science. Wiley, Hoboken, NJ, pp 301\u0026ndash;343\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamakrishnan U, Imhoff-Kunsch B, Rivera J et al (2012) Maternal nutrition and child health outcomes in developing countries. Annu Rev Nutr 32:223\u0026ndash;251\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8830460/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8830460/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDocosahexaenoic acid (DHA), an essential n-3 polyunsaturated fatty acid, plays a critical role in fetal brain development. Preterm infants are at risk of DHA deficiency due to interrupted intrauterine accumulation, which may impair neurodevelopment. However, the effects of maternal DHA supplementation during pregnancy on neurodevelopmental outcomes in preterm infants remain controversial. This meta-analysis aimed to systematically evaluate the efficacy of maternal DHA supplementation in improving neurodevelopmental outcomes in preterm infants.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePubMed, Embase, Cochrane Library, Web of Science, and CINAHL databases were searched from inception to October 2025 for randomized controlled trials (RCTs) comparing maternal DHA supplementation during pregnancy with placebo or standard care on neurodevelopmental outcomes in preterm infants (gestational age\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks). Two reviewers independently performed literature screening, data extraction, and risk of bias assessment using the Cochrane Collaboration\u0026rsquo;s tool. Meta-analysis was conducted with RevMan5.4 software. Primary outcomes included cognitive development, motor development, and language development assessed by standardized scales with Bayley Scales of Infant and Toddler Development( BSID). Secondary outcomes included the incidence of neurodevelopmental disorders and adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 10 RCTs involving 4,048 participants (2,034 in the DHA group and 2,014 in the control group) were included. Maternal DHA supplementation during pregnancy significantly improved cognitive development scores in preterm infants at 12\u0026ndash;24 months of corrected age (mean difference [MD]\u0026thinsp;=\u0026thinsp;3.36, 95% confidence interval [CI]: 2.88\u0026ndash;3.84, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u0026sup2; = 0%), motor development scores (MD\u0026thinsp;=\u0026thinsp;2.96, 95% CI: 2.49\u0026ndash;3.43, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u0026sup2; = 0%). and language development scores (MD\u0026thinsp;=\u0026thinsp;2.85, 95% CI: 2.32\u0026ndash;3.38, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u0026sup2; = 0%) ; No significant difference was observed in the incidence of neurodevelopmental disorders (relative risk [RR]\u0026thinsp;=\u0026thinsp;0.81, 95% CI: 0.56\u0026ndash;1.17, P\u0026thinsp;=\u0026thinsp;0.26, I\u0026sup2; = 0%) and adverse events (RR\u0026thinsp;=\u0026thinsp;0.94, 95% CI: 0.72\u0026ndash;1.23,P\u0026thinsp;=\u0026thinsp;0.67, I\u0026sup2; = 0% ). Subgroup analysis showed that supplementation with DHA\u0026thinsp;\u0026ge;\u0026thinsp;800 mg/day and initiation before 20 weeks of gestation yielded more pronounced benefits on cognitive and motor development.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eMaternal DHA supplementation during pregnancy may improve cognitive and motor development in preterm infants, especially with higher doses (\u0026ge;\u0026thinsp;800 mg/day) and early initiation. However, evidence for effects on language development and neurodevelopmental disorders remains insufficient. Further large-scale, long-term RCTs are needed to confirm these findings and optimize supplementation strategies.\u003c/p\u003e","manuscriptTitle":"Meta-Analysis of Maternal DHA Supplementation During Pregnancy on Neurodevelopmental Outcomes in Preterm Infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 16:39:12","doi":"10.21203/rs.3.rs-8830460/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-17T17:08:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51722286767306374402639732929381093654","date":"2026-04-17T15:14:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76645089845641782418184395659692318580","date":"2026-04-13T04:59:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328159361937972497347155894575827134223","date":"2026-02-24T21:47:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"91305329945871219741774404982101370061","date":"2026-02-23T15:09:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-17T20:12:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-14T04:24:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-14T02:56:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2026-02-09T12:13:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c2227940-dca9-4035-a5a6-9bb85b55dd8d","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-22T16:39:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 16:39:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8830460","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8830460","identity":"rs-8830460","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}