FISH OIL















  • Reference: AHA website
Fish Omega-3 fatty acids per 3 oz serving
Salmon 1100 - 1900 mg
Flounder or sole 480 mg
Pollock 450 mg
Crabs 270 - 400 mg
Scallops 180 - 340 mg
Catfish 220 - 300 mg
Shrimp 290 mg
Clams 250 mg
Canned tuna 170 - 240 mg
Cod 150 - 240 mg





  • Maximum effect seen after 12 weeks of therapy
  • References [1-7, 33,34,35]
Effect of 3 - 4 grams/day of fish oil on triglycerides
Baseline triglyceride % reduction
> 600 mg/dl 30 - 50%
< 600 mg/dl 20 - 30%


REDUCE-IT trial - Vascepa® vs Mineral Oil for the Prevention of CVD Events, NEJM (2018) [PubMed abstract]
  • The REDUCE-IT trial enrolled 8179 patients with documented CVD or with DM and one additional risk factor for CVD
Main inclusion criteria
  • Established CVD or ≥ 50 years old with DM and one additional risk factor for CVD
  • Fasting triglycerides of 135 - 499 mg/dl
  • LDL 41 - 100 mg/dl
  • Stable statin dose for ≥ 4 weeks
Main exclusion criteria
  • HgA1C > 10%
  • Severe heart failure
  • Severe liver disease
Baseline characteristics
  • Median age 64 years
  • Established CVD - 71%
  • Type two diabetes - 58%
  • Median triglyceride level - 216 mg/dl
  • Median LDL - 75 mg/dl
  • Median HDL - 40 mg/dl
  • Triglyceride distribution: < 150 mg/dl: 10% | 150 - 200 mg/dl: 29% | > 200 mg/dl: 60%
Randomized treatment groups
  • Group 1 (4089 patients) - Vascepa 2 grams twice daily
  • Group 1 (4090 patients) - Mineral oil capsules (placebo) twice daily
  • Non-study fish oil products were prohibited
Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction (including silent myocardial infarction), nonfatal stroke, coronary revascularization, or unstable angina in a time-to-event analysis
Results

Duration: Median of 4.9 years
Outcome Vascepa Mineral oil Comparisons
Primary outcome 17.2% 22% HR 0.75, 95% CI [0.68 - 0.83], p<0.001
Overall mortality 6.7% 7.6% HR 0.87, 95% CI [0.74 - 1.02]
Fatal or nonfatal MI 6.1% 8.7% HR 0.69, 95% CI [0.58 - 0.81], p<0.001
Fatal or nonfatal Stroke 2.4% 3.3% HR 0.72, 95% CI [0.55 - 0.93], p=0.01
Serious bleeding event 2.7% 2.1% p=0.06
Atrial fibrillation 5.3% 3.9% p=0.003
Hospitalization for A fib/flutter 3.1% 2.1% p=0.004
Peripheral edema 6.5% 5.0% p=0.002
Constipation 5.4% 3.6% p<0.001
Median change in triglycerides at 5 years -38 mg/dl -3 mg/dl p<0.001
Median change in LDL at 5 years -0.8 mg/dl +6.2 mg/dl p<0.001
  • For patients without documented CVD at baseline (primary prevention), there was no significant difference in the primary outcome (8.2% vs 9.8%, HR 0.88, 95%CI [0.70 - 1.10])
  • The observed cardiovascular benefits were similar across baseline levels of triglycerides (<150, ≥150 to <200, and ≥200 mg/dl)

Findings: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo
STRENGTH trial - Epanova® vs Corn Oil for the Prevention of CVD Events [PubMed abstract]
  • The STRENGTH trial enrolled 13,078 patients with a history of CVD or multiple risk factors for CVD
Main inclusion criteria
  • One of the following:
    • History of CVD
    • Diabetes + 1 risk factor (smoking, hypertension, hs-CRP ≥ 2 mg/L, albuminuria)
    • Age > 50 (60 for women) + 1 risk factor (fam hx of premature CAD, smoking, hypertension, hs-CRP ≥ 2 mg/L, impaired renal function, CAC > 300)
  • Statin therapy for ≥ 4 weeks
  • LDL < 100 mg/dl or taking maximum tolerated statin
  • Triglycerides 180 - 499 mg/dl
  • HDL < 42 mg/dl (47 mg/dl for women)
Main exclusion criteria
  • Consuming > 1 gram of prescription fish oil or supplement
  • CVD event within 30 days
Baseline characteristics
  • Average age 63 years
  • Baseline CVD - 56%
  • Diabetes - 70%
  • Median LDL - 75 mg/dl
  • Median triglyceride - 240 mg/dl
  • Median HDL - 36 mg/dl
Randomized treatment groups
  • Group 1 (6539 patients): Omega-3 carboxylic acid (Epanova) 4 grams/day. Each one gram Epanova capsule contains EPA 550 mg and DHA 200 mg [38]
  • Group 2 (6539 patients): Corn oil 4 capsules/day (placebo)
  • Fibrates and non-study fish oil products were prohibited
Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina
Results

Duration: After a median of 42 months, the study was stopped early due to futility
Outcome Epanova Corn oil Comparisons
Primary outcome 12% 12.2% p=0.84
Primary outcome (patients with CVD at baseline) 15.6% 16.6% p=0.27
CV death 3.5% 3.2% p=0.37
Nonfatal MI 3.3% 3.5% p=0.77
Nonfatal stroke 2.2% 1.9% p=0.28
Revascularization 6.3% 6.7% p=0.41
Overall mortality 5.7% 5.1% p=0.11
A fib 2.2% 1.3% p<0.001
Median triglyceride at 1 year 191 mg/dl 235 mg/dl N/A
Median LDL at 1 year 76 mg/dl 75 mg/dl N/A
  • A secondary analysis that looked at the difference in the primary outcome between Epanova-treated patients who achieved the highest EPA and DHA plasma levels and coin oil-treated patients also found no significant difference between the therapies. [PMID 33993205]

Findings: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 carboxylic acid, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.
ORIGIN Trial - Fish Oil vs Placebo for Prevention of CVD, NEJM (2012) [PubMed abstract]
  • The ORIGIN trial enrolled 12,536 patients at high risk for cardiovascular events
Main inclusion criteria
  • ≥ 50 years old
  • Diagnosis of early diabetes or impaired glucose tolerance
  • ≥ 1 risk factor for CVD event (e.g. history of MI, stroke, LVH, PVD)
Main exclusion criteria
  • HgA1C > 9%
  • CABG within 4 years
  • Heart failure
Baseline characteristics
  • Average age 64 years
  • History of CVD - 59%
  • Median triglyceride level - 141 mg/dl
  • Average LDL - 112 mg/dl
  • Median HgA1C - 6.4%
  • Taking statin - 54%
  • Median dietary DHA/EPA intake - 210 mg/day
Randomized treatment groups
  • Group 1 (6319 patients) - Fish oil 1000 mg (465 mg of EPA | 375 mg of DHA) once daily
  • Group 1 (6292 patients) - Olive oil 1 gram once daily (placebo)
  • No specific dietary recommendations regarding fish were made
  • Nonstudy supplements containing n-3 fatty acids were discouraged
Primary outcome: Death from cardiovascular causes
Results

Duration: Median of 6.2 years
Outcome Fish oil Olive oil Comparisons
Primary outcome 9.1% 9.3% HR 0.98, 95% CI [0.87 - 1.10], p=0.72
Myocardial infarction (fatal and nonfatal) 5.5% 5.1% HR 1.09, 95% CI [0.93 - 1.27], p=0.28
Stroke (fatal and nonfatal) 5.0% 5.4% HR 0.92, 95% CI [0.79 - 1.08], p=0.32
Revascularization procedure 13.8% 14.3% HR 0.96, 95% CI [0.87 - 1.05], p=0.39
Overall mortality 15.1% 15.4% HR 0.98, 95% CI [0.89 - 1.07], p=0.63
Decrease in triglycerides 23.5 mg/dl 9 mg/dl p<0.001

Findings: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events




  • Reference [33,35]
  • ✝Only reported in Epanova® PI
  • Doses of 4 grams a day
Side effect Fish oil 4 grams/day
 Placebo
Belching 3 - 4% 1%
Upset stomach 3 - 5% 2%
Abnormal taste in mouth 4% 1%
Diarrhea✝ 15% 2%






















Atrial fibrillation
Fish oil vs Placebo to Prevent A fib Recurrence, J Am Coll Cardiol (2014) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=337 | length = average of 271 days) in adults with symptomatic paroxysmal or persistent A fib within 6 months of enrollment
  • Treatment: Fish oil two capsules (EPA 400 mg/DHA 200 mg per capsule) twice daily vs Placebo two capsules (1 gram of safflower) twice daily
  • Primary outcome: Time to first asymptomatic or symptomatic A fib recurrence lasting ≥ 30 seconds. Recurrence of A fib was monitored by weekly trans-telephonic monitor transmissions to detect potentially asymptomatic episodes, whereas symptomatic episodes were assessed by transtelephonic monitor strips, 12-lead electrocardiography or any implanted device
  • Results:
    • Primary outcome: Fish oil - 64.1%, Placebo - 63.2% (p=0.48)
  • Findings: High-dose fish oil does not reduce A fib recurrence in patients with a history of A fib not receiving conventional antiarrhythmic therapy. Furthermore, fish oil does not reduce inflammation or oxidative stress markers in this population, which may explain its lack of efficacy.
Fish oil vs Placebo to Prevent Postoperative Atrial Fibrillation, JAMA (2012) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=1516 | length = 10 days) in adults undergoing cardiac surgery
  • Treatment: Fish oil vs Placebo. Fish oil was given as 1 gram capsules (EPA 465 mg/DHA 375 mg) with a dose of 10 grams over 3 - 5 days before surgery followed by 2 g/day until discharge or postop day 10.
  • Primary outcome: Occurrence of postoperative A fib lasting longer than 30 seconds
  • Results:
    • Primary outcome: Fish oil - 30%, Placebo - 30.7% (p=0.74)
  • Findings: In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative atrial fibrillation
Fish oil vs Placebo to Prevent Recurrent A Fib, JAMA (2010) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=663 | length = 24 weeks) in adults with symptomatic paroxysmal or persistent A fib
  • Treatment: Lovaza 1 gram capsule (EPA 465 mg/DHA 375 mg) vs Placebo. Lovaza was dosed at 8 grams/day for the first 7 days followed by 4 grams a day thereafter.
  • Primary outcome: Symptomatic recurrence of A fib (first recurrence) in participants with paroxysmal A fib (N=542). Biweekly transtelephonic monitoring was used to document asymptomatic recurrences of A fib and assess symptomatic events.
  • Results:
    • Primary outcome: Fish oil - 52%, Placebo - 48% (p=0.26)
  • Findings: Among participants with paroxysmal A fib, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent A fib over 6 months

Autoimmune disease
Fish Oil vs Placebo for the Prevention of Autoimmune Disease, BMJ (2022) [PubMed abstract]
  • Design: Secondary analysis of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
  • Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
  • Primary outcome: All incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others
  • Results:
    • Primary outcome: Fish oil - 1.0%, Placebo - 1.1% (p=0.19)
  • Findings: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).

Cancer prevention
VITAL study - Fish Oil vs Placebo for the Primary Prevention of Cancer, NEJM (2018) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=25,871 | length - median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years with no history of cancer
  • Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
  • Primary outcome: Invasive cancer of any type
  • Results:
    • Primary outcome: Fish oil - 6.3%, Placebo - 6.2% (p=0.56)
  • Findings: Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo

Cardiovascular disease (CVD)
Fish Oil vs Placebo for the Secondary Prevention of CVD in Elderly Patients, Circulation (2020) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=1,027 | length = 2 years) in patients 70 - 82 years old with a history of myocardial infarction
  • Treatment: Fish oil (930 mg EPA and 660 mg DHA) once daily vs Placebo
  • Primary outcome: Composite of non-fatal AMI, unscheduled revascularization, stroke, all-cause death, heart failure hospitalization after two years
  • Results:
    • Primary outcome: Fish oil - 21.4%, Placebo - 20% (p=0.60)
  • Findings: We could not detect reduction in clinical events in our elderly patients with a recent AMI, treated with 1.8 g n-3 PUFAs daily for 2 years
VITAL study - Fish Oil vs Placebo for the Primary Prevention of CVD, NEJM (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=25,871 | length - median of 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years with no history of cardiovascular disease
  • Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
  • Primary outcome: Composite of myocardial infarction, stroke, and death from cardiovascular causes
  • Results:
    • Primary outcome: Fish oil - 2.98%, Placebo - 3.23% (p=0.24)
  • Findings: Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo
Fish Oil vs Placebo to Prevent Cardiovascular Events in Patients with DM or Prediabetes, NEJM (2012) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=12,536 | length - median of 6.2 years) in patients with diabetes or prediabetes
  • Treatment: Fish oil 1 gram once daily vs Placebo
  • Primary outcome: Death from cardiovascular causes
  • Results:
    • Primary outcome: Fish oil - 9.1%, Placebo - 9.3% (p=0.72)
  • Findings: Daily supplementation with 1 gram of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events
Fish Oil and ALA vs Placebo for the Secondary Prevention of CVD, NEJM (2010) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=4,837 | length - 40 months) in patients 60 - 80 years old with a history of myocardial infarction in the past 10 years
  • Treatment: Daily intake of 4 different margarines: Margarine with no additional n−3 fatty acids (placebo margarine) vs Margarine with 400 mg of EPA–DHA per day vs Margarine with 2 g of ALA per day vs Margarine with combination of EPA–DHA and ALA
  • Primary outcome: The rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions
  • Results:
    • Primary outcome: During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20)
  • Findings: Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy

Depression
Fish oil vs Placebo to Prevent Depression or Depressive Symptoms in Adults, JAMA (2021) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=18,353 | length - median 5.3 years) in men aged 50 years or older and women aged 55 years or older. The study was an ancillary study of another study.
  • Treatment: EPA 465 mg + DHA 375 mg once daily vs Placebo
  • Primary outcome: Coprimary outcomes were (1) risk of depression or clinically relevant depressive symptoms and (2) longitudinal mood scores
  • Results:
    • Primary outcome (annual depression risk): EPA/DHA - 1.39%, Placebo - 1.23% (p=0.03)
    • No significant differences were observed comparing omega-3 with placebo groups in longitudinal mood scores (p=0.19)
  • Findings: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with omega-3 supplements compared with placebo yielded mixed results, with a small but statistically significant increase in risk of depression or clinically relevant depressive symptoms but no difference in mood scores, over a median follow-up of 5.3 years. These findings do not support the use of omega-3 supplements in adults to prevent depression.

Diabetes
EPA/DHA 1 gram/day vs Placebo for Prevention of Kidney Disease in Diabetes , JAMA (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=1312 | length = 5 years) in adults with type 2 diabetes
  • Treatment: EPA 465 mg + DHA 375 mg once daily vs Placebo. The study had another factor that included vitamin D.
  • Primary outcome: Change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5
  • Results:
    • Primary outcome (decrease in GFR): EPA/DHA - 12.2 ml/min, Placebo - 13.1 ml/min (p=0.27)
  • Findings: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes.
Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus, NEJM (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trials (N=15,480; length = 7.4 years) among patients with type 2 diabetes and no history of CVD
  • Treatment: Fish oil (460 mg of EPA + 380 mg DHA) once daily vs Placebo (olive oil)
  • Primary outcomes: First serious vascular event, which was defined as a composite of nonfatal myocardial infarction or stroke (excluding confirmed intracranial hemorrhage), TIA, or vascular death excluding intracranial hemorrhage
  • Results:
    • Primary outcome: Fish oil - 8.9%, Placebo - 9.2% (RR 0.97, 95%CI [0.87 to 1.08], p=0.55)
  • Findings: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n−3 fatty acid supplementation and those who were assigned to receive placebo.

Dry eyes
n-3 Fatty Acid Supplementation vs Placebo for the Prevention of Dry Eye Disease, JAMA Ophthalmol (2022) [PubMed abstract]
  • Design: Secondary analysis of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
  • Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
  • Primary outcome: Incidence of clinically diagnosed dry eye disease confirmed by review of the medical records in patients without symptoms or a diagnosis of dry eyes at baseline (N=23,523)
  • Results:
    • Primary outcome: Fish oil - 2%, Placebo - 2% (HR 0.97; 95%CI [0.81-1.16])
  • Findings: In this randomized clinical trial, long-term supplementation with 1 g per day of marine ω-3 fatty acids for a median (range) of 5.3 (3.8-6.1) years did not reduce the incidence of diagnosed dry eye disease or a combined end point of diagnosed dry eye disease or incident severe dry eye disease symptoms. These results do not support recommending marine ω-3 fatty acid supplementation to reduce the incidence of dry eye disease.
n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease, NEJM (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=535 | length = 12 months) in patients with moderate-to-severe dry eye disease
  • Treatment: Fish oil 3 grams once daily vs Placebo
  • Primary outcome: Mean change from baseline in the score on the Ocular Surface Disease Index (OSDI; scores range from 0 to 100, with higher scores indicating greater symptom severity)
  • Results:
    • Primary outcome (OSDI decrease): Fish oil - 13.9, Placebo - 12.5 (p=0.21)
  • Findings: Among patients with dry eye disease, those who were randomly assigned to receive supplements containing 3000 mg of n-3 fatty acids for 12 months did not have significantly better outcomes than those who were assigned to receive placebo

Osteoarthritis
Fish oil for knee osteoarthritis, BJM (2016) [PubMed abstract]
  • Design: Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose
  • Findings: In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation.

Overall health/Physical fitness
Vitamin D, Fish oil, and Exercise for a Variety of Health Outcomes in Elderly Patients, JAMA (2020) [PubMed abstract]
  • Design: Randomized, 2 X 2 X 2 factorial, placebo-controlled trial (N=2157 | length = 3 years) in adults ≥ 70 years old with no major health events in the last 5 years
  • Treatment: Patients were randomly assigned to Vitamin D3 2000 IU/day vs Placebo, Fish oil 1 gram/day vs Placebo, and Strength-training exercise program vs None
  • Primary outcome: The 6 primary outcomes were change in systolic and diastolic blood pressure, Short Physical Performance Battery, Montreal Cognitive Assessment, and incidence rates of nonvertebral fractures and infections over 3 years.
  • Results:
    • Primary outcome: Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years
  • Findings: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.

Prenatal / infant development
DHA vs Soy Emulsion in Preterm Infants for Intelligence at 5 Years, NEJM (2022) [PubMed abstract]
  • Design: Substudy of a randomized controlled trial (N=656 | length = 5 years) in infants born before 29 weeks gestation (main study)
  • Treatment: Enteral emulsion with DHA 60 mg/kg/day vs Soy (control). Treatment was given from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first.
  • Primary outcome: Full-scale intelligence quotient (FSIQ) score on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age
  • Results:
    • Primary outcome (mean score): DHA - 95.4, Control - 91.9 (p=0.03)
  • Findings: In infants born before 29 weeks’ gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding.
DHA vs Placebo for Prevention of Bronchopulmonary Dysplasia in Breastfed Preterm Infants, JAMA (2020) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=461 | length = up to 36 weeks postmenstrual age) in women who delivered preterm infants before 29 weeks and were breastfeeding
  • Treatment: DHA 1.2 grams/day vs Placebo. The DHA or Placebo was given to the mothers. Treatment was started within 72 hours of delivery and continued to 36 weeks' postmenstrual age.
  • Primary outcome: Bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age
  • Results:
    • Primary outcome: DHA - 54.9%, Placebo - 61.6% (p=0.18)
    • Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study
  • Findings: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination.
DHA/EPA vs Placebo for Prevention of Preterm Delivery in Pregnant Women, NEJM (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=5517 | length = 9 months) in pregnant women
  • Treatment: DHA 800 mg + EPA 100 mg once daily vs Placebo starting before 20 weeks gestation and continuing until 34 weeks gestation or delivery
  • Primary outcome: Early preterm delivery, defined as delivery before 34 completed weeks of gestation
  • Results:
    • Primary outcome: DHA/EPA - 2.2%, Placebo - 2.0% (p=0.50)
  • Findings: Supplementation with n−3 long-chain polyunsaturated fatty acids from early pregnancy (< 20 weeks of gestation) until 34 weeks of gestation did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries than control.
DHA vs Placebo on Developmental Outcomes of Toddlers Born Preterm, JAMA Pediatrics (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trials (N=377 | length = 6 months) among children born < 35 weeks gestation who were 10 - 16 months corrected age
  • Treatment: DHA 200 mg + arachidonic acid (AA) 200 mg once daily vs Corn oil (placebo)
  • Primary outcomes: Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), cognitive composite score at 16 to 22 months corrected age
  • Results:
    • Primary outcome: cognitive scores did not differ between the DHA+AA and placebo groups (difference in change, 0.5, 95%CI [-1.8 to 2.8]; effect size, 0.05; P = .66)
  • Findings: Daily supplementation with 200 mg of DHA and 200 mg of AA for 6 months resulted in no improvement in cognitive development and early measures of executive function vs placebo, and may have resulted in negative effects on language development and effortful control in certain subgroups of children. These findings do not support DHA supplementation in the second year of life for children who are born preterm.
DHA vs Soy Emulsion for Bronchopulmonary Dysplasia in Preterm Infants, NEJM (2017) [PubMed abstract]
  • Design: Randomized controlled trial (N=1273 | length = 36 weeks) in infants born before 29 weeks gestation
  • Treatment: Enteral emulsion with DHA 60 mg/kg/day vs Soy (control). Treatment was given from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first.
  • Primary outcome: Bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first
  • Results:
    • Primary outcome: DHA - 49.1%, Control - 43.9% (p=0.02)
  • Findings: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk.
Fish Oil vs Olive Oil in Pregnancy for Prevention of Wheeze and Asthma in Offspring, NEJM (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=736 | length = 3 years) in pregnant women at 24 weeks gestation
  • Treatment: n−3 LCPUFA (fish oil) 2.4 grams/day vs Olive oil
  • Primary outcome: Persistent wheeze or asthma during the first 3 years of life in offspring
  • Results:
    • Primary outcome: Fish oil - 16.9%, Olive oil - 23.7% (p=0.035)
  • Findings: Supplementation with n−3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third.
Fish Oil vs Vegetable Oil During Pregnancy for Offspring Development and Prevention of Postpartum Depression, JAMA (2010) [PubMed abstract]
  • Design: Randomized controlled trial (N=2399 | length = 18 months postpartum) in pregnant women who were less than 21 weeks' gestation with singleton pregnancies
  • Treatment: DHA 800 mg/day vs Vegetable oil. Treatment was given from study entry to birth
  • Primary outcomes: 1. Postpartum depression at 6 weeks and 6 months 2. Cognitive and language development in offspring as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition, at 18 months.
  • Results:
    • Primary outcome (postpartum depression): DHA - 9.67%, Vegetable oil - 11.19% (p=0.09)
    • Primary outcome (cognitive development): Mean cognitive composite scores (adjusted mean difference, 0.01; 95% CI, -1.36 to 1.37; P = .99) and mean language composite scores (adjusted mean difference, -1.42; 95% CI, -3.07 to 0.22; P = .09) of children in the DHA group did not differ from children in the control group
  • Findings: The use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood.