Advanced 4 in 1 Extra Strength by Schiff MegaRed

POSSIBLY EFFECTIVE

• Hyperlipidemia. Most research shows that taking oral DHA alone or with eicosapentaenoic acid (EPA) seems to modestly reduce triglyceride levels. However, DHA does not decrease total cholesterol and may increase levels of low-density lipoprotein (LDL) cholesterol. Details: Clinical research shows that taking DHA 1.25-4 grams daily for up to 7 weeks can reduce triglyceride levels by 17% to 24% in adult patients with mild hyperlipidemia, dyslipidemia, or hypertriglyceridemia (6143,48013,48338). Also, taking DHA-enriched fish oil providing DHA 810 mg plus EPA 210 mg daily for 8 weeks reduces triglyceride levels by 23% in premenopausal adults with mild hypertriglyceridemia (99131). Most clinical research suggests that DHA does not decrease total cholesterol (6143,48013,99131). Although some conflicting research exists, most research suggests that DHA modestly increases HDL cholesterol (6143,48013,48338,99131,109216). Most clinical research shows that DHA increases LDL cholesterol by about 8% to 13.6% (6143,48174,48338,109216). However, it may actually decrease levels of small, dense LDL particles (48174). There are conflicting results regarding the effects of DHA on cholesterol levels in children. One preliminary clinical study in children with primary hyperlipidemia shows that taking DHA 500 mg alone or along with EPA does not improve cholesterol levels when compared with control. However, this study was probably too small to detect statistically significant changes (90712). Other research in children aged 9 years and up with familial hypercholesterolemia or familial combined hyperlipidemia shows that taking DHA (DHASCO oil, Martek Biosciences Corp.) 1.2 grams daily for 6 weeks along with the National Cholesterol Education Program Step II (NCEP-II) diet actually increases total cholesterol and LDL cholesterol when compared to following the diet alone (48078,48083). However, some clinical research shows that DHA increases the large buoyant type of LDL particles, but actually decreases the small, dense type (48083).
• Preterm labor. Most research shows that oral DHA seems to prevent preterm labor in those with low DHA status at baseline. Details: A large clinical trial shows that taking DHA 1000 mg daily during pregnancy, starting at 12-20 weeks' gestation and continuing until delivery, results in an early preterm birth rate of 1.7%, compared with 2.4% in those taking DHA 200 mg daily. Benefits were strongest in those with low DHA status at baseline, with no benefit in those with high DHA status at baseline and in those with high adherence to DHA 1000 mg daily (109204,110360). A secondary analysis of two studies shows that taking DHA 800 mg from algal oil or 1000 mg from fish oil modestly reduces the early preterm and preterm birth rates in those with a low DHA status at baseline compared with taking DHA 200 mg (110361). However, conflicting evidence exists. Some clinical research shows that taking DHA during pregnancy does not reduce the risk of preterm delivery. One study has used a specific fish oil supplement (Incromega DHA 500TG) 900 mg containing DHA 800 mg and eicosapentaenoic acid (EPA)100 mg daily, starting at 20 weeks' gestation and continuing to delivery or 34 weeks' gestation (101505). In another clinical trial, use of a high-DHA fish oil, providing EPA 100 mg and DHA 800 mg daily, from before 20 weeks' until 34 weeks' gestation, increases the risk of preterm birth prior to 34 weeks' gestation when compared with placebo in patients with baseline omega-3 status of greater than 4.9%. However, the risk is reduced from 3.2% to 0.7% in patients with baseline omega-3 status below 4.1%. In addition, taking this high-DHA fish oil had no effect on the risk of preterm birth prior to 37 weeks' gestation (103496). The reasons for any discrepancies may be due to the baseline omega-3 status, the use of algal or fish oil as the source of DHA, and/or the specific timing of preterm labor.

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Most research shows that taking oral DHA alone or with other ingredients does not slow or improve cognitive decline associated with age. Details: Most clinical research, from individual studies and a meta-analysis, shows that taking DHA orally, alone or with additional eicosapentaenoic acid (EPA) for up to 36 months, does not slow or improve age-related cognitive decline (97175,103313). In contrast, results from one large clinical study show that taking DHA 900 mg daily in the absence of EPA for 24 weeks improves episodic memory and visuospatial learning when compared with placebo in patients with age-related cognitive decline. However, DHA did not affect working memory or executive function (90717).
• Alzheimer disease. Taking oral DHA does not seem to slow Alzheimer disease progression. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 37% reduced risk of Alzheimer disease when taken for 2-21 years (15041,96527). However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527). Furthermore, clinical research shows that taking DHA 2 grams daily for 18 months does not slow cognitive or functional decline in patients with mild to moderate Alzheimer disease (48290). DHA has also been examined in combination with other ingredients. Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking DHA 500 mg, as part of fish 1 gram with eicosapentaenoic acid (EPA) 150 mg, and along with lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of DHA alone is unclear from this study.
• Attention deficit-hyperactivity disorder (ADHD). Most research shows that taking oral DHA does not improve ADHD symptoms. Details: Low plasma levels of DHA are associated with ADHD in children (7599,15496). Although some preliminary clinical research shows that DHA might improve aggression, emotional problems, and social relationships in children with ADHD (15494,100940), taking DHA 345-500 mg daily or 3.6 grams weekly does not seem to improve objective or subjective measures of ADHD symptoms when compared with placebo (7599,15495,100940).
• Bronchopulmonary dysplasia. Most research shows that oral DHA does not prevent bronchopulmonary dysplasia (BPD) in preterm infants. Some research suggests that it might increase the risk of BPD in infants born before 29 weeks gestation. Details: One meta-analysis of clinical research in over 3,500 preterm infants shows that administration of EPA and DHA as part of formula or as a direct oral dose, starting within one month of birth, does not increase or decrease the risk for BPD, regardless of the dose of DHA administered (102390). A more recent meta-analysis of four clinical trials limited to infants born less than 29 weeks gestation also shows that administration of DHA at levels of at least 40 mg/kg, or at levels of at least 0.4% total fatty acids in breast milk or formula, does not increase or decrease the risk of bronchopulmonary dysplasia (110359). However, in this latter meta-analysis, when only clinical trials using a more stringent definition of bronchopulmonary dysplasia were included, there was a modest INCREASED risk (110359). Similar findings occurred in a study that was terminated early. This research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on mortality of breastfed infants or survival without BPD at 36 weeks postmenstrual age. However, the occurrence of BPD and severe BPD in surviving infants of mothers taking DHA were increased when compared to those whose mothers took placebo (104559). The conclusions of this study are limited by the early termination, the provision of intravenous DHA-rich lipids to some infants per standard of clinical care, and the increased number of infants born via cesarean delivery to the mothers randomized to DHA. A more recent clinical trial has investigated the inclusion of arachidonic acid in an enteral emulsion providing DHA. One clinical trial in preterm infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age does not increase the risk of bronchopulmonary dysplasia or other major morbidities compared to control (MCToil, Nutricia) emulsion. Also, infants given the arachidonic acid and DHA required 17 fewer days of respiratory support (110356).
• Cognitive function. Most research shows that oral DHA does not improve cognitive function in healthy adults. Details: Most clinical research shows that taking DHA 250-1000 mg daily for up to 6 months does not improve cognitive function in healthy children, healthy adults, or older females (48194,48216,48266,90668,90708,104560). Also, cognitive function does not seem to be improved when compared with placebo in trials in which omega-3 products containing higher ratios of DHA to eicosapentaenoic acid (EPA) were used. These trials have used a specific product (Efamol Ltd) containing DHA 1.16 grams and EPA 0.17 grams daily (90707), DHA 900 mg plus EPA 270 mg (Accelon DHA EE, BASF) daily (109215), or fish oil (Dasbrain, Max Biocare) providing DHA 520 mg or 270 mg daily (109310), for 3 or 6 months in children and adults. However, some clinical research shows that taking algal oil containing DHA 600 mg daily for 16 weeks improves reading scores when compared with placebo in a subgroup of children ages 6-10 years who are below the 20th percentile for reading (90699). However, these results could not be replicated in a later study that included only children below the 20th percentile for reading (98542). The reason for this discrepancy is not clear. Taking DHA does not appear to improve reading scores in children at or above the 20th percentile for reading, and there does not appear to be any benefit of DHA on working memory in any children (90699).
• Cystic fibrosis. Most research shows that oral DHA does not improve symptoms of cystic fibrosis. Details: Clinical research in infants, children, and young adults with cystic fibrosis shows that taking DHA (DHA-basic, CASEN Fleet SLU) 50 mg/kg daily for 48 weeks does not improve spirometry measures, reduce Pseudomonas aeruginosa primary infections, or reduce the number of, or time to, total or severe pulmonary exacerbations when compared with placebo (109217). Also, small clinical studies show that taking DHA 70 mg/kg daily for 6 weeks, or 100 mg/kg daily for one month and then 1 gram daily for 11 months, does not improve lung function or overall health in patients with cystic fibrosis (48119,90665).
• Depression. Most research shows that oral DHA does not improve depression, regardless of the type. Details: Taking DHA orally does not seem to relieve symptoms of major depression, peripartum depression, or postpartum depression in most patients (10869,48030,48238,90680,90691,90692,89353,102391). Also, taking DHA for two weeks prior to the start of interferon-alpha therapy does not appear to prevent depression during interferon-alpha treatment in patients with hepatitis C, although it may delay depression onset by about 6 weeks (90710).
• Macrosomia. Taking oral DHA during pregnancy does not seem to prevent fetal macrosomia. Details: Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of macrosomia when compared with taking DHA 200 mg daily (109218).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Increased dietary consumption of DHA is associated with a decreased risk of AMD (10324). Preliminary clinical research shows that taking a combination of DHA 280 mg, lutein 12 mg, and zeaxanthin 0.6 mg daily for one year increases macular pigment optical density by 31% when compared with placebo in patients with AMD. Increased macular pigment optical density is associated with improve vision performance and a reduced risk of AMD (90678). However, other clinical research suggests that adding DHA plus EPA to an AREDS formula, with or without lutein and zeaxanthin, does not reduce the time to development of AMD or vision loss in patients at high risk of progression to advanced AMD when compared with the AREDS formula alone (60281).
• Allergic rhinitis (hay fever). Although there has been interest in using oral DHA for allergic rhinitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Atopic dermatitis (eczema). It is unclear if adding DHA to infant formula prevents atopic dermatitis. Details: Evidence from an observational, open-label study shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months does not prevent the development of eczema when compared to control formulas without DHA and arachidonic acid (92505).
• Atopic disease. It is unclear if oral DHA during pregnancy prevents atopic disease in the infant. Details: Clinical research shows that supplementation with DHA during pregnancy may modestly protect against some respiratory symptoms in the infants of atopic mothers. Prenatal supplementation with DHA 400 mg, taken daily from 18-22 weeks gestation until delivery, reduces the incidence of phlegm with nasal discharge or nasal congestion in the infant by the age of 18 months by approximately 22% and the incidence of fever with phlegm and nasal discharge or nasal congestion in the infant by approximately 47% when compared with placebo (90676). However, it is unclear if these symptoms are due to atopy or infections.
• Atrial fibrillation. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research suggests that adipose tissue levels of DHA are not associated with a decreased risk of atrial fibrillation (90700). However, clinical research suggests that taking 2 grams per day of a combination of DHA plus EPA (2:1 ratio), starting 7 days before cardiac surgery and continuing until hospital discharge, reduces the relative risk of post-cardiac surgery atrial fibrillation by 72% when compared with placebo. These patients also received vitamin C 1 gram daily plus vitamin E 400 IU daily, starting 2 days prior to surgery and continuing until discharge (90701).
• Autism spectrum disorder. It is unclear if oral DHA is beneficial for autism. Details: One preliminary clinical study shows that taking DHA 200 mg daily for 6 months does not improve autism symptoms in children and may even worsen some behaviors (90713). Another preliminary clinical study in children and adults with autism shows that taking a specific product (SUNTGA40S, Aravita, Suntory Ltd) containing DHA, arachidonic acid, and astaxanthin daily for 16 weeks does not improve overall symptoms when compared with placebo, although the combination product may improve certain symptoms such as social withdrawal or social communication (90716).
• Behcet disease. Although there has been interest in using oral DHA for Behcet disease, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Bipolar disorder. It is unclear if oral DHA is beneficial for bipolar disorder in adults. Details: A small clinical trial shows that taking DHA 1250 mg daily for 12 weeks does not improve cognitive function when compared with placebo in patients with bipolar disorder (103312).
• Breast cancer. It is unclear if oral DHA is beneficial for breast cancer treatment or prevention. Details: Population research has found no association between dietary fatty acid intake, including DHA, and the risk of breast cancer (96528). The effect of DHA supplementation on breast cancer risk is unknown. Some early research has investigated the effects of DHA in patients with breast cancer. Preliminary clinical research shows that taking DHA (DHASCO, Martek Biosciences Corp.) 600 mg three times daily for 7-10 days prior to chemotherapy initiation, and then for 5 months during chemotherapy, induces complete or partial response in 44% of breast cancer patients. Patients with a greater increase in DHA levels (at least 2.5%) show a longer time to progression and longer survival when compared to those with a smaller increase in DHA levels (90671).
• Cancer. Taking oral DHA with oral eicosapentaenoic acid (EPA) does not seem to decrease the risk of cancer in patients with cardiovascular disease and may actually INCREASE the risk of cancer in females. The effect of DHA alone is unclear. Details: Clinical research suggests that taking a combination of EPA 400 mg plus DHA 200 mg, with or without B vitamins, for a median of 4.7 years does not reduce the risk of cancer in middle-aged and elderly patients with cardiovascular disease. Furthermore, this combination appears to increase the risk of cancer in females (90666).
• Child development. It is unclear if oral DHA is beneficial for child development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Clinical research shows that giving infants DHA-supplemented formula during infancy does not appear to improve language and school readiness by the age of 2-3.5 years, or improve neurodevelopment by the age of 6 years (90674,92503). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). There is some evidence to suggest that maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694); however, this benefit did not have lasting effects at 5-6 years of age (99133).
• Cognitive impairment. It is unclear if oral DHA is beneficial for cognitive impairment in the elderly. Details: Clinical research shows that taking DHA 800 mg daily, alone or with folic acid 800 mcg daily for 6 months, modestly improves some measures of cognitive function when compared with placebo in elderly patients with mild cognitive impairment (103978). Also, taking a specific product (Vayacog, Enzymotec Ltd.) providing phosphatidylserine 300 mg, DHA about 59 mg, and eicosapentaenoic acid (EPA) about 20 mg daily for 15 weeks improves verbal immediate recall when compared with placebo (94665). However, other research in elderly patients with mild cognitive impairment disagrees. One clinical trial shows that taking DHA 1491 mg plus EPA 351 mg daily for 12 months does not improve cognitive measures when compared with placebo (109220). In addition, taking DHA along with EPA and other ingredients for up to 24 weeks does not significantly improve memory, forgetfulness, or other measures of cognition in elderly patients with mild cognitive impairment (90704,94665). Also, a small clinical study shows that taking DHA 720 mg daily along with EPA and other ingredients for 12 weeks does not significantly improve memory, forgetfulness, or other measures of cognition (62847).
• Coronary heart disease (CHD). It is unclear if oral DHA is beneficial for CHD. Details: Increased dietary consumption of DHA may reduce the risk of death in patients with CHD (10322). However, the effect of DHA supplements is unclear.
• Crohn disease. It is unclear if oral DHA is beneficial for Crohn disease prevention. Details: Population research suggests that increased dietary intake of DHA is associated with a reduced risk of Crohn disease (90673).
• Dementia. It is unclear if oral DHA is beneficial for dementia prevention. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 14% reduced risk of dementia when taken for 2-21 years. However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527).
• Developmental coordination disorder (DCD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in children with DCD shows that taking a tuna fish oil product providing DHA 480 mg daily for 4 months, in combination with evening primrose oil providing arachidonic acid 35 mg and gamma-linolenic acid 96 mg, thyme oil 24 mg, and vitamin E 80 mg (Efalex, Efamol Ltd.), modestly decreases movement disorders as determined by objective measures when compared with baseline (5708). It is unclear if these benefits are due to DHA, other ingredients, or the combination. Also, the validity of this finding is limited by the lack of a comparator group.
• Diabetes. It is unclear if oral DHA is beneficial for glycemic control or the prevention of type 1 or gestational diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking DHA orally does not improve levels of low-density lipoprotein (LDL) cholesterol or decrease blood sugar or glycated hemoglobin. However, triglyceride levels are reduced (10321). DHA has also been evaluated for the prevention of gestational or type 1 diabetes. Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of gestational diabetes when compared with taking DHA 200 mg daily (109218). Additionally, population research suggests that maternal serum levels of DHA are not associated with the risk of childhood onset of type 1 diabetes (90705).
• Diabetic retinopathy. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic macular edema related to diabetic retinopathy receiving ranibizumab shows that taking a combination supplement containing DHA 1050 mg daily along with other free fatty acids, minerals, and vitamins (Brudyretina, Brudy Lab S.L.) for 2 years reduces macular thickness, but not visual acuity, when compared with ranibizumab alone. The effect of DHA alone is unknown (96526).
• Diarrhea. It is unclear if infant formula containing DHA is beneficial for diarrhea prevention. Details: Preliminary clinical research suggests that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the incidence of diarrhea requiring medical attention when compared to control formulas (92505).
• Dyslexia. It is unclear if oral DHA is beneficial for improving night vision in children with this condition. Details: One small clinical study in children with dyslexia shows that taking fish oils rich in DHA, providing 480 mg daily for one month, seem to develop significantly better dark adaptation when compared with controls (5708).
• Dysmenorrhea. Although there has been interest in using oral DHA for dysmenorrhea, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Fractures. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not prevent fractures in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Hypertension. It is unclear if oral DHA is beneficial for reducing blood pressure in adults or if prenatal supplementation reduces blood pressure in children. Details: Clinical research shows that taking DHA-enriched canola oil containing 63% oleic acid and 6% DHA for 4 weeks reduces systolic blood pressure by 3% and diastolic blood pressure by 4% when compared to baseline in adults with at least one cardiovascular risk factor (26466). A meta-analysis of clinical research in adults with dyslipidemia shows that supplemental DHA reduces diastolic, but not systolic, blood pressure when compared with control (102389). A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not reduce blood pressure levels in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly. About 39% of the individuals included in this study were diagnosed with hypertension and about 50% were using antihypertensives (104619). The effect of DHA alone on blood pressure levels in a population of adults with diagnosed hypertension is unclear. Prenatal supplementation with DHA has also been evaluated for the prevention of hypertension in children. A secondary analysis of a large clinical trial shows that overweight children or children with obesity whose mothers took DHA 600 mg daily, starting at about 14.5 weeks' gestation and continuing until birth, have lower diastolic and systolic blood pressure at 5 years of age when compared with those whose mothers took placebo. Systolic and diastolic blood pressure were reduced by about 4 mm Hg and 5 mm Hg, respectively, in the children exposed to DHA during pregnancy when compared with those exposed to placebo. The blood pressure of the children exposed to DHA during pregnancy was similar to that of children with normal weight (98891). Results of this study are limited by the fact that confounding factors, such as shorter duration of breast-feeding and increased sodium intake for children with obesity in the placebo group, may have also contributed to differences in blood pressure. It is unclear if this reduction in elevated blood pressure during childhood reduces the risk of hypertension in adulthood.
• IgA nephropathy. Although there has been interest in using oral DHA for IgA nephropathy, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Infant development. Infant supplementation with DHA does not seem to improve development. Also, most evidence shows that maternal supplementation with DHA is not beneficial for infant cognitive development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Most clinical research shows that giving healthy, full-term infants formula supplemented with DHA 0.32% to 0.96% modestly improves measures of visual acuity at 2, 4, and 12 months of age when compared with standard infant formula (14403,15003,47980,48355,90670). However, formula supplemented with DHA 0.15% does not appear to improve visual acuity by about 12 months when given to preterm infants (48008). There is some evidence that giving healthy, full-term infants DHA-supplemented formula during infancy might improve language comprehension and development, as well as fine motor skills, by the age of 12-14 months when compared with standard formula (48247,48356). However, most clinical research, including meta-analyses of high-quality clinical trials, shows that giving infants formula supplemented with DHA during infancy does not improve overall cognition or motor skills at 12-14 months of age, regardless of DHA dosing or prematurity status (48247,48356,89363). Experts generally recommend breast-feeding as the preferred feeding method over DHA-supplemented formula; however, if formula is used, some experts suggest a formula providing at least 0.2% of lipids from DHA (14403). Some population research suggests that higher maternal DHA levels are associated with improved use of gestures and problem solving in infants (90709,99132). However, population research suggests that higher maternal DHA levels also appear to be associated with worsening mental development (90709), and most clinical research shows that maternal ingestion of DHA has little effect on fetal or infant development. Maternal ingestion of DHA 33-133 mg daily from an egg source or 400 mg daily from an algal-based source does not seem to significantly increase weight, length, or head circumference at birth (14395,48286). Also, maternal ingestion of DHA 200-400 mg daily from week 15-22 of pregnancy until term does not significantly improve visual or auditory development in term infants (14393,90706). A small clinical trial shows that taking DHA 1440 mg daily from fish oil also providing eicosapentaenoic acid (EPA) 260 mg, from 22-24 weeks gestation until delivery, does not improve most measures of developmental or behavioral milestones in the infant at 6 months, when compared with olive oil placebo (110354). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect growth to age 18 months or visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). However, there is some evidence to suggest that maternal supplementation with DHA 214 mg daily may improve infant sleep patterning on the first day of life (90687). Also, maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694). However, this benefit did not have lasting effects at 5-6 years of age (99133).
• Intraventricular hemorrhage. It is unclear if oral DHA is beneficial for preventing intraventricular hemorrhage in premature infants. Details: Preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of intraventricular hemorrhage when compared with a control emulsion (110356).
• Keratoconus. It is unclear if oral DHA is beneficial for improving vision in people with keratoconus. Details: A small clinical trial in patients with early to advanced keratoconus shows that taking DHA 1000 mg daily for 3 months does not improve corneal thickness, measurements of corneal curve, or most other ophthalmological measures when compared with taking no DHA (110358).
• Lower respiratory tract infections. It is unclear if formula containing DHA is beneficial for preventing lower respiratory tract infections in infants. Details: Clinical research shows that giving preterm infants formula or breast milk containing high-dose DHA (1% of fatty acids) does not prevent hospitalizations due to bronchiolitis and other lower respiratory tract conditions when compared with giving breast milk or formula containing 0.35% DHA (90667). However, preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the risk of bronchiolitis and croup when compared with control formulas (92505).
• Male infertility. It is unclear if oral DHA is beneficial for improving fertility. Details: Clinical research shows that taking DHA (NuaDHA, Nua Biological Innovations SL) 0.5, 1, or 2 grams daily for 3 months increases progressive sperm motility by 24% to 30% when compared with placebo in men with a history of infertility. The greatest effects were seen in men with asthenozoospermia, with an overall effect of 35 (99134). It is unclear if the effects of DHA on sperm function correlate with increased fertility rates.
• Metabolic syndrome. Although there has been interest in using oral DHA for metabolic syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Migraine headache. Although there has been interest in using oral DHA for migraine headache, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Muscle strength. It is unclear if oral DHA is beneficial for increasing muscle strength. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not increase muscle strength in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Necrotizing enterocolitis (NEC). It is unclear if oral DHA is beneficial for preventing NEC in preterm infants. Details: Clinical research in preterm infants shows that providing DHA (Neuromins for Kids life's DHA; DSM Nutritional Products Inc.) 75 mg/kg for 14 days from the first enteral feed reduces the risk of confirmed NEC by 7% when compared with a control oil. Treatment of 15 infants with DHA would be needed to prevent one case of NEC (109213). However, preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks' gestation, has no effect on the incidence of NEC in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of NEC when compared with a control emulsion (110356).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral DHA is beneficial for NAFLD. Details: Preliminary clinical research shows that taking DHA (Martek Biosciences Corporation) 250-500 mg daily for 6-24 months reduces the risk of severe liver steatosis when compared with placebo in children with NAFLD (48295,90695,90696).
• Obesity. It is unclear if oral DHA is beneficial for improving weight loss in overweight or obese adults. Details: Preliminary clinical research shows that taking 2.8 grams daily of an oil emulsion containing approximately 46% DHA for 12 weeks decreases carbohydrate and fat intake, but does not reduce body weight or improve body composition, when compared with placebo in overweight or obese adults (90681).
• Otitis media. It is unclear if DHA in infant formula is beneficial for preventing otitis media in infants. Details: Preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) for 12 months does not prevent the development of ear infection when compared with control formulas (92505).
• Phenylketonuria (PKU). It is unclear if oral DHA is beneficial for PKU. Details: Children with PKU consume very low amounts of DHA. Clinical research shows that taking DHA up to approximately 7 mg/kg daily for 6 months improves DHA status, but not neurological function, in children aged 5-13 years with PKU (99631). The effect of higher doses of DHA, or the effect of DHA supplementation on neurological function in younger children with PKU, have not been determined.
• Physical performance. It is unclear if oral DHA is beneficial for increasing physical performance in older adults. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not improve physical performance in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Postoperative pain. It is unclear if oral DHA is beneficial for reducing postoperative analgesic use. Details: A post-hoc analysis shows that enteral DHA 75 mg/kg administered perioperatively to infants born at greater than 34 weeks gestation who are undergoing cardiac surgery reduces the cumulative analgesic dose and shortens the duration of buprenorphine during the postoperative period when compared with placebo. However, the use of fentanyl or ketorolac were not reduced (96524).
• Prematurity. It is unclear if oral DHA during lactation or early in infancy is beneficial for increasing growth or neurodevelopment of the premature infant. Details: Clinical research in lactating individuals who delivered prior to 29 weeks' gestation shows that taking DHA 1.2 grams daily, starting within 72 hours of delivery and continuing until the infant reached 36 weeks postmenstrual age, might have beneficial effects on the growth of female infants, but not male infants, when compared with placebo. Weight velocity and weight gain were significantly increased in the female infants, with a weight gain of 52.6 grams. However, weight gain and weight velocity were not improved in the male infants, and weight at 36 weeks postmenstrual age was 89 grams less than those whose mothers took placebo (109221). In addition, there was no improvement in neurodevelopmental outcomes at 18 to 22 months corrected age (110364). Other clinical research in infants born before 29 weeks' gestation shows that giving enteral DHA 60 mg/kg daily until 36 weeks corrected gestational age does not improve most measures of intelligence at 5 years when compared with placebo (110363).
• Prostate cancer. It is unclear if oral DHA is beneficial for prostate cancer prevention. Details: Observational research has found that higher consumption of DHA is associated with a reduced risk of total, advanced, and aggressive prostate cancer when compared to lower consumption of DHA (12961,25937). However, a meta-analysis of multiple population studies has found that higher DHA blood levels are associated with a 2.5-fold higher risk of aggressive prostate cancer, but not low-grade prostate cancer, when compared with lower blood percentages of DHA (25936). Another meta-analysis of population research has found that a higher blood level of DHA is associated with a slight increased risk of non-aggressive prostate cancer (90677).
• Psoriasis. Although there has been interest in using oral DHA for psoriasis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Raynaud syndrome. Although there has been interest in using oral DHA for Raynaud syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Restenosis. It is unclear if oral DHA is beneficial for preventing restenosis in people with stents. Details: Observational research has found that initiation of statin therapy in patients receiving stent placement after an acute coronary event is associated with a reduction in DHA levels. These reductions in DHA are associated with a greater prevalence of in-stent restenosis. From these results, researchers postulate that patients newly started on a statin after stent placement for acute coronary syndrome might benefit from DHA supplementation (100939). However, the effect of DHA supplementation is unknown.
• Retinitis pigmentosa. Evidence for the use of oral DHA for retinitis pigmentosa is inconsistent and contradictory. Details: Some clinical research shows that taking DHA 1200 mg daily for 4 years does not improve eye function in patients with retinitis pigmentosa who are also taking vitamin A when compared with placebo (48070). Also, taking DHA 600-3600 mg daily for 4 years does not maintain rod or cone function in boys or men with retinitis pigmentosa when compared with placebo (90683). However, a report of ancillary outcomes from this study shows that taking DHA might slow the rate of decline in final dark-adapted thresholds and visual field sensitivity in these patients (95738). Also, some research shows that taking DHA 400 mg daily for 4 years does maintain rod and cone function in some patients, although visual function is not improved when compared with placebo (48057,48115).
• Retinopathy of prematurity. It is unclear if maternal or infant supplementation with oral DHA is beneficial for preventing retinopathy of prematurity. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of retinopathy of prematurity in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of retinopathy of prematurity when compared with a control emulsion (110356).
• Rheumatoid arthritis (RA). Although there has been interest in using oral DHA for RA, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Schizophrenia. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking EPA 1000 mg, DHA 500 mg, and alpha-lipoic acid 150 mg twice daily for up to 2 years after discontinuing antipsychotic treatment does not prevent relapse in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder (90675).
• Sepsis. It is unclear if oral DHA is beneficial for preventing sepsis in premature infants. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of sepsis in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of sepsis when compared with a control emulsion (110356).
• Spinocerebellar ataxia (SCA). It is unclear if oral DHA is beneficial for SCA. Details: Preliminary clinical research in patients with SCA shows that taking DHA 600 mg daily for 16 weeks reduces ataxia and improves cerebellar hypometabolism upon brain imaging when compared with placebo. These beneficial effects are sustained when DHA is taken for an additional 40 weeks (96525).
• Stroke. It is unclear if oral DHA is beneficial for stroke prevention. Details: Population research has found that serum DHA levels may be associated with a reduced risk of ischemic stroke, as well as any specific type of ischemic stroke, including cardioembolic stroke, atherothrombotic stroke, and lacunar stroke (90715).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral DHA for SLE, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Systemic lupus erythematosus (SLE) nephritis. Although there has been interest in using oral DHA for SLE nephritis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Ulcerative colitis. Although there has been interest in using oral DHA for ulcerative colitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Vascular dementia. It is unclear if DHA is beneficial for improving dementia severity. Details: Preliminary clinical research in patients with vascular dementia shows that taking DHA 0.72 grams daily for one year improves dementia severity based on the Hasegawa's Dementia Rating Scale and Mini-Mental State Examination Scale scores when compared to baseline (47940). More evidence is needed to rate DHA for these uses.

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LIKELY SAFE ...when used orally and appropriately. DHA has been used safely in studies lasting up to 4 years (1016,1043,6413,10321,10869,11333,90684). Fish oil supplements containing DHA have also been safely used in studies lasting up to 7 years (1016). While doses of DHA up to 4 grams orally daily have been used safely in some clinical research (6143), there is some concern that high intake of omega-3 fatty acids such as DHA might increase the risk of bleeding. For this reason, the US Food and Drug Administration (FDA) recommends that consumers limit intake of DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid also found in fish oil, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

POSSIBLY SAFE ...when used intravenously and appropriately, in combination with eicosapentaenoic acid (EPA), short-term. Daily infusions with an omega-3 fatty acid-based lipid emulsion (Omegavenous 10%, Fresenius Aktiengesellschaft) providing 4.2 grams/day of DHA and EPA has been used safely for 14 days (1004).

POSSIBLY UNSAFE ...when used orally in high doses. Doses greater than 3 grams daily might decrease platelet aggregation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

CHILDREN: LIKELY SAFE
when used orally and appropriately. DHA is a component of some infant formula (424,1045,5708,5941,7599,14403,15003,15495,17735,48088)(48194,48266,48343,90665,90713,90716,110357). In children 7 years and older, DHA 30 mg/kg daily has been used safely for up to 4 years (90684). Also, DHA 0.4-1 grams daily has been safely used in children ages 4 years and older for up to 1 year (11333,90665,100940,104560).

CHILDREN: POSSIBLY UNSAFE
when used orally in preterm infants born less than 29 weeks gestation. Although not all findings agree (110356,110359), supplementation with an enteral emulsion containing DHA 40 mg/kg to 60 mg/kg daily might increase the risk of developing or worsening bronchopulmonary dysplasia compared to control emulsion (96523,110359).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. An intake of DHA 650 mg daily from food and/or supplements during pregnancy seems to be required to prevent a reduction in DHA status before delivery (110329). DHA is commonly used during pregnancy and lactation and is a component of some prenatal supplements. DHA is a normal component of breast milk, with higher levels in breast milk following term vs. preterm pregnancies (14393,14394,14396,14400,14403,14397,20000,47977,47994,48095)(90672,90718,110355). When taken as a prenatal supplement, DHA increases DHA levels in breast milk (90685). Doses of DHA ranging from 300-600 mg daily beginning during the first trimester of pregnancy have been used safely in clinical research (90672,90676,90687,90694). When taken during lactation, DHA increases DHA levels in breast milk (109214,110362). When initiated within 72 hours of delivery of a very preterm infant, taking DHA 1.2 grams daily increases DHA levels in breast milk within 14 days (109214). One study found that DHA supplementation during lactation increased the risk of bronchopulmonary dysplasia in breast-feeding infants born less than 29 weeks gestational age (104559); however, it is unclear if this was due to DHA or various confounding factors. The tolerable upper intake level of DHA during pregnancy or lactation has not been established; most experts recommend DHA 200-300 mg daily. While it is typically advised that this need is met by consuming 8-12 ounces of seafood weekly during pregnancy and 4-8 ounces weekly during lactation, those with nutrient deficiency or those following a vegan diet may meet this need with supplementation (95740,95741).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, DHA may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Although some clinical evidence suggests that DHA might reduce collagen-stimulated platelet aggregation and thromboxane release, most clinical evidence suggests that DHA alone does not affect blood clotting (11112,11113,48020). However, theoretically, when given in combination with EPA as fish oil, concomitant use with anticoagulant or antiplatelet drugs (including aspirin) might increase risk of bleeding.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking DHA with antidiabetes drugs might reduce the effects of these medications.  Details In people with type 2 diabetes, including those taking oral hypoglycemic medications, DHA seems to increase fasting blood glucose levels (10321).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking DHA with antihypertensive drugs might increase the risk of hypotension.  Details Fish oils containing DHA can lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,1030,1033,47944,48013,48020,48163); use with caution.

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General ...Orally, DHA is generally well-tolerated when used in doses up to 3 grams daily. Intravenously, DHA seems to be well tolerated.
Most Common Adverse Effects:
Orally: Belching, fishy aftertaste, loose stools, and nausea.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with high doses of fish oil containing DHA.

Cardiovascular ...Orally, DHA might increase low-density lipoprotein (LDL) cholesterol levels. However, this appears to be primarily due to increases in the large buoyant type of LDL particles. The small, dense type of LDL particles are reduced (6143,48013,48078,48083,48174,48338).

Dermatologic ...Orally, DHA has been associated with one report of rash and one report of warmth on hands in one clinical study (48217). In another clinical study, two patients taking DHA 400 mg daily reported acne (11333). In another clinical study, one parent of a pediatric patient treated with DHA 600 mg daily reported increased hair loss beginning 6 weeks after completion of supplementation (90699). It is unclear if this adverse effect is specifically related to DHA intake.

Gastrointestinal ...Orally, DHA may cause gastrointestinal upset, fishy aftertaste, belching, flatulence, heartburn, loose stools, anorexia, and dry mouth (10869,11333,48217,109218). There is also some evidence that increased serum levels of DHA might be associated with an increased risk for atrophic gastritis associated with Helicobacter pylori infection, but further research is needed to clarify this finding (8709).
For fish oils containing EPA and DHA, side effects can include fishy taste, belching, nausea, and loose stools (1009,1313,8699,10007). Three people with pre-existing familial adenomatous polyposis were diagnosed with malignant lesions during the course of long-term fish oil use (999).

Genitourinary ...Orally, one patient in one clinical study who was taking DHA 1, 2, or 4 grams daily (specific dose unclear) reported decreased libido (48217).

Hematologic ...Orally, DHA might cause nose bleeds, but this is uncommon. Onset of severe nose bleeds has been reported in one clinical study in one child who took DHA 600 mg daily (98542). Although most clinical research shows that DHA does not affect blood clotting when taken alone (11112,11113,48020), there is some concern that taking high doses of oils providing DHA along with eicosapentaenoic acid (EPA) might decrease blood coagulation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of EPA plus DHA to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

Neurologic/CNS ...Orally, DHA may cause dizziness, headache, insomnia, fatigue, and anxiety (10869,11333,48217). In one clinical study, one parent of a pediatric patient treated with DHA 600 mg daily reported increased disruptive behavior in the child (90699).

Ocular/Otic ...Orally, DHA may cause watery eyes but results are inconsistent. In one clinical study, five of 167 infants fed formula containing 0.32% or 0.64% DHA experienced watery eyes. However, none of the infants fed formula containing 0.96% DHA experienced watery eyes (90670). In one clinical study, one patient taking DHA 400 mg daily experienced an ear infection. It is unclear if this event was related to DHA supplementation.

Oncologic ...Orally, DHA may increase the risk of prostate cancer, but additional research is needed to clarify this finding. A meta-analysis of data from observational studies found that higher dietary intake of DHA is associated with a non-linear increased risk of prostate cancer (90677). It is unclear if supplemental DHA intake is associated with increased risk of prostate cancer.

Pulmonary/Respiratory ...Orally, worsened asthma symptoms were reported by one parent of one patient with asthma taking DHA 600 mg daily (90699).

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